Organic Chemistry

Harold Hart
and Robert D. Schuetz

Third Edition
 ^Functional
FUNCTIONAL GROUP TYPE OF COMPOUND I. U. P. A. C. ENDING

Saturated Hydrocarbon -one

Olefin -ene

Acetylene -yne

Polyolefin dlene

OMH Alcohol -ol

Ether

Aldehyde al

cMoi Ketone -one

Carboxylic acid oic acid

Amine
Qroups NAMES
SPECIFIC EXAMPLE COMMON i. U. P. A. C.

H-C-C-H I
Ethane Ethane
I

H H

C=C Ethylene Ethene

/ \
H H

H-C=C-H Acetylene Ethyne

CH2=CH-CH=CH2 Butadiene 1 ,3-Butadiene

CH3CH2-OH Ethyl Alcohol Ethanol

CH3CH2-O-CH2CH3 Ethyl Ether Ethoxyethane

O II

CH,-C-H Acetaldehyde Ethanal

O
II

CH3-C-CH3 Acetone Propanone

O
II

CH3-C-OH Acetic acid Ethanoic acid

CH3-NH2 Methylamine Aminomethane

 Digitized by the Internet Archive
in 2010

http://www.archive.org/details/organicchemistryOOhart
ORGANIC CHEMISTRY
 9i

X
••./

Miim$F

ORGANIC
HAROLD HART and ROBERT D. SCHUETZ

HOUGHTON MIFFLIN COMPANY

CHEMISTRY Third Edition

Michigan State University

BOSTON • New York Atlanta Geneva, III Dallas Palo Alto

 II

Copyright © 1966, 1959 by Harold Hart and Robert D. Schuetz. Copyright 1953 by

Harold Hart and Robert D. Schuetz. All rights reserved, including the right to

reproduce this book or parts thereof in any form. Printed in the U.S.A.
Preface

This book was written with the hope of fulfilUng a twofold need. It

is designed to serve those students in agricuhure, home economics, nursing, and

veterinary science, and those preparing for the study of medicine, dentistry, and
pharmacy who must acquire a sound knowledge of organic chemistry but do not
need all the detail required by those who will make chemistry their career. The
majority of these students will proceed to courses in biochemistry and will
therefore have a strong interest in those aspects of organic chemistry concerned
with biological systems. For this reason, biochemical apphcations of organic
chemistry have been stressed.
In addition to this practical or utilitarian need, there is another which we feel
isperhaps even more important. The well-informed citizen of today, living in
an era of scientific revolution, must be aware of science in a more than casual
manner; he must learn something of it at first hand. The subject matter of
organic chemistry is closer to the everyday living of most people than any
other branch of chemistry; its manifold discoveries affect one's daily hfe in
many ways. A one-semester course in organic chemistry can illustrate the fun-
damental principles of chemistry, of the structure of matter, and of the factors
which govern molecular behavior and at the same time can be vitally interest-
ing to the non-science major because of the beautiful logic and close relation-
ship of organic chemistry to things practical. It is with this dual purpose that
this book has been written.
This book is not a condensation of a larger text, and it is written solely for
the student who is not majoring in chemistry. For this reason, many devices
have been introduced to arouse and maintain interest. The text has been
profusely illustrated to depict the practical uses of the many compounds dis-
cussed. Drawings of molecular models, often to scale, have been included to
emphasize and to help the student visualize the structural aspects of organic
chemistry. An introductory paragraph points up the importance of the material
to be discussed in each chapter, and a brief summary of new terms and con-
cepts, together with a set of exercises, concludes each chapter.
In a brief course, much subject matter has to be omitted, and the problem of
selection becomes central. We have included primarily those reactions which
vi • Preface

are of practical importance, which lead to useful products, or which illustrate

an important principle. The dozen or more methods for making saturated
hydrocarbons, for example, have been reduced to but three. Such classics for
the chemistry major as the malonic ester synthesis or the Diels-Alder reaction
have been presented in skeletal fashion only, to be either omitted or augmented
by the instructor depending on his judgement as to their suitability to his par-
ticular students. Reactions of biochemical interest and those important to in-
dustrial developments have been stressed. The theory and mechanisms of
certain reactions have been introduced, especially when it was thought that
these might be helpful in explaining to the curious student the "why" of organic
chemistry.
Teachers who used earlier editions of this text will find this one a thorough
revision, although the general plan is nearly unchanged. An integrated treat-
ment of aliphatic and aromatic chemistry is maintained throughout. Molecular
orbitals have replaced the more classic treatment of structure in earlier editions.
The three-dimensionahty of organic molecules and the geometric aspects of
mechanisms have been emphasized much more than in previous editions. It is
our experience that this approach helps students visualize reactions and remem-
ber them.
Reactions or structures important in biochemistry have been further empha-
sized by the mention of phosphate esters, disulfides, certain heterocychc sys-
tems, nucleic acids, and more frequent demonstrations of the importance of
hydrogen bonding. The order of Chapters 10 and 11 has been reversed in re-

sponse to many requests and to take advantage of a knowledge of ^-ketoacids

in the discussion of fat metaboHsm. Many questions from the second edition
are retained, but some have been revised and several new ones have been added
to each chapter, particularly to cover the new material. The entire text has been
reset.
We wish to thank here our many friends, both teachers and students, who
used earlier editions and generously gave of their time to make helpful sugges-
tions. Our special thanks go to Professor Milton Orchin in this regard. Similar
comments on this edition are invited.

Harold Hart

Robert D. Schuetz
Introduction

Before becoming immersed in the details of organic chemistry, one

might like to know in a general way what to expect. Let us briefly survey a
few achievements of organic chemists. By examining some of the contributions
organic chemical research has made to our modem civilization, one may get an
idea of the kinds of substances which are involved and of the methods and tech-
niques that are used in organic chemistry.
Prior to 1828. organic chemists were concerned only with compounds pro-
duced by living organisms, plant and animal. It was thought that a vital force
was necessary for the synthesis of these substances. The science therefore dealt
largely with the isolation of pure chemicals from natural sources, though some
eff'ort was expended on learning their constitution and possible utihty. In that
year, through a chance observation, the German chemist Friedrich Wohler
synthesized urea, a well-known constituent of human urine, from inorganic
compounds. This experiment and others which followed gradually led to an
overthrow of the vital force theory and to the founding of modern synthetic
organic chemistry. At the present time, the organic compounds which have
been synthesized in research laboratories far outnumber those isolated from
natural sources, although the study of natural products is still an important
branch of the science.
Of the natural products, perhaps the most familiar are the carbohydrates,
lipids, proteins, and vitamins which make up the organic part of our diet. In
order to ascertain the detailed structure of these complex molecules, the organic
chemist first uses analytical techniques. These may include not only an ele-
mental analysis, which gives the empirical formula, but also a variety of
chemical and spectroscopic methods which give much information about the
arrangement of atoms in the molecular framework. If these do not dehneate
the structure, the compounds may be degraded or broken down into simpler
fragments which are easier to examine than the complicated original. If one
can find and identify all the pieces, the only problem which remains is to dis-
cover how they fit together. The crowning achievement, then, is the synthesis
of the complex molecule from simpler fragments. The process is sometimes
long and difficult, but it has been completed for many natural products. Simple

VII
VIII Introduction

sugars have been completely characterized and synthesized, although the more
complex carbohydrates still offer many problems.
(starch, cellulose) The con-
stitution of many lipids known and some have been synthesized. Even the
is

proteins, notorious for their complexity and intricate structures, are now begin-
ning to yield to the ingenuity and persistence of the synthetic chemist. The
constitution of most of the known vitamins has been established and many,
though not all, have been synthesized.
Many natural products other than foodstuffs have been examined in order
to determine their constitution. Among the more important are petroleum,
natural rubber, alkaloids (morphine, nicotine, quinine) which are derived from
various plants, the pigments of many flowers, the steroids (of which the sex hor-
mones are among the better known), the antibiotics (penicillin, aureomycin),
and recently the organic compounds involved in heredity, RNA and DNA.
Large volumes have been written about each of these. The chemistry of these
natural products is very complex and can only be approached through a pre-
liminary study of simple organic molecules. It will be possible in this introduc-

tory text to lay only the foundation of fundamental organic chemistry which is

necessary to an understanding of the structures and chemical behavior of the

various natural products cited above.
Man's constant desire has been to improve upon his environment. Discovery
of the constitution of certain natural products led to attempts to synthesize
molecules with similar structures but with superior properties. Examples are
almost too numerous to mention, and we shall cite only a few important ones.
Not many years ago, a little over a century, there were no synthetic dyestuffs.
Coloring matter for various textile fabrics obtained from plant sources was
Hmited in availability and involved rather costly isolation procedures. Colored
cloth was available only to the wealthy. But, as a result of the development of

Friedrich Wohler (1 800-1 882). His synthesis of

urea from inorganic compounds did much to
overthrow the "vital force" theory of organic
chemistry. At theage of 27, he discovered the
element aluminum. He is known for many out-
standing contributions to both inorganic and
organic chemistry. (Bettmann Archives.)
 Introduction • ix

organic chemistry in the nineteenth and twentieth centuries, Hterally thousands

of shades and hues now can be manufactured synthetically from inexpensive
raw materials. The supply virtually unlimited, and great numbers of people
is

now enjoy color variations in their clothing, furniture coverings, and other fab-
ricswhich were not available to kings a century ago. And these colors can now
be accurately reproduced by means of the organic dyes used in color
photography.
Just as the chemist has succeeded in synthesizing new dyestuffs not available
from nature, so he has also been able to make new fabrics. The development
of rayon made available to a great multitude of people a material similar to ex-
pensive silks. Perhaps even more fabulous are the strictly synthetic fibers, such
as nylon, Orion, and Dacron, which in many respects are far superior to any
natural fiber. Certainly the future will bring even greater developments in the
textile area.
Petroleum, one of our greatest and most versatile natural resources, has been
improved by the organic chemist. He has designed methods for transforming
it, through the use of huge catalytic crackers, hydroformers, and alkylation
units, and by the addition of lead tetraethyl, to automobile and aviation fuels
which are tailor-made for particular uses. The constituents of petroleum have
been used to manufacture synthetic rubber which is superior for certain pur-
poses to the natural product. Many plastics which were undreamed of a few
decades ago are now made from petroleum, among other raw materials. All of
these products result from the imagination and genius of organic chemists.
The prime contributor to the development of new drugs and medicinals has
been the organic chemist. The great variety of sulfa drugs are synthetic, as
are analgesics, fungicides, and local anesthetics of various types. Many im-
provements in modern medicine would not have occurred were it not for the
close cooperative research by organic chemists and medical investigators.
It is now obvious to the reader that a very large number of the material arti-

cles with which one has daily experience fall within the realm of organic chem-
istry.We shall try, during the remainder of the text, to point out the nature of
many of these substances, what they are, how they are made, and what their
chemical behavior is. All this can be understood, however, only by a careful
preliminary study of certain fundamentals.
Perhaps, at this point, the reader may be willing to consider a few suggestions
which can facilitate the study of this subject. The importance of getting a good
start cannot be overemphasized. A new and rather extensive vocabulary will be
developed, the understanding of which is essential for subsequent progress. Be
certain that you understand each new term and each new concept as it is devel-
oped, since what follows will depend in an integral fashion upon what has gone
before. If you are very thorough at the beginning of this study, you will find
that the subject matter unfolds itself in a logical and clear pattern, requiring a
minimum of memory work and giving a maximum of understanding.
Contents

Preface d
Introduction uii

1 General Principles 7

2 Saturated Hydrocarbons 77
3 Unsaturated Hydrocarbons 39
4 Aromatic Hydrocarbons 73

5 Alcohols and Phenols 91

6 Ethers 772

7 Organic Halogen Compounds 123

8 Aldehydes and Ketones 135

9 Carboxyhc Acids and Their Derivatives 163

10 Substituted and Unsaturated Acids 194

1 Fats, Oils, Waxes, and Detergents 208

12 Organic Nitrogen Compounds 224

13 Optical Isomerism 252

14 Carbohydrates 269

15 Amino Acids and Proteins 293

16 Natural Products 315

Index 339

XI
 J There are more than a million organic chemicals, each
of which contains th e tetravalent elernent carbon, usually in
combination with hydrogen, oxygen, nitrogen, or certain
other elements. The unique property of the carbon atom
which enables it la form so many different substances is its

ability to combine with other carbon atoms through covalent

bonds. Carbons may Join to form long chains, branched
'chains, or rings. The infinite possible arrangements account
for the variety and large number of organic compounds.
Many of these constitute the common material articles of
everyday living, such as foodstuffs, clothing, fuels, plastics,
and others.

General Principles

Organic chemistry is the chemistry of substances which contain the element

carbon. Although the term "organic" was used originally to designate com-
pounds of plant or animal origin^_contemporary usage includes many synthetic
"substances as well!

The Unique Role of the Carbon Atom

Upon reading the above definition of organic chemistry, one's immediate
reaction is to ask the question — why single out the element carbon? What are
the unique properties of this element, that the study of its compounds should con-
stitute a separate branch of chemistry?
The position of carbon in the periodic table throws some light on the reason
for its particular importance (see Table 1-1). In the fourth group of the second
period, with an atomic number of six, carbon has a total of six orbital electrons.
Two of these comprise the first complete shell of electrons, leaving four electrons
General Principles

TABLE 1-1 Periodic Classification of Elements of the

First Three Periods
 General Principles

Figure 1-1. Sodium chloride (Na+CI~), on ionic

crystal. The light spheres represent sodium ions,
Na+, and the dark spheres chloride ions, Cl~.

volve a transfer of electrons from one atom to another. Sodium chloride is a

typical example of a compound formed by such a process.

Na- + -CI: -> Na+ + :C1: (1-1)

sodium and chloride ions_are held together by the electrostatic

In the crystal, the
between the positive and negatjxgjfinsjOsge Figure 1-1).
attractiv e force "~"

Of more interest to the organic chemist is th e cova lent bond, formed by a

mutual sharing of electron pairs between atoms. A simple example is the forma-
tion of a hydrogen molecule from two hydrogen atoms.

H- + H H:H (1-2)

Here, the two nuclei of the hydrogen atoms are held together by the mutual
attractive forces of both electrons of the electron pair for both nuclei. This is
illustrated in Figure 1-2, which shows the distribution of the negative charge as
the electrons move about the two positive nuclei.
Whereas the ionic jiondin sodium chloride is formed between atoms of widely
_dffierenr electronegativity, the covalent bond of the hydrogen molecule is
formed between atoms of identical electronegativity. Between these extremes,""
there are many compounds
in which the bonds involve unequal sharing of
electron pairs between atoms of intermediate difference in electronegativity.
These are called polar bonds. In the hydrogen chloride molecule, the hydrogen

Figure 1-2. Electron cloud in the covalent bonds of a hydrogen molecule (non-
polar) and a hydrogen chloride molecule (polar).

Ho HCl
4 • General Principles

and chlorine atoms are held together by a covalent bond. However, because
chlorine is more electronegative than hydrogen, the bond is not a symmetrical
one. The concentration of negative charge is greater around the chlorine atom
than around the hydrogen (see Figure 1-2). The hydrogen chloride molecule
may be represented as
H -^ S+ 5-
H:C1: or H:C1:

keeping in mind that the chlorine is slightly negative with respect to the hydro-
gen. This is sometimes indicated by an arrow, the head of which is negative and
the tail marked with a plus sign. Alternatively a partial charge (5+ or 6 — , to

be read "delta plus" or "delta minus") may be shown.

In order to determine which end of an unsymmetrical covalent bond is more
negative and which is more positive, one can generally rely on the periodic table
(see Table 1-1). ^_As_we_proceed4ipoml€ft to right within a given period (across
the table) t he elements b^ comg_increasiii.gly-£lectrQrLega_tiye^_As we proceed
from lop bottom of the taMe_within.a-^iven group (dowiiJhe_coIurnn)Jhe
to
eterrteiits'ljecomeT^ss'electronegative. From these generalizations, one might
predtet^ idt the at o m o n therighf in each of the following bonds would be nega-
tive with respect to the atom on the left:

C— CI C— Br
H— C—
C— s—
The carbon-hydrogen bond, so prevalent in organic compounds, requires
special mention. C arbon and hyd rogen have nearly the same electronegativity
(note that the atoms of each of thes? elements needlwice^s many clcctr(
they have in order to complete their valence shells); hence. _th e C — H bond Ls

nea rly pure c ovalent, with a sHght preference by the electrons for the hydrogen
atom.
""Siwe shall see, the chemical behavior of organic compounds can often be
predicted if the direction in which the bonds are polarized is known. For^-
ample^^sioceoxygen is mu ch in org,--el££tronegative-4harL_carb on. one mi g h t
predict thatcoinpoimds~wHichTiave a hydrogen atom attached to oxygen will
e more acidic ihaiftEose witK"'oirfy'cafbon^^liydreg€fH70nd^^^

-0:H — O:- + H (1-3)

C:H C:- + H (1-4)

/
can be easil}^_broke n t^ furnish proton s_laetdte~-behaviori _tlm-d€etf€aL pair
remaming with th e_elgc tron-at tracting oxy gen ato nL_But C H bonds are —
-usuaUynot acidic unless a very~sffoiTg''base^ is used to attracTThe'^roioft^^ec:
unles sthe~Tnolecirtezx^^ ti i resLwhich~stabilize the
negative carbon ion (carbanion).
 General Principles

Structural Formulas

Although organic compounds generally contain only a few elements, they

may contain many atoms of these elements per molecule. For this reason,
molecular formulas are of little use in organic chemistry. For example,
there are thirty-five known organic chemicals with the molecular formula C9H20-
Each of these compounds has its own characteristic boihng and freezing point,
as well as other properties which distinguish it from all the others; yet the molec-
ular formulas are identical. The only possible explanation for these differences
must be that, altjiough the kind-ajuLrmrrLbf^r r>f at^ms ar^ identical^he arrange- _
ment of the ato ms within hp mnlfru/p must he difikrpnt We can illustrate these
"ditlerences m arr angement b y_jising_gtnLctural fornrulas.
— in writing^cHemical formulas it is frequently convenient to allow a dash to
stand for a pair of electrons shared between two atoms (a chemical bond). Thus
the water molecule may be represented as

H:0: or H— 6:
H H
Note that the ordinary valence of an element is indicated by the number of
bonds attached to it. In the formula for water, each hydrogen atom has one
bond; the oxygen atom, two.
As stated previously, carbon, more than any other element in the combined
form, has the ability to unite or make bonds with itself. These bonds may in-
volve the formation of a continuous chain of carbon atoms:

VX - c
^^
< - c -^ ^
/ \
^ /
or a "branched" chain;

/ \ / \ / \

/ \ A\ / \
or a ring

Q
X Q
C C
X
Note each skeleton formula, every carbon atom has/owr bonds.
that, in
_02^igen_.andjiitiX!^en,4requeiTtlyXresent uTofganic compounds, have cuilF
mnnvaWirps nf twoandthrge, respectively; thus-one may find skeleton struc-
tures such as
 General Principles

C
/ \
N
vV
c- -N
I

\
The, hQndsjiQLJis£d_LQ..construct^^ bind
^jother-^temem^^-esfieci ally hydrogen , to it. Oxygen and nitrogen have~^two~or
one pair of unshared electrons, respectively (compare with the electronic
formula for water, page 5).
We are now in a position to account for the existence of more than one com-
pound with the same molecular formula.

Isomerism

The existence of sever al differen t compounds that have the same molecular
formirfCS c all ed isgrn erisni; compo u nds-4^avin gth&-sam€^^
'
ut differin^g^iLstructural formulas^ar&-eallcd isoiii CTS^__J

Jider the molecuIaFtofmula C2H6O. After several trials, one soon comes
to the conclusion that there are two and only two ways in which these atoms can
be arranged in accordance with the ordinary valence rules:

V H H H / \ H

o H .C.
/ \
H H HH H o
c H H
A B — C- G
Note that in each of these formulas the ordinary valences of four fbr carbon, two
for oxygen, and one for hydrogen obtain. Corresponding to these two possible
arrangements, two and only two substances have been found with the formula
C2H6O. One ethyl (grain) alcohol; the other, a gas called dimethyl ether.
is

Because of the different arrangement of the atoms within the molecules, these
compounds exhibit different physical and chemical properties. Note that the

Figure 1-3. Three-dimensional models of ethyl alcohol (left) and dimethyl ether
(right).
 General Principles

Figure 1-4. Three-dimensional models of five carbon atoms arranged in three

possible ways to give three isomeric structures.

Structural formulas A andB tell us that these substances are different, whereas
the molecular formula C2H6O does not. The three-dimensional structures of
these molecules are indicated in Figure 1-3. How, without being able to
examine the individual molecules, one is able to decide which of the above
formulas is that of ethyl alcohol and which is dimethyl ether is part of the
beautiful logic of organic chemistry. In this case, the matter is rather simply
determined. Ethyl alcohol reacts with metallic sodium to liberate one-sixth of
its hydrogen as a gas; dimethyl ether is inert to sodium. The only reasonable
interpretation of these experimental facts is that ethyl alcohol is represented by
formula A, where one hydrogen and different (bound to oxygen) from
is acidic
the other five (bound to carbon). Sometimes the distinction is not so obvious,
but diligence and ingenuity go not unrewarded in determining structures.
Another example of isomerism is illustrated in Figure 1-4.

Multiple Bonds Between Atoms

Two bonded atoms may more than two electrons between them. If
share
they share two pairs of electrons, the bond is said to be a double bond; if three
pairs, a triple bond. For example, the bond between carbon and oxygen in car-
bon dioxide is a double bond. Sixteen electrons (four from carbon and six from
:0::C::0: or :0=C=0:
each oxygen) bind the three nuclei in such a way that each nucleus has eight
electrons around it. If one counts bonds as a measure of valence, carbon still
has a valence of four, although only two atoms are bound to it (and oxygen has
its usual valence of two).

A carbon atom can also form multiple bonds with other carbon atoms.
Examples of skeleton formulas, with eight electrons surrounding each atom in
all cases, then become possible as shown
8 • Genera! Principles

w< o
c— c—
N/ — c— c=c-
/
c=c
When atoms more than one electron pair, the nuclei are
are held together by
pulled closer together than when only a single electron pair binds them. The
distance between nuclei (or the bond length) is shorter, and the bond may also

be thought of as "tighter": that is, atoms attached by a double bond vibrate

along the bond axis at a higher frequency than atoms attached by a single bond.
The frequencies which covalent bonds vibrate are comparable to the
at
frequencies of infrared radiation. When such radiation passes through covalent
molecules, some of that radiation may be absorbed, if it has the same frequency
as the vibrations (or bending motions, or rotations) of the particular bonds in
the molecule. This is analogous to the absorption of visible hght by colored

Figure 1-5. Infrared spectrum of allyl alcohol (CH2=CH — CH2OH) in carbon

tetrachloride solution. The C=C stretching frequency ( 1 ,650 cm.~i) is higher than
that of C — C and C — O stretching and bending frequencies which appear in the
region from 1,500 to 900 cm.~i.

Wavelength, /x

100

4000 3000 2000 1800 1600 1400 1200 1000 800

Frequency, cm."^
 General Principles • 9
molecules. An infrared spectrum, then, can give much
information about the
types of bonds present in a molecule. From
shown in Figure 1-5,
the spectrum
one can see experimental verification of the assertion made above, that multiple
bonds vibrate with higher frequencies than single bonds.

The Geometry of Carbon Bonds

We have seen that carbon may be bound to four, three, or only two other
atoms, depending upon whether the bonds are single or multiple. The geometric
arrangement depends on the number of atoms attached to carbon and is there-
fore determined by the orbitals used for bonding.
The four valence electrons of an unbound carbon atom, although they are in
a single valence shell,do not in fact have exactly the same energies. An electron
may be in an s orbital, which is spherically syrmnetrical around the nucleus, or
it may be in one of three p orbitals, which are mutually perpendicular and

shaped as shown in Figure 1-6. An electron in the s orbital has a somewhat

lower energy (i.e., is closer to the nucleus, and therefore more stable) than an
electron in the p orbital.
Toward the latter part of the nineteenth century, chemists deduced that, when
a carbon atom had four other atoms attached to it, these atoms had to be located
at the comers of a tetrahedron. The experiments and reasoning which led to
that deduction will be discussed in Chapters 2 and 13. Much later (only about
30 years ago) theoreticians showed that this tetrahedral concept was consistent
with and a logical deduction from theories of chemical bonding. When four
atoms are attached to carbon (by four pairs of electrons), one electron of each
pair comes from carbon. It can be shown that the best bonding (i.e., the most
stable molecule) will result if all four electrons are in identically shaped orbitals
which are hybrids (combinations) of one s and three p orbitals (called an sp^
hybrid orbital). These orbitals are directed from the carbon nucleus toward the
corners of a regular tetrahedron (see Figures 1-7 and 1-8). Chemical bonds are
then formed by the overlap of suitably shaped orbitals (see Figures 1-9, 1-10,
and 1-11). The angles between these bonds are 109.5°, the angle obtained when
Unes are drawn from the center of a regular tetrahedron to two of its corners.

Figure 1-6. The shapes of s and p orbitals used by the valence electrons of car-
bon. The nucleus is at the center of the spherical s orbital and at the origin of the

three coordinate axes of the p orbitals.

y
y
/

Is 2px ^Pv 2/?2

10 • General Principles

Figure 1-7. An sp-^ orbital. A bond con be

formed in the direction of the arrow.

The value of this angle has been confirmed experimentally by studying the
diffraction of X-rays by crystals, or the diffraction of an electron beam by
gaseous molecules. The angle may be a little greater or less than 109.5°,
depending on the particular atoms attached to carbon.
The nature of the bonding and its geometric consequences when only three
or two atoms are bound to carbon will be taken up later (see especially
Chapter 3).

Representation of Organic Formulas

The true representation of molecules requires three dimensions, but their

geometry can sometimes be indicated in a two-dimensional figure. For
example, a chain of five carbon atoms might be represented by

Figure 1-8. Four sp^ orbitals are directed toward

the corners of a regular tetrahedron.
 General Principles • 1

Figure 1-9. A C — H bond formed by overlap of

an sp^ carbon orbital with a hydrogen s orbital
(one electron from each atom). The direction of
the bond is on a line joining the two nuclei.
This type of bond, symmetrical about the axis
joining the atoms, is called a sigma (a) bond.

where ordinan' bonds are in the plane of the paper, dash hne bonds extend
below the plane of the paper, and black wedge-shaped bonds extend above the
plane of the paper toward the reader. This representation will occasionally be
useful, but. for most purposes, to conser\'e space such a formula can be written
as

— c—c— c— c— c—
! ! ! ! I

i I i I I

but one must bear in mind that this is an oversimpUfication. If the molecule is

C5H12, it may be indicated as

H H H H H
H— C— C—C— C—C—
I

I I i

H H H H H
or abbreviated still further to

Cri3 — CH2 — CH2 — CH2 — CH3

or e\'en to

Cri3Cri2Cri2CH2Crl3

Figure 1-10. A C — C bond (also a a bond) formed by overlap between two car-
bon sp"^ orbitals. it has the same symmetry as the bond in Figure 1-9.
1 2 • General Principles

Figure 1-11. A molecule of methane, CH4, formed

by overlap of the four sp^ carbon orbitals with

the s orbitals of four hydrogen atoms. The

resulting molecule has the geometry of a tetra-

hedron.

A molecule which is an isomer of this compound may be represented in any of

the following ways:

H H H H
H c-
 General Principles • 13
A:B
I
A+ :B- A:- B+ A- B
la lb II

When the bond spHts according to la or lb, the products are charged particles, or
ions, whereas a according to II yields neutral fragments called radicals, with
split
an odd number of electrons. Any one of these types of cleavage may occur in
organic reactions. If A is a carbon with three other groups attached to it, the
three possible fragments are a carbonium ion, a carbanion, or a free radical.

carbonium carbanion free radical

ion

Of these, the carbonium ion and radical hsLVQ less than the normal eight electrons
around the carbon atom; they are extremely reactive fragments which may
exist for a fraction of a second as reaction intermediates but are rarely the end-
products of a reaction. A carbanion, though it has the necessary eight electrons
around carbon, prefers, if possible, to share its unshared electron pair with a
species capable of accepting them. This is because carbon, with its central
position in the periodic table, has no strong attraction for unshared electrons.
Examples of stable carbonium ions, carbanions, and free radicals are known,
but the groups attached to the central carbon atom must have special structures
which allow the charge, or odd unpaired electron, to be stabilized.
If the A part of an A:B bond is a carbon fragnifnt thp hnndxWvagp i<; most
likely to lead to a carbonium ion (A+) when B has a strong attr action for
electrons: thaFIs. if B^ ^ ^ <;talala-;wt< in snrh p ^
i

sodium the A R bond would more

r blnridp i nn O i- TthoTttB^jC
hand, if B were^ajTietal,_su cli an •

likely break
'
tTT-gw^-^^^^grKgrnnri -(
^ -) nnri tlif> pr>r i fivp m ptallir and B
inn (gayr^N^a+] If A
are similar in electronegativity, the chance that the electron pair would be sptilr
^^Tp-givg'two radicalvAr and D , vvould be4iieieasfid:i^z::^^^£.^ilLsee_gj^amples, in
our^iiHy oj" all three types of bond breaking.
organic reactions, of Ionic rea^
lioiis~will b£-favQred by solvents which are polar (water, alcohols) whereas
Radical reaetions aTeTetetively4€ss -susceptible to solvent polarity.

The Organization of Organic Chemistry

A branch of science which concerns itself with a million or more compounds
might be very difficult to study were it not possible to classify these compounds
into a relatively small number of groups, based upon the reactive parts or func-
tional groups within the molecules.
Let us recall an illustration from inorganic chemistry. We learned that
chloride ion will react with silver ion to form, in aqueous solution, a white
insoluble substance, silver chloride. This reaction is characteristic of the
 14 • General Principles

chloride ion and enables us to know a little bit of the chemistry of any substance
which contains chloride ions. Thus, although we may try the experiment in the
laboratory using sodium chloride, we might predict that potassium chloride,
barium chloride, magnesium chloride, cupric chloride, etc., would also give a
white precipitate of silver chloride when treated in aqueous solution with silver
nitrate.
^ ^In organ ic chern istry, of a particular functional group in an
too, the presence
...QlganicjnolefiiikJmglltsijQJt ^^
Shoul d an uigauic i i iolecule
— ontain a hydroxyl g raup^^i^QHXJt-wilLejdiibircertanr^
of that group, whether the substancebe

H H H H H H
H— C— OH H— C— C— OH or H— C— C— C— OH
H
I II
H H
III
H H H
Compounds containing t he hydroxyl group ar e known as alcohols. Other
classes of compounds which will l)e studied are hsted in tabular form on the
inside front cover of this text. Our study of organic chemistry begins at the
top of this Ust, with compounds of carbon and hydrogen only, and proceeds
down the list in the order presented.
We compounds which contain more than one functional
shall then consider
group and study their interaction when present in the same molecule. This
fundamental study will enable us to examine then some of the more complex
and fascinating organic substances, such as dyestuffs, proteins, carbohydrates,
and plastics.

NEW CONCEPTS. FACTS. AND TERMS

1. Carbon is tetravalent. It can combine with other carbon atoms to form chains or rings
of carbon atoms.
2. Electronegativity — the affinity of an atom for electrons. In general, the electronega-
tivity of elements increases as one proceeds from left to right, and from bottom to top,
in the periodic table.
3. Types of bonds
a. Ionic— transfer of electrons between atoms that differ widely in electronegativity
b. Covalent — mutual sharing of electrons between atoms of similar electronegativity
c. Polar — unequal sharing of electrons between atoms of intermediate difference in
electronegativity
4. Structural formulas — necessary to show the arrangement of atoms within molecules.
5. Isomers — compounds with the same molecular formulas but different structural
formulas.
6. Multiple bonds — may be formed by sharing two or three electron pairs between atoms.
Infrared absorption spectra give information about the types of bonds present in a
molecule. Double bonds are shorter and vibrate with higher frequencies than corre-
sponding single bonds.
 General Principles • 15
The geometry of carbon bonds —
is determined by the number of atoms attached.

When bonds are single, they are said to use sp^ hybrid orbitals on carbon. These
all

extend from the carbon nucleus to the corners of a regular tetrahedron. Bonds are
formed by the overlap of appropriately shaped orbitals, two electrons per bond.
—
Organic reactions usually involve covalent bonds. Carbonium ions, carbanions, or
radicals may be reactive intermediates during a reaction. These have, respectively,
positive, negative, or neutral carbon atoms, with only three groups attached.
Functional groups — the reactive parts of a molecule; can be used to classify the myriads
of organic compounds for systematic study.

EXERCISES AND PROBLEMS

(Use the foUowing atomic weights: C = 12. H = 1. O = 16. N= 14. S = 32, CI = 35.5,
Br = 80.)

1. When a solution of salt (sodium chloride)

in water is treated with a silver nitrate solu-
(^^^-tion. a white precipitate forms immediately; when carbon tetrachloride is shaken with
aqueous silver nitrate, no such precipitate is produced. Explain these facts in terms of
the types of bonds in the two chlorides.
2. Using position in the periodic table (page 2) as a criterion of electronegativity, classify
,^ the following substances as ionic or covalent: NaF, CI2, CH4, MgO. SFe, SO2, AICI3.
/ i Draw structural formulas for each of the following covalent molecules. Which bonds
are polar? Indicate the direction of polarity by an arrow (-| — >) over the bond, the
head of the arrow representing the negative end: HBr, H2O, CO2, H2, CH3CI,
CH3OH.
4. Using dots to represent valence electrons and remembering that each element has the
number of valence electrons corresponding to the group (Table 1-1) in which it appears,
write electronic formulas for each of the following substances: C2H6, H2SO4, HNO3,
CH3OH, NH3, F2, CH3NH2, CH3NO2.
5. Group the following compounds according to those which might be expected to exhibit
^- similar chemical behavior.
a. CH3OH d. C5H12 g. CH3CH2OCH2CH3
b. CH3OCH3 e. C4H9OH h. CH2CI2
c. C3H5(OH)3 /. CH2Br2 /. C3H7OH
-^ Draw the structural formula for each.
6.\Draw a plausiblestructural formula (similar to those on pages 1 1 and 12) for each of
\ ythe following molecular formulas: C4H10, C2H6O, C5H12, CaHsO, C2H7N (nitrogen
usually is tricovalent in organic compounds), C3H3Br3.
7. Draw all possible structural formulas for each of the following molecular formulas,
using only the conventional valences (C = 4. H= 1, O = 2): C6H14, C4H10O.
8. Which of the following molecular formulas are plausible, and which are not: C3H9,
C4H10, CsHii, C2H6CI, C2H4CI2? Write a plausible molecular formula for a compound
containing: a. C, H, and O; b. C, H, and Br; c. C. H, and N; d 7 C's and sufficient H's;
e. C. H, O, and CI.
9. Calculate the weight percent of carbon in each of the following compounds: a. C4H10;
b. C2H6O; c. C4H6CI2S; d C2H5NO2.
10. Blood sugar (glucose) contains 40.0% C, 6.7% H, 53.3% O. Calculate its empirical
formula. From its freezing point depression in water, the molecular weight was deter-
mined to be 180. What is its molecular formula?
16 • General Principles

11. The combustion of 0.300 g. of an organic compound containing only C, H, and O gave
0.660 g. of CO2 and 0.360 g. of H2O. What is its empirical formula? Its molecular
weight was determined to be about 60. What is the molecular formula? Suggest two
possible structural formulas for the compound.
12. A white, crystalline soHd isolated from human urine had a molecular weight of 60 and
contained C, H, O, and N. Combustion of a 0.250 g. sample gave 0.178 g. of CO2 and
0.146 g. of H2O. Another 0.250 g. sample, when boiled with excess alkah, liberated all
the nitrogen as ammonia. The ammonia generated was sufficient to neutralize 41.8 ml.
of 0.200 A'^ hydrochloric acid. Calculate the correct molecular formula of the substance.
13. Draw structures for each of the following, using atomic orbitals, appropriately hy-
bridizedwhen necessary. Show the expected geometry for each molecule.
a. H2O; b. NH3; c. HF; d. BF3; e. NH4+.
14. Carbon, in forming some compounds, uses three equivalent sp^ hybrid orbitals, or two
equivalent sp hybrid orbitals. Using the idea that there should be maximum separation
of orbitals (i.e., minimum repulsion between the electrons in such orbitals), what
geometry would be expected in each case?
15. The covalent bond in HCl is about 40% longer than the covalent bond in HF, yet 70%
less polar. Explain.
 n"2n-\-2

Petroleum and natural gas are resources which fur-

nish a large percentage of our energy —
they are rich in
organic chemicals. Saturated hydrocarbons comprise the
major portion of these vital substances. Because they are
relatively unreactive, they were originally known as paraf-
fins, meaning that they had ''little affinity" for other chemi-
cals. Through extensive research, however, many processes
have been discovered for converting them into industrially
important organic compounds. They are also the fuels used
in automobiles, airplanes, diesel railroad engines, and
trucks, and in many industrial operations. Saturated hydro-
carbons are also of interest as the parent compounds from
which the structures of all other organic molecules can be
derived.

Saturated Hydrocarbons

Our study of organic chemistry begins with the simplest possible organic
compounds from the point of view of structure, the saturated hydrocarbons.
As the name implies, hydrocarbons_coiitai n only the elements rarbnn and hy-
le Je rm "sa turated" means that only single covalen t bonds are

"prese nt within the molecule. Smce the hygrocarBofis contain only carbon and
iiydTogen, most of the more complex organic compounds may be thought of as
having been derived from saturated hydrocarbons by replacement of hydrogen
atoms with other atoms or groups of atoms.
In addition to being the roots of the family tree of organic chemistry, the satu-
rated hydrocarbons are of considerable importance in their own right. Natural
gas, which is used extensively for fuel purposes both in domestic gas ranges and
by industry, consists primarily of methane, CH4, the simplest saturated hydro-
carbon. Petroleum, one of our natural resources which has contributed tre-

17
18 Saturated Hydrocarbons

mendously our high standard of Hving, contains high percentages of hydro-

to
carbons. It oils, vaseline and paraffin wax, tar,
furnishes gasoUne, lubricating
and pitch, all of which are rich in saturated hydrocarbons. Petroleum also
supplies raw materials for the manufacture of many useful products plastics, —
synthetic fibers and rubber, alcohol, antifreeze, and innumerable others.

Structures of Some Saturated Hydrocarbons

The simplest saturated hydrocarbon is methane.

H
H— C— or CH4
H
methane

Figure 2-1. Three-dimensional models of o meth-

ane molecule. Two types of molecular models
will be illustrated throughout this text. At left, the
structural model has distorted bond lengths to
show the consecutive attachment of the atoms.
At right, the scale model more closely represents
the actual molecular form.

By increasing the number of carbon atoms in a chain, one can develop addi-
tionalcompounds in this series.

H H
H— C— C— or CH.CH,
H H
ethane

Figure 2-2. Models of ethane.

 Saturated Hydrocarbons • 1

Figure 2-3. Models of propane.

H H H
H— C— C— C— H or CH3CH2CH3
H H H
propane

Figure 2-4. Models of butane.

H H H H
H— C— C—C—C— H or CH3CH2CH2CH3 or CH3(CH2)2CH3
H H H H
normal butane

The names of the four members of this series are common names which
first

should be memorized. As the length of the chain increases, the root of the name
is derived from the number of carbon atoms, and the -ane ending is retained.
H H H H H H H H H H H
H— C— C—C— C— C- H H— C— C—C—C— C— C—
H H H H H H H H H H H
pentane hexane
 20 • Saturated Hydrocarbons

HHHHHHH HHHHHHHH
H— C— C—C— C— C— C— C— H— C— C—C—C— C— C— C— C—
HHHHHHH heptane
HHHHHHHH octane

Compounds like these in which there is a single continuous chain of carbon

atoms are sometimes called normal, or, in this case, normal paraffin hydrocar-
bons. These are contrasted with "branched" chain compounds.

Homologous Series

Saturated hydrocarbons conform to a general formula CnH2„+2, in which n

isthe number of carbon atoms in the molecule. The reader should test this
formula and note that it appUes to all the compounds listed above. Further
examination of these formulas shows that each compound differs from the next
one by a CH2— —
or methylene group. A series of compounds so related is
,

called ahomologous series. Members of such series are usually closely related
in both physical and chemical properties. See, for example, the smooth curve
which represents the boiling points of the normal paraffins as the chain length
is increased (Figure 2-7).

Nomenclature
In view of the multitude of saturated hydrocarbons possible because carbon
atoms can form continuous or branched chains, it became necessary to devise
some systematic method for naming these compounds. An international sys-
tem of nomenclature has been devised which is recognized and used by organic
chemists throughout the world. The system has been recommended by the
International Union of Pure and AppUed Chemistry, and is sometimes desig-
nated by the initials I.U.P.A.C.
The rules of the I.U.P.A.C. system are few and simple to use:
1 _The_general name for paraffin or saturated hydrocarbons is alkanes.

2. For branched chain hydrocarbons, determine the longeliTcontiriTious chain

of carbon atoms in the molecule^ Use the name of the paraffin hydrocarbon
coffespohd^ingn:o~thts mimber of carbon atoms as the basis for the name of the"
compound. Thus, the longest continuous chain of carbon atoms in the com-
pound has six carbon atoms; the lasf part of the name will therefore be hexane.

CH3
CH3— CH— CH2— CH2— CH2— CH3
1 2 3 4 5 6

3. Number the carbon atoms of the continuous chain, beginning at the end
'

nearest Ihe braTiehlng.~ 1 his has l)een done in the above formula?""
—4. -The substitiierits7 other than hydrogen atoms, which are attached to the
chain are given names and numbers. The name of the substituent is taken from
 Saturated Hydrocarbons • 21

the paraffin h ydrocarbon with the same numbgr of carbon atoms by changing
ihp- mjc ending tn^r~ TTiie substituent in the above formula has only one carbon
atom. It is derived from the hydrocarbon methane and called the methyl group.

H
22 • Saturated Hydrocarbons

hydrogen atoms. The first two groups are

H H H
H— C— or CH3— H— C— C— or CH3CH2—
H H H
methyl ethyl

There are two possible groups which can be derived from propane

H H H
H— C— C— C—
H H H
propane

One of these, which involves removal of hydrogen from one of the end carbon
atoms, is

H H H
H— C— C— C— or CH3— CH2— CH2—
H H H
normal propyl
(n-propyl)

The other, in which a hydrogen is removed from the central carbon atom, is

H H H
H— C— C— C— H or CH3— CH— CHs
IIIH
H
I

isopropyl

These alkyl groups are not capable of independent existence for any apprecia-
ble time, but are particularly useful for naming organic compounds. This is

illustrated in the following formulas.

CH3 CH3
1 2| 3 4| 5 6
CH3CHCHCHCH2CH3 CH3CHCH3
CH2 CI
Isopropyl chloride
CHc^ (2-chloropropane)
2,4-dimethyl-3-ethylhexane

To write astructure without designating a specific alkyl group, the symbol R

is frequently used to represent any alkyl group. For example, the formula
R — CI represents any member of the homologous series of alkyl chlorides
(methyl chloride, ethyl chloride, etc.).
 Saturated Hydrocarbons • 23

y^"
H X^

H H

H(H)

(H)H' H(H)
eclipsed staggered
conformation conformation

Figure 2-5. Two possible conformations of ethane. Rotation from one to the
other is easily possible as shown by the curved arrows. The lower formulas show
how the hydrogens would be arranged if the molecule were viewed end on along
the carbon-carbon bond axis.

Conformations
The distance between two carbon atoms joined by a single electron pair is

relatively independent of the remaining structure of the particular molecule and

is usually about 1.54 A.f Since the bond is symmetrical about the axis joining
the two nuclei (see Figure 1-10, page 11), rotation about a single bond is
possible.
At first it would seem as if an infinite number of ethane molecules might exist,
depending upon the angle of rotation of one carbon atom with respect to the
other. It is indeed true that an infinite number of conformations is possible for
ethane, two of which are shown in Figure 2-5. But at room temperature the
ethane molecule has sufficient thermal energy so that rotation about the single
bond from one conformation to another is easily possible. Therefore only one
ethane (and no isomer of it) is known. However, there is a preference for
staggered conformations over eclipsed ones, because of less interference between
the hydrogen atoms on adjacent carbons.
Two possible conformations of n-butane are shown in Figure 2-6; of these the
lower is preferred because it minimizes repulsions between the hydrogens.

Physical Properties

The alkanes are insoluble in water, and those which are liquid are considera-
bly less dense than water and float on it. The attractive forces between alkane

fThe symbol A means an Angstrom unit, or 0.00000001 cm.

24 • Saturated Hydrocarbons

Figure 2-6. Two conformations of n-butone.

molecules are small, because the molecules contain no polar groups, multiple
bonds, or unshared electron pairs. As a result, alkanes tend to have lower boil-
ing points for a given molecular weight than any other hydrocarbon-derived
organic compounds.
A summary of the boiling points of the normal saturated hydrocarbons is

given in Figure 2-7. It is seen that the boiUng point is directly related to the
molecular weight or chain length. At ordinary temperatures and pressures, the
first four members of the series are gases, whereas those with more than twenty

carbon atoms are waxlike soUds. Compounds with intermediate numbers of

carbon atoms are colorless liquids.
Isomeric hydrocarbons (those having the same molecular formula but
diff'erent structural formulas) have different physical properties. Usually the
more branched the chain, the lower the boiling point. This is illustrated in the
inset in Figure 2-7 for the various isomers of pentane, C5H12.
 Saturated Hydrocarbons 25

100
26 • Saturated Hydrocarbons

tion of the molecular structure) is by displacement or substitution of one atom

or group for another.
Chlorine and bromine react very slowly with paraffin hydrocarbons at room
temperature. At higher temperatures, and particularly in the presence of sun-
light, hydrogen atoms in the hydrocarbon can be replaced by halogen atoms.
The reactions are called halogenation (chlorination or bromination). The
reaction may be represented for methane by the following equations:

:Ci:Cl: (2-1)

(2-2)
 Saturated Hydrocarbons • 27
H H
CI— CI + H— C— CI CI— C— CI
I

+ HCl (2-5)
I

H H
dichloromethane
(methylene chloride)

H H
CI— CI + CI— C— CI CI— C— CI + HCl (2-6)

H CI
trichloromethane
(chloroform)

H CI

CI— CI + CI— C— CI - CI— C— CI + HCl (2-7)

I

CI CI
tetrachloromethone
(carbon tetrachloride)

In practice, a mixture of products is usually obtained.

When more than one carbon atom, the process may be-
the hydrocarbon has
come even more complex. Thus the first substitution product of ethane is ethyl
chloride.

H H H H
CI— CI + H— C— C— heat or
sunlight
H— C— C— CI + HCl (2-8)

H H H H
ethane chloroethane
(ethyl chloride)

When a second hydrogen is replaced, two alternatives are possible, and a mix-
ture of both products is obtained:

H CI

H— C— C— CI
I I

H H
H H 1 ,1-dichloroethane

CI— CI + H— C— C— CI heat or

sunUght
+ HCl (2-9)

H H H H
CI— C— C— CI
H H
1 ,2-dichloroethane
28 Saturated Hydrocarbons

When propane is halogenated, a mixture of products can be obtained, even at

the first step:

H H H
H— C— C— C— CI
H H H
H H H 1 -chloropropane
(n-propyl chloride)

CI— CI + H— C— C— C— heat or

sunhght
+ HCl
H H H H H H
propane (2-10)
H— C— C— C—
H CI H
2-chloropropane
(isopropyl chloride)

Because of the multipHcity of products, halogenation of saturated hydro-

carbons may not always be a useful laboratory reaction. But cychc hydrocar-
bons, because of their symmetry, can be converted to monosubstituted deriva-
tives in good yield (equation (2-11)).

A
CI

CH,
CH2 CH2 + CI2 he^'"'-
)
CH2 CH^ + HCl (2-11)
sunlight \ /

CHs CH2 CH2 — CH2

cyclopentane cyclopentyl chloride

A petroleum fraction consisting mainly of pentane and 2-methylbutane is

chlorinated commercially to give a mixture of chlorinated pentanes which are
not separated but used directly (for example, in the manufacture of solvents for
automobile lacquers).
Nitration. Another commercially important substitution reaction involves
the reaction of saturated hydrocarbons with nitric acid vapor:

H H
H— C— H
1

+ HO— NO2 400°

> H— C— NO2 + H2O (2-12)

H (HNO3) H
nitric acid nitronnethane

Nitration is somewhat different from halogenation in that only mononitration

is observed and, with higher alkanes, breaking of carbon-carbon bonds occurs.

 Saturated Hydrocarbons • 29
""^"^
CH3CH2CH3 )

propane

CH3CH2CH2NO2 + CH3CHCH3 + CH3CH2NO2 + CH3NO2 (2-13)

l-nitropropane
NO nitroethane nitromethane

2-nitropropane

The products are excellent solvents, ingredients of special racing and model
engine fuels, as well as intermediates for the synthesis of drugs, insecticides, and
explosives.

Oxidation

Perhaps the most important use of hydrocarbons is as fuels. Hydrocarbons

burn in an excess of oxygen to form carbon dioxide and water. The reaction is
accompanied by the evolution of large quantities of heat.

CH4 + 2 O2 > CO2 + 2 H2O + 212,800 calories (2-14)

C7H16 + 11 O2 > 7 CO2 -I- 8 H2O + 1,151,300 calories (2-15)

This reaction is the basis for the important use of hydrocarbons as sources of
heat (natural gas) and power (gasoline in the internal combustion engine).
Gasoline consists of hydrocarbons which boil from about 30° to 200° C.| and
contain from five to twelve carbon atoms per molecule. The equation for the
combustion of these substances shows that the reaction involves the formation
of large volumes of gases. It is this sudden expansion of gases that drives the
pistons in an automobile engine. Pyrofax, or "bottled gas," is mainly propane
which, through pressure, has been condensed to a Hquid so that it may be com-
pactly stored and shipped in metal cylinders or tanks.
In the absence of suflficient oxygen for complete reaction, partial combustion
may occur. The products may be carbon monoxide or even carbon.
2 CH4 4- 3 O2 > 2CO -^ 4 H2O (2-16)

CH4 + O2 > C + 2 H2O (2-17)

The effects of incomplete combustion are well known to every motorist in the
form of carbon deposits in the head and on the pistons of the motor, and the
toxic carbon monoxide in the exhaust fumes. Incomplete combustion of
natural gas is done purposely to manufacture carbon blacks, particularly lamp-
black, a pigment for ink, and channel black, used in automobile tires.

Cracking

Hydrocarbons are generally very stable compounds which can be distilled

without decomposition. But if they are heated to temperatures well above their
boiling points in the absence of air, the molecules can be caused to disintegrate or
"crack" into several smaller fragments. Higher hydrocarbons yield a mixture

% All temperatures in this book are Centigrade unless otherwise stated.

30 Saturated Hydrocarbons

of saturated and unsaturated hydrocarbons of lower molecular weight. This

reaction is carried out extensively in the petroleum industry to convert hydro-
carbons of very high molecular weight with about fifteen to eighteen carbon
atoms into gasoline hydrocarbons in the range of five to twelve carbon atoms.
The "cracking" process has made available a considerably larger quantity of
motor fuel than is directly obtainable from crude petroleum. Catalysts have
been developed which allow the process to be carried out at lower temperatures
than was formerly possible (see Figure 2-8).

Other reactions important to petroleum chemistry will be discussed in the

next chapter.

Preparation

The most common source of paraffin hydrocarbons is petroleum, from which

they may be obtained by fractional However, a particular hydro-

distillation.

carbon sometimes has to be tailor-made or synthesized for research studies. To

do this, several laboratory-scale methods have been developed.

Synthesis from Acids

Q
//
The carboxyl group, — C — OH, is characteristic of organic acids. Acetic acid

(constituent of vinegar) has the structure CH3 — C — OH and reacts with bases
to form salts (equation (2-18)).

(
 Saturated Hydrocarbons • 31

//
P P
// -
CH3— C— OH + Na+OH- > CH3— C— O: Na+ + H2O (2-18)
acetic acid sodium acetate

When an electric current passes through such a salt solution, the acetate ions
migrate to the anode and give up one electron. The resulting radical rapidly
loses carbon dioxide, giving a methyl radical; two of these methyl radicals com-
bine to give ethane.
P P
CH3— C— O: -=^ CH3— C— O- (2-19)

P.. .. ..

CH3Q3r^^ > CH3- + :0=C=0: (2-20)

2CH3- > CH3-CH3 (2-21)

The sodium ions discharge at the cathode, producing sodium hydroxide and
hydrogen. This synthesis, first performed in 1849 by the German chemist
Herman Kolbe, is general for the doubUng up of organic radicals.
O
^'"'^"'-^"^
2 R-C-0-Na+ + 2 H2O >

R— R -^ 2 CO2 + 2 NaOH + H2 (2-22)

anode cathode

The loss of carbon dioxide from the salt of an organic acid (decarboxylation)
can also be accomplished by heating the sodium salt of the acid with soda lime
(a mixture of sodium and calcium hydroxides). This reaction works reasonably

CHdC \

[
0-Na+ -h Na+OIH- ^^^ CH4 + Na2+C03= (2-23)

sodium acetate / from \ methane

\soda lime/

well for preparing methane, but is accompanied by undesirable side reactions

when the carbon chain in the acid is long.

The Wurtz Reaction

In 1855 the French chemist Charles Adolphe Wurtz discovered that ethane
was obtained when methyl iodide was treated with metalhc sodium.
H H H H
H-C^"r+ 2 NaTi^C-H > H-C-C-H + 2 Na+I" (2-24)

H H H H
methyl
iodide
32 • Saturated Hydrocarbons

It is likely that this reaction proceeds by way of an organosodium compound,

formed as in equation (2-25). This then reacts with a second molecule of methyl
iodide to form the final product (equation (2-26)).

CHg:!: -f 2Na- > CH3:-Na+ + Na+:I:- (2-25)

methylsodium

CH3:-Na+ + CHs:!: > CHgiCHa + Na+:I:- (2-26)

The reaction may be extended to more complex alkyl halides. For example,
ethyl bromide gives a good yield of /7-butane:

H H H H
H— C— C—,|Br"+ 2 Na""+ B^^^ C—C—H >

H H H H
ethyl bromide

H H H H
H—C—C— C—C—H + 2 Na+Br- (2-27)

H H H H
n-butane

Note that the hydrocarbon which is formed is symmetrical and has twice as many
carbon atoms as the original alkyl halide. The carbon atoms that join are those
which originally held the halogen atoms.

Reduction of Halogen Compounds

In the Wurtz an organic halide is converted to a hydrocarbon by
reaction,
doubUng up the Halogen compounds can be converted to hydro-
alkyl radicals.
carbons with the same number of carbon atoms by a variety of reducing agents
which replace the halogen by hydrogen. The general equation is

RX -^^ RH (2-28)

Zinc and acetic acid make a good reducing combination for this purpose.

Proof of Structure

The Wurtz reaction affords an excellent example of how the organic chemist
can determine the structure of an organic compound. It is possible to obtain
from natural petroleum two hydrocarbons with the formula C4H10. One boils

§ [H] signifies a reducing agent.

 Saturated Hydrocarbons • 33
at 0°; the other, at —10°. From valence considerations, we arrive at two
possible formulas:

CH3CH2CH2CH3 CH3CHCH3
CH3
n-butane isobutane

How can the organic chemist determine which compound is which? The
reasoning involved goes somewhat as follows: Ethane can form only one
monobromination product, since all six hydrogens of ethane are equivalent (see
page 27). Ethyl bromide, when it reacts with sodium in the Wurtz reaction (see
equation (2-27)), must give A7-butane. The product obtained from the Wurtz
reaction with ethyl bromide boils at 0°. Therefore, the isomer of C4H10 which
boils at 0° must be «-butane, and the one that boils at — 10° must be isobutane.
This is an example of proof of structure by synthesis.

Cycloalkanes

Carbon atoms can form rings as well as chains. The simplest of these ring
compounds are the cycloalkanes. Rings containing as many as thirty carbon

CH2
/CH2 Cfi9
12XH.
V"2
CH2 CH2— CH2 CH2
\^' CH2 /' CH2/CH2
CH2— CH2 CH2— CH2 CH2-CH2 CH2
cyclopropane cyclobutane cyclopentone cyclohexane

atoms have been prepared. Although the general formula for these compounds
is C„H2n, the structures are analogous to the open-chain saturated hydrocar-

bons, all bonds being single. Except for the first two members of the series (C3
and C4), the reactions of cycloalkanes are very similar to those of their open-
chain analogs.
— —
Cyclopropane is a planar molecule. The C C C angles are appreciably
less than the normal tetrahedral angle, and for this reason the ring is under some

strain. In chemical reactions, there may be a tendency to reheve this strain by

opening the ring. Thus, although cyclopropane can be chlorinated in the pres-
ence of ultraviolet light to give cyclopropyl chloride, it reacts with bromine to
give an addition rather than a substitution product (equation (2-29)). 1,3-

Dibromides can be converted to cyclopropanes with zinc dust, a reaction similar

to the Wurtz reaction but intramolecular.

CH2— CH2 + Br2 > CH2-CH2-CH2 (2-29)

CH2 Br Br
1 ,3-dibromopropane
Zn dust I
34 Saturated Hydrocarbons

Despite the strain, the cyclopropane ring occurs in many natural products,
including chrysanthemums, caraway seeds, and the proteins of pear juices. The
cyclobutane ring, also strained, nevertheless occurs in natural products, perhaps
the most common being pine oil (Chapter 16).
In recent years, much has been learned about the nature of chemical bonding
by studying highly strained molecules. Some of the more unusual carbon skele-
tons which have been synthesized are shown.

XH—^CH
CHH CH
HoC
CH2 CH CH
bicyclobutane spiropentane Cuban

Five- and six-membered rings are relatively free of strain; cyclopentane is

nearly planar, with just a shght puckering to accommodate the difference be-
tween the tetrahedral angle and the internal angle of 108° in a flat pentagon. In
cyclohexane, the diff'erence (120°vs. 109° 28') can be accommodated by either

of two arrangements, a chair or a boat form (see Figures 2-9 and 2-10). The
chair form is much preferred, partly because of interference between the two
"jutting" hydrogens on carbons 1 and 4 of the boat; also, the chair form has all
the hydrogens in staggered conformations with respect to their nearest neigh-
bors, very much like the staggered conformation of ethane (see page 23).

At ordinary temperatures, most cyclohexanes exist in the chair form. Examination

this form (see Figure 2-9) shows that six of the bonds to hydrogen lie
of models of
roughly in the plane of the ring (the lower bonds on Ci, C3, and C5 and the upper
bonds on C2, C4, and Ce). These are called equatorial bonds. The remaining six
bonds extend roughly at right angles to this plane and are called axial bonds (the lower

Figure 2-9. The chair form of cyclohexane.

 Saturated Hydrocarbons • 35

Figure 2-10. The boat form of cyclohexane.

bonds on C2, C4, and Ce and the upper bonds on Ci, C3, and C5). Models show that
axial hydrogens on the same side of the ring come very close to one another. For this
reason, when groups larger than hydrogen are attached to a cyclohexane ring, they
prefer an equatorial position, if such an arrangement is possible. Since many natural
products contain the cyclohexane ring, an understanding of these conformational
effects has been of paramount importance in working out their chemistry.

The reactions of cyclopentanes and cyclohexanes are much hke those of the
open-chain saturated hydrocarbons; that is, substitution. There is no tendency
for the rings to open. These rings are by far the most common and occur widely
in nature (see the many examples throughout the text, but especially in Chap-
ters 14, 15, and 16).

Larger rings than six are less common, but not nearly as rare as was once
thought. For a few examples of such rings in natural products, see Chapter 16.

NEW CONCEPTS. FACTS. AND TERMS

1. Saturated hydrocarbons, paraffins, alkanes
a. They contain only carbon and hydrogen, and only single covalent bonds
b. The simplest members are methane, ethane, propane, butane
c. Their general formula is C„H2n+2
2. Homologous series — compounds of the same type which differ only by — CH2
groups.
3. I.U.P.A.C. — the International Union of Pure and Applied Chemistry, which devised a
system for naming organic compounds. The rules for nomenclature of saturated hydro-
carbons are on pages 18-22.
4. Alkyl groups — derived from saturated hydrocarbons, by removing one of the hydrogen
 36 • Saturated Hydrocarbons

atoms. The -ane ending is changed to -yl Methyl from methane, ethyl from ethane,
normal propyl and isopropyl from propane. Useful in naming organic compounds.
5. —
Physical properties of alkanes the distance between carbon atoms joined by single
bonds is 1.54 A. Rotation of one atom with respect to another leads to many confor-
mations, but since rotation from one conformation to another is facile, no new readily
separable isomers are produced.
6. Reactions of alkanes
a. Substitution reactions —displacement of one atom or group by another — halo-
genation, nitration. Free radical chain reactions
b. Oxidation
c. Cracking
7. Preparation of alkanes
a. Kolbe electrolysis of organic acid salts
b. Decarboxylation of organic acids
c. Wurtz reaction (alkyl haUde + sodium)
d. Reduction of halogen compounds
8. Cycloalkanes —
saturated hydrocarbons in which the carbon atoms form a ring. The

small rings are strained, but five- and six-membered rings are much less so. Cyclo-
hexane prefers the chair conformation.

^'
EXERCISES AND PROBLEMS
\
6

^
-^
*n^ Write structural formulas for the following compounds: J
^

a. 2-methylhexane /. 2,2-dichloropropane
b. 2,3-dimethylbutane ^ methylcyclobutane
.,^1-chloro-l-methylcyclohexane
c. 3,3-dimethyl-4-ethylhexane
d. l-bromo-3-methylpentane W^ 1,1,1 -trichlorobutane

'fe^2,2,4-trimethylpentane j. 2,2-dibromo-3-chloro-3-methylheptane
'^(Write expanded formulas for and name the following compounds using the I.U.P.A.C.
system: c
"^
(^ CH3(CH2)2CH3 J. CH3CHCICH2CI Ly\
b. CH3CH(CH3)CH2CH3 g. CH3CH(CH3)CHC1CH3
^^ ,

/C7) CH3CH2CH2CH(CH3)2 h. CH2BrCH2Cl

d. CH3CH2C(CH3)3 0) CH3CHBrCH(C2H5)CH3
e. CH3CH2CHBrCH3 ^;,CH2C1(CH2)2CH(CH3)CH(CH3)2
3. Give a common and an I.U.P.A.C. name for the following compounds:
a. CH3CI e. CHCI3
b. CH3CH2Br .
/. CH3CHBrCH3
c. CH2Br2 g. CBr4
d. CH3CH2CH2I h. CH2— CHCl
/
CH2
\(As In each of the following lists of compounds, which structural formulas represent identi-
cal substances?

A B
a. CH3CH2CH2CH(CH3)2 a. CH2C1CH(CH3)CH2CH3
b. CH3CH(C2H5)CH2CH3 b. CH3CH(CH2C1)CH2CH3
c. (CH3)2CHCH2CH2CH3 c. (CH3)2CC1CH2CH3
 Saturated Hydrocarbons * 37
d. CH3C(CH3)2CH2CH2CH3 d. (CH3)2CHCHC1CH3
e. CH3CH2C(CH3)2CH3 e. (CH3)2CHCH2CH2C1
/. CH3CH(CH3)CH(CH3)2 /. CH3CH2CH(CH2C1)CH3
g. CH3CH2CH(CH3)CH2CH3
h. (CH3)3CCH2CH3
C
a. CH3CH2CHBr2 e. CHBr2CH2CH3
b. CHaCBrgCHa /. CH2BrCHBrCH3
c. CH3CHBrCH2Br g. (CH3)2CBr2
d CH2BrCH2CH2Br
5. Explain why the following names are objectionable and give a correct name in each
case.
(O. 3-methylbutane /. 2,2,1-trichloroethane
lb. 4-methylhexane g. 2,2-diethylbutane
c. 2,3,3-trimethylbutane ^. 1,4-dimethylcyclobutane
d. 3,3-dichlorobutane /j^ l-chloro-l-methylpropane
(e.; 2-ethylpropane /7> 1,1,2-trimethylbutane
^ Write the structural formulas for aU the isomers (numbers indicated in parentheses) for
each of the following compounds, and name each isomer by the I.U.P.A.C. system:
(2:>C5Hi2 (3) (p CsHnCl (8) e. C3H6CI2 (4)
b. C6H14 (5) d C2H3CI3 (2) /. C4H8CI2 (9)
7. Name the alkane which has the indicated molecular weight and which can have only
the number of substitution products shown. Name the substitution products.
a. 16; 1 monochloro c. 58; 2 monobromo e. 86; 3 monobromo
b. 44; 2 monobromo d. 70; 1 monobromo /. 42; 1 monochloro
8. In the industrial chlorination of pentanes, which of the following procedures would be
expected to give the best yield of wonochlorinated products? Why?
a. C5H12 + excess CI2 c. addition of the CI2 to the C5H12
b. CI2 + excess C5H12 d. addition of the C5H12 to the CI2
9. Using structural formulas, write equations for the following reactions and name each
organic product. Indicate necessary catalysts and conditions.
a. Complete combustion of butane
b. Vapor phase nitration of propane
c. Pyrolysis of sodium acetate with solid sodium hydroxide
d Electrolysis of CH3CH2C02-Na+
10. What hydrocarbons would be expected from the reaction of the following alkyl haUdes
with sodium?
^ ^) Q jl^ Cfl^CK^ f3u-l- Nl(i ->^^ ^A
a. methyl bromide c. «-propyl chloride j— -i

b. ethyl bromide d. isopropyl chloride

''^
j ^^'^ H- A' ty^ A/ (< t j^ -^ ^^
1 1 /7-Butane can be prepared by two different combinations of alkyl bromides, employing
the Wurtz reaction. Write equations for each, and explain which of the two is

preferable.
12. A pure hydrocarbon is known to be either 2,3-dimethylbutane or 2,2-dimethylbutane.
By what synthetic method (give equation) could the structure of the substance be
proved?
13. Write equations, using structural formulas, to show how each of the following com-
pounds could be converted to ethane:
a. methyl bromide b. ethyl iodide c. propionic acid (CH3CH2COOH)

C5 -^ ' c - C - c - c - c - I
,
J
38 • Saturated Hydrocarbons

14. The energy required to break each of the following bonds into the corresponding atoms
is indicated below in kilocalories per mole.
C— H 87.3 H— CI 102.7 CI— CI 57.8 0=0 119.1
C— CI 66.5 H— Br 87.3 Br— Br 46.1
C— Br 54.0 H— I 71.4 I— I 36.2
C— I 45.5 H— O 110.6 C=0 192.0
Would you expect the reaction of chlorine with methane to give methyl chloride and
hydrogen chloride to release or absorb energy? How much? Can you explain why
chlorination and bromination of methane are possible, but iodination is not?
15. Design a simple chemical test to distinguish cyclopropane from propane. Give
equations, and describe what would be observed in the laboratory. Explain whether
such a test would distinguish cyclohexane from «-hexane.
16. Using the bond energies given in Problem 14, determine whether energy would be
released or absorbed in the conversion of chloromethane to dichloromethane; dichloro-
methane to chloroform; chloroform to carbon tetrachloride. Could the reaction of
excess chlorine with methane be explosive? Explain.
17. An alternative mechanism for the chlorination of methane to that given in equations
(2-2) and (2-3) involves the chain: CI- + CH4 > CH3CI + H; H- + CI2 —^
HCl + C1-. Calculate the energy released or absorbed for each step. Why is this
sequence less likely to occur than the accepted one?
18. Arrange the following hydrocarbons in order of increasing boiUng points without
referring to tables:
a. 2-methylhexane b. «-heptane c. 3,3-dimethylpentane
d. «-hexane e. 2-methyIpentane
19. Using structural formulas similar to those on p. 24, show four possible conformations
of 1 ,2-dibromoethane. Which would be expected to be the most stable? Explain.
20. Would a rocket fueled with liquid CH4 and liquid O2, burning the methane to CO2 and
H2O, be more or less efficient than a rocket fueled with liquid CH4 and Uquid CI2, con-
verting the methane to CCI4 and HCl? Explain your answer. (Hint: use bond energies
to calculate the amount of energy released in each reaction.)
 Carbon atoms may share more than one pair of elec-
trons between them. Molecules formed in this manner are
said to be unsaturated. The cracking ofpetroleum produces
large quantities of unsaturated hydrocarbons which are
highly reactive substances. They combine with many rea-
gents: halogens, acids, saturated hydrocarbons, and even
with themselves. Antiknock fuels, synthetic rubber, plastics 'n"2n—2
of various types, solvents, and permanent antifreeze are
among the many useful products into which they may readily
be transformed.

Unsaturated Hydrocarbons

Unsaturated hydrocarbons are distinguished from paraffins by the presence

of muhiple bonds between carbon atoms. The alkenes, or olefins,* contain a
carbon-carbon double bond, whereas the alkynes, or acetylenes, have a carbon-
carbon triple bond.

Nomenclature of Alkenes
Alkenes, or olefins, have the general formula CnH2n. The simplest members
of the series usually are best known by their common names, which have roots
derived from the corresponding saturated hydrocarbons, and the ending -ylene.

CH2=CH2 CH3— CH=CH2 CH3— C=CH2

CH3
ethylene propylene isobutylene

* The word olefin means "oil-forming," a name originally given to ethylene because it formed an
oil when treated with chlorine. The term "olefin" now appUes to all hydrocarbons with carbon-
carbon double bonds.

39
40 • Unsaturated Hydrocarbons

In addition to the isomerism which is possible by aUeration of the arrangement of

the carbon atoms (similar to the paraffin hydrocarbons), isomerism also results
from a shift in the position of the double bond without changing the carbon
skeleton.

CH3—CH2— CH2— CH=CH2 CH3— C=CH— CH3

CH3— CH2— CH=CH— CH3 <^H3

CH2=C— CH2— CHs CH3— CH— CH=CH2

CH3 CH3
Rules of the I.U.P.A.C. system are similar to those for the saturated hydro-
carbons, with a few additions to include the double bond in the name. The
general class name is alkene. The ending -ene added to the root derived from
is

the corresponding saturated hydrocarbon. The carbon atoms in the longest

chain containing the double bond arenumbered in a manner such that the carbon
atoms of the double bond have the lowest possible numbers. The position of the
double bond is indicated by the number of the lower numbered carbon atom of
the double bond. This number, when necessary, is placed before the name of
the compound, as in the following examples:

12 3 4
 Unsaturated Hydrocarbons • 41

Figure 3-1. A top view of three sp'^ hybrid

orbitals.

There are several important consequences of this model for a double bond.
Perhaps the most obvious is that the relatively free rotation possible for singly
bound carbons is no longer possible. Rotation of one carbon with respect to
another would require the 77 bond to be broken (see Figure 3-3). This does not
occur ordinarily, although it can be brought about by supplying the molecule
with a great deal of energy, as, for example, by heating it to a high temperature
or by exposing it to ultraviolet radiation.
As a result of this geometric restriction on a double bond, the carbon atoms
involved and the four atoms attached to them must all lie in a single plane
(Figure 3-4). If the two atoms attached to each carbon are different, two
isomers are possible; in one of these, similar groups are on the same "side" of
the double bond, and in the other, they are on opposite "sides." An example is
seen in Figure 3-5. This phenomenon is called geometric or cis-trans isomerism
{cis = on the same side; trans = across). Such isomers always have different
physical properties and may also show different chemical behavior.

Figure 3-2. A side view of a trigonal carbon show-

ing the remaining p orbital perpendicular to the

plane of the sp^ orbitals.

42 • Unsaturated Hydrocarbons

Two sp-'-hybridized carbons with p

orbitals parallel.

/ N
a bond is formed by two electrons .

in overlapping sp'-^ orbitals. \

a
c c
77 bond is formed by two electrons
overlapping p orbitals.
^r
^
in

/ Two sp--hybridized carbons with p

orbitals perpendicular; double bond

^ \
cannot be formed.

Figure 3-3. Schematic formation of carbon-carbon double bond. Two sp"^ carbons
form a a bond (overlap of two sp"^ orbitals) and a pi (77) bond (overlap of properly
aligned p orbitals). In the lower left, the two p orbitals are perpendicular and
cannot overlap.
 Unsaturated Hydrocarbons 43

Ethylene Propylene

Figure 3-4, The four atoms attached to a double bond must lie in o single plane.

It should be pointed out that, if two of the groups attached to one of the doubly
bound carbon atoms are identical, as in I, only one isomer is possible. It is seen that

I is identical with II by rotating it 180° out of the plane of the paper. The two groups

B X
/ \
B X A X
I II

attached to each carbon must be different for cis-trans isomerism to be possible. For
example, only one structure for propylene (Figure 3-4) is possible.
Since rotation is impossible for carbon atoms in ordinary sized rings, geometric
isomerism is also found in such molecules, as shown for III and IV.

H
CH
c
CH
>c
CH.
cis-l ,2-dimethylcyclobutane frans-l ,2-dimethylcyclobutane

IV

Figure 3-5. Two isomers of 1 ,2-dichloroethene ore possible because rotation

around the double bond is restricted. This is an example of geometric isomerism.

c/'s-l ,2-dichloroethene trans- 1 ,2-dichloroethene

 44 • Unsaturated Hydrocarbons

The carbon-carbon double bond is shorter than a single bond, the distance
between nuclei being 1 .34A (0.2A less than that in a single bond). This is be-
cause two pairs of electrons draw the two nuclei closer together than only one
pair.

Physical Properties of Alkenes

The alkenes are very similar to the alkanes in physical properties. Those with
four carbon atoms or less are colorless gases, whereas the pentenes and higher
homologs are liquids. Some properties of a few alkenes are given in Table 3-1.

Reactions of Alkenes

The most important distinction between saturated and unsaturated hydro-

carbons is the general type of reaction which each undergoes. Saturated hydro-
carbons react by substitution, whereas the characteristic reaction of olefins is
'addition to the^double bond. By way of illustration, one may contrast the reac-
tions of ethane and of ethylene with bromine.
- c - C ' w u_ CHs— CHs + Bra > CHgCHsBr + HBr substitution (3-1)

'(yt. bromoethane

CH2=CH2 + Brs CH2- CH2 addition (3-2)

Br Br
1 ,2-dibromoethane
I

ij-t- Some Alkenes

TABLE 3-1 Physical Constants of

I.U.P.A.C.
NAME
 z:^
Unsaturated Hydrocarbons • 45
The-additinn reaction proceeds at a very rapid rate, even at low temperatures^^
whereas the substitution reaction frequently requires catalysis and elevated
temperatures.

Mechanism of Addition to Double Bonds

The 77 electrons o f a double bond, being further from the carbon nuclei than
the a electrons, are less firmly bound to them. A double bond is, in effect,
plf-ctron-rirh and can act as a supplier of electrons to a reagent which may seek
them (an electrophilic reagent). Electrophilic reagents are usually positive ions
capable offorming a covalent bond with carbon (for example H"*", but not Na+)
or they may be radicals seeking but one electron to complete their electronic
"structure. In the following discussion, it will be assumed for convenience that
the reaction is ionic (i.e., that the electrophile isseeking a. pair of electrons), but
a similar sequence can be written for free radicals.
Reaction between a carbon-carbon double bond begins by attack of the
electrophile on the it electrons, in a direction perpendicular to the plane formed
by the two carbons and the four atoms attached to them.

Ultimately the electrophile approaches sufficiently close to use the it electrons

to form a covalent bond with one or the other of the two carbon atoms.

T]iis-appiopriation of the form the C E bond leaves thp nthpr

77 electrons to —
Sflrbnn atom with only six electrons and an empty p orbital. It is t hef^fnre

pf^ tively charg ed, a carbonium ion, a nd combin es with a nucleophile, usually
<;i

a negative ion which can supply it with an electron pair. The nucleophile could
come in from the top or bottom side of the plane; in most cases, it reacts from
46 Unsaturated Hydrocarbons

:N cr

7 N

the side opposite the entering electrophile. The over-all reaction is the addition
of two groups to the double bond, the electrophile to one carbon atom, and the
nucleophile to the other.

E
C=C' + EI— (3-3)

N
Let us consider the mechanism by which bromine adds to ethylene. Although
an electron pair is shared by the two atoms it unites, at any one instant the pair

may be closer to one of the atoms than to the other. The covalent bromine
molecule V, for example, may have some small contributions to its structure by
ionic species of the types Va and Vb.

Br : Br: Br+ :Br: Br:- Br:

Va Vb

The bromonium ion, :Br+, with only six valence electrons, is a very reactive
electrophile; it may recombine with bromide ion to form a bromine molecule or
it may, competitively, grab the 77 electrons from an olefin present:

Br— Br ^ : Br+ + : Br (3-4a)

Br+ + CH2=CHi ^ CH2- (3-4b)t

Br

The sequence can be completed when the carbonium ion produced in equation
(3-4b) reacts with either a bromine molecule or a bromide ion:

CH2- CH2+ -F :Br: Br: > CH2— CH2 -h Br+ (3-4c)

Br t J- Br Br

t The curved arrow in the formula for ethylene indicates a shift in a pair of electrons from between
the carbon atoms to one of them.
 Unsaturated Hydrocarbons • 47
CH2— CH2+ + :Br:- > CH2— CH2 (3-4d)

Br Br Br

If equation (3-4c) occurs, the ionic chain reaction sequence expressed by equa-
tions (3-4b) and (3-4c) will continue until one of the reagents is consumed. The
over-all equation is simply

CH2=CH2 + Br2 > CH2— CH2 (3-5)

Br Br

One canreadily prove experimentally that in aqueous solution the addition is

stepwise, and that a positive and a negative halogen must be involved in the
reaction. If the bromination of ethylene is carried out in a solution which con-
tains chloride ions (Cl~), a mixture of 1,2-dibromoethane and l-bromo-2-chloro-
ethane is obtained, but no 1,2-dichloroethane is formed. This can be explained
by the formation of the intermediate carbonium ion as in equation (3-4b) above,
followed by reaction of this positive ion with either of the negative ions, Br~ or
Cl~, present in the solution.

CH2— CH2 _
:Br:- Br Br CI

CH2— CH2+ -f and

-
> and % (3-6)
'

Br
: CI : CH2— CH2
Br CI

The alternative explanation, that the bromo-chloro is formed by compound

by treating the dibro-
reaction of the dibromide with chloride ion, can be tested
mide with chloride ion under the same reaction conditions. It is found that no
replacement of Br by CI occurs.
But some product containing a hydroxyl group and a bromine atom is also
formed. Once again, this comes about by reaction of the intermediate car-
bonium ion with a nucleophile, this time the water molecule. Again, the alter-

native explanation can be ehminated by direct experimental test.

CH2— CH2* + :0:H - CH2-CH2 + H+ (3-7)

Br OH
 48 • Unsaturated Hydrocarbons

Br— Br ^=^ 2: Br- (3-8a)

:Br- + CH2=CH2 > CH2-CH2 •

(3-8b)

Br

CH2— CH2- + Br— Br > CH2— CH2 + :Br- (3-8c)

Br Br Br

CH2— CH2- + :Br- . CH2— CH2 (3-8d)

Br Br Br

1,2-Dibromoethane (commonly known as ethylene dibromide) is manufac-

tured commercially from ethylene and bromine; it is added to gasolines which
contain tetraethyl lead in order to prevent the accumulation of lead in the
engine. The lead is converted to volatile lead bromide and ehminated through
the exhaust.

Other Addition Reactions

There are a great many substances other than bromine which are capable of
addition to the double bond of alkenes. In general, the reactions proceed by
mechanisms analogous to those described in detail for bromine.
Of the other halogens, chlorine adds readily.

CH2=CH2 + CI2 > CH2— CH2 (3-9)

CI CI
1 ,2-dichloroethane

Iodine does not readily add to the carbon-carbon double bond, and with fluorine
the reaction is in most cases too vigorous to be of use. The addition of bromine
to alkenes is frequently used as a simple qualitative test for unsaturation. Bro-
^J^^uiiQ isdark red-brown, whereas the alkene and the alkene dibromide are both
^^colorless. Thus a solution of bromine in some inert solvent, such as carbon
tetrachloride, is rapidly decolorized when added to an alkene.
Hvdro s^en. under pressure and in the presgace-of an appropriate catalyst
(finely divided platinum, palladium, or nickel), transforms alkenes to the corre-
spondin g saturated hydrocarbons. sAddition of^oth of hydrogen which
.

are adsorbed on the catalyst-surface, - '

— atorrrs
—

CH2=CH2 + H2 ^'- ^'^- °' ^'

> CH3— CH3 (3-10)
ethylene ethane

ocguxs-fre m the same-side o

- f' thtr-double bond (cis addition).
 Unsaturated Hydrocarbons • 49

H H H H
C=C -> /C-C^ (3-11)

H H HH H H
catalyst catalyst

^ JElydrofieoation (see Figure 3-6) is an important industrial process which is used

in the manufacture of high octane automobile and aviation fuels, in the conver-
sion of natural vegetable oils to sohd cooking fats, and in the industrial prepa-
ration of synthetic detergents.
The proton (H+) is a good electrophile which readily attacks the tt electrons
_c\fi\ ^^v^'^ v>r>nrt Thus, a \aiiet_\ of acids \m11 add to the carbon-carbon double
bond. The hydrogen Tialii/es add wit h increasing ease as we proceed down the__
periodic table (lHf>HBr > UCl^

CH2=CH2 -h H I CI CH3CH2CI (3-12)

ethyl chloride

Ethyl chloride is used as a local anesthetic, causing anesthesia by freezing.

Sulfuric acid yields an alkyl hydrogen sulfate.

Crl2 — CH2 -|- H OSO2OH CH3CH2OSO2OH (3-13)

sulfuric acid ethyl hydrogen sulfate
(H2SO4)

Figure 3-6. Apparatus for catalytic hydrogena-

tion. The substance to be hydrogenated and the
catalyst are placed in a steel bomb. After the air
is flushed out, the bomb is pressured up with
hydrogen, rocked, and heated. The reaction is

followed by decreasing pressure as hydrogen is

consumed; when the pressure no longer drops,

reaction is complete. (Courtesy of American
Instrument Company.)
50 Unsaturated Hydrocarbons

As will be seen later, this is the first step in the industrial manufacture of ordi-
nary alcohol from a petroleum starting material.
The hypohalous acids add as HO —
CI, Br, or HO — HO —
I; there is no tend-

—
ency to add as H OX. Reaction is initiated by the positive halogen.

CH2=CH2 + HO CI -> CH2— CH2 (3-14)

OH CI
hypochlorous ethylene
acid chlorohydrin

Addition to Unsymmetrical Double Bonds

Markownikojf's Rule. When an alkene is symmetrical about the double bond,

as ethyleneis, the product formed in an addition reaction is the same no matter

which way the addend becomes attached to the alkene.

CH2=CH2 + HBr > CH3— CHgHr

t I

identical

CH2=CH2 + HBr > BrCH2— CH3

t I

If, however, both the alkene and the addend are unsymmetrical, two alterna-
tives are possible:

i^)^^ ' CH2-CH2-CH3

(a)
Br
CH2=CH— CHs + HBr n-propyl bromide (3-15)
(b)
propylene

(b) —> CHs— CH— CHs

Br
isopropyl bromide

Experimentally one finds that isopropyl bromide is the major product of addi-
tion of hydrogen bromide to propylene.
After studying a large number of such addition reactions, the Russian chemist
Vladimir Markownikoff formulated the following rule which generalizes the
experimental observations. When an unsymmetrical reagent adds to an unsym-
metrical double bond, the positive part of the addend becomes attached to the double-
bonded carbon atom which bears the greatest number of hydrogen atoms. The
following examples illustrate the use of this rule.

CH2=CH— CHs + HOSO2OH CHs— CH— CHs (3-16)

t
)S020H
propylene isopropyl hydrogen sulfate
 Unsaturated Hydrocarbons • 51

CH, CH3
CH3— C=CH2 + HBr CH3— C— CH3 (3-17)
t
Br
2-methylpropene 2-bromo-2-methylpropane

CH2=CH— CH2— CH3 + HOCl CH2— CH— CH2CH3 (3-18)

^: I

CI OH
1 -butene 1 -chloro-2-butanol

Markownikoflf 's rule can be rationalized in terms of modern organic chemical

theory. Consider the addition of an acid to propylene. Reaction is initiated by
addition of the proton, yielding two possible carbonium ions. At this point,
then, the direction of addition is determined, for the position taken by the
nucleophile in the final step must be at the carbon atom bearing the positive
charge. Since experimentally one obtains a product corresponding to the
isopropyl rather than the ^-propyl structure, one must conclude that the car-
bonium ion with the isopropyl structure is the more stable.

(a) +
(a) ^-^ CH3CHCH3
I I

CH3CH=CH2 + H+ — isopropyl cation

(3-19)
t I

(b)
^ CH3CH2CH2
(b)
n-propyl cation

From the study of many reactions which proceed via carbonium ions it has
become clear that the more highly substituted carbonium ions are the more
stable. Carbonium ions may be classified as tertiary, secondary, or primary,
depending on whether three, two, or only one alkyl group is attached to the

carbonium carbon atom. Their stabihty decreases in the order shown.

R H H
R— C+ > R— C+ > R— C+
I I

R R H
tertiary (3°) secondary (2° primary (1 °)

(most stable) (least stable)

Markownikoff's rule may now be restated: addition of an unsymmetrical re-

agent to an unsymmetrical double bond proceeds in such a direction as to involve
the most stable intermediate carbonium ion.
52 • Unsaturated Hydrocarbons

Markownikoff 's rule is a specific example of a general principle true of all chemical
reactions — a reaction will proceed by the best possible path available to it. That is,
reactants will pass through the most stable possible transition state or intermediate on
their way toward products. Free radical intermediates show the same relative order
of stability as carbonium ions (i.e., 3^ > 2" > F), whereas for carbanions this order is
reversed.

Petroleum Refining
Petroleum, as it comes from the oil well, is a crude and complex mixture of
hydrocarbons, with small amounts of nitrogen- and sulfur-containing com-
pounds. It is not useful as such, but can be refined to give useful products with
much narrower specifications (boiling range, combustibility). The first step in
this refining process is Chemical processes like
distillation, a physical process.
cracking, isomerization, alkylation, and aromatization have been developed,
mainly to increase the yield of motor and aviation gasohne from crude oil.

Antiknock Fuels
In order to compare gasolines, it was necessary to set up an arbitrary knock-
rating scale. Isooctane (2,2,4-trimethylpentane),

CH3 CH3
CH3— C— CH2— CH— CH3
CH3
a pure hydrocarbon with excellent knock properties, was assigned an octane
number of 100, and normal heptane,

CH3CH2CH2CH2CH2CH2CH3
a very poor gasoline fuel, was assigned the octane number 0. The octane num-
ber of a gasoline, then, is the percentage of isooctane in a mixture of isooctane
and /7-heptane that has equivalent knock properties to the gasoline, when both
are tested in a standard engine. Just as with temperature scales, once the units
have been assigned, the scale can be extended above and below the original
limits.
A fuel can be improved in two ways. Small amounts of "additives" (such as
may be introduced, or the fuel itself may
tetraethyl lead, in the case of gasohnes)
be improved by increasing the percentage of molecules with superior burning
properties. Both techniques are employed. Diesel and jet fuels can use large
percentages of straight-chain hydrocarbons, whereas high-octane fuels are im-
proved by chain-branching. Isomerization, alkylation, and aromatization are
important in making high-octane gasoline.

Isomerization

Straight-chain saturated hydrocarbons can be isomerized to branched chain

isomers by certain catalysts. For example, aluminum chloride at 100° isomer-
izes «-pentane to isopentane.
 Unsaturated Hydrocarbons • 53

CH3CH2CH2CH2CH3 ^i^ CH3CHCH2CH3 (3-20)

CH3
The mechanism, which is complex, probably involves carbonium ions. The
reaction isimportant in the manufacture of gasohnes, but is not generally prac-
tical as a laboratory synthetic method.

Alkylation of Olefins

In the presence of appropriate catalysts (aluminum chloride, sulfuric acid, or

hydrofluoric acid), certain hydrocarbons add to the double bond of an alkene.
The process is called alkylation, since an alkyl group is added to the alkene. The
product is a highly branched hydrocarbon. The reactions proceed by a car-
bonium ion mechanism.

CH3 CH3
CH3— C=CH2 -f H— C— CH3 J1h52i^ CH3— CH— CH2— C— CH3 (3-21)

CH3 CH3 CH3 CH3

2,2,4-trimethylpentane

Reaction is initiated by addition of a proton from the catalyst to an alkene

molecule to yield a carbonium ion:

CH3— C^CH2 + H+ > CH3— C— CH3 (3-21a)

CH3 CH3
This carbonium ion adds, according to Markowiukoflf's Rule, to another alkene
molecule forming a new carbonium ion:

CH3 CH3
CH3— C+ + CH^C— CH3 > CH3— C— CH2— C— CH3 (3-21b)

CH3 CH3 CH3 CH3

The chain is completed by a very fast reaction, the abstraction of hydrogen with
its electron pair (hydride ion, H~) from the saturated hydrocarbon.

f .^ v_ f ^

CH3— C— CH2— C— CH3 + C— CH3 (^HO

^

>

CH3 CH3 CH3

CH3 H CH3
CH3-C-CH2-C-CH3 + ^C-CH3 (3-21c)

CH3 CH3 CHs

The chain is then continued as in equations (3-2 lb) and (3-2 Ic).
54 • Unsaturated Hydrocarbons

Alkenes may undergo self-alkylation, in which case the process is called

polymerization. By the judicious choice of catalyst and conditions, the reaction
may be controlled so that the product has a small number of units, such as a
dimer (two olefin units), trimer, or tetramer.
When isobutylene is treated with cold sulfuric acid, two molecules of the
olefin combine by addition to form octenes:

CH2
CH3-C + CH2=C-CH3 -^^^
CH3 CH3
CH3 CH3
CH3— C— CH2— C=CH2 + CH3— C— CH=C— CH3 (3-22)

CH3 CH3 CH3 CH3

2,4,4-trimethyl-l -pentene 2,4,4-trimethyl-2-pentene

These highly branched olefins may then be hydrogenated to give 2,2,4-trimethyl-

pentane, the same product which was obtained above by the alkylation of iso-
butylene with isobutane (equation (3-21)). Polymerization therefore provides
an alternative route to high octane fuels. The tetramer of propylene, which would
be a twelve-carbon branched olefin, is used commercially in making synthetic
detergents (page 217).
Self-alkylation also proceeds by a carbonium ion mechanism. The first two
steps are the same as those in equations (3-2 la) and (3-2 lb). Since there is no
saturated hydrocarbon to furnish a hydride ion, the carbonium ion produced in
equation (3-2 lb) stabilizes itself by losing a proton (H+) from either carbon 1 or
3 to yield the products shown in equation (3-22).

Aromatization

Many hydrocarbons, when heated over special catalysts, produce a new class
of substances called aromatic hydrocarbons (see Chapter 4), which have good
octane ratings and are important synthetic raw materials as well.

CH3
platinum (^
CH3CH2CH2CH2CH2CH2CH3 '7'^^'
) HC^ \h + 4H2 (3-23)

HC. ^CH
C
H
toluene

This type of reaction, called hydroforming, is an important part of petroleum

refining operations.
 Unsaturated Hydrocarbons 55

Gasoline Blending

The above processes provide the raw materials for a motor gasohne, but they
must be blended properly for efficient use. Sufficient aromatics and branched
chain compounds are included to provide a high octane number, and tetraethyl
lead is added to improve knock rating. Ethylene dibromide is included to
remove the lead oxide after combustion. Additives, which reduce fouUng of
spark plugs, lubricate engine parts, and prevent carburetor icing in winter, and
a dye to identify the gasoline brand may be included. In winter, "low-boilers"
summer they are omitted for they evaporate
(butanes) help ignition, but in
readily.The motor gasohne used today is a complex, carefully blended mixture
of hydrocarbons and additives designed for the modern high compression
engine.

Other Reactions of Alkenes

High Polymerization
When many small molecules unite, a giant molecule called a polymer is pro-
duced. These polymers are the basis of the plastics, synthetic textiles, and other
industries. Among the important commercial polymers are those of the simple
olefins. Ethylene, for example, when heated under pressure in the presence of
certain catalysts, may unite with itself to form chains eight hundred or more
carbon atoms in length. The product is known as polyethylene. The tough but
flexible plastic produced in this way has been useful as an electrical insulator,
as well as in the fabrication of nonbreakable plastic cups, refrigerator dishes,

Figure 3-7. Figure at left shows the structure of a polymer plastic, polyisobutene, obtained from
polymerizing isobutene at temperatures as low as 1 35 degrees below zero. One of the main
applications of polyisobutene is in adhesives such as in band-aids. Another common plastic is

polyethylene. A familiar use of it is the squeeze bottle. (Photo at /eff courtesy of Esso Research
and Engineering Company.)
56 • Unsaturated Hydrocarbons

etc. Annual production of polyethylene in the United States exceeds two billion
pounds.
High-pressure catalytic polymerization of ethylene, typical of many poly-
merizations, is a free radical chain reaction. Reaction is initiated by a catalyst
which is a thermally unstable organic compound that readily yields free radicals
on heating (organic peroxides are the most common catalyst type). A catalyst
radical (R'') attacks the double bond of ethylene, taking only one of its electrons:

Rx + CH2::CH2 R^CHsiCH^ (3-24)

This leaves an odd electron on one of the carbon atoms, which can then attack
another ethylene molecule in a similar fashion.

R?CH2:CH2- + CH2::CH2 > R^CH2:CH2:CH2:CH2- (3-24a)

This process continues until the radical becomes so large that its energy is in-

induce further radical formation, or it may be terminated by the

sufficient to
combination of two radicals. Alternatively, the growing polymer chain may
take a hydrogen atom from its own back, so to speak, causing chain-branching:

•CH2, CH, CH
H
CH..=CH, ._^ ,
g^^ (3.25)

The over-all result is a giant molecule with long and short carbon chains.

Recently, a new class of catalysts was discovered which allows ethylene to be

polymerized at low pressures and temperatures; the product is nearly linear
(that is, essentially no back-biting occurs), corresponding to the formula

-fCH2-CH2^
where « is a large integer. Low-pressure polyolefins produced this new way
have higher melting points and greater strength than the older type of polymer.
A mixture of trialkylaluminums, R3AI, and titanium tetrachloride, TiCU, is one
of the catalyst combinations which produces low-pressure polyethylene.

Oxidation

The 77 electrons of a double bond are readily susceptible to attack by oxidizing

agents. This property distinguishes alkenes from alkanes. Alkenes are
 Unsaturated Hydrocarbons 57
oxidized by potassium permanganate. In the process, the permanganate, which
is reduced to the brown manganese dioxide, Mn02. This
purple in color, is

color change indicates that oxidation has occurred. Saturated hydrocarbons

are not oxidized under these mild conditions, and thus show no change in the
purple permanganate color. The test is sometimes called the Baeyer test after
its discoverer, Adolph von Baeyer.
Ozone, which can be prepared by passing an electric discharge through
oxygen, reacts rapidly and quantitatively with alkenes. The formed
initially

products are called ozonides. These are usually not isolated, for they are often
explosive, but they may be decomposed by hydrolysis or reduction (equation
(3-26)).

:0:
O
o
O3
(the net equation) (an unusual rearrangement) (3-26)

V=o
/
+ o=c^
\
^-22^
Zn H-/\
+ YV /\

ozonide

The over-all result of ozonization is the breaking of the alkene at the double
bond into two fragments, each of which has an oxygen atom doubly bound to
the original olefinic carbons.
Ozonization can be used to locate the position of a double bond. Consider,
for example, the isomeric butenes:

CH2=CH— CH2— CH3 CH3— CH=CH— CH3

1 -butene 2-butene

Both compounds have the same percentage composition; both decolorize

bromine and give a positive Baeyer test. How, then, to distinguish them?
Ozonolysis provides the answer, for one of these olefins will give two prod-
ucts (CH2=0 and 0=CHCH2CH3) whereas the other gives only one
(CH3CH=0).
Substitution

Although olefins commonly react by addition, they do have C H bonds and, —

under special conditions, substitution may occur. This reaction is the basis of
some important commercial processes. Ethylene can be chlorinated at high
temperatures to vinyl chloride, a starting material for some important polymers.
58 • Unsaturated Hydrocarbons

CH2=CH2 + CI2 ^^ CH2=CHC1 + HCl (3-27)

1 -chloroethene
(vinyl chloride)

—
(The vinyl group is CH2^CH .) The polymer made from this chloride is a
plastic which can be molded or extruded; it can also be used as a lacquer for
coating metals.

Preparation of Alkenes

A double bond is usually introduced in a saturated molecule by removing

two elements or groups from adjacent carbon atoms. One group leaves with its
bonding electron pair, the other without. The pair of electrons left behind then
forms an additional bond between the carbon atoms involved.

X Y
R— CH^CH— R' > R— CH=CH— R' + X:Y (3-28)

—
The compound X Y is usually a small inorganic molecule such as water
— — —
(H OH) or a hydrogen hahde (H Br or H CI). The entire process is called
an elimination reaction, because the molecule X—Y is eUminated; ehmination
is the reverse of the addition reaction.

Dehydration of Alcohols
When molecule X—Y in equation (3-28) is water, the process is called dehy-

dration, and the starting material is an alcohol. Alcohols can be dehydrated by

strong acids (sulfuric, phosphoric) as shown in equation (3-29).

H H H H H H
H— C— C— H -^ H— Cj^C— H -122U H— C=C— H -h H+ + :0—
H :0— H .-O— ^''^y'^"^
H
ethyl alcohol H (3-29)

For some alcohols, such as 2-butanol, elimination can proceed in either of two
directions.A mixture of alkenes results (equation (3-30)), with the alkene
H H H H
H— C=C— C—C—
TT TT TT TT 20%^^
H H H H ^^^
I

H H
I

H— C— Qn^C— C— H „^^
^-h^\ene
(3.30)

[H ioH H] i
H ^^^^^ H H H H
2-butanol H— C— C=C— C—
H H
2-butene (cis and frans)
 Unsaturated Hydrocarbons • 59
having the most substituted double bond predominating. Dehydration may be
accompUshed catalytically by passing the alcohol vapor over a catalyst, such as
activated alumina, which has a strong affinity for water.

H H H H
H— C— C— H -^i22i^ H— C=C— H + HgO (3-31)

ethyl alcohol

Dehydrohalogenation
The elimination of a molecule of a hydrogen hahde, dehydrohalogenation, can
be accomplished with an alcohohc solution of a strong base.

H H H^-^ H H
H— C— C-^C— H 4^:6h . H— C— C=C— H + H:0:H + :Br:-

H Br H H H
2-bromopropane propylene (3-32)

As with the alcohols, when elimination can occur in more than one direction, a
mixture of alkenes will be formed.

Olefins from Cracking

Cracking of petroleum produces large quantities of mixtures of olefins.

These result from fundamental changes in the structure of saturated hydro-
carbons, brought about by high temperatures and catalysts (see page 29). The
possible reactions which may occur are indicated for normal butane as follows:

f ^^-^^^^ CH4 + CH2=CH-CH3

^
^'J

CH3^CH2-/-CH2— CH3 (3-33)

'^^ CH2=CH2 + CH3-CH3
When the cracking stock consists of hydrocarbons in the Cio to Cie range, a very
wide variety of products is obtained.
Cracking is the major source of ethylene and propylene, raw materials for the
industrial synthesis of alcohols, permanent antifreeze, polyethylene, ethylene di-
bromide, and numerous other products. Cracking also furnishes butenes, which
may be converted to high-octane fuels and synthetic rubber.

Acetylenes
The Triple Bond
The gaseous hydrocarbon acetylene has a molecular formula C2H2 and may
be readily transformed into ethylene or ethane by addition of hydrogen. This
suggests that its structural formula is

H— C=C— H or H:C:::C:H
 60 • Unsaturated Hydrocarbons

Two sp-hybridized carbons aligned

for bonding.

1 r

P P
I
\

p _ -
sp ^P" sp c" v/; 1- sp Q^ sp

\ "r I
'R

\ /
Top view of sp-hybridized carbon
showing 2 sp and 2 p orbitals.
P

-^sp -
 Unsaturated Hydrocarbons • 61

Figure 3-9. The carbon-carbon triple bond.

H
Nomenclature
Hydrocarbons which contain a triple bond are known as acetylenes or
alkynes. The general rules for nomenclature are identical with those of the
alkenes, except that the ending is -yne. The following examples serve to illus-
trate the rules.

CH,— C=CH CH3— C=C— CH. HC=C— CH— CH3

CH3
propyne 2-butyne 3-methyl-l -butyne

Addition Reactions

The reactions of the triple bond are analogous to those of the double bond.
The same reagents which add to alkenes also add to alkynes. Addition may be
illustrated by the reaction of acetylene with bromine.

Br Br Br Br

H— C=C— Bro
H- C=C— Bro
H- C—C— (3-34)

Br Br
acetylene 1 ,2-dibromoethene 1 ,1 ,2,2-tetrabromoethane

Although the reaction may be thought of as a stepwise process, it is sometimes

difficult to halt the reaction at the olefin stage. Tetrachloroethane, prepared in
an analogous manner, used in the manufacture of varnishes and paints, and
is

as a solvent in the extraction of fats from wool.

Addition to the triple bond follows Markownikoff 's Rule.

Figure 3-10. Models of acetylene.

62 Unsaturated Hydrocarbons

CI H
H— C=C— HCI
> H— C=C— HCl
^ H— C—C— (3-35)

CI H CI H
1,1 -dichloroethane

I/H I
j: V HI
CH.— C=CH ^ CHs— C=CH HI
^ CH3-C-CH3 (3-36)

2,2-diiodopropane

The triple bond may also be reduced to a double or single bond with hydrogen
and a catalyst (platinum, nickel or palladium).

H H H H
R— C=C— R'
R— C=C— R'
R— C— C— R'
I I I I

-> (3-37)

H H
By employing a limited amount of hydrogen and a special catalyst, the reaction
may be stopped at the olefin stage. This is especially useful for preparing cis-
olefins, since both hydrogens add to the triple bond from the same side (i.e. from
the catalyst surface).
Acetylenes are readily oxidized by potassium permanganate in a manner
somewhat analogous to the olefins. Acetylene, in the presence of certain
catalysts, combines with one mole of hydrogen cyanide to form acrylonitrile,

H— C=C— H -f HCN CH2=CH— CN (3-38)

acrylonitrile

an important starting material for the textile fibers Orion and Acrilan. The
polymer may be obtained by free radical polymerization, as with polyethylene
(see page 56). Sweaters and fabrics made from this polymer are in popular use.

:h2=ch - (3-39)
 Unsaturated Hydrocarbons • 63
Acetylides are more frequently prepared using sodamide in liquid ammonia as
the base to remove the proton.

HC=CH + NaNHa ^^^

NH3
HC=C-Na+ + NH3 (3-41)

The sodium acetylide is highly reactive and can be used to synthesize higher
homologs of acetylene. Thus, with ethyl bromide, it yields 1-butyne

HC=CNa + CHsCHsBr > HC^CCHaCHs + NaBr (3-42)

l-butyne

The process can be continued in a stepwise fashion with the other hydrogen.

HC=CCH2CH3 + NaNH2 ^^ NH NaC^CCHaCHs + NH3 (3-43)

+ -
NaC=CCH2CH3 + CH3I > CH3C=CCH2CH3 + Nal (3-44)
2-pentyne

This is a general laboratory method for making alkynes of known structure.

The reaction may also be used as a laboratory test to distinguish a 1-alkyne from
an alkene. When heavy metal ions are used, the acetylide is insoluble in water
and has a characteristic color.

2 CH3C=CH + CU2CI2 + 2 NH4OH >

(CH3C=C)2Cu2i + 2 NH4+CI- + 2 H2O (3-45)

red precipitate

CH3C=CH -h Ag(NH3)2^ ^ CH3C=CAg + NH4+ + NH3 (3-46)

white precipitate

The compounds CH3C=CCH3 and CH3CH=CH2 give no reaction. The silver

and cuprous acetyUdes are explosive solids when dry, and may detonate even
when touched with a feather.

Preparation

Acetylene is prepared commercially in large quantities from limestone and

coke, as shown in the two-step process below.

3 C + CaO ^^ CaC2 + CO (3-47)

coke lime calcium carbide
(calcium acetylide)

CaC2 + 2 HOH ^ H— C=C— H + Ca(OH)2 (3-48)

Acetylene is produced by breaking down saturated hydrocarbons rapidly

also
at high temperatures. Many products are formed, but both acetylene and ethyl-
ene can be profitably separated from the others. The production of acetylene by
64 • Unsaturated Hydrocarbons

partial combustion of methane depends on a thermal cracking reaction. The

energy for this endothermic reaction is supplied by combustion of part of the

2 CH4 > H— C^C— H + 3 H2 - heat

methane with air. This reaction is important in this country because of the
abundance of natural gas (methane).
Laboratory methods for introducing a double bond can be modified to pro-
duce a triple bond. Dehydrohalogenation is an example.

[H Br

R— C—C— H + 2 K+OH- J^22h2U RC=CH + 2 K+Br" + 2 H2O (3-49)

!Br H]

Thus, by the following series of reactions, an alkyne might be prepared from an

alkyl hahde.

RCH2CH2CI 4^ RCH=CH2 -^ RCH—

alcohol
I
CH2
I
'^'^"">
alcohol
RC=CH
Br Br (3-50)

Acetylene is used extensively in the oxy-acetylene torch for welding and

cutting metals. When burned with oxygen, its flame reaches a temperature of
about 3,000°. As already noted, it is also a source of many organic chemicals.

Polyolefins

Many hydrocarbons contain more than one point of unsaturation. The

chemistry of these substances is similar to that of the mono-olefins, except for
the influence that one double bond may have upon another when both are
present in thesame molecule. Of the diolefins, or alkadienes, by far the most
important type is the one with alternating double and single bonds, as in

12
CH2=CH— CH=CH2
3 4

1 ,3-butadiene

This alternating arrangement is known as a conjugated system.

Conjugated diolefins undergo addition reactions in a somewhat unusual fash-
ion, but one that is wholly intelUgible in terms of their electronic structure.
Addition of one mole of bromine to 1,3 -butadiene, in an inert solvent, gives a
mixture of 3,4-dibromo-l-butene and rra«.?-l,4-dibromo-2-butene. The first
product results from 1,2-addition to one of the double bonds and does not
appear extraordinary, but the second product results from addition to the
terminal (1,4) positions, with establishment of a new double bond between car-
bons 2 and 3. This latter process is known as 1,4-addition and becomes rational
if one considers the mechanism of the reaction in terms of the orbital picture.
 Unsaturated Hydrocarbons 65

H Br Br Br
/
H
Bro /
CH^ ^ CH2=CH— CH— CH2 + CH2—
C=CH2 3,4-dibromo-l -butene
\C— CHsBr
H
\Tan%-\ ,4-dibromo-2-butene

(3-51)

Reaction of bromonium ion (:Br+; see page 46) at the terminal carbon, ac-
cording to Markownikoff 's rule, gives the intermediate carbonium ion shown:

H H
/ +/
Br+ +XH>=C BrCH,
.C=CH2 C=CH2 (3-52)
/
H H
This ion contains three adjacent trigonal {sp^) carbon atoms, each with a p
orbital perpendicular to the molecular plane. As produced in equation (3-52),
the carbonium ion would be represented with an empty p orbital at carbon 2,

Br— CHo— C -6 ^ Br —CH,— C

but filled orbitals at carbons 3 and 4 (structure A). But an equally plausible
arrangement, if the orbitals are properly aligned, two electrons at
is to put the
carbons 2 and 3, leaving carbon 4 positively charged (structure B). Completion
of the reaction with structure A leads to 1,2-addition; with structure B, to
1,4-addition (equation (3-51)).
In fact, the actual structure of the carbonium ion is not represented accurately
by either structure A or B; these are simply extreme forms of a structure which
is a hybrid of these, in which the two electrons are placed in a molecular orbital

Br CH2 C
66 • Unsaturated Hydrocarbons

which extends over all three carbon atoms. In more conventional language, the
ion is said to be a hybrid of the structures shown:

BrCHa— CH-^Sl^CHs < . BrCHa— CH=

A B

or the composite structure: BrCH2 — CH=^CH=^CH2

The phenomenon in which two or more equivalent structures for a compound can
be written which involve identical positions of the atoms but differ in the arrange-
ment of the electrons is called resonance. The true structure of the molecule is
said to be a resonance hybrid of the various classical structures one can write.
A double-headed arrow between the classical structures is used to represent a
resonance hybrid. The resonance hybrid is more stable than any of the separate
structures which contribute to its structure.
Initial attack of a positive ion (or a free radical) on the conjugated butadiene

system of double bonds invariably occurs at the terminal carbon atoms, because
the resulting cation (or radical) can be stabilized by resonance (equation (3-53)).

1 2 3 4
CH2=CH— CH=CH2
X+ attack at Ci
(preferred)

CH2— CH— CH=CH2 CH2— CH— CH=CH2 (3-53)

X X
cannot delocalize the charge; ion can be stabilized
no resonance hybrid is possible by resonance (see A and B above)

The concept of resonance not only accounts for 1,4-addition, but for many
other phenomena in chemistry; we shall see additional examples in the following
chapter.
Many natural products, such as rubber, plant-coloring materials, and certain
vitamins, may be thought of as having been derived from conjugated dienes by
polymerization in a 1,4-manner.

Natural and Synthetic Rubber

Natural rubber is a complex hydrocarbon. Thermal decomposition of natural

rubber in the absence of air leads mainly to the conjugated diolefin, isoprene.

pyrolysis
natural rubber
p^'"'^'"
> CH2=C— CH=CH2 (3-54)
 Unsaturated Hydrocarbons • 67

Figure 3-1 . The figure at the left shows sheets of rubber being hung on racks which are wheeled
into large ovens for drying and smoking. The figure at the right shows one of the modern uses
of rubber. Low-pressure steam passing through two test lengths of plastic pipe distorts the lower
pipe made of conventional plastic, but does not affect the pipe at the top which is made from a
new rubber-plastic mixture. (Courtesy of the United States Rubber Company.)

to form a polymer similar to, although not identical with, natural rubber. In
this polymer, isoprene units were joined to one another either by 1,2- or 1,4-addi-
tion. But in natural rubber, the structure is that which would result from almost
exclusive 1,4-addition.Furthermore, the remaining double bonds are all cm,
whereas ordinary free radical polymerization of isoprene led to mainly trans
double bonds.

CH2=^C^CH:^civ
CH, CH.,

-CHc ^CH2-CH2^ ^CH2-CH2^

\
/
c=c\
CHs H CHs H
CIS C/S CIS

segment of natural rubber molecule (all c/s double bonds)

68 • Unsaturated Hydrocarbons

In 1955. both Goodyear and Firestone research chemists found that the same
type of catalyst that gave linear polyethylene (see page 56) also produced a
polymer from isoprene essentially identical with natural rubber, by an almost
exclusive 1,4-addition, all cis. There may be as many as two thousand isoprene
units per rubber molecule.
Isoprene is might be expected that diolefins similar to
rather expensive, but it

isoprene would also yield rubberlike products when polymerized. This has been
found correct, and several types of synthetic rubber are now manufactured. It
will be noted that the term synthetic rubber applies to rubberlike materials which
may or may not bear any resemblance in structure to natural rubber. These
synthetic products are sometimes called elastomers. Neoprene is a synthetic
rubber made from acetylene and hydrogen chloride.

cuprous

2H—C=C— H '"""'''

ammonium
> CH2=CH— C=CH -^ CH2=CH— C=CH2 I

chloride 1 -butene-3-yne yLii

(vinylacetylene)
2-chloro-l ,3-butadiene
(chloroprene)

(3-56)

CH2=CH— C=CH2 '"""y^'

>
f CH2— CH=C— CH2^ (3-57)

CI

Note the similarity in structure between chloroprene and isoprene.

Some colored substances containing many double bonds are of particular
significance in biochemistry. Of these, we may mention the yellow coloring
matter carotene, present in many plants such as carrots, spinach, and tomatoes.

CH3 CH3 „'''

I

/^\/
/C— CH:^CH— C=CH— CH4=CH— C=CH— CH
1 I

CH2
/ I

II

CH^ C — CHsi
>CH2
/3-carotene

The dotted Hnes indicate that the molecule is composed of eight isoprene units.
Closely related to carotene is vitamin A (see page 317).
Squalene is a hexaene (six double bonds) first isolated from shark liver oil.
It is made up of six isoprene units, with trans geometry at the four double bonds
capable of geometric isomerism. It is a biochemical precursor of cholesterol
and other steroids (see page 321).
 Unsaturated Hydrocarbons • 69

squalene

NEW CONCEPTS. FACTS. AND TERMS

1. Alkenes, or are unsaturated hydrocarbons — compounds
olefins, containing one or
more double bonds.
2. Nomenclature of alkenes, page 39.
3. Geometry of the double bond, sigma (a) and pi (tt) orbitals. Cis-trans or geometric
isomerism.
4. Addition reactions; mechanisms of bromine addition; electrophiUc and nucleophihc
reagents.
5. Reagents which add to unsaturated hydrocarbons
a. Chlorine, bromine
b. Hydrogen
c. Acids (HX, H2SO4, HOX)
6. Markownikoff's Rule gives the correct orientation for the addition of unsymmetrical
reagents to unsymmetrical alkenes.
7. Petroleum refining
a. Fuels; octane number
b. Isomerization
c. Alkylation
d. Polymerization
e. Aromatization
8. Other reactions of alkenes
a. High molecular weight polymerization; polyethylene

b. Oxidation; Baeyer test; ozonolysis

c. Substitution
9. Preparation of alkenes
a. Dehydration of alcohols
b. Dehydrohalogenation of alkyl haUdes
c. Cracking

10. Alkynes, acetylenes— the triple bond; nomenclature, page 61.

11. Addition reactions of acetylenes; bromine, chlorine, HX, H2, HCN.
12. Acidity of the hydrogen attached to a triple-bond carbon.
13. Preparation of acetylenes: from calcium carbide, cracking of methane, and from
sodium acetyhde and an alkyl hahde.
14. Polyolefins, alkadienes; nomenclature, page 64.
15. Conjugated system— alternating single and double bonds; 1,4-addition to conjugated

systems; resonance; resonance hybrid.

16. Natural and synthetic rubber; isoprene; squalene.
 70 • Unsaturated Hydrocarbons

EXERCISES AND PROBLEMS

( Kj Write structural formulas and I.U.P.A.C. names of all possible unsaturated hydro-
carbons with the indicated molecular formulas:

Alkvnes
C5H10 a. C3H4 c. C5H8
C6H12 b. C4H6 d. CeHi^^
/^Jzl^Name the following compounds by the I.U.P.A.C. system:
^ Ay (CH3)2C=CHCH3
^3, ^. (CH3)2C=C(CH3)2
b. CHBr=CHCH(CH3)2 CH2-C-CH3 '%
CH2=CH2
<^. """" I II

g>CH2=CHCH=CHCl loW^-U'.'/^'^^^^^^^"
\Cy e.CH3C=CCH^CH3 CH2
"7'. (JH=^CHfCH^)CHoC^C| |^^^^^
i. C H=CC(CH3)2CHBrCH3
""'"
/\^- Wrife structural formulas for the following compounds:
( J a. 2,3-dichloro-l-butene /. 2-bromo-l,3-pentadiene
h. 4-ethyl-2-heptene /^ 2-methyl-l,3-cyclohexadiene
c. 1.4-hexadiene ^ h. 1,4 -h.exadiyiie _
d. 3-methyl-l-pentyne /. vinylacetylene
e. 4,4,5-trimethyl-2-hexyne j. 2-bromo-l,3-butadiene
/-^^>^ 4. why the
Explain following names are incorrect and give a correct name in each case.
^3-butene ^..^.a^dimelhyl-l-propyne
f'o. '2,4-pentadiene "J' 2-chloro-2-ethyl-3-butene
3-chloro-l,3-butadiene 3,3-dimethyl-4-pentene
\V'-^ ~c.

d. 2-ethyl-l-propene
g.
h. 2-methylcyclohexene

/3^ Write the structural formulas and names of the products formed when each of the fol-
lowing unsaturated hydrocarbons reacts completely with bromine:

fCsHio with a branched carbon chain

C6H12 with a normal carbon chain
"igj^CsHg with a normal carbon chain
JU^CsHg with a branched carbon chain
^^?) Write equations for the reactions of 1-butene with the following compounds:
f^chlorine d. hypobromous acid
£X hydrogen iodide e. potassium permanganate
^c. sulfuric acid /. bromine, in aqueous solution containing sodium
^<>—,, chloride
^ i77 Illustrate, by means of a structural formula or an equation, the meaning of the following
terms:
olefin /. Markownikoff 's Rule
fc.
addition reaction
conjugated diene
g.
h.
alkylation
acetylenic compound
^^ substitution reaction /. isoprene unit
e. 1,4-addition j. polymerization
*8^ Using reactions studied in and the previous chapter, write equations showing how
this
each of the following could be prepared from 2-bromopropane.
©propane /. I-bromo-2-hydroxypropane
^propene g. 2,3-dimethylbutane
 Unsaturated Hydrocarbons • 71

c. 2-iodopropane /?. 1 ,2-dibromopropane

d. propyne /. 4-methyl-2-pentyne
e. 2,2-dibromopropane j. 2-methylpentane
Starting with calcium carbide and any other morganic chemicals, write equations for

the preparation of:

a.j acetylene /. butane
/ K; ethylene g. chloroprene
^ethane h. 1,1,2,2-tetrachloroe thane
^ ethyl bromide /. 1,1-dibromoethane
e. vinylacetylene j. 1-butyne
Each of the following conversions involves several combinations of reactions described
o
/iO.
in this chapter. Write equations to show how each could be carried out.
-a. 72-propyl iodide to propene to 1,2- /. 1,2-dichloropropane to propane
J;- dibromopropane g. ethyl bromide to 1,1-dichloroethane
b. isopropyl alcohol to propene to iso- h^ ethyl alcohol to acetylene
propyl iodide /. ethyl chloride to ethylene chloro-
«-propyl bromide to isopropyl bro- hydrin
e mide (2 steps) j. «-propyl bromide to 2,2-dibromo-
2-butene to 1,3-butadiene (2 steps) propane
isopropyl alcohol to propyne (3

steps)
1 1. A cyUnder contains one of the following gases: propane, propylene, or propyne. What
chemical tests could be apphed to identify the contents?
12. How many grams of bromine are required to saturate the following quantities of un-
saturated hydrocarbons? (Atomic weights: C = 12, H = 1, Br = 80)
a. 13 g. of acetylene c. 27 g. of 1,3-butadiene
b. 14 g. of 2-butene d. 41 g. of cyclohexene
13. A 10 g. mixture of butane and 2-butene reacts with just 8.0 g. of bromine (dissolved in

carbon tetrachloride). Calculate the percent of butane in the original mixture.

14. A sample of gas is known to be either ethane, ethylene, or acetylene. Complete com-
bustion of a 10 ml. sample of the gaseous hydrocarbon required 30 ml. of oxygen. Show
how these data can be used to identify the gas.
15. What simple laboratory test could be used to distinguish between the following pairs
of compounds?
a. butane and 2-butene c. 1-butyne and 2-butyne
b. 1-pentene and 1-pentyne cyclohexene and cyclohexane
d.

16. A hydrocarbon has an empirical formula corresponding to that of the alkynes, C„H2„-2,
yet adds only one mole of bromine or hydrogen per mole of hydrocarbon. What type
of structure must the unsaturated hydrocarbon have?
17. An unknown compound A has a molecular formula C5H8. When it is treated with an
excess of bromine, a new substance B, C5H8Br4, is formed. The original compound. A,
forms a precipitate with ammoniacal silver nitrate. Give at least one structure for A
and for B which satisfies these data. Write equations for each reaction mentioned.
18. The following facts are known about a compound:
a. molecular weight: 82
b. analysis: C, 88%; H, 12%
c. one mole of the compound takes up two moles of bromine
d. when shaken with cuprous chloride solution, the compound produces a copper-
containing precipitate
From these data suggest a possible structural formula for the compound.
72 • Unsaturated Hydrocarbons

u
19. Which of
their cis
the following
and trans
compounds can
structures.
exist as geometric {cis-trans) isomers? Draw

a. propene g. 1-bromopropene
b. 2-butene h. 3-chloropropene
c. l-bromo-l-chloroethene /. 1,1-dimethylcyclopropane
d. 1,2-dibromoethene j. 1,2-dichlorocyclopropane
e. 2-methyl-2-butene k. 3-chloro-4-methyl-3-hexene
/. 1-hexene
20. When ethylene is treated with a methyl alcohol (CH3OH) solution of bromine, the com-
pound BrCH2CH20CH3 is formed, in addition to 1,2-dibromoethane. How can this be
accounted for?
21. Give the formulas of the alkenes which on ozonolysis gave:
a. H2C=0 + CH3CH=0 c. only CH3CH2CH==0
b. H2C=0 + (CH3)2CHCH=0 d. only (CH3)2C=0
22. Give the structural formulas of the alcohols which on dehydration will give only:
a. 2-pentene b. cyclopentene c. 4-methylcyclohexene
23. Which unsaturated hydrocarbons would react with what reagents to form the following
compounds?
a. CH2CICH2CI d. CH3CHOHCH2CI
b. CH3CBr2CH3 e. (CH3)2CHOS020H
c. CH3CH2CHICH3 /. (CH3)2CHCH3
24. A hydrocarbon, C5H8, on catalytic hydrogenation absorbs only one mole of H2.
Ozonolysis of the hydrocarbon gave a single product, 0=CHCH2CH2CH2CH^O.
Give a structural formula for the hydrocarbon.
 The development of the coal tar industry in Germany
during the nineteenth century was a great stimulus to the
systematic study of organic chemistry. When coal is con- m
verted to coke and coal gas for processing iron and steel, a
portion of the coal remains as a tarry residue. Although this
unpleasant-looking material comprises only a small percent-
age of the original coal, it nevertheless amounts to many tons
annually, because of the tremendous quantity of coal proc-
essed. Distillation of coal tar produces many useful prod-
ucts, all related in structure to the aromatic hydrocarbon,
benzene. The pharmaceutical, dyestujf, and explosives in-
dustries are based largely upon these aromatic chemicals.

Aromatic Hydrocarbons

Early in the development of organic chemistry it became evident that a class

of hydrocarbons exists which is not included in any of the categories previously
discussed. Since the derivatives of these compounds frequently had rather
fragrant odors, the compounds were called aromatic. We now know that the
parent compound of all these aromatic substances is benzene, first obtained in

1825 by Michael Faraday from illuminating gas. Coal tar is an important

source of benzene, although some benzene is present in petroleum, and large
amounts are produced from petroleum hydrocarbons by aromatization of
alkanes (see page 54).

Structure

Analysis and molecular weight determination show that the molecular for-
mula of benzene is CqRq. The ratio of carbons to hydrogens suggests that the
73
74 • Aromatic Hydrocarbons

molecule is But benzene does not readily decolorize bromine, nor

unsaturated.
is it by permanganate; and both of these are characteristic tests
easily oxidized
for the double bond. The usual reaction of benzene with bromine, particularly
in the presence of iron as a catalyst, is one of substitution:

Fe
CeHe + Br2
catalyst
CeHsBr + HBr (4-1)

bromobenzene

The fact that only one monobromo derivative of benzene is obtained implies that
all of the hydrogens are equivalent (or that certain of the hydrogens are non-
replaceable, an unhkely situation).
When bromine or chlorine reacts with benzene in the absence of oxygen, and
in the presence of sunlight, an addition product is formed:

sunlight
CqHq -f- 3 Br2 CeHeBre (4-2)

Hydrogen adds to benzene, in the presence of finely divided nickel or platinum,

to form cyclohexane:

/CH2
Ni
CH2 ^CH2
CeHe -|- 3 H2 (4-3)
catalyst

^CH2
cyclohexane

These experiments suggest a cyclic formula for benzene. In 1 865, Kekule pro-
posed formula I or la, a hexagon of carbon atoms with alternating single and

Figure 4-1 . Friedrich August Kekule ( 1 829-1 896)

was a pioneer in the development of structural
formulas in organic chemistry. The tetrocovalence
of carbon, the importance of chains of carbon
atoms, and the structure of benzene were among
his major contributions to chemistry. (Courtesy of
Professor Ralph E. Oesper, University of Cincinnati.)
 Aromatic Hydrocarbons • 75
H H

W"
76 Aromatic Hydrocarbons

ene, with angles of 120° between the atoms. Each carbon has an additional
p orbital at right angles to the plane of the ring with one electron in it. An
overlap of these six/? orbitals (Figure 4-3) leads to three vr orbitals, the net resuU
of which an electron cloud above and below the plane of the atoms, as shown
is

in Figure 4-4. Some organic chemists represent this electronic arrangement by

the symbol |( )1, but in this text we will use the Kekule-contributing struc-

tures,

recognizing that the bonds are not fixed as shown. Kekule structures are
particularly useful in visualizing the mechanisms of aromatic substitution
reactions.

Some Common Aromatic Hydrocarbons

Several types of aromatic hydrocarbons are known. Some of the more com-
mon are partly aromatic and partly aliphatic,* such as

CHs CH2CH3 CH=CH2

tolue ethylbenzene styrene

Figure 4-3. A molecular orbital representation of the bonding in benzene.

/
* The term aliphatic originally referred to compounds derived from fats, just as the term aromatic
referred to natural products with a characteristic aromatic odor. These words have now been gener-
alized in terms of the structures of molecules. AUphatic compounds are substances related to meth-
ane; that is, saturated or unsaturated open-chain or cyclic compounds not containing a benzene ring.
Aromatic compounds are substances whose structure is related to that of benzene. Later, the third
large class of organic substances, the heterocyclic compounds, will be briefly discussed. These are
cyclic chemicals with at least one element other than carbon as a member of the ring. The hetero
atom may be oxygen, nitrogen, sulfur, or some other element.
 Aromatic Hydrocarbons • 77

Figure 4-4. The electron distribution in benzene. ^^^ ^^-. ^ ^

Others have more than one aromatic ring

biphenyl triphenylmethane

or have "condensed" rings with two carbons shared between more than one
ring, as in

naphthalene anthracene phenanthrene

Note that in the condensed ring compounds, the non-ending cychc conjugated
system of double bonds is extended to several rings.

Figure 4-5. Scale model of toluene.

78 • Aromatic Hydrocarbons

Figure 4-6. Scale models of biphenyl (left) and naphthalene (right).

Nomenclature
Since aromatic chemistry developed in a haphazard fashion for many years
before systematic methods of nomenclature were developed, of the names many
of aromatic compounds are common names. There are, however, some ele-
ments of system. The general class name for aromatic hydrocarbons is arenes.
The benzene ring with one hydrogen atom removed

is called the phenyl

the original discovery of benzene in illuminating gas).
O
group (from the Greek pheno,
This is an example of an
"I bear light," a reference to

arylgroup derived from an aromatic compound, as contrasted with alkyl groups

derived from ahphatic compounds. The symbol Ar- is used to designate an aryl
group. Thus we have biphenyl and triphenylmethane (see above). If more
than one hydrogen is substituted, a numbering system becomes necessary.
There are three possible disubstituted benzenes:

1 ,2- or ortho 1,3- or meta

Thus we have

ortho-xylene meta-bromoiodobenzene pora-dichlorobenzene

( 1 ,2-dimethylbenzene) ( 1 -bromo-3-iodobenzene) (1 ,4-dichlorobenzene)
 Aromatic Hydrocarbons • 79
Although the prefixes ortho (o), meta (m), and para (p) are commonly used for
disubstituted benzene derivatives, a numbering system is used when three or
more substituents are present. The system for designating the number one
carbon is not always consistent; sometimes it is done alphabetically, sometimes
for the most reactive or important substituent.

Reactions

The most common reactions of the aromatic ring involve substitution or

replacement of the hydrogen atoms by other atoms or groups.

Substitution

With chlorine or bromine, halogenation occurs readily, usually in the presence

of iron or an iron halide as a catalyst.

+ CI2 -^ + HClt (4-4)

||

J
chlorobenzene

When an alkyl side chain is present, one can cause the process to follow either
of two paths by controUing the reaction conditions (and therefore the reaction
mechanism).

CH3 CH2CI

^"""g"
+ CI2 >
II I
+ HCl (4-5)
(no catalyst)

Fe catalyst^
^
i,

^
,

^^^ j^^j ^^_^^

(dark)

p-chlorotoluene
(some ortho and a little
meta isomer is also formed)

Nitration can be accomphshed usually with a mixture of concentrated nitric

and low temperatures.

sulfuric acids at relatively

t The hydrogen atom of the hydrogen chloride does not

appear exphcitly on the left-hand side of the
equation. It is imphed, however, in the ring fonnula for benzene, just as it is also implied that the
carbon atom to which the chlorine is attached is not bound to a hydrogen atom in the formula for
chlorobenzene. The same comment apphes to all equations representing aromatic substitution.
80 • Aromatic Hydrocarbons

+ HO-NO2 -^^^ II I
+ H2O (4-7)

nitric acid
nitrobenzene

Benzene does not react with cold concentrated sulfuric acid, but at elevated
temperatures, sulfonation slowly occurs.

SO3H

+ HO-SO3H ^^^^
(H2SO4)
II
\^ + H2O (4-8)

sulfuric acid benzenesulfonic acid

Mechanism of Electrophilic Aromatic Substitution

An aromatic ring, like a carbon-carbon double bond, can act as a supplier of

electrons for positive, electronically deficient reagents (electrophiles). Halo-
genation, nitration, and sulfonation of benzene take place by similar mecha-
nisms.The active reagent in each case is an electronically deficient particle, the
bromonium ion (equation (4-9)), the nitronium ion (equation (4-10)), or sulfur
trioxide (equation (4-1 1)). The proton itself may attack an aromatic ring (just

:Br— Br: + FeBrg > : Br+ + FeBr4- (4-9)

bromonium
ion

.. p; .. . ..

H— O— + H+ > :0=N=0: (or NO2+) + H2O (4-10)

O '•
nitronium ion

nitric acid

:6: :0:

H— O— S— O— H + H+ > +S— 6— H (+SO3H or SO3 + H+) -h H2O

:0. :0:
^ ^
sulfuric acid protonated sulfur
trioxide

as it attacks a double bond in the addition of HX); the reaction can be demon-
strated by deuterium exchange (equation (4-12)).

+ D2SO4 > + HDSO4 (4-12)

 Aromatic Hydrocarbons 81

Electrophiles react with the benzene rmg to form an intermediate resonance-

stabilized carbonium ion (compare with 1,2- or 1,4-addition of bromine to a

conjugated diene, p. 64) as shown in equation (4-13). In addition reactions

to the carbon-carbon double bond, the process is usually completed by
attachment of an anion at one of the positive carbons. But in the present

+ Br^ (4-13)

H Br H Br H Br

case, reaction is completed by loss of a proton, thus reforming the highly

resonance-stabilized aromatic ring (equation (4-14)); the over-all result is
replacement of hydrogen by bromine (or NO2, SO3H, D).

+ H (4-14)

In special cases, salts of the intermediate carbonium ions have actually been
isolated, as in the reaction of mesitylene (1,3,5-trimethyI benzene) with hydrogen
fluoride and boron fluoride (equation (4-15)). On warming, the salt decomposes to
mesitylene (or deuteromesitylene); the C — H bond breaks more readily than the
C— D bond.

CHc

-30°
+ DF + BF 3 ^
warm
BF,
(60%)
(40%) CH3 X
H D
CH3

yellow salt, m. p. —15°

CH,

+ HF -h BFs (4-15)

CH..

Alkylbenzenes

Certain benzene derivatives with alkyl groups attached to the rmg are isolated
from coal tar; by far the majority of these, however, have very short side-chains
(rarely longer than two carbon atoms).
General methods for the laboratory synthesis of these compounds are of
interest. The first of these was discovered by Fittig in 1864. By the action of
sodium on a mixture of an alkyl hahde and an aromatic (aryl) hahde, the Wurtz

reaction (see page 31) was extended to the preparation of alkylbenzenes.

82 • Aromatic Hydrocarbons

Br + 2Na + BrCHzCHsCHs >

n-propyl bromide

CH2CH2CH3^2Na+Br- (4-16)

n-propylbenzene

Ar— X + 2 Na + X— R > Ar— R + 2 Na+X"

This is known as the Wurtz-Fittig Reaction.
In 1878, the French chemist, Charles Friedel, and his American collaborator,
James M. Crafts, discovered that an alkyl haUde will condense with an aromatic
hydrocarbon in the presence of aluminum chloride as a catalyst.

+ CH3CH2CI ^ [P^CH2CH3 ^

ethylbenzene
^^^^ ^4_^^

Ar— H + R— CI ^i^ Ar— R + HCl

The reaction goes by their names (Friedel-Crafts Reaction). It is an electro-

philic substitution, the electrophile being an alkyl carbonium ion (equation

(4-18)).

CH3CH2CI + AICI3 ^=± CH3CH2+AICI4-

+ CH3CH2+AICI4- > + AICI4- (4-18)

[I
J
H CH2CH3

AICI3 + HCl +

CH2CH.
This process, alkylation, can be extended to introduce several alkyl groups on
the ring.

CH2CH3

+ 3 CH3CH2Br ^^L^ + 3 HBr (4-19)

24 hrs. /A [| |

^.^i^^
CH3CH2^^^^CH2CH3
1 ,3,5-triethylbenzene
(and some other isomers)
 Aromatic Hydrocarbons • 83
With polyhalogen compounds, several aromatic rings can be combined in one
molecule.
H H
+ CI— C-Cl ^^ /~\-C^^y
~ + 3 HCl (4-20)

CI
trichloromethane
(chloroform)

triphenylmethone

The alkylation reaction is frequently accomphshed commercially with alkenes in

place of the alkyl halide. Ethylbenzene is manufactured in quantity this way

from benzene and ethylene.

^i^ ^^n2^n3
fr^^CH2CH3
^U
AICI3
+ CH2=CH2 HCl
(4.21)

ethylbenzene

Its principal use is for conversion to polystyrene.

Figure 4-7. The structure below, 80 feet in diameter, is a new dome-shaped ceiling roof for a
theater-convention hall in Traverse City, Michigan. Styrofoam insulation is used as the sole
structural component in the roof, a process that was developed by the Dow Chemical Company.
(Courfesy of the Dow Chemical Company.)
84 • Aromatic Hydrocarbons

aCH2CH3 catalyst

^^IJ
f| ^— CH^CH2 — y^
catalyst

^
[| ./, ^^^

''-'''

styrene
_^CH— CHs"^
polystyrene

Alkylation with higher olefins produces branched-chain alkyl aromatics, as

might be predicted from the mechanism (the most stable carbonium ion is the
electrophile; isopropyl > w-propyl).

CH3— CH— CH3

+ CH2=CH— CH3 ^i^ II I

(4-23)

isopropylbenzene
(2-phenylpropane)

Oxidation of the Side Chain

The behavior of alkylbenzenes when treated with strong oxidizing agents

offers a striking illustration of the unusual stability of the benzene nucleus.
When toluene is heated with alkaline potassium permanganate it is converted
almost quantitatively to benzoic acid.

CV^"^ ^^ {^/oH (4-24)

toluene benzoic acid

In spite of the customary ease with which unsaturated compounds are attacked
by permanganate and the stability of saturated hydrocarbons toward the same
reagent, the aliphatic side chain is oxidized, rather than the aromatic ring.
Longer side chains are completely oxidized to the acid. For example:
O
<^y-CH2CH2CH3 ^^j^ f~^^C-OH (4-25)

n-propylbenzene

The remaining carbon atoms of the chain are oxidized to carbon dioxide. When
two alkyl groups are on the ring, they both may be oxidized.
CH3 COOH

(4-26)

I The symbol [O] is used to indicate an oxidizing agent.

 Aromatic Hydrocarbons 85
This reaction has become commercially important during the last few years,
because polymers made from these acids are used to make synthetic fibers such
as Dacron (see page 190).

Orientation in Substitution Reactions

When considering the substitution reactions of benzene (nitration, halogena-

tion, sulfonation, or alkylation), it was noted that aU six positions of the benzene
ring were equivalent. It is possible, however, to introduce more than one sub-
stituent. When this occurs, several alternatives exist for the structure of the
product. To illustrate, when a substituent X replaces a hydrogen atom on a
ring which already has a substituent Y attached to it, three products

may be formed, X taking position 2, 3, or 4.§ On a statistical or chance basis,

one might anticipate 40 per cent of A, 40 per cent of B, and 20 per cent of C. Li
practice, however, results are obtained which do not agree at all with the hypoth-
esis of randomness.

By way of illustration, let us examine the experimental results obtained when

benzene is alternately chlorinated, then nitrated, and vice versa.

NO NO.

(4-27)

NO2
o-nitrochlorobenzene p-nitrochlorobenzene
33% 67%

Nitration followed by chlorination yields mainly the meta isomer, but the re-
and para isomers. From these and
verse process gives rise to a mixture of ortho
numerous similar results, we infer that the group Y which is already present in the
ring determines the position which will be taken by the entering group X. We see

§ It is apparent that positions 2 and 6 are equivalent, as are 3 and 5.

86 • Aromatic Hydrocarbons

that the nitro group directs the entering CI to the meta position, whereas the
chloro group, in the lower equation, directs the entering nitro group mainly to
the para position, with some of the ortho isomer and a trace of meta isomer also
being formed.
This behavior seems to be rather general. It is found that certain substituents
are meta-directing, that is, cause the entering group to assume a position meta to
themselves, whereas other groups are ortho-para-directing, yielding a mixture
of the ortho- and para-substituted isomers. It has also been noted that meta-
directing groups decrease the activity of the ring toward further substitution,
whereas ortho-para-directing groups usually have the opposite effect. Of the
—
groups studied thus far, the nitro ( NO2) and the sulfonic acid ( SO3H) groups —
are meta-directing; the alkyl ( —
R) and halogen ( CI, Br) groups direct to— —
the ortho and para positions. As we progress further in our study of various
functional groups, we shall indicate their orienting effect when attached to the
aromatic nucleus.

These experimental observations follow as logical deductions from the mechanism

of electrophilic aromatic substitution.For example, the intermediate in para substi-
tution of chlorobenzene would be the carbonium ion A, in which the positive charge
can be stabilized by use of the unshared electron pairs on the chlorine, as shown in the
third contributing structure to this resonance hybrid. A similar charge distribution
would obtain for ortho substitution, but meta substitution (via carbonium ion, B) does

:C1: :C1+ :C1:

H X H X H X

not permit such charge delocaUzation onto the chlorine. Therefore substitution is
predominantly ortho and para (para usually predominates, perhaps because of steric
factors).

Alkyl groups similarly favor ortho-para substitution, because the intermediate

carbonium ion is stabiUzed (tertiary structures are possible).

CH3 CH

is more stable than

H X
para (or ortho) substitution meta substitution

On the other hand, the nitrogen of the nitro group is positively charged; structure
(C) which places a positive charge adjacent to this nitrogen is less stable than structure
(D) with the charge further from the nitrogen; therefore the nitro group is meta-
 Aromatic Hydrocarbons • 87

is less stable than

directing. A similar argument applies to the sulfur atom of the sulfonic acid (SO3H)
group, making it meta-directing. Furthermore, the electron-withdrawing effects of
the NO2 and SO3H groups tend to remove electrons from the aromatic ring, making
it less reactive toward electrophiles than it would otherwise be.

Simple Benzene Derivatives

Even the few reactions of aromatic compounds which we have discussed thus
far can lead to the synthesis of some rather well-known substances. 2,4,6-
trinitrotoluene (TNT) is manufactured by the nitration of toluene, usually in
several steps. Note that the methyl group directs the entering nitro groups
ortho and para to itself. The over-all reaction is

CH3 CH3
02N^^L^N02
+ 3 HONO2 JM2i^ 11 +3 H2O (4-28)
nitric
y

toluene acid
XTO
2,4,6-trinitrotoluene
(TNT)

The well-known moth-repellant, p-dichlorobenzene, is prepared by the

dichlorination of benzene.

+ 2 CI2 -^^^ II I
+2 HCl (4-29)

p-dichlorobenzene

Some of the ortho isomer is also formed, and it is useful as a special solvent.
As we consider other functional groups, numerous examples of drugs, dye-
stuffs, plastics, and biologically important compounds which contain an aro-
matic ring will be discussed.
88 • Aromatic Hydrocarbons

NEW CONCEPTS. FACTS, AND TERMS

1. Aromatic substances; benzene.
2. Structure of benzene; Kekule formula.
3. —
Resonance two or more equivalent structures with identical positions of the atoms
but different electron arrangements. Resonance hybrid formula for benzene.
4. Common aromatic hydrocarbons; toluene, styrene, xylene, naphthalene.
5. Nomenclature — aryl group; ortho, meta. para (page 78).
6. Substitution reactions
a. Halogenation (chlorine, bromine)
b. Nitration (nitric acid)
c. Sulfonation (sulfuric acid)
d Deuterium exchange
7. The mechanism of electrophihc aromatic substitution
8. Alkylbenzenes (preparation)
a. Wurtz-Fittig (alkyl halide, aryl hahde, and sodium)
b. Friedel-Crafts (aromatic hydrocarbon, alkyl halide or alkene, and aluminum
chloride)
9. Oxidation of aUphatic side chains.
10. Orientation — rules
and mechanism; the most stable intermediate determines the
and halogens are ortho-para-directing, nitro and sulfonic acid
orientation; alkyl groups
groups are meta-directing and ring-deactivating.
11. Benzene derivatives: TNT, /j-dichloro benzene.

EXERCISES AND PROBLEMS

1. Write structural formulas for the following compounds:
a. l-chloro-4-nitrobenzene /. /-butylbenzene
b. /?-nitrotoluene g. /7-bromobenzoic acid
c. o-diethylbenzene h. m-chlorobenzenesulfonic acid
d 1,3-dibromobenzene /. triphenylchloromethane
e. 2-phenylpentane j. 3-isopropyl-4-bromo-2,6-dinitrotoluene
2. Name the following compounds:

CI CH
N0.2 CH.
c. e.

CH CH;
d. /•

CH2CH3
 Aromatic Hydrocarbons • 89
CHs Br

3. Tell how the resonance formula for benzene explains its reactions and physical
properties.
4. Compare the reactions with bromine of cyclohexane, cyclohexene, and benzene, with
^ regard to reaction type and conditions.
'^
% Write the structural formulas for all possible monobromo substitution products of the
following compounds. (Omit any formulas which have bromine in the side-chains.)
a. /j-xylene h. o-xylene _!' c. w-xylene "3

Does your answer indicate a method which could be used to determine the relative
positions of identical substituents on a disubstituted benzene?
/6~^ Write all possible structural formulas for aromatic compounds with the following
molecular formulas:
a.

How many
C7H8 „ , ^
;'
^J
i^jr
QHio %
CgHio *^ ^^^^'CgH^^ ,C^T
'
^
different monosubstitution products are possible in the following
C/. C6H3CI3 3 com-
pounds?
a. benzene c. anthracene e. triphenylmethane
h. naphthalene tetraphenyhnethane
d. biphenyl /.
8. Using structural formulas or equations wherever possible, indicate the meaning of each
of the following terms.
a. resonance /. aryl group
h. Wurtz-Fittig reaction g. meta-directing group
c. side-chain halogenation h. catalytic hydrogenation
d. Friedel-Crafts reaction /. side-chain oxidation
e. ortho-para-directing group j. aromatic alkylation

9. Three isomeric tribromobenzenes are known, with melting points at 44°, 87°, and 119°.
When each is nitrated (under conditions which introduce a single nitro group), they
give, respectively, three, two, and one mononitro-tribromobenzenes. Assign structures

to the tribromobenzenes and their nitration products.

10. Using structural formulas, illustrate with equations the halogenation, nitration, and
sulfonation of benzene and toluene, introducing only a single substituent in each case.
11. Indicate the main monosubstitution products in each of the following reactions, keep-
.^' ing in mind that certain substituents are meta-directing and others are ortho-para-
directing.
a. toluene -f- chlorine (Fe catalyst)
h. nitrobenzene -|- concentrated sulfuric acid (heat)
c. bromobenzene -|- chlorine (Fe catalyst)
d. benzenesulfonic acid -|- concentrated nitric acid (heat)
e. chlorobenzene -|-bromine (Fe catalyst)
/. ethylbenzene -i- bromine (Fe catalyst)
g. nitrobenzene + concentrated nitric acid (heat)
h. iodobenzene -h bromine (Fe catalyst)
 90 • Aromatic Hydrocarbons

12. Write equations for each of the following reactions:

a. isopropylbenzene + potassium dichromate
b. /7-bromoethylbenzene + methyl bromide + sodium
c. preparation of 1,3-dimethylcyclohexane from m-xylene
d alkylation of/7-xylene with ethyl chloride
e. toluene + Br2 (catalyzed by sunUght)
/. preparation of benzenehexachloride from benzene
13. Would ethylbenzene be the only organic product from the reaction: bromobenzene +
ethyl bromide + sodium? Explain, using equations.
/ 14. Write equations to show how each of the following conversions, which may involve
several steps, could be accomplished.
a. benzene to w-bromonitrobenzene /. benzene to isopropylbenzene
b. benzene to /7-bromonitrobenzene g. benzene to benzoic acid
^toluene to benzyl bromide /l benzene to /?-nitrobenzoic acid
d toluene to /^-xylene /. benzene to ethylcyclohexane
e. benzene to styrene benzene to dicyclohexylmethane
j.

15. An acid C7H6O2 results from the oxidation of an aromatic hydrocarbon whose formula
is Suggest two possible structures for the original hydrocarbon.
C9H12.
16. A hydrocarbon with the molecular formula C9H12 yields o-phthalic acid as the only
organic product of oxidation. What is the structural formula of the hydrocarbon?
17. Describe a chemical test, giving reagents, experimental observations, and equations,
that can be used to distinguish between:
a. styrene and ethylbenzene benzene and cyclohexene c.

b. phenylethylene and phenylacetylene benzene and benzenesulfonic acid

d.

18. A compound with the molecular formula C11H8O2, upon heating with soda hme, gave
naphthalene. Suggest two structural formulas for the original compound.
19. An aromatic compound has the molecular formula C8H9CI. Oxidation of this sub-
stance with permanganate yields C8H6O4, which gives only one monobromo derivative
on bromination. Deduce the structure of the original chloro compound.
20. The amount of heat evolved when one mole of cyclohexene is hydrogenated to cyclo-
hexane is —28.6 kilocalories. The comparable quantity for 1,3-cyclohexadiene is
nearly twice that, —55.4 kOocalories. Calculate the expected heat of hydrogenation
of benzene to cyclohexane, assuming that benzene behaves as if it were 1,3,5-cyclohexa-
triene. The experimental value for the heat of hydrogenation of benzene is only —49.8

kilocalories. Explain the difference between the calculated and the experimental values
in terms of the stability of benzene.
21. 1,3,5,7-Cyclooctatetraene has a heat of hydrogenation of —110.0 kilocalories, about
4 times the value for cyclohexene. Knowing this, would you expect it to be more or
less stable than benzene? Explain. (Compare with Problem 20.)

22. The structure of the nitro group, — NO2, is usually shown as R— (page 87).

Yet experiments show that the two N — O bonds have the same length. 1.21 A, as com-
pared to 1.36 A for the N— O single bond and 1.18 A for the N— O double bond. Draw
structural formulas which explain this observation.
 ArOH
Alcohols and phenols contain the hydroxy I unit as
their functional group. This is the first class of compounds
we shall study which contains an element other than carbon
and hydrogen. Ethyl alcohol has been known since an-
tiquity, although its chemical structure was not understood

until the nineteenth century. It was first produced by the

fermentation offruits. Since the first World War, industrial
developments in the synthesis of a score of alcohols have been
rapid. The production ofphenols for use as antiseptics, and
in the synthesis of medic inals, plastics, and dyes tuffs, par-
alleled the development of the coal tar industry.

Alcohols and Phenols

Alcohols are derived from saturated or unsaturated hydrocarbons by re-

placing a hydrogen atom by a hydroxy! group (—OH). If a hydrogen atom
attached to an aromatic ring is replaced by a hydroxyl group, the compound is
known as a phenol. The chemistry of alcohols and phenols, then, involves the

properties of a hydroxyl group attached to carbon ( — C — OH).

In another light, alcohols and phenols may be considered as organic analogs
of water in which one of the hydrogen atoms has been replaced by an organic
group.

H— OH R— OH Ar— OH
water alcohol phenol

It will not be too surprising, therefore, to find some similarity in the chemical

behavior of water and its organic counterparts.

91
92 • Alcohols and Phenols

Classification

The chemistry of alcohols sometimes depends upon whether the hydroxyl

group is attached to a carbon that is bound to one, two, or three other carbon

atoms. The compounds are known, respectively, as primary, secondary, or

tertiary alcohols.

H H R
R— C— OH R— C— OH R— C— OH
I I I

I I
I

H R R
primary secondary tertiary

Some specific examples of these three classifications are

CH3 CH3
CH3CH2— OH CH3CH2CH— OH CH3CH2C— OH
primary secondary Au
L.I-I3

tertiary

Nomenclature
For the lower members of the alcohol series, common names consisting of —
the alkylgroup names followed by alcohol are frequently used. —
CH3OH methyl alcohol CH3CH2CH2OH ^-propyl alcohol
CH3CH2OH ethyl alcohol CH3CHCH3 isopropyl alcohol

OH
The four four-carbon alcohols (derived from n- and isobutane) are also generally
known by their common names.

CH3CH2CH2CH2OH CH3— CH— CH2OH

normal butyl alcohol C^'V\

isobutyl alcohol

CH3CH2CHCH3 CH3
OH CH3— C— OH
secondary butyl alcohol
CH3
tertiary butyl alcohol

The I.U.P.A.C. system is used for naming more complex alcohols. The
longest chain of carbon atoms which includes the hydroxyl group is the basis for
thename, and the ending -ol is used to indicate the alcohol function. The posi-
tion of the hydroxyl group is indicated by the number of the carbon atom to
which it is attached.
 Alcohols and Phenols • 93

Figure 5-1. Models of methyl alcohol

12 3 4
CH3CH2OH CH2CH2CH2CH2 / ^KCHCH3
ethanol
(ethyl alcohol)
OH OH ~ OH
1 ,4-butanediol 1 -phenylethonol

CH3
1 2| 3 5 4 3 2 1

CH3-C-CH3 CH3CH=CH— CH— CH3

OH OH
2-methyl-2-propanol 3-pentene-2-o!
(t-butyl alcohol)

Phenols are usually named as derivatives of the parent compound

OH OH

phenol

p-chlorophenol 2,4,6-tribromophenol

Figure 5-2. Models of isopropyl alcohol.

94 Alcohols and Phenols

Figure 5-3. Scale model of phenol.

^
or by common names. Some of the more important of these are indicated
below.

OH OH OH
CH.

o-cresol

OH
OH

CH,
a-naphthol /S-naphthol
m-cresol

Methods of Preparation
There are several general methods for preparing alcohols. In addition,
methods are employed for the lower members of the series.
special industrial

Hydrolysis of Alkyl Halides

Alkyl halides can be converted to the corresponding alcohols by heating with

aqueous alkali.

CHaCHsCHaBr + OH" > CH3CH2CH2OH + Br" (5-1)

n-propyl bromide n-propyl alcohol

When is a primary alcohol, it has been found that

the alcohol being prepared
depends upon the concentration of both reactants (alkyl hahde
the reaction rate
and hydroxide ion). The hydroxide ion is said to displace the bromide ion; it
approaches the carbon from the side opposite to which the bromine is attached,
and the bonds to carbon turn inside out (invert) when displacement occurs.
 Alcohols and Phenols 95

H H
HO--C-- Br
/\
CH2CH3 H CH2CH3
transition state

H
+ Br- (5-2)
YH2CH3
Evidence that this is true will be presented in Chapter 13. This mechanistic
pathway is common to many dispkcement reactions, and is described as Sn2
(S = substitution; N= nucleophilic— the hydroxide ion is nucleophilic, seeking
a positive carbon; 2 = bimolecular— both reactants are involved in the rate-
determining step).
One might imagine that, if the alcohol were tertiary, approach of the
hydroxide ion by the Sn2 path would be sterically hindered.

H
\
HO Br
H i hJ
H c
w H
approach to the back-side of the
—
C Br bond is sterically hindered

Experimentally it is found that tertiary alcohols are readily prepared from

tertiary halides, but that the reaction rate independent of hydroxide ion con-
is

centration. The rate-determining step, therefore, cannot involve hydroxide ion.

These reactions proceed through carbonium ion intermediates. The alkyl
groups not only hinder Sn2 attack, but also stabilize the intermediate carbonium
ion (see page 51). This mechanistic pathway is described as SnI (Sn as above;
1 —
= unimolecular only one reactant, the alkyl halide, is involved in the rate-
determining step).

CH3 CH3
slow
HsCV^- Br > .C+ + Br-
H3C' >CH3
H2O
fast
-> (CH3)3COH + H+ (5-3)

Secondary alcohols may be produced from secondary halides by either

mechanism; strongly alkaUne conditions and less stable carbonium ions favor
96 • A Icohols and Phenols
the Sn2 path. An interfering side reaction, particulariy for tertiary hahdes, is

their dehydrohalogenation to alicenes (page 59).

Aromatic hahdes are ordinarily not converted to phenols by alkah.

/ ^Br + OH" > no reaction (5-4)

Hydration of Alkenes

Hydration of a double bond can be accomplished by addition of cold con-

centrated sulfuric acid to an alkene and hydrolysis of the resulting alkyl hy-
drogen sulfate.

H H H H
H— C=C— H + H+-OSO3H -^^^ H— C— C— OSO3H (5-5)
ethylene sulfuric acid tt tt

ethyl hydrogen sulfate

H H H H
H— C— C— OSO3H + H— OH > H— C—C— OH + HOSO3H (5-6)

H H ''^°"'
H H
ethyl alcohol

This sequence, the net result of which is the addition of water to a double bond
in accord with Markownikoff 's rule, is used commercially for the manufacture
of ethyl, isopropyl, secondary butyl, and tertiary butyl alcohols. The olefins
are readily available from petroleum sources, and the sulfuric acid is recovered
in the process. The inexpensive production of isopropyl alcohol from propyl-
ene in this way has led to its widespread medicinal use as rubbing alcohol,
replacing denatured ethyl alcohol for that purpose.

Hydroboration
Diborane (B2H6), generated from sodium borohydride (NaBH4) and boron
with alkenes to form trialkylboranes. These may be oxidized
trifluoride, reacts
with hydrogen peroxide to trialkylborates which, on alkaUne hydrolysis, give
the alcohol. The over-all result of equations (5-7) and (5-8) is the addition of

6 RCH=CH2 + B2H6 > 2 (RCH2CH2)3B (5-7)

(RCH2CH2)3B -^^^ (RCH2CH20)3B -^^ 3 RCH2CH2OH (5-8)

water to the alkene, but in the reverse fashion to Markownikoff 's rule (this is
because the boron hydride adds as hydride ion (H~) and positive boron). This
method, therefore, supplements the conventional hydration with sulfuric acid.
 Alcohols and Phenols • 97

Special Methods
Methanol is sometimes known as wood alcohol, because at one time it was
produced by the destructive distillation of wood. At present, however, less than
10 percent of the methanol produced in this country is made in this way. It is
now manufactured synthetically from carbon monoxide and hydrogen. High
temperatures (400°) and pressures (about 150 atmospheres) are employed.
The catalyst may be a mixture of the oxides of zinc, copper, and chromium.
Normal propyl alcohol and isobutyl alcohol are by-products of this synthesis.

CO + 2 H2^ '^'''

pressure.
> CH3OH
^ (5-9)
^ '

catalyst

Methanol is the starting material in the manufacture of formaldehyde and is

also used as an antifreeze and as a solvent for shellacs and varnishes. It is highly
toxic, causing permanent bhndness if taken internally. It is added to grain

alcohol to make the latter unfit for human consumption, when the grain alcohol
is to be used for industrial purposes rather than in beverages.

Ethanol is the most important industrial alcohol. It can be prepared by the

fermentation of blackstrap molasses, the residues which result from the purifica-
tion of cane sugar. The molasses is fermented with yeast, an organic catalyst
which transforms the sugar into alcohol and carbon dioxide. The starch in
potatoes, grain, and similar substances can be converted by malt into sugar
which, when fermented, gives ethyl alcohol. Because of its source, ethyl alcohol
is sometimes known as grain alcohol.

C12H22O11 + H2O ^^^ 4CH3CH2OH + 4CO2 (5-10)

cane sugar ethyl alcohol

The most important method for producing ethyl alcohol industrially involves
the hydration of ethylene (equations (5-5) and (5-6)).
Ordinary commercial alcohol is a constant-boiling mixture of alcohol (95%)
and water (5%) which cannot be further purified by distillation. Absolute al-
cohol can be prepared from 95% alcohol by chemical methods, as, for example,
with quicklime (CaO) which reacts with the water but not the alcohol.
Ethanol has been known since earliest times, particularly as an ingredient in
all m
fermented beverages. The itim proof reference to alcoholic beverages is
twice the percent of alcohol present. Ethanol is a raw material for the industrial
synthesis of the anesthetic ether and for synthetic rubber. The solvent proper-
ties of ethanol are used in making resins and varnishes and in certain medicines

(for example, tincture of iodine is a solution of iodine in ethanol).

Another alcohol produced by a fermentation process is 1 -butanol It is used to
manufacture quick-drying solvents for automobile lacquers and varnishes.

Polyhydric Alcohols

Alcohols with more than one hydroxyl group per molecule are prepared by
reactions that are modifications of the general methods discussed above. Ethyl-
9S • A Icohols and Phenols
ene glycol (compounds with two —
OH groups are called glycols) may be pre-
pared from ethylene by the following sequence of reactions:

CH2=CH2 + HO-C1+ > CH2-CH2 , "g, _ > CH2— CH2 (5-11)

hypochlorous acid
qj^ q^ qj^ qjj
(chlorine + water)
ethylene ethylene
chlorohydrin glycol
(1,2-ethanediol)

Aqueous sodium carbonate is basic, and the hydroxide ions displace chloride

ions from ethylene chlorohydrin.

Ethylene glycol, a permanent antifreeze, is completely miscible with water,
lowers its freezing point, and is not as volatile (b.p. 197°) as methanol (b.p. 65°).
Glycol is also one of the two raw materials used to manufacture Dacron (see
page 190).
Glycerol, an alcohol with three hydroxyl groups, is now manufactured syn-
thetically from propylene.

CH3CH=CH, -£^ CH.-CH=CH. -^^ CH.-CH=CH.

CI OH (5-12)
allyl chloride allyl alcohol
(2-propene-l-ol)

This first step involves the substitution of halogen, rather than addition. The
allyl alcohol is subsequently treated with hypochlorous acid followed by
hydrolysis.

CH2— CH=CH2 -^^^^ CH2— CH— CH2 ^^:^^_ > CH2— CH— CH2
OH OH OH CI OH OH OH
* glycerol
(1,2,3-propanetriol) (5-13)

Glycerol is also a major by-product in the manufacture of soap (see Chapter 1 1).
In recent years, with the increasing use of synthetic detergents, less glycerol has
been available from ordinary soap manufacture, but considerable quantities
have been obtained from the fats consumed in the production of fatty acids and
fatty alcohols used in the manufacture of synthetic detergents and other
products.
Glycerol (glycerine)is a syrupy, colorless, high-boiling hquid with a distinctly

sweet taste.mixes with water and alcohol in all proportions. Glycerol is used
It

as a moistening agent in tobacco, for its soothing quahties in shaving and toilet
soaps, and in the manufacture of plastics, explosives (page 106), cellophane, etc.
(see Figure 5-4). Annual consumption of glycerol is in the neighborhood of
280 milUon pounds.
 Alcohols and Phenols • 99
Tobacco
Explosives

Alkyds Other

Cellophane

Monoglycerides and Foods

Drugs and Toilet Goods (including Toothpastes)

Figure 5-4. Glycerol serves many industries. It is used in the manufacture of olkyd resins for

protective coatings, as a plasticizer for cellophane and plastics, as a moistening agent in

tobacco products. Its unique combination of properties has made it an important ingredient in

drugs, cosmetics, and toilet goods. It has also found increasing use in foods and beverages.

Phenols

The methods described for the synthesis of alcohols are, in general, unsatis-
factorywhen apphed to the phenols. An old method suitable for laboratory as
well as commercial synthesis of phenols involves the fusion of aromatic sulfonic
acids with alkaU.

SO.H S03-Na+

Na+OH- solid Na+OH-

room temp. 300°

benzenesulfonic acid sodium

(page 80) benzenesulfonate

O-Na

+ Na2+S03= + H2O (5-14)

sodium
phenoxide

The free phenol may be liberated from the sodium phenoxide by acid.

0-Na+ OH

+ H+Cl- > + Na+Cl- (5-15)

100 A Icohols and Phenols

The reaction is an example of a nucleophilic aromatic substitution and involves

attack of hydroxide ion on the carbon holding the sulfonate group (equation
(5-16)). Such reactions usually require severe reaction conditions, unless the
negative charge in the intermediate can be stabilized by electron-withdrawing
groups in the ortho or para positions.

SO. OsS^OH OH
OH-
+ S03= (5-16)

^
This synthesis may be applied to substituted sulfonic acids and to disulfonic
acids.

SO,H O-Na- OH
excess
H2SO4 NaOH
heat 270°
SO3H 0-Na+ "^ OH
m-benzenedisulfonic acid resorcinol

(5-17)

In the Dow Chemical Company process, chlorobenzene is converted to

phenol with alkali at high temperatures and pressures.

CI ONa^
300°
+ 2 Na+OH 150 atm.
+ Na+Cl- + H2O (5-18)

chlorobenzene sodium
phenoxide

The phenol is liberated from its sodium salt by treatment with carbon dioxide.

0-Na+ OH

+ CO2 + H2O + Na2+C03= (5-19)

phenol

A newer process uses cumene (isopropylbenzene), available by the

Still

Friedel-Crafts alkylation of benzene with propylene (page 84).Air is blown

into liquid cumene, converting it to a hydroperoxide which on acid catalysis
decomposes to phenol (and the ketone by-product, acetone; see Chapter 8).
 Alcohols and Phenols 101

CH,— C— CH, CH CH; OH

O
II

+ CH3— C— CH3 (5-20)

cumene phenol acetone

hydroperoxide

Phenols, which are also obtained commercially from coal tar by distillation
and extraction with base, have many uses. Phenol itself is used to manu-
facture such materials as aspirin, oil of wintergreen, and plastics of the Bakehte
type. Naphthols are used in the synthesis of many industrial dyes.

Physical Properties

The physical properties of some of the lower members of the alcohol series
are given in Table 5-1. The similarity between the lower members of the
series and water is indicated by their miscibility with water in all proportions.
This is true when the carbon chain is short; that is, when the hydroxyl group
comprises a significant percentage by weight of the alcohol molecule. As the
size of the alkyl group is increased, the molecule gradually becomes more like a
hydrocarbon and less like water. The solubihty in water decreases with increas-
ing chain length.
Phenol is a colorless, crystalhne, low-melting sohd with a medicinal odor, and
is moderately soluble in cold water. It causes burns when in contact with the
skin and must be handled with care. In dilute solutions, it is used as an anti-
septic and disinfectant, as are the cresols (Lysol). Hexylresorcinol is an effec-
tive antiseptic used in mouth washes. The phenol coefficient of antiseptics is a
measure of their effectiveness as bactericidal agents when compared to phenol
as a standard.
OH
HO CH2CH2CH2CH2CH2CHC

hexylresorcinol

TABLE 5-1 Physical Properties of Normal Primary Alcohols

NAME
102 • Alcohols and Phenols

The Hydrogen Bond

boiling points of the alcohols are high for their molecular weights.
The
Ethanol, CH3CH2OH, boils at 78°, whereas its isomer, dimethyl ether,
CH3— O— CH3, with the same molecular weight, is a gas which boils at —24°.
This phenomenon has probably been encountered by the reader previously in
his study of inorganic chemistry. Water, H2O, and hydrogen sulfide, H2S, are
both hydrides of elements in the sixth periodic group. Although the formula
weight of hydrogen sulfide is nearly twice that of water, its boiling point is 160°
below that of water. This is due to association of water molecules in the liquid
state, the molecules being held together by hydrogen bonds. The bonding force

H— O • • • • H— O • • • • H— O • • • •

H H H
is largely electrostatic, the small, partially positive hydrogen having some attrac-
tion for the negative oxygen in a neighboring water molecule. This type of
association is also possible in the alcohol series

H— O • • • •
H— O • •
.
•

\ \
R R
but is not possible for molecules with the ether structure, where no suitable
hydrogen atoms are available for hydrogen bonding.

R—
\
R
This accounts for the large difference in the boiling points of the isomers ethyl
alcohol and dimethyl ether, and also explains why the lower alcohols are soluble
in water.
The infrared spectra of alcohols provide direct evidence for hydrogen bond-
ing. In very dilute solution in an inert solvent (carbon tetrachloride) alcohols
show a sharp band at a frequency of about 3,640 cm.~i (see Figure 1-5 for the
infrared spectrum of allyl alcohol in carbon tetrachloride solution). This is due
to the O— H stretching in single, unassociated alcohol molecules. But as the
concentration of alcohol increases, the possibiUty for hydrogen bonding in-
creases and alcohol molecules form dimers and new, broad band trimers. A
appears at lower frequencies (about 3,325 cm.~i; a less "tight" bond) due to
hydrogen-bonded hydroxyl groups. Ultimately, in pure alcohol, the "free"
OH band disappears altogether, and only the broad band due to hydrogen-
bonded hydroxyl remains.
Hydrogen bonds are exceedingly important in connection with the structures
of proteins and nucleic acids, as we shall see later.
 Alcohols and Phenols 103

Figure 5-5. Scale models showing association

through hydrogen bonding in water (HOH) and
alcohols (ROH) which is not possible in ethers
(ROR).

Reactions

Acidity

Although the presence of a hydroxyl group might suggest basicity, the alco-
holsand phenols are in fact weak acids. Alcohols are considerably weaker acids
than water; it is not possible, therefore, to form the sodium salt of an alcohol by
treatment with aqueous alkah.

ROH + Na+OH- > no reaction (5-21)

In other words, the hydroxide ion OH~ is too weak a base to take a proton away
from the more strongly basic alkoxide ion OR~. The sodium salt of an alcohol
can be obtained, however, by the action of metalhc sodium on the alcohol. This
is analogous to the formation of the sodium salt of water (sodium hydroxide) by

the same procedure.

2H— OH + 2Na 2 Na+OH- + Hst (5-22)

sodium hydroxide

2 R— OH -h 2 Na > 2 Na+OR" + Hat (5-23)

sodium alkoxide

For methanol, the reaction is

2 CH3OH + 2 Na -> 2 Na+OCHs" + H2T (5-24)

sodium methoxide

In alcohohc solution, the alkoxides are strong bases (analogous to sodium

hydroxide in water). Potassium, magnesium, and other active metals react
with alcohols in a similar manner to form the corresponding metal alkoxides
and liberating hydrogen. Alkoxides are useful as basic catalysts for organic
reactions (for example, dehydrohalogenation of alkyl hahdes to alkenes, p. 59).
When the hydroxyl group is attached directly to the aromatic ring, the result-
ant compound, although only a weak acid, is far more acidic than either water
104 • Alcohols and Phenols

or the alcohols. The sodium salts of phenols may be formed by the action of
aqueous alkaU.

\
/ VOH + Na+OH- > / Vo-Na+ + H2O (5-25)

sodium phenoxide

Phenols can therefore be extracted from organic mixtures by aqueous base.

The free phenol can then be obtained by acidifying the basic extract (see equa-
tion (5-15)).
The acidic nature of phenol is reflected in its common name, carbolic acid.
The phenolate ion is stabihzed by resonance, as shown. Since this allows dis-

tribution of the negative charge over several atoms, the anion is more stabilized
by resonance than is the parent phenol molecule (note: resonance structures for
the phenol molecule require charge separation rather than redistribution). The
result is that phenols are very much more acidic than alcohols, where resonance
stabilization of the alkoxide ionis not possible. The acidity of phenols can be
enhanced by the introduction of electron-attracting groups on the ring in the
ortho and para positions. Picric acid, 2,4,6-trinitrophenol, is a very strong acid,*
whose ammonium salt is a high explosive employed m the warhead of naval shells.

O2N

NO2
picric acid

Replacement of the Hydroxyl Group

The hydroxyl group of alcohols can be replaced by several different groups.
With hydrogen halides, for example, alcohols give alkyl halides.

H+Cl- + CH3CH2OH -^^^

heat
CH3CH2CI H- H2O (5-26)
ethyl alcohol ethyl chloride

*The approximate ionization constants are for ethanol, IO-20; water, lO""; phenol, IQ-i"; and
picric acid (2,4,6-trinitrophenol), 10~i.
 Alcohols and Phenols 105
This equation can be generalized to

H+X- + ROH ^ RX + H2O (5-27)

This reaction proceeds under increasingly mild conditions as one goes from
primary to secondary to tertiary alcohols. Tertiary butyl alcohol reacts with
concentrated hydrochloric acid at room temperature in a few minutes to form
tertiary butyl chloride, whereas normal butyl alcohol requires zinc chloride as a
catalyst and heat for several hours. The nature of the halide is also important,
hydrogen iodide reacting the fastest, hydrogen chloride the slowest, and hydro-
gen bromide is intermediate.
Other reagents which bring about the replacement of hydroxyl by halogen
are indicated in the following equations:

3 ROH + PCI3 -> 3 RCl + H3PO3

phosphorus phosphorous ocid
trichloride

CH3CH2CH2CI H3PO3 (5-28)

3CH3CH2CH2OH + PCI3 3 4-

6 CH3CHCH3 + 2 P + 3 I2 6 CH3CHCH3 + 2 H3PO3

OH I

ROH + SOCI2 ^ RCl + S02t + HClt

thionyl chloride

CH— CH3 + SOCI2 CH— CH3 + S02t + HClt '

(5-29)

OH CI
1 -phenylethanol 1 -phenyl-1 -chloroethane

Unhke the reaction with hydrogen halides, which is reversible, these reactions

proceed to completion in the direction shown.

The preparation of alkyl halides from alcohols is an important reaction which
usually gives pure products. Contrast this with the mixtures of alkyl hahdes
which are obtained by the direct halogenation of saturated hydrocarbons (see
page 27). The alkyl halides are important intermediates in the synthesis of
many organic compounds. (See Chapter 7.)

Inorganic Esters

Alcohols react with common inorganic acids to replace one or more of the
hydrogens by alkyl groups. The products are known as esters. For example,

ROH + HONO2 > RONO2 + H2O (5-30)

nitric acid alkyl nitrate

nitrates may be prepared from alcohols and nitric acid. This reaction is par-
ticularly important with the polyhydric alcohol, glycerol.
1 06 'A Icohols and Phenols
CH2OH CH2ONO2
CHOH + 3 HONO2 "^'^"^
> CHONO2 +3H2O (5-31)

CH2OH CH2ONO2
glycerol glyceryl trinitrate
(nitroglycerine)

Glyceryl trinitrate is the principal explosive ingredient in dynamite. It is also

used as a vasodilator to reduce arterial tension in heart disease.
When sulfuric acid reacts in the cold with alcohols (particularly primary), the
products are alkyl hydrogen sulfates.

ROH + HOSO3H > ROSO3H -f- H2O (5-32)

sulfuric acid alkyl hydrogen
sulfate

When R has many carbon atoms (about twelve) the sodium salts of the alkyl
hydrogen sulfates are excellent detergents. One such is commercially known as
Dreft.

CH3CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH20S03-Na+
sodium lauryl sulfate (Dreft)

Alkyl hydrogen sulfates are intermediates in the synthesis of ethers from alco-
hols (p. 1 14).
Phosphate esters are particularly important in many biochemical processes.
They are synthesized in the cell by enzymatic processes. All three types of esters
are known, as well as esters of di- and tri-phosphoric acids. Phosphates are
important in many enzymatic reactions and in the structure of nucleic acids.

— 0— p—II
 Alcohols and Phenols • 107
O O
ROH + R— C— OH -^ R'— C— OR + H2O (5-33)
alcohol carboxylic ester
acid

Reactions of the Aromatic Ring in Phenols

The hydroxyl group on an aromatic ring is ortho-para -directing and ring-

activating in electrophiUc substitutions. This is because the unshared electron
pair on oxygen can stabihze a positive charge adjacent to it.

intermediate in electrophilic substitution

para to a phenolic hydroxyl group

Phenol can be nitrated with dilute aqueous nitric acid.

A^^OH + HONO2 > O2N-Y VOH + H2O (5-34)

p-nitrophenol

It can also be brominated rapidly with bromine water.

OH OH

+ 3 Br2 -^^ T T +3 HBr (5-35)

2,4,6-tribromophenol

But typical phenolic properties are destroyed when the aromatic ring is hydro-
genated.
OH

+ 3 H. ^. ™^
M?"^ (5-36)
""' CH2 ^CHj
CH2
cyclohexanol

Cyclohexanol behaves like a secondary ahphatic alcohol, not a phenol.

Sulfur Analogs of Alcohols and Phenols

Sulfur is in the same group as oxygen in the periodic table, and forms sunilar
compounds. The sulfur analogs of alcohols are called thiols or mercaptans.
The —
SH group is known as the sulfhydryl group. Perhaps the most distin-
108 • Alcohols and Phenols

guishing feature of thiols is their disagreeable odor; «-butyl mercaptan

(CH3CH2CH2CH2SH; 1-butanethiol) is the compound responsible for the odor
of the skunk's defense mechanism. Mercaptans are more acidic than alcohols
and form insoluble salts with heavy metal ions, such as mercury (hence the
origin of their name; to capture mercury).

RSH + Hg++ ^ (RS)2Hg + 2 H+ (5-37)

mercaptan mercaptide

Mercaptans are readily oxidized to disulfides.

2 R— SH + H2O2 > RS— SR + 2 H2O (5-38)

mercaptan disulfide

These reactions are important in protein chemistry, since the amino acid
methionine (page 296) contains a sulfhydryl group.

A Helpful Hint

Although only a few specific examples have been cited for each reaction in this
chapter, it should be recalled that these reactions are due to the hydroxyl group,

and that, in general, most organic compounds that contain the alcohol or phenol
function will behave in a similar fashion chemically. The student should learn
these reactions whenever possible in terms of the general formulas R OH and —
—
Ar OH and apply them to specific cases by substituting the appropriate group
for R —
or Ar —
in the compounds.

NEW CONCEPTS. FACTS. AND TERMS

1. Alcohols, phenols; primary, secondaiy, and tertiary alcohols.
2. Nomenclature, pages 92-94. The I.U.P.A.C. ending for alcohols is -oL The four
butyl groups (normal, secondary, iso, and tertiary). Common names for phenols
(cresol, resorcinol, naphthol).
3. Preparation of alcohols
a. Hydrolysis of alkyl halides (with aqueous alkaU); Sn2 and SnI reactions
b. Hydration of olefins (via alkyl hydrogen sulfates)
c. Hydroboration
d. Special industrial methods
/. High pressure (CO + H2); methyl, ^-propyl, and isobutyl alcohols
//. Fermentation; ethyl, n-butyl alcohols
///. From olefins; ethyl, isopropyl, secondary, and tertiary butyl alcohols
e. Polyhydric alcohols (ethylene glycol, glycerol)
4. Preparation of phenols
a. From sulfonic acids and alkali; nucleophihc aromatic substitution
b. Dow process
c. From cumene hydroperoxide
5. Physical properties — hydrogen bonding; association.
6. Reactions of alcohols and phenols
a. Acidity; displacement of hydrogen by active metals; resonance of phenolate ions
b. Replacement of the hydroxyl group by halogen (HX, PX3, SOCI2)
 Alcohols and Phenols • 109
c. Inorganic esters (nitrates, sulfates, phosphates)
d. Organic esters
e. Reactions of the aromatic ring in phenols
/. Nitration
a. Bromination
///. Hydrogenation
7. Sulfur analogs — mercaptans (thiols).

EXERCISES AND PROBLEMS

1. /Write structural formulas for the following compounds:
^ a. 2.3-dimethyl-3-pentanol /. p-bromobenzyl alcohol ^ ^ r
^-^
b. o-chlorophenol g. 2-butene-l-ol
"^c. 2,3-butanediol h. potassium phenoxide
d. 3.3-diphenyl-l-propanol /. 2-methylcyclohexanol ;
j ^j
-^, e. isopropyl hydrogen sulfate j. 3-bromo-2-methyl-2-pentanol
2. Name each of the following compounds

a. CH3CH(OH)CH(CH3)^-^r^^^
^(/^^'^^
^'
b. CH2— CHOH
^
CH2— CH2
^ (CH3)2CHCHBrCH20H
d. OH '^-^Uervt^^ ^ '^'' "
"^,^CH2CH20H

Br h. CH2=CH— CH2OH
e. (CH3)3CCH(OH)CH3 ^^^^ /^ ^OH

j. CH2(OH)CH(OH)CH2Br
3. Explain why each of the following names is unsatisfactory and give a correct name.
a. isopropanol e. phenyl alcohol
b. 2,2-diethyl-3-pentanol /. 5-methyl-l-cyclohexanol
c. 3-ethyl-2-butanol g. 1,1 -dime thyl-1-ethanol

d. 2-bromo-3-butanol h. 4,6-dinitrophenol
4. Write equations, showing necessary catalysts and conditions, for the preparation of each
of the following:
a. methyl alcohol from carbon /. allyl alcohol from propene
monoxide g. glycerolfrom propene
b. ethyl alcohol from ethylene h. ethylene bromohydrin from
c. benzyl alcohol from toluene ethylene
d. isopropyl alcohol from isopropyl /. a-naphthol from naphthalene
iodide j. 2,4,6-tribromophenol from
e. ethylene glycol from ethylene phenol
5. Write structural formulas which show clearly the distinction between:
a. alkyl sulfonic acids and alkyl hydrogen sulfates

b. nitro compounds and nitrates

/no • Alcohols and Phenols

6. Arrange the compounds in each of the following groups in order of increasing solubihty
in water, and explain briefly the principles on which your answer is based.
a. C5H11OH; CH3OH; C4H9Br
b. «-hexyl alcohol; 1,2-hexanediol; CH20H(CHOH)4CH20H
c. phenol; benzene; sodium phenoxide
7. Arrange methanol, water, and dimethyl ether, first in order of increasing boiling points
and then in order of increasing formula weight. Explain why these series might have
been expected to parallel one another and why, in fact, they do not.
8. Show by means of equations the reactions which occur when the following reagents
react with (1) water and (2) an alcohol, ROH.
a. potassium c. thionyl chloride
,
^ b. phosphorus tribromide
( 9. Illustrate, with equations, how ethyl alcohol and phenol diff'er or behave similarly to-
ward the following reagents:
a? potassium \^. phosphorus tribromide
C
b.sodium hydroxide e. thionyl chloride

c. hydrogen bromide

10. When treated with an excess of sodium, 4.6 g. of an unknown alcohol liberated 1,120 ml.
of hydrogen, measured at standard conditions. Calculate the molecular weight of the
alcohol.
11. Indicate how the following mixtures of compounds could best be separated, by means
other than fractional distillation.
a. rt-hexane and methanol c. phenol and cyclohexanol
b. /7-nitrophenol and benzene d. /j-cresol and benzyl alcohol
12. How many liters of propylene (at standard conditions) would be required to form 1 80 g.
of isopropyl alcohol by reactions similar to those shown on page 96 (equations (5-5)
and (5-6))?
13. How many tons of propylene would be needed to produce 9.2 tons of glycerol by the
reactions shown on page 98, if the over-all efficiency of the process is only 70%?
14. Give equations to show the several steps necessary in each of the following conversions:
a. /j-propyl alcohol to isopropyl bromide /. ethyl alcohol to butane
b. benzene to cyclohexanol g. toluene to benzyl alcohol
c. 1-butanol to 1,2-dichlorobutane h. 1-butanol to 2-butanol
d. /7-cresol to 4-methylcyclohexene /. 1-hexanol to hexane
e. 1-hexanol to 1-hexyne j. I-propanol to allyl alcohol
15. Describe a simple chemical test (reagent, equation, and readily detectable change)
which will distinguish:
a. ^-pentane from «-butyl alcohol
b. phenol from cyclohexanol
c. ethanol from 1-hexene
d. «-butyl alcohol from /-butyl alcohol
e. isopropyl alcohol from 1-hexyne
/. aUyl alcohol from «-propyl alcohol
16. A pure hquid. A, reacts with metaUic sodium to evolve hydrogen. It reacts with con-
centrated hydrochloric acid to yield an alkyl halide which, on treatment with alcohoUc
potassium hydroxide, gives only 1-pentene. What is the formula for A? Write equa-
tions for the reactions described.
17. A crystalline solid CeHsClO reacts with sodium to liberate hydrogen. It is insoluble in
water but soluble in dilute aqueous sodium hydroxide. Treatment of CeHsClO with
 Alcohols and Phenols • 111

bromine yields only one monobrominated compound, C6H4BrC10. Give a structural

formula for the original compound and write equations for each reaction.
18. a. Which of the pentanols, when dehydrated, will yield only 2-pentene?
b. Which alcohols containing six carbon atoms give only a single alkene on dehy-
dration?
19. A colorless sohd aromatic compound, A, is insoluble in water but soluble in dilute
aqueous alkali. Onmonobromination, it yields only a single product, B. When
catalytically reduced, A adds three moles of hydrogen to yield C which is insoluble in
dilute alkali but reacts with sodium to liberate hydrogen. Dehydration of C yields only
one cyclic olefin, D, which on catalytic hydrogenation yields methylcyclohexane. Draw
structural formulas for compounds A, B, C, and D, and give equations for all reactions
described.
20. l-Bromo-2,2-dimethylpropane (neopentyl bromide) reacts very slowly in Sn2 reactions.
Draw a model of the transition state which explains this fact.
21 Mercaptans generally have considerably lower boiUng points than their corresponding
alcohols. Suggest an explanation for this fact.
 ArOR

To the layman, the word ether is usually synonymous

with the well-known anesthetic. To the organic chemist,
however, ethers are a general class of compounds whose
characteristic arrangement involves an oxygen atom to
which two organic groups are attached. When the two
groups are ethyl, the substance is the common anesthetic.
But other organic groups impart different properties so
diverse that the materials can be used as artificial flavors,
solvents, and refrigerants. Ethers are relatively inert toward
most chemical reagents. This makes it possible to usethem
as solvents in organic chemical reactions.

Ethers

We have seen that alcohols can be considered as derivatives of water in which

one of the hydrogen atoms is replaced by an alkyl group. Although unrelated
chemically to water, ethers are structurally related to it with both hydrogens
replaced by organic groups. Ethers are isomers of alcohols with the same num-
ber of carbon atoms.
Ethers may be either ahphatic, aromatic, or mixed. The organic groups of an
ether may be identical, as in simple ethers, or different, as in mixed ethers. As a
rule, common names are used for the ethers. The I.U.P.A.C. names are given
in parentheses below to illustrate the system.

CH3OCH2CH3 CH3CH2OCH2CH3 / VOCH3

methyl ethyl ether diethyl ether or anisole
(methoxyethane), simply ethyl ether methyl phenyl ether
a mixed ether (ethoxyethane), (methoxybenzene),
a simple ether a mixed ether

In naming a simple ether, the prefix di- is not essential, but it is often used.

172
 Ethers • 113

H— O—
water

R— O—
alcohol

R— O—
ether

Figure 6-1. Models showing the structural rela-

tionship between water, alcohols, and ethers.

Preparation

Ethers are generally prepared from alcohols bv one of the following methods.

Dehydration of Alcohols

When an alcohol is dehydrated, water may spht out either intramolecularh"

(that is. within the molecule itself) to yield an olefin, as shown in the following
equation.

H H H H
H— C— C— OH - -. H— C=C— H + HoO (6-1)

TT TT ethylene

or intermolecularly (between two molecules) to form an ether.

H H H H H H H H
H— C— C- h" o— c— c- H— C— C— O— C— C— H
j I

-OH -H + H2O
H H H H H H H H (6-2)
ethyl ether

TTie course of the reaction depends upon the conditions, and these may be con-
trolled to prepare either the olefin or the ether.
In practice, sulfuric acid is frequently used as the dehydrating agent. In the
manufacture of ethyl ether, the common anesthetic ethanol is dissohed in sul-

form the intermediate ethylsulfuric acid.

furic acid to

CH3CH2OH -r HOSO3H CH3CH2OSO3H + H2O (6-3)

ethylsulfuric acid
(ethyl hydrogen sulfate)
114 • Ethers

This solution is then heated to about 140°, and more alcohol is added, where-
upon the ether distils.

CH3CH2OSO3H + HOCH2CH3 -i^ CH3CH2OCH2CH3 + HOSO3H

(6-4)

At this temperature, the main product of the reaction is ether, whereas higher
temperatures give increasing quantities of ethylene. Note that dehydration of
an alcohol yields a simple ether.
A mixture of two alcohols, when dehydrated, may give three ethers, the two
simple ethers from each of the alcohols and the mixed ether containing one
alkyl group from each alcohol.

f
ROR 1

'^'y'"""g>
ROH + R'OH agent
ROR' + H2O (6-5)

( R'OR' J

a mixture of
three ethers

The need for a method whereby a mixed ether might be prepared in its pure
form is obvious.

Williamson Synthesis

In 1851, the British chemist Alexander William Williamson devised a general

method for the synthesis of pure ethers. The reactants are the sodium salt of an
alcohol or phenol and an alkyl halide.

RO-Na+ + R'X > ROR' + Na+X- (6-6)

The R
and R' groups may be identical or different, producing simple or mixed
Both reactants can be prepared from alcohols. One se-
ethers, respectively.
quence for making methyl «-propyl ether is:

2 CH3OH + 2 Na > 2 CH30-Na+ + H2 (6-7a)

CH3CH2CH2OH + HBr > CH3CH2CH2Br + H2O {6-lb)

CH30-Na+ + CH3CH2CH2Br > CH3OCH2CH2CH3 + Na+Br" (6-7c)

sodium n-propyl methyl n-propyl
methoxide bromide ether

In equation (6-6), R' may not be an aromatic ring, unless strongly electron-
withdrawing substituents are ortho or para to the halogen; neither may R' be a
tertiary alkyl group, because elimination to form an alkene will take place in-
stead of displacement of the halogen. But within these hmitations (which can
often be circumvented, by making the offending group R rather than R') the
WiUiamson synthesis is very general. Alkyl sulfates may replace alkyl hahdes,
especially for preparing methyl or ethyl ethers of phenols:
 Ethers • 115

/^^OH + (CH3)2S04 ^^^^^ /^^-OCHs + CH30S03-Na+ (6-8)

phenol methyl sulfate anisole

Properties

Dimethyl and methyl ethyl ether are gases, whereas ethyl ether and higher
homologs in the aliphatic series are liquids. Aromatic ethers are liquids or
sohds. Ethers are only slightly soluble in water. Ordinary (ethyl) ether is an
unusually good solvent for many organic compounds, and is frequently used to
extract desirable organic products from plants or other sources. It dissolves the
organic matter, but leaves salts and other inorganic substances behind. Ether
is only slightly soluble in water, and separates from it as an upper layer. Its low

boihng point (35°) makes it easy to remove from an extract, and easy to recover.
Ethyl ether is particularly flammable, however, and one must exercise caution
in handling it. It is also easily oxidized by air to a nonvolatile, explosive perox-
ide; distillations of ether extracts must not be carried to dryness with excessive
heating.
The most notable chemical property of ethers is their lack of reactivity. The
ether linkage is particularly stable to dilute acids or alkalies, and to many oxidiz-
ing and reducing agents. Sodium does not react with ethers, a property that
distinguishes them from their isomers, the alcohols. In general, ethers resemble
saturated hydrocarbons in their inert chemical behavior. Ethers are, however,
soluble in concentrated sulfuric acid, a property that may be used to distinguish
them from saturated hydrocarbons.
Concentrated mineral acids, when heated with ethers, cleave them according
to the following equation:

CH3OCH2CH2CH3 + HI > CH3I + CH3CH2CH2OH (6-9)

methyl n-propyl ether methyl n-propyl alcohol

iodide

or, with an excess of hydriodic acid:

CH3OCH2CH2CH3 -h 2HI -^^^ CH3I + CH3CH2CH2I -hH20 (6-10)

The reaction involves protonation of the ether by strong acid, followed either by
an Sn2 displacement by iodide ion or, if R is tertiary, an SnI ionization of the
protonated ether followed by reaction with iodide ion.

H
R— O— R' + H R— O— R' Sn2
RI + R'OH
(R is primary
SnI or secondary) (O-l 1)
(R is tertiary)

RI ^-^ R+ + R'OH
116 • Ethers

Aromatic ethers readily yield phenols by the same type of reaction:

/ V-OCHgCHs + HBr > / V-OH + CHsCHaBr (6-12)

phenetole phenol

Aromatic ethers undergo normal substitution in the benzene ring, the alkoxyl

—
group (RO ), like the hydroxyl, being ortho-para-directing.

OCH3 OCH3 OCH

+ Br2 -^ II I +11 I
+ HBrt (6-13)

anisole ortho- and para-bromoanisole

Some Important Ethers

Dimethyl ether is manufactured industrially for use as a refrigerant. It may

also be used as an anesthetic, but its effect is very short-lived. The most im-
portant ether is diethyl ether, the common anesthetic. Like other anesthetics,
ether is toxic in high concentrations, but the spread between the concentration
necessary to produce anesthesia and its lethal action is sufficient to permit safe
usage. Diphenyl ether

diphenyl ether

isobtained in large quantities as a by-product in the commercial production of

phenol by the Dow process (see page 100). It has a high boihng point (259°)
and is a rather inert liquid which is used extensively as a medium for the transfer
of heat.
Certain important, naturally occurring aromatic compounds contain the ether
linkage, as, for example, eugenol (oil of cloves) and anethole (oil of anise).

CH2=CH— CH2^ ^OH CH3— CH=CH^ VOCHs

eugenol anethole
 Ethers • 117

Sulfur Analogs of Ethers

Thioethers, or sulfides, can be prepared from mercaptans by a method

analogous to the Williamson synthesis.

RS-Na+ + R'X > RSR' + Na+X- (6-14)

a sodium thioether
mercaptide (sulfide)

CH3S-Na+ + CHgCHsBr > CH3SCH2CH3 + Na+Br"

methyl ethyl sulfide

Sulfides react further with alkyl hahdes to form crystalline sulfonium salts
(sulfur analogs of ammonium salts)

^
R— S— R + CH3I R— S— I- (6-15)

CH3
sulfonium salt

Sulfides may be oxidized to sulfoxides or sulfones.

R— S— R -^^^^ Pv— S+— R "^°^

> R— S++— R (6-16)

•9--

sulfide sulfoxide sulfone

Dimethyl sulfoxide (b.p. 189°) has remarkable solvent properties (miscible with
water, a solvent for certain polymers) and is said to reheve arthritic pain on
topical application.
(CH2^CHCH2)2S, is the chief constituent of oil of garlic, and is
Allyl sulfide,
present in onions. During World War I, a dichlorinated thioether was used as a
poisonous war gas, known as mustard gas. It can be synthesized from ethylene
and sulfur monochloride.

2 CH2=CH2 + S2CI2 > CICH2CH2— S— CH2CH2CI -F S (6-17)

2,2'-dichlorodiethyl sulfide
(mustard gas)

Ethylene Oxide

Ethylene oxide, a cyclic ether with but two carbons and an oxygen in a three-
membered ring, was first synthesized by Wurtz m
1859. Since 1930 it has been
an important commercial chemical, being second in production only to ethanol,
as a derivative of ethylene. About 30% of ethylene production goes into its
manufacture. Two commercial processes are used, the most important involv-
ing direct oxidation of ethylene with air:
118 • Ethers

CH2 finely divided

CH2
silver catalyst
+ O2 (6-18)
350^. pressure
(from
r~'iJ_^ air)
CH2
ethylene ethylene oxide

Ethylene oxide is also prepared via ethylene chlorohydrin:

CHs CH,-0 H CH,

KOH
+ HO C1+ :0 + K+Cl- + H2O (6-19)

hypochlorous
CHc ch2'l-cI CHs
acid
ethylene
chlorohydrin

Annual United States production capacity for ethylene oxide exceeds 2.2 billion
pounds.
The commercial importance of ethylene oxide rests on its remarkable re-
enabhng its conversion to many useful products. The carbon-oxygen
activity,
bond is broken far more readily than the same link in an ordinary ether. The
reason for this is the strain due to the abnormally small angles necessitated by
the compound's structure. Its cleavage involves opening the ring, thus relieving
the strain. In this respect, ethylene oxide undergoes addition reactions similar
to those of cyclopropane (page 33). One of the C — O bonds breaks and the
positive part of the addend becomes attached to the more electronegative
oxygen atom.
The reactions of ethylene oxide may be summarized by the general equation

I I

CH2^CH2 + H+Z CH2— CH2 (6-20)

OH Z
where Z may be any group that has a reactive hydrogen atom attached to it.

Some of the more important addends are water, alcohols, and ammonia.
The mechanism for the acid-catalyzed addition of water to ethylene oxide to
make ethylene glycol is typical.

O
ethylene oxide

H
H V-H
c—c. (6-21)
OH H OH \
ethylene glycol
 Ethers • 119
More than half the ethylene oxide produced goes into the manufacture of
ethylene glycol which is consumed primarily as permanent antifreeze, but is also

used in the manufacture of fibers and films, and, as glycol dinitrate, in low-
freezing dynamite. Some glycol may react with additional ethylene oxide to
produce diethylene glycol and higher polymers:

CH2— CH2 + CH2— CH2 -^ CH2— CH2— O— CH2— CH2 (6-22)

O OH OH OH OH
diethylene glycol

Over 50 milhon pounds of diethylene glycol are produced annually; it is used as a

used to bind cork granules in gaskets and tile, as a solvent
plasticizer in the resin
for dyes, and as a selective solvent in petroleum refining.
Alcohols yield products which have both the ether and the alcohol linkages
and are known as cellosolves:

I
-^
I

CH2— CH2 + H— OCH3 CH2— CH2 (6-23)

0< 1

OH OCH3
methyl cellosolve

The cellosolves are widely used as solvents in varnishes and lacquers. They are
good solvents for organic substances (due to the ether linkage) and are also
soluble in water (due to the hydroxyl group). Butyl cellosolve (from «-butyl
alcohol) is used in brake fluids and as an intermediate for low-volatihty weed
killers.

When ammonia reacts with ethylene oxide, a water-soluble organic base called
ethanolamine is formed. It is used to absorb acid gases from refineries, and,
in dry-ice manufacture, for the recovery and concentration of carbon dioxide.

^ +NH3
CH2— CH2 + NHs > CH2— CH2 ^=± CH2— CH2 (6-24)

O"^ O- OH NH2
ethanolamine

Triethanolamine an intermediate for mild soaps used in formulating sham-

is

poos, textile cleaners, cosmetics, and rubless floor polishes. It is also a corrosion
inhibitor in engine coolants and lubricating oils.

CH2CH2OH
3 CH2— CH2 -f- NH3 > N— CH2CH2OH (6-25)

O CH2CH2OH
triethanolamine
1 20 • Ethers

Olefins other than ethylene can also be converted to oxides, known as

epoxides (or oxiranes).

R— CH=CH— R' -^ R— CH— CH— R'

V
an epoxide
(6-26)

Epoxides react analogously to ethylene oxide and are finding increasing com-
mercial utility. The sulfur analogs (thiiranes) can also be prepared.
The inertness of ordinary ethers and the high reactivity of epoxides illustrate
how important structural influences (in this case, ring strain) can be on the
chemical behavior of a single functional group.

NEW CONCEPTS. FACTS. AND TERMS

1. Structure of ethers — relation to water and alcohols.
2. Nomenclature (page 112), simple and mixed ethers.
3. Methods of preparation
a. Dehydration of alcohols

b. Williamson synthesis (sodium salt of an alcohol or phenol with an alkyl halide)

4. Properties
a. Inert to dilute acids and alkaUes, many oxidizing and reducing agents, and sodium
b. May be cleaved at the —
C O hnk by hot concentrated mineral acids
c. — OR group is ortho-para-directing
5. Some important ethers
a. Diethyl (anesthetic, solvent)
b. Dimethyl (refrigerant)
c. Diphenyl (heat transfer)
6. Sulfur analogs of alcohols and ethers; sulfides, sulfonium salts, sulfoxides, sulfones.
7. Ethylene oxide — a cychc ether, highly reactive due to ring strain
a. Preparation from ethylene
/. By air oxidation
//. Through the chlorohydrin
h. Reaction by addition of water, alcohols, and ammonia

EXERCISES AND PROBLEMS

Write structural formulas for each of the following:
a. ethyl ether /. ethanolamine
b. isopropyl ether g. diethylene glycol
c. «-butyl ether h. ethyl cellosolve
d. m-nitroanisole /. «-butyl mercaptan
e. phenyl ethyl ether j. 2,2'-dibromodiethyl ether
 Ethers • 121

Name each of the following:

a. CH3CH2CH2OCH2CH2CH3 e.CH3(CH2)30CH2CH20H
b. CH3CH2OCH2CH2CH3 / C6H5OC6H5
^v^^O— CH(CH3)2 g. CH3CH2SCH2CH3

BrCH20CH2Br
CH2OHCH2OH
CHaQH— CHz ^.^v^OCHs
V JkJ
3. Ethyl /7-propyl ether may be prepared by heating a mixture of ethyl and /7-propyl
alcohols with sulfuric acid. What other ethers might be simultaneously produced?
by writing equations.
Illustrate

4. Give equations for two different combinations of reagents for preparing the following
ethers by the Williamson method:
a. methyl ethyl ether b. ethyl isopropyl ether
5. Write equations for the following conversions (some may involve more than one step):

a. «-propyl alcohol > «-propyl ether

b. «-butyl ether > /7-butyl iodide

c. phenol and ethylene * phenyl ethyl ether

d. isopropyl ether > propene
e. benzene and methyl alcohol > anisole
/. ethyl ether > «-butane
g. ethylene > ethyl cellosolve
h. /7-cresol and methyl alcohol > /;-methylanisole
6. Starting with ethylene oxide, give equations for synthesizing the following compounds:
a. CH20HCH2Br d. HOCH2CH2OCH2CH2OH
b. CH2OHCH2OH e. N(CH2CH20H)3
C. CH2NH2CH2OH /. CH3CH2OCH2CH2OH
7. What chemical method could be used to distinguish the compounds in each pair?
a. CH3CH2OH and CH3OCH3
OH CH2OH

^^^
b.
X \

CHaO^^^ CH3O'
c. CH30(CH2)20H and CH30CH(CH3)2
d CH2=CHCH20CH3 and CH3CH2OCH3
8. Diphenyl ether is a by-product in the Dow synthesis of phenol. Write equations that
can account for its formation in this process.

9. Write structural formulas and names for all the alcohols isomeric with the following
ethers:
a. methyl ether b. ethyl ether c. methyl ethyl ether
10. An unknown ether, when heated with excess hydrogen bromide, gives only one alkyl
halide containing 65.0% of bromine. Write a structural formula for an ether that could
yield this result (Br = 80, C = 12, H= 1).

11. Write equations for the reactions of CH2=CHCH(OCH3)CH20H with the following
reagents:
a. dilute KMn04 c. aqueous sodium hydroxide e. bromine
b. potassium d. excess HBr and heat
If no reaction would be expected, indicate this.
1 22 • Ethers

12. An organic compound with the molecular formula C4H10O3 shows the properties of
both an alcohol and an ether. When treated with an excess of hydrogen bromide, it

yields only one organic compound, ethylene dibromide. Draw a structural formula for
the original compound.
13. An aromatic ether A, on catalytic hydrogenation, added three moles of hydrogen per
mole to yield B which was also an ether. Bromination of A gave a single monobromo
derivative C. With excess hydrogen iodide and heating, B yielded two organic prod-
ucts, methyl iodide and l-iodo-4-methylcyclohexane. Draw structural formulas for
A, B, and C
and write equations for each reaction.
14. Equation (6-7c), the main reaction in the Williamson synthesis, is an example of what
general class of reactions? Draw a model for the transition state.
15. Treating a mixture of methyl and r-butyl alcohols with sulfuric acid gives a high yield
of methyl /-butyl ether (rather than dimethyl or di-/-butyl ether). Write a mechanism
which explains this fact.

16. In the synthesis of ethyl phenyl ether by the WiUiamson synthesis only one possible
combination of reagents can be used. What are these reagents? Explain your answer.
17. Suggest a mechanism for the formation of ethylene oxide from ethylene chlorohydrin
and strong base (equation (6-19)). (Hint: the reaction is an intramolecular Sn2 dis-
placement, or intramolecular WilUamson reaction.)
 The classes of compounds discussed thus far have their
origins in natural sources. Compounds containing only
carbon, hydrogen, and a halogen, however, are entirely man-
made. Those with only a single halogen atom are the work-
horses of synthetic organic chemistry, being rather reactive
chemicals from which many useful compounds may be
derived. Organic molecules with more than one halogen
atom are frequently of use in their own right. Chloroform,
carbon tetrachloride, and DDT are a few examples of a class
of compounds which offers such diverse materials as dry-
cleaning agents, anesthetics, insecticides, fire extinguishers,
disinfectants, and refrigerants.

Organic Halogen Compounds

some of the chemistry of aUphatic and aromatic hahdes

In previous chapters,
has been discussed.Here we shall correlate and extend this material, beginning
with compounds in which a single halogen is the principal functional atom.

Preparation

Direct Halogenation

The direct halogenation of hydrocarbons generally leads to mixtures of alkyl

hahdes when apphed to aliphatic hydrocarbons (page 27), although in some
cases a single isomer predominates and is easily separated from polyhalogenated
products by distillation, as in the vapor phase chlorination of cyclopropane.
ultraviolet
CH2-CH2 + CI2 » CH2 —;.CHC1 -(- HCl (+ some dichloro compounds)
light

CH2 \h2 (7-1)

123
1 24 • Organic Halogen Compounds

Direct halogenation is most frequently applied, however, in the aromatic series

(see page 79).

Br

+ Br2 -^ [I

J
+ HBr (7-2)

bromobenzene

Naphthalene, under similar conditions, produces predominantly the alpha (a)

halogenated isomer.
CI

+ HCl (7-3)

The betaisomer must be prepared by an indirect method.

()8)

Mixtures may
be obtained even with aromatics, as in the ortho and para
chlorination of toluene (page 79), but they are usually amenable to separation
without difficulty. Thus o- and /7-chlorotoluenes, freezing at —34° and -1-7.5°,

respectively, can be separated by fractional crystalUzation.

Side-chain halogenation (page 79) usually places a substituent on the carbon
adjacent to the aromatic ring. This is because the intermediate free radical can
be stabiUzed by resonance when the odd electron is adjacent to the aromatic
ring, but not when it is further out on the side chain.

CH3— CH— CH3 CH3— C— CH3

+ Br2 -i^ii^i^ (Tj + HBr (7-4)

cumene a-bromocumene

From Alcohols
Alcohols may be converted to alkyl halides by the use of such reagents as
hydrogen hahdes, phosphorus trihalides, or thionyl chloride (review pages
104-105). Phenols cannot be converted to aromatic halides in this way,
but alcohols which contain an aromatic ring do undergo the reactions, as, for
example:

21 2 1

CH2CH2OH ^^^CHaCHzCl
+ HCl ^^^ 11 -f- H2O (7-5)

2-phenylethanol 2-phenyl-l -chloroethane

(oil of roses)
 Organic Halogen Compounds • 1 25
Unsaturated alcohols, if sufficiently reactive, may be converted to unsaturated
halides; the water present inhibits addition to the double bond.

CH2=CH— CH2OH '""'•

heat
"^'
CH2=CH— CH2CI (7-6)

allyl alcohol allyl chloride

From Olefins
Alkyl halides may also be prepared by the addition of hydrogen haUdes to
olefins. Addition follows Markownikoff 's Rule (page 50).

12
CH=CH2 ^'-^i^j^^^CH
12
— CH3
-^
+ HCl
IJ <L, (7-7)

styrene 1 -phenyl-1 -chloroethane

(phenylethylene)

From Other Halides

Iodides and fluorides are frequently made from other halides (chlorides or
bromides) by exchange of one halogen atom for another. Organic iodides can
be prepared from organic chlorides and sodium iodide when acetone is used as
the solvent. The equilibrium is shifted to the right because sodium chloride is
considerably less soluble in acetone than is sodium iodide. The reaction is

an Sn2 displacement which proceeds best when R is a primary group.

R— CI + Na+I- c
''"""' >
R— I + Na+Cl-j (7-8)

Alkyl fluorides can be prepared from the corresponding chlorides by treat-

ment with metallic fluorides.

2 R-Cl + HgFs -^^^ 2 R-F + HgCls (7-9)

The introduction of fluorine into an aromatic ring requires special methods

(see page 244).

Displacement Reactions of Alkyl Halides

The versatihty of alkyl hahdes in organic synthesis is due to the ease with
which the halogen may be displaced by a number of other functional groups.
The general reaction involves displacement of the halide ion by some other
negative ion, and usuaUy proceeds by an Sn2 mechanism (see page 95). Some

Z- + R— X ^=± R— Z -h X- (7-10)

of the more common anions capable of displacing the hahde ion are indicated
(with their mostcommon sources in bold type beneath them) in the following
equations:
1 26 • Organic Halogen Compounds

Anion (nucleophile)

OH-
 Organic Halogen Compounds 127
reaction proceeds through an intermediate in which the negative charge on the
aromatic ring can be stabilized by the nitro groups (cf. equation (5-16), page 100).
A variant of this reaction has been particularly useful in determining the se-
quences of amino acids in proteins (see Chapter 15).

The Grignard Reagent

The French organic chemist, Victor Grignard, discovered that,when alkyl or
aryl halides are stirred withmagnesium turnings in anhydrous ethyl ether as
solvent, the metal gradually dissolves. The resulting solution is known as a
Grignard reagent. It is an alkyl or aryl magnesium halide.

R— X + Mg (7-19)
1 28 • Organic Halogen Compounds

Grignard reagents are highly reactive. In practice, no attempt is made to

from its ether solution. Instead, it may be treated, in ether
isolate the reagent
solution, with any of a wide variety of substances to prepare useful organic
products.
If water is added to a Grignard reagent, it is converted to a hydrocarbon.
- + + -
RMgX + H— OH > R— H + Mg++OH-X- (7-22)

CHsCHaCHsMgCl + HOH > CH3CH2CH3 + Mg^+OHCl"

n-propyl magnesium chloride propane basic magnesium
chloride

The strained ring of the cyclic ether, ethylene oxide (page 1 1 7), opens readily
with Grignard reagents to produce alcohols.

RMgX + CH2— CH2 > R— CH2CH2— OMgX (7-23)

RCHsCHsOMgX + HOH > RCH2CH2OH + Mg++OH-X-

Thus the perfume constituent, 2-phenylethanol (oil of roses), can be prepared

from phenyhnagnesium bromide and ethylene oxide.

CH2-CH, ^^^CH2CH20MgBr ^.-^ rH2CH20H

MSB. -^^(j ^(y
2-phenylethanol
(oil of roses)

(7-24)

Note that this is a convenient way of increasing the length of an alkyl chain by
two carbon atoms at a time.

ROH -^ RX -^
etiier
RMgX
^
^^i^>^
oxide

RCH2CH20MgX -^^ RCH2CH2OH (7-25)

The sequence of reactions may be continued more or less indefinitely.

Grignard reagents react with silicon tetrachloride to give a mixture of prod-
ucts containing from one to four organic groups in place of the chlorines. For
example:

2 RMgX + SiCU > R2SiCl2 + 2 Mg++X-Cl- (7-26)

dichlorodialkyi
silone
 Organic Halogen Compounds • 1 29
The products, when hydrolyzed, form silicone polymers, which to a marked
R R
— Si— O— Si— O—
I I

RaSiCls + H2O . + HCl (7-27)

R R
silicone polymer

extent are not wettable and are resistant to rather high temperatures. These
polymers are used in automobile poUshes, waterproof films, high temperature
lubricants, and in many other ways.
Certain other metals behave similarly to magnesium. Among the more useful
in organic synthesis are the alkyl and aryl hthium compounds.

RX + 2 Li > R-Li+ + Li+X- (7-28)

Treatises over 1000 pages long, concerned only with the chemistry of Grignard
reagents, have been written. Several other synthetic applications of Grignard
reagents will be discussed in subsequent chapters.

Miscellaneous Reactions

Other reactions of alkyl and aryl haUdes which have been previously discussed
and which the student should now review are the Wurtz reaction (page 31), its
Wurtz-Fittig modification (page 82). the Friedel-Crafts synthesis (page 82), and
the elimination of HX from ahphatic hahdes to form olefins (page 59).

Polyhalogen Compounds
Many halogen compounds have more than one halogen atom on a given
carbon atom, and several of these are of sufficient industrial significance to
mention here. Carbon tetrachloride, CCI4, is manufactured by chlorination of
carbon disulfide obtained by heating sulfur with coke in an electric furnace.
Both products, CCI4 and S2CI2, are liquids and are separated by fractional

CS2 + 3 CI2 (7-29)

130 Organic Halogen Compounds

Chloroform is sometimes used as an anesthetic, ahhough it is somewhat toxic.

Treatment of chloroform with a strong base results in a rather remarkable reac-
tion in which a hydrogen and halogen are lost from the same carbon atom. The
resulting species, carbon dichloride or dichlorocarbene, is extremely reactive
and cannot be isolated. But if the reaction is carried out in the presence of an
alkene, CCI2 adds to the double bond, producing a three-membered ring.
:

r-butyl
CHCI3 + + K+-Or-Bu alcohol
potassium
cyclohexene f-butoxide

CI
+ K+Cl- + /-BuOH (7-31)
1

Methylene chloride (CH2CI2), prepared technically by the chlorination of

methane, is an excellent, low-boihng, noninflammable solvent. Methylene
iodide (CH2I2) can be obtained by reduction of iodoform (CHI3); it reacts with a
zinc-copper couple and alkenes to produce cyclopropanes. The reaction is

Figure 7-2. Water forms tiny beads without penetrating Quarpel-treated fabric even after seven
days of steady rainfall in an army "rain room." A fluorocarbon is the key ingredient of Quarpel;
the fabric is used to make water-repellent military uniforms. (Courtesy of E. /. DuPont DeNemours &
Company, Inc.)
 Organic Halogen Compounds • 131

general and probably proceeds via iodomethylene zinc iodide (ICH2ZnI), a

reagent analogous to the Grignard reagent.

CH3CH=CHCH3 + CH2l^
Zn-Cu
> CH3CH —-CHCHs + Znl2 (7-32)

CH2

The mixed chlorofluoromethanes are known as Freons. These are colorless

gases which are nontoxic, noninflammable, and noncorrosive. They are used
extensively as industrial and domestic refrigerants, in air conditioning and deep-
freeze units. Freons are produced commercially from carbon tetrachloride and
antimony fluoride.

SbCls
3 ecu + 2 SbFa
catalyst
3 CCI2F2 + 2 SbClj (7-33)
dichlorodifluoromethane
(Freon)

Production of Freons has soared during the last few years, owing to their use as
the inert propellant in aerosol bombs (bombs used for insecticides, hair sprays,
paints, suntan lotions, shave creams, etc.)
Polychloroethylenes can be made from acetylene by the route shown (equa-
tion (7-34)). Several hundred milHon pounds of tri- and tetrachloroethylene are
produced each year for use as dry-cleaning solvents.

HC=CH ^^ CHCI2CHCI2 '^'^""'^

>

1. CI2
CHCl=CCl2 Ca(OH)2
CCl2=CCl2 (7-34)
2.

trichloroethylene tetrachloroethylene

A fluorocarbon polymer. Teflon, is made by polymerization of tetrafluoro-

ethylene, CF2=CF2. It is a chemically inert waxy plastic which finds special
uses where unusual resistance to oxidation and corrosion is necessary. It is an
excellent electrical insulator.
Certain well-known insecticides are polychlorinated organic compounds.
Among these are DDT (<i/chloroJ/phenylrr/chloroethane) and chlordane.

CI CH fX CI

CCI3
DDT
 132 Organic Halogen Compounds

NEW CONCEPTS. FACTS. AND TERMS

ij Preparation of alkyl and aryl halides
a. Direct halogenation (mainly for aryl halides)
b. From alcohols by replacement of the — OH group. (HX, PX3, SOCI2)
c. Addition of HX to alkenes
d. Replacement of one halogen by another (especially for iodides and fluorides)

Displacement reactions of alkyl halides

( 2j
a. OH- — alcohol
OR-
b.

c. CN- — ether
cyanide
NH2- —
d.

t:p^sH- — ^ amine
mercaptan
SR- sulfide
/•
g. RC^C- — > alkyl acetylene
3. Nucleophilic displacements of aromatic haUdes with electron- withdrawing substituents.
4. Grignard reagent (RMgX)
a. Preparation of the reagent (aUcyl or aryl haUde + magnesium in anhydrous ether
as the solvent)
b. With water, gives a saturated hydrocarbon
c. With ethylene oxide, gives an alcohol with two more carbon atoms
d. SiUcones
5. Polyhalogen compounds (carbon tetrachloride, chloroform, methylene halides, Freons,
chloroethylenes, Teflon, DDT, chlordane).

EXERCISES AND PROBLEMS

(fLj Write structural formulas for the following compounds:

\^-~y
'""^ _ _i *„i
^ a. /?-bromotoluene (,/. benzyl chloride
b. 2,2-dichloropropane ^^Tyj-bromochlorobenzene
c. triiodomethane un) dibromodichloromethane
d. 1 -phenyl- 2-bromo-3-chlorobutane / . }3-bromo- 1 -butene
e. /-butyl bromide /r7^\ ethylene bromide
^^r^ame the foflowing compounds:

a.
Br CHsBr

Br CH,
Br
b. (CH3)2CHCH2l
c. CH3CH2CH(Br)CH(CH3)CH2Cl
d.C6H5CH2CH2CH2Br Br" -^'
XI
(^ CH3CH2CBr2CH3 Qr)CH2=CClCH3

..(QCHsCHzMgBr
 Organic Halogen Compounds • 1 33
3. Write equations for the following reactions:
a. 5-butyl iodide with silver hydroxide
b. isopropyl bromide with sodium ethoxide
c. 2-bromobutane with sodium hydrosuMde
d. ^butyl chloride with magnesium in ether
e. ^-propyl iodide with sodium cyanide
/. 1-chloropentane with sodium iodide
g. /-butyl chloride with water
h. «-butyl bromide with sodium
/. ethyl bromide with sodium acetylide
j «-butyl bromide with sodium amide
.

4. Write equations for preparing each of the following:

a. /7-chlorotoluene /. 2,2-dimethyl-l-chloropropane
b. 1-bromo-l-phenylethane g. /»-bromonitrobenzene
c. ^-propyl fluoride h. l-bromo-2-phenylethane
d. 2,2-dichloropropane /. m-chloronitrobenzene
e. /-butyl bromide j l,4-dibromo-2-butene
.

5. Give equations for three methods, each using a different reagent, for preparing
2-bromobutane. What are the advantages and disadvantages of each?
6. A Grignard reagent can be used in the following conversions. Give the equations for
each.
a. 5-butyl chloride to butane
b. ethyl bromide to «-butyl alcohol
c. methyl alcohol to /t-propyl alcohol
d. /7-bromotoluene to toluene

e. bromobenzene to 4-phenyl-l-butanol

^ T.\ Each of the following compounds can be prepared by the method indicated; give the
equations.
a7 hexane (Wurtz) ^ /7-xylene (Wurtz-Fittig)
^ 3,4-dimethylhexane (Wurtz) 'T> toluene (Friedel-Crafts)
i'c^^^-butylbenzene (Wurtz-Fittig) /. i/j-ethyl toluene (Friedel-Crafts)
8. One gram of a bromide was treated with excess magnesium in dry ether and then with
water; 182 ml. (STP) of gas were evolved in the hydrolysis. The gas did not decolorize
permanganate. Suggest a formula for the original bromide assuming the reactions to
be quantitative. (C = 12, H = 1, Br = 80, Mg = 24.3)
•Q How might the following conversions, which may require several steps, best be
accomplished?
fOJ «-propyl bromide to isopropyl bromide
\^ toluene to benzyl iodide
[^ «-butyl alcohol to 5-butyl «-butyl ether
(^ 2-chlorobutane to 2,2-dibromobutane
&7) toluene to /»-bromobenzyl chloride
J^'^benzene to /(-bromochlorobenzene
10. Quantitative chemical analysis of an alkyl halide showed that it contained 70.3% chlo-
rine. What is the smallest possible molecular weight that can be assigned to this com-
Dound? Suggest a molecular formula.
1^ 1. Write equations for
1 the preparation of each of the following compounds using unsatu-
V ^^rated hydrocarbons as starting materials.
a. 1,1-dibromoe thane c. 1, 2,3,4- tetrabromobutane
b. 1,2-dichlorohexane d. 1,1,2,2-tetrachlorobutane
1 34 • Organic Halogen Compounds

e. cyclohexyl bromide h. 2,4-diiodopentane

/. 2,2-diiodopropane /. l,l-dichloro-2-methylcyclopropane
g. 1 -phenyl- 1-bromoethane
12. Suggest a plausible explanation, in terms of electronic and resonance structures, of why
aliphatic halides are more susceptible to displacement reactions than are aromatic
halides.
13. Give a structural formula which satisfies each of the following statements. The same
compound may be used more than once.
a. used as a fire extinguisher
b. used as a dusting powder for wounds
c. used as a refrigerant
d. used as an anesthetic
e. made from ethene and a halogen

/. on hydrolysis gives ethyl alcohol

g. on hydrolysis gives ethylene glycol
h. made from carbon disulfide
/
. reacts with alcoholic potash to give ethene
j. made from carbon tetrachloride
14. Write out a detailed mechanism for equation (7-18) showing the structure of the inter-
mediate (include at least two important contributors to the resonance hybrid).
15. Arrange ethyl bromide, chloride, and iodide in order of decreasing rate of reaction with
aqueous base. What is the major product in each case?
16. Methyl lactobacillate, the methyl ester of lactobacillic acid, a Cig-acid isolated from
Lactobacillus arabinosus, can be synthesized from methyl vaccenate, CH3(CH2)5CH=
CH(CH2)9COOCH3, methylene iodide, and zinc-copper couple. What is the formula
for methyl lactobacillate?
 RCHO

I
^""y^.

The use of formaldehyde as a disinfectant and as a

preservative for biological specimens has long been known.
A t present, however, its most important use is for the pro-
duction of a variety ofplastics and resins, particularly Bake-
lite and the binders in plywoods. Formaldehyde is the sim-
plest of a series of compounds built around a carbonyl group
(a carbon atom linked to an oxygen by a double bond). Like
other unsaturated compounds, the aldehydes and ketones
are highly reactive and undergo addition to the carbonyl
group. Many natural substances are aldehydes and ketones;
among them are the various flavors from almonds, cinna-
mon, and the vanilla bean, perfumes, camphor, some vita-
mins, and sex hormones.

Aldehydes and Ketones

Aldehydes and ketones contain the carbonyl group, ^C^O. If one of the

two groups attached to the carbonyl atom is a hydrogen atom, the compounds
O
are aldehydes. The aldehyde group is — C — H, sometimes abbreviated — CHO.
The remaining group may be another hydrogen atom or an alkyl or aryl group.

o
136 Aldehydes and Ketones

Figure 8-1. Models of formaldehyde.

o
 A Idehydes and Ketones 137
The simpler ketones are usually referred to by common names. These are
derived by naming the hydrocarbon groups attached to the carbonyl, though
in certain cases special names are employed.

O o o
II

CH3CCH3 CH3CCH2CH3 CH3CH2CCH2CH3

acetone methyl ethyl ketone diethyl ketone

o
o
cyclohexanone ocetophenone benzophenone
(methyl phenyl ketone) (diphenyl ketone)

Names more complex aldehydes or ketones are developed according to

for
the I.U.P.A.C. system. The characteristic ending for the aldehydes is -al,
derived from the first syllable of aldehyde, and that for the ketones is -one, de-
rived from the last syllable of ketone. The examples below illustrate this
method of naming.
O o
4 3 2 ill 4 3 2 ill

CH3- -CH2— CH2— CH CH3— CH— CH2— CH

butonol
CH3
3-methylbutanal

o o
1 3 2II 4 1 2II 3 4 5
CH3-C-CH2 CH2- CH3 CH3— C— CH2— CH— CH3
2-pentanone
CH3
4-methyl-2-pentanone

Figure 8-2. Models of acetone.

138 Aldehydes and Ketones

The aldehyde group must appear at the end of an alkyl chain. For this reason,

it is usually not necessary to indicate that it is in the one (1) position.

Occurrence and Properties

Except for formaldehyde, which is a gas, the simpler ahphatic aldehydes are
colorless Uquids. The lower members of the series have a penetrating odor,
but with increasing molecular weight the odor becomes more fragrant. This is
particularly true in the aromatic series, where many of the aldehydes are used
for their flavor or perfume. The ketones also are not unpleasant in odor, and
are used extensively in the blending of perfumes. Acetone, the simplest ketone,
is particularly useful as a solvent, since it dissolves most organic compounds yet

is completely miscible with water. It is a common solvent for coatings, ranging

from nail polish to exterior enamel paints.
Some of the common natural substances in which important carbonyl com-
pounds occur are almonds (benzaldehyde), cinnamon (cinnamaldehyde), the
bean (vanillin), the sex hormones (testosterone, progesterone), camphor
vanilla
(from the camphor tree), oil of citronella (citronellal), the anti-hemorrhagic
vitamin K, the perfume fixative derived from the musk deer (muscone, a cyclic
ketone with a remarkably large ring), and innumerable others.

O
CH=CH— CH

OCH3
benzaldehyde
(almonds)
cinnamaldehyde
(cinnamon)
OH
vanillin

(vanilla)

OH CH, CH
CH
.CH2
CH3CH /C=^
(CH2)l2
muscone
(musk deer)
testosterone camphor
(male sex hormone)

Some Naturally Occurring Carbonyl Compounds

 Aldehydes and Ketones • 139

Figure 8-3. Model of benzaldehyde.

CH3
140 Aldehydes and Ketones

However, when two hydroxyl groups are attached to the same carbon atom, the
compound is usually not sufficiently stable to be isolated. Attempts to isolate these
substances usually lead to the loss of a molecule of water from the two hy-
droxyl groups. Thus, all attempts to isolate carbonic acid, H2CO3, lead only to
carbon dioxide and water.

H O.
:c=o 0=C=0 + H2O (8-1)

HO
carbonic acid carbon dioxide

The oxidation products of methane indicated above by successive hydroxylation

of the carbon atom may now be represented by their correct formulas, with
0, 1,2, 3, and 4 bonds from carbon to oxygen.

H
1
 Aldehydes and Ketones • 141

H r
I
I'dHT—
II"!
-^ R— C— OlH
;

-H20
R— C— OH R-C=0 (8-4)
I

R' R' R'

J
secondary alcohol ketone

CH3— CH— CH3 -^ CH3— C— CH3 (8-5)

OH O
2-propanol proponone
(acetone)

The aldehydes formed in this process are far more easily oxidized than the
They must therefore be removed from the oxidizing medium
starting alcohol.
as thev are formed. Fortunately, aldehydes have lower boiling points than their
corresponding alcohols. By carrying out the oxidation at a temperature slightly
above the boihng point of the aldehyde, it may be removed by distillation from
the reaction mixture as it is formed.
^'^''^'
CH3CH2CH2OH
"^
dil. H2SO4
> CH3CH2CHO
-i '^ (8-6)y
V

(b.p. 97=) (b.p. 49 =

)

Potassium permanganate in alkaline solution or potassium dichromate in

is the most commonly used oxidant.
sulfuric acid

Dehydrogenation of Alcohols
The oxidation of alcohols to aldehydes or ketones may be carried out cata-
lyticallyby passing the alcohol over copper gauze or powder at about 300°.
When performed in this way. the reaction is spoken of as dehydrogenation,
since hydrogen gas is formed in the process.

CH2— CH2 CH2— CH2

CH2 \:H0H -^ CH2 ^C=0 + H2 (8-7)

CH2— CH2 CH2— CH2

cyclohexanol cyclohexonone

Hydrolysis of Dihalides

Halogenation of a hydrocarbon, followed by hydrolysis, gives indirectly the

oxidation product of the hydrocarbon. The hydrolysis of a dihalide should
yield a dihydroxy compound. If both halogens are on the same carbon atom,
however, the monohalo monohydroxy compound first formed immediately loses
hvdrogen hahde to form an aldehyde or ketone. The hydrolysis of 1.1-dihahdes
gives good yields of aldehydes, whereas similar dihahdes whose halogens are
not on a terminal carbon atom form ketones. Thus, benzaldehyde is prepared
commercially from toluene by chlorination of the side chain, followed by
hydrolysis.
1 42 'A Idehydes and Ketones

CH3 CHCI2

2Clo
 A Idehydes and Ketones 143
The gaseous product may then be dissolved in water to prepare formalin, a
40 percent aqueous solution. Formaldehyde is used for the silvering of mirrors,
as a disinfectant and fumigant, as a preservative for biological specimens, and
in the synthesis of various resins, plastics, and synthetic glue.
Acetaldehyde may be prepared by a similar oxidation of ethanol. A better
commercial synthesis of acetaldehyde, however, involves hydration of acetylene.
Dilute sulfuric acid and mercuric sulfate are the catalysts for the addition of
water to the triple bond. The nature of the intermediate and its immediate
conversion to the acetaldehyde structure are discussed on page 152. The prepa-
ration of acetaldehyde from acetylene makes it a very inexpensive industrial
chemical, since the original raw materials are hmestone, coke, and water or
methane. Numerous important chemicals, including acetic acid, DDT, and
butadiene, are manufactured from acetaldehyde.

H OH H O
r H2^S04=
H— C=C— H H— C=C—
I

+ HOH HC— CH
I

-> (8-13)
Hg--S04=
I I

acetylene enol intermediate

H
acetaldehyde

Hydration of substituted acetylenes follows Markownikoff's rule, giving

ketones.
Acetone an important solvent used in the manufacture of explosives,
is

lacquers, paint removers, plastics, drugs, and disinfectants. There are several
commercial sources of this compound. It is prepared by the catalytic dehydro-
genation of isopropyl alcohol, which is readily available by hydration of pro-
pylene from petroleum (see equation (8-5)). Large quantities are also made by a
fermentation process discovered during the first World War by Chaim Weiz-
mann, British chemist and later first president of Israel. Sugar derived from
cornstarch or molasses, when fermented with the bacterium Clostridium aceto-
butylicum, yields about 30 percent acetone, 60 percent A7-butyl alcohol, and 10
percent ethyl alcohol. Acetone is also a by-product from the manufacture of
phenol from cumene hydroperoxide (see equation (5-20)).
In still another method, acetic acid is passed over a catalyst of manganous or
thorium oxide, forming acetone and carbon dioxide.

CH3— C^OH o
MnO or
» CH3CCH3 + CO2 + H2O (8-14)
ThOz
heat acetone

CH3VC— OH
acetic acid
1 44 'A Idehydes and Ketones

Figure 8-4. Bonding in the carbonyl group.

Nature of the Carbonyl Group

A carbonyl carbon atom is trigonal, being attached to oxygen and two other
atoms. The orbitals are therefore of the sp"^ type (see Figures 3-1, 3-2). The
remaining p orbital overlaps with a similar orbital on oxygen to form a it bond
above and below the plane formed by the carbonyl carbon and three atoms
attached to it (Figure 8-4). The carbonyl group therefore has a geometry similar
to that of a carbon-carbon double bond (compare with Figure 3-3). But the
carbon-oxygen double bond involves two atoms with widely different electro-
negativities. The electrons are not shared equally, but are strongly pulled
toward the oxygen atom. The carbonyl group may be described as a resonance
hybrid of the two structures

C=^: < — . yC—O:

Unhke the carbon-carbon double bond which acts as a supplier of electrons to

electrophilic reagents, the carbonyl group reacts predominantly with nucleo-
philic reagents which can supply an electron pair to the electronically deficient,
partially positive carbonyl carbon atom.
—
The C=0 bond distance is only 1.24 A, whereas the C O distance (in ethers
or alcohols) is about 1.43 A. The carbonyl group vibrates with a higher fre-
quency (1,650-1,750 cm-i) than the C—
O single bond (about 1,000-1,100 cm-i),
as shown by the infrared spectra of typical compounds. Because of the polar
carbonyl group, aldehydes and ketones have higher boiUng points than hydro-
carbons of equal molecular weight. Hydrogen bonding in pure aldehydes and
ketones is unimportant, but the lower members of the series probably owe their
water solubility in part to hydrogen bonding between the carbonyl oxygen and
water molecules.

Reactions

Oxidation

An important difference between aldehydes and ketones lies in their behavior

toward oxidizing agents. Aldehydes are easily oxidized to acids containing the
same number of carbon atoms.
 Aldehydes and Ketones • 145
O O
R— C— H -^ R— C— OH (8-15)
aldehyde acid

Ketones, however, have no hydrogen attached to the partially oxidized carbon

atom. They may be oxidized only under more severe conditions, and the oxida-
tion cleaves the ketone into fragments with fewer carbon atoms.

O
R^C— R'
II

one of these carbon-carbon

bonds must be broken in oxidation

This great difference in susceptibility toward oxidation is used to distinguish

aldehydes from ketones. ammoniacal solution of
In ToIIens' test, in which an
silver nitrate is employed, the silver ammonia complex ion* is reduced to

metallic silver within a few minutes at room temperature. The equation for the
reaction may be written as:

O O
II II

RCH + 2 Ag(NH3)2+ + 3 OH" > RC— O" + 2 Agj + 4 NH3T + 2 H2O

aldehyde silver ammonia acid anion silver

complex ion mirror (8-16)

(colorless)

or in the less precise, but more easily remembered form, illustrated for formalde-
hyde:

O O
^"^°"
HCH + 2AgOH > HC— OH + 2Ag| + HgO (8-17)

formaldehyde formic acid

If the beaker in which the test is performed is thoroughly cleaned, the silver will

deposit as a mirror on the glass surface. This reaction is commonly used in

silvering glass,formaldehyde usually being the aldehyde employed. Ketones

do not react with Tollens' reagent.

Addition Reactions

The carbonyl group in aldehydes and ketones, being unsaturated, undergoes

addition reactions. Studies show that the attackinggroup is a nucleophile
(supplier of an electron pair) which approaches the carbonyl carbon from a
direction perpendicular to the molecular plane

* As silver hydroxide is insoluble, the silver ion must be complexed to keep it in solution in a basic

medium.
146 'A Idehydes and Ketones

^ -'>C— O: (8-18)

Reaction is completed by attachment of a positive group, usually a proton, at

the oxygen atom.

Z Z
\ ••- \
--C— O: + H+ > __-C— OH (8-19)

The net result is the addition of H+Z" to the double bond, the negative part of
the addend becoming attached to the carbonyl carbon.

Z
JZ=0 + H+Z- > --C— OH (8-20)

Ketones are generally less reactive than aldehydes in addition reactions. This
isbecause {a) two R groups around the carbonyl carbon are bulkier than one R
and an H and {b) R groups are electron-releasing compared with hydrogen, and
this tends to neutralize the partial positive charge on carbon more in ketones
than in aldehydes.
Hydrogen Cyanide. The addition of hydrogen cyanide to the carbonyl group
leads to a class of compounds known as cyanohydrins.

CN CN
^C=0 + CN- > _,-C— O- -^ _-^C— OH (8-21)

cyanohydrin

CHs CH3 OH
\=0 + HCN > C (8-22)

CH3 CH3 CN
acetone acetone cyanohydrin

Usually the carbonyl compound is mixed with aqueous sodium or potassium

cyanide, and mineral acid is added slowly. The reaction rate depends on the
concentration of carbonyl compound and cyanide ion; the first step in equation
(8-21) is therefore rate-determining.
Cyanohydrins, as will be seen later, are useful as intermediates in the synthesis
of hydroxy acids, amino acids (the building blocks of proteins), and sugars.
Aldehydes and methyl ketones or cyclic ketones react with hydrogen cyanide as
indicated.
Water. Some aldehydes react with water to form hydrates. This is a reversi-
ble reaction which, in the case of aqueous solutions of formaldehyde, is probably

shifted considerably toward the right. Higher aldehydes are not appreciably
 A Idehydes and Ketones • 147
H^ H OH

H
C=0
I
I
+ H-OH
1

1
^=^
H
V OH
(8-23)

hydrated. Chloral (trichloracetaldehyde). however, forms a stable crystalline

hydrate, probably because unfavorable dipole-dipole repulsions in the aldehyde
Choral hydrate is one of the few stable compounds with
are reduced in the diol.
two hydroxyl groups on the same carbon atom. It is used in medicine as a
hypnotic and narcotic.

C^ 40 + H— OH C^ OH
CI— C— C > CI— C— CH^ (8-24)

CI H CI OH
^ \~ chloral hydrate

Alcohols. Acids can be used to catalyze addition of rather weak nucleophiles

to carbonyl compounds. A proton attaches to the carbonyl oxygen, rendering
the carbonyl carbon even more electron-deficient.

Z
^C=0: ^^ h;C=^0:H < — > ^C— OH ^-^ --^C— OH (8-25)

In the presence of an acid catalyst, alcohols, using the unshared electron pair on
oxygen for attack, are sufficiently nucleophihc to react with most aldehydes.

O^ 1

OH
R— CH + R'OH ^^ R— CH (8-26)
t I
^OR'
aldehyde alcohol hemiacetal

The addition is reversible. In the presence of an excess of alcohol, further reac-

tion occurs with the formation of water and an acetal.

OH OR'
R— CH— OR' + R'OH -^ RCH— OR' + H2O (8-27)

hemiacetal acetal

The reaction involves protonation of the hemiacetal hydroxyl group and loss of
water to form a resonance-stabilized carbonium ion

RCH— OR' < — > RCH=OR'

which then reacts with another alcohol molecule For acetaldehyde:

148 • Aldehydes and Ketones

9 ?" 0CH3
II I
r^H OH /
CH3CH + CH30H ^=^ CH3CH— 0CH3 '
> CH3CH + H20
dry \
acetaldehyde hemiacetal HCl OCH3
acetaldehyde
dimethyl acetal (8-28)

The two ether linkages at the same carbon atom.

acetal structure involves
Like ethers, acetals are stable toward alkali, but are readily cleaved by acids to
give the alcohol and aldehyde from which they were prepared. Hemiacetal and
acetal structures are important in connection with the chemistry of carbohy-
drates (see Chapter 14). Similar structures derived from ketones are called
ketals.
Ammonia and Its Derivatives. The unshared electron pair on nitrogen enables
ammonia and its derivatives to act as nucleophiles toward carbonyl compounds.

remove H"^ from

, the ammonium-
NH^
L3
type .on and
•". .
j^u
i'Nn2
I 1

1
I
\ place It on \

more bas.cO^
^C=6: -FNH3 ^=^ --C-Or the
^C-QH (8-29)

This reaction is reversible, and the products from ammonia itself are relatively

unimportant except with formaldehyde, a special case in which the reaction

yields an unusual product. When a mixture of formalin and concentrated
ammonium hydroxide is evaporated, a white crystalline sohd, hexamethylene-
tetramine, is formed. It has a remarkable cage-like structure with four equiva-
lent six-membered rings, each in a chair conformation. Hexamethylene-
tetramine (urotropine) is employed in medicine as a urinary antiseptic. In the
acidic medium of the urine, urotropine is decomposed slowly to formaldehyde,
which acts as an antiseptic. Hexamethylenetetramine is also used in the
production of plastics, drugs, and "canned heat" tablets. When nitrated, it
gives a high explosive known as cyclonite (RDX).

6 CH2O -F 4 NH3 ^
I I
+6 H2O (8-30)

hexamethylenetetramine
(urotropine)

Certain compounds ammonia, but with one hydrogen replaced by

related to
various other groups, react with aldehydes and ketones to form products that
are frequently crystaUine soUds, useful for identifying specific carbonyl com-
pounds. The more common of these compounds are:
 Aldehydes and Ketones 149

NH2— OH NH2— NH2 NH2— NH-Y > NH2— NH-^ ^^ NO2

6 5
hydroxylamine hydrazine phenylhydrazine
2,4-dinitrophenylhydrazine

In each case, the reaction involves the —

NH2 group, the nitrogen adding to the
carbonyl carbon and the hydrogen adding to the oxygen atom. The inter-
mediate loses water to form the final product.

\ ^ 1

H20
C=0 + NH2— OH > C=N— OH (8-31)
/ '^ I

OH
With hydroxylamine, the products are called oximes. With hydrazine and its
derivatives, the products are known as hydrazones.

O
<^^CH -H NH2NH-^~\ -^il^ <^~VcH=N-NH-^\
benzaldehyde phenylhydrazine benzaldehyde phenylhydrczone (8-32)

Phenylhydrazine was important in elucidating the structures of sugars (page

277).
Grignard Reagent. Grignard reagents react with carbonyl compounds,
usually by addition to the carbonyl group. The Grignard reagent behaves
as if it were an ionic compound, R^'^MgX.
R
\ - +
-C=0 + R MgX ,--C— O MgX (8-33)
t I

intermediate addition product

When the intermediate addition product is hydrolyzed, usually with an aqueous

acid solution, an alcohol results.

R R
\ - + + \ X-
--C— O MgX + HCl- > --C— OH + Mg++ (8-34)
/ ci-
an alcohol

This reaction is exceedingly versatile and can be used to prepare primary,

The class of alcohol formed depends upon
secondary, or tertiary alcohols.
whether the carbonyl compound is formaldehyde, any other aldehyde, or a
ketone. When the carbonyl compound is formaldehyde, a primary alcohol is
formed.
150 'A Idehydes and Ketones
H.
R
\ RMgX v
c=o ^ H'->C— OH (orRCHsOH)
1.

^ / (8-35)
/ 2. H20,H+ u^
H H
All other aldehydes give secondary alcohols.

r: R
RMgX \
,c=o -> R'_--C— OH (or RR'CHOH) (8-36)
H
Ketones lead to tertiary alcohols.

R'-
R
\, 1. RMgX \
,c=o R/_--C— OH (or RR'R"COH)
/
R"
2. H20,H+
R y (8-37)

The decision as to which Grignard reagent and which carbonyl compound

should be used to prepare a particular alcohol made as follows: One of the
is

R groups attached to the carbon bearing the OH must come from the Grignard
reagent; the rest of the structure has its source in the carbonyl compound. Some
alcohols can be obtained from more than one combination of reagents. In this
most available pair is used. As a typical example, 1 -phenyl- 1-ethanol
case, the
may be prepared from acetaldehyde and phenylmagnesium bromide or from
benzaldehyde and methylmagnesium bromide.

CHs
r
CH + f V-MgBr
acetaldehyde phenylmagnesium
bromide
OMgBr OH
CHsCH-^A H+Cl-
^ CH3CH

0^ 1 -phenyl-l-ethanol

^^-CH-^ CHsMgBr + Mg++Cl-Br-

benzaldehyde methylmagnesium (8-38)

bromide

Sodium Bisulfite. Aldehydes, and a few ketones, react with saturated aqueous
sodium bisulfite to form white crystalline addition products. The equihbrium
is shifted to the right by employing excess bisulfite.

O^ ^OH
R— CH + HS03-Na+ ^ R— CH (8-39)
t \o3-Na+
bisulfite addition compound
 Aldehydes and Ketones • 151
These addition compounds may
readily be reconverted to the aldehydes by
treatment with acid or base. Thus, bisulfite addition compounds may be used
to separate aldehydes from mixtures with other compounds. The solid bisulfite
addition compound of formaldehyde is sometimes used as a convenient way of
transporting or storing the gaseous aldehyde.
A qualitative test for aldehydes is based upon their addition of bisulfite.
Fuchsin (magenta) is a dyestuff which, on treatment with sulfur dioxide, forms
a colorless substance. When this reagent is treated with an aldehyde, a new
colored compound is formed, and the solution changes from colorless to pink.
This is known as Schiff' s test for aldehydes.
Reduction. Aldehydes and ketones can be reduced to the corresponding
alcohols either by catalytic hydrogenation under pressure or by chemical
reducing agents. Hydrogenation requires a catalyst (nickel, copper chromite)
and may be pictured as the addition of hydrogen to the carbonyl group.

\f
/= + H-H —- /Cx (8-40)

For example:

/"A-C-CHs
— + H2 -^^ ^^^CH-CHs
—
(8-41)

Q pressure
^^
acetophenone 1 -phenyl- 1 -ethanol

Recently metallic hydrides have found extensive use as reducing agents in

organic chemistry. The most common, lithium aluminum hydride, can be made
from lithium hydride and aluminum chloride.

4 LiH + AICI3 > LiAlH4 + 3 LiCl (8-42)

lithium aluminum
hydride

In many instances, it will reduce a carbon-oxygen double bond to the corre-

sponding alcohol without affecting a carbon-carbon double bond.

O
CH3— CH=CH— CH -ti^lMi^ CH3— CH=CH— CH2OH (8-43)
crotonaldehyde crotyl alcohol

The addition reactions of aldehydes and ketones are summarized in Table 8-2.
152 • Aldehydes and Ketones

TABLE 8-2 Addition Reactions of Aldehydes and Ketones

 Aldehydes and Ketones • 1 53

V C ^° X /°"
--^C— ^=^ [enolate anion] ^=± C=C (8-45)
R ^ ^R
keto enol

Carbonyl compounds with an a-hydrogen are in equilibrium, via the enolate

anion, with the corresponding enol. The carbonyl form is referred to as the
keto form, and the phenomenon is known as keto-enol tautomerism. It is

different from resonance, because keto-enol forms differ in the location of a hydro-
gen atom as well as in electron distribution.
Most simple aldehydes and ketones exist predominantly in the keto form (for
example, only 0.0003% enol is present in ordinary acetone). Reactions which
should lead to an enol, as for example the hydration of acetylene (equation
(8-13)), give the keto form instead. But some stable enols are known, the most
familiar being the phenols (Chapter 5). Here, the keto structure would disrupt
the aromatic ring.

O—
(8-46)

enol keto

Aldehydes and ketones undergo a number of important reactions which are

initiatedby removal of the a-hydrogen by base.
The A Idol Condensation. Aldehydes and some ketones, which have a hydro-
gen atom on the a-carbon, undergo self-addition reactions under the influence
of alkali. With acetaldehyde, the reaction proceeds as follows:

O O
CHsCH + OH- ^=± CHs— CH -\- HgO (8-47a)

^O o o- O
CHaCHyCHa— CH > CH3CHCH2CH (8-47b)

00 OH
CH3CHCH2CH
O
OH-
CH3CHCH2CH -h H2O > -{- (8-47c)

aldol or
butanal-3-ol

The product is a yS-hydroxy aldehyde, called an aldol (aldehyde and alcohol).

Note that the a-carbon of one aldehyde molecule bonds with the carbonyl
carbon of the other. The aldol condensation affords an excellent method for
increasing the length of a carbon chain. It is employed industrially for the
manufacture of «-butyl alcohol, butadiene, and other useful chemicals.
1 54 'A Idehydes and Ketones
OH O O
CH3CHCH2CH "^^^;
— H2O
> CH3CH=CHCH ^^
aldol crotonaldehyde

""'^^
CH3CH2CH2CH2OH — H2
> CH2=CH— CH=CH2 (8-48)
n-butyl alcohol 1 ,3-butadiene

Note that the aldol dehydrates to form a double bond conjugated with the
carbonyl group.
When a higher aldehyde is used, branching results at the a-carbon in the aldol
formed. For example, «-butyraldehyde yields 2-ethylhexanal-3-ol.

0< H O OH O
OH-
CH— CH
II II II

CH3CH2CH2CH— CH— CH
I I

CH3CH2CH2CH + T^^-- (8-49)

CH2 CH2
CH3 CHs
2-ethylhexanal-3-ol

The product may be reduced to the corresponding diol, which in this case would
be 2-ethylhexane-l,3-diol. This substance is used extensively as a mosquito
repellent, sold under the trade name of 6-12.

OH
I

CH3CH2CH2CHCHCH2OH
CH2
CH3
• 2-ethylhexane-1 ,3-dlol (6-1 2)

Aldehydes that do not have a hydrogen atom on the a-carbon, such as formal-
dehyde (which has no a-carbon atom) and benzaldehyde, do not give aldols.
They can, however, act as the acceptor for another carbonyl compound which
does have a-hydrogens. For example, cinnamaldehyde, the flavor constituent
of cinnamon, can be prepared from acetaldehyde and benzaldehyde, the latter
acting only as an acceptor.

0< 1 O OH O
A~V-CH + HC-CH ^^^± ^^CH-CH2-CH -=^
benzaldehyde acetaldehyde an aldol

O
/ \-CH=CH— CH (8-50)

cinnamaldehyde
 Aldehydes and Ketones • 155
Halogen Substitution. The hydrogens on the a-carbon atoms of aldehydes
and ketones are readily replaced by halogens in alkaline solution. This is
probably due to reaction of the enolate anion with the halogen.

O O
CH3CH + oh"
(base)
^ CH2—CH + H2O
(anion)
(8-51)

o o
-II II - (8-52)
CH2CH + CI— CI > CICH2CH + CI
chloroocetaldehyde

Due to the electron-withdrawing effect of the a-chlorine, the remaining a-hydro-

gens become even more acidic, and displacement continues until all of the hy-
drogens attached to the a-carbon have been replaced by halogen.

O O
CH3CH + 3 CI2 -F 3 oh" . CCI3CH + 3 H2O + 3 C\ (8-53)
chloral

The bond to the a-carbon is now weakened, because both it and the carbonyl
carbon carry partial positive charges due to heavy substitution with electron-
withdrawing substituents. Hydroxide ion readily cleaves such compounds.

Cl:a Cl:0:) CI O
I r
OH
- \^W -
CI— C^C-R
I II

Cl-C-C^^-R + . > Cl-C: -h C-R (8-54a)

CI CI OH CI OH
trichloromethyl an acid
anion

O O
R— C— OH + CCI3 > R— C— O + CHCI3 (8-54b)
chloroform

The methane (haloform) and the salt of an acid. This

result is a trihalogenated
is When bromine or iodine is used, the corre-
called the haloform reaction.
sponding bromoform (CHBr3) or iodoform (CHI3) is obtained. The reaction is
given by acetaldehyde and methyl ketones. Since alkaline solutions of halogens
are rather good oxidizing agents, ethanol (which is oxidized to acetaldehyde)
and alcohols with the structure CH3CH(OH)R (which are oxidized to methyl
ketones) also yield haloforms when treated with this reagent. When the halogen
employed in the reaction is iodine, the reaction may be used as a test for the
O
CH3 — C — group or for one easily oxidized to it. Iodine is added to an alkaline
solution of the carbonyl compound. Iodoform, a product of the reaction,
156 A Idehydes and Ketones

precipitates as a yellow crystalline solid with a characteristic medicinal odor

easily detected. The iodoform test may be used, for example, to distinguish be-
tween ethanol (positive test) and methanol (negative test).
Chloral (equation (8-53)), which is manufactured industrially from ethanol
and chlorine, is a starting material for the manufacture of the insecticide, DDT.
Chloral condenses with chlorobenzene in the presence of sulfuric acid as a
catalyst according to the equation:

+ H2O

chlorobenzene p,p'-c/ichloroc/iphenyltrichloroethane
(DDT) (8-55)

In addition to the reactions involving oxidation, addition, or the a-hydrogen,

aldehydes and ketones undergo a number of important special reactions.

Polymerization

In the presence of concentrated alkah, aldehydes which have a hydrogen atom

on the a-carbon polymerize of indefinite structure (resins),
to large molecules
as a result of successive aldol condensations. There are, however, some more
distinct, simpler polymers which aldehydes may form. The lower aldehydes,
with dilute acid, form cyclic trimers which exhibit no aldehydic properties, but
which may be decomposed by heat or acids to furnish the corresponding
aldehyde. Like bisulfite addition compounds, these polymers are sometimes
convenient ways of storing or transporting the aldehydes.

CH3

O O o
CH— CH3
I 1 I

CH3-CH
I

CH2 CH2
o o
trioxane paraldehyde
(formaldehyde trimer) (acetaldehyde trimer)

Formaldehyde also forms a linear, low-molecular weight polymer known as

polyoxymethylene, or paraformaldehyde, by slow evaporation of an aqueous
solution of the aldehyde. Complete removal of water permits further poly-
merization to a high-molecular weight polymer. This can still "unzip" to

O
«HCH ^ HOCH2(OCH2)„OCH20H (8-56)

paraformaldehyde
Figure 8-5. Delrin is a tough, rigid, thermoplastic
acetai resin made by DuPont. Its many uses range
from clothespins to business machines and it is

widely used in the manufacture of piping. The men

shown are constructing a natural gas line of Delrin
piping. (Courtesy of E.I. DuPont DeNemours &
Company, Inc.)

formaldehyde on heating, but if the terminal hydroxyl groups are protected (by
forming an ester), the resulting polymer is stable and can be extruded or molded
into many useful articles. This polymer is marketed by the DuPont Company
under the trade name Delrin.

Bakelite

Formaldehyde condenses with phenols, in the presence of alkali, in a reaction

which in some respects is similar to the aldol condensation.

OH
OH

phenolate anion

(8-57)

OH
.CH2OH tautomer-
ization HoO
CH2OH <

o-hydroxybenzyl alcohol

Condensation occurs ortho or para to the phenohc hydroxyl. By continuous

heating under pressure, the initial condensation products react further with

157
158 A Idehydes and Ketones
phenol, eliminating water to form methylene ( —
CH2 ) bridges. Various —
degrees of polymerization may
be attained by appropriate adjustment of reac-
tion conditions. The products may be molded into useful items of commerce,
employed in the manufacture of laminated plywood, or modified for use as
protective coatings. Substituted phenols may be used to modify the character
of the product. In general, these phenol-formaldehyde resins are known as
Bakelite, and possess structures similar to that indicated below.

OH OH

CHs-r ^l-CHs-
OH ^^ OH
A Partial Formula for Bakelite

The Cannizzaro Reaction

In the presence of concentrated alkali, aldehydes containing no a-hydrogens
undergo self-oxidation and reduction. The reaction is important primarily
with aromatic aldehydes.

rxln
2 f ^CH
benzaldehyde
^ fv CH.OH
benzyl alcohol
ry^Lo
potassium
K (8-58)

benzoote

Pentaerythritol, C(CH20H)4, is manufactured from acetaldehyde and formal-

dehyde by a combination of the aldol condensation and Cannizzaro reaction.
It is used to make plastics and resins. Its tetranitrate is a high explosive used in

tank-piercing rockets and in medicine to control high blood pressure.

Ca(OH)2 HCHO
3 HCHO + CH3CHO (aldol)
(HOCH2)3CCHO OH-
C(CH20H)4
(Cannizzaro) pentaerythritol

(8-59)

Aromatic Substitution
The aldehyde group is too sensitive to oxidation by nitric acid or halogens to
withstand any of the typical aromatic substitution reactions. Aromatic ketones,
however, may undergo nuclear substitution. The orientation is predominantly
in the meta position.
 Aldehydes and Ketones • 1 59

Aldehydes and ketones, as we have seen, are among the most reactive of
organic compounds and can furnish many useful products. As a guide in
organizing the large amount of material presented in this chapter, the student
should make good use of the outhne which follows.

NEW CONCEPTS. FACTS. AND TERMS

O
1. The carbonyl group, ^C^O; aldehydes, RCHO; ketones R C R. — —
2. Nomenclature (page 136): -o/ ending for aldehydes; -one ending for ketones. Many
common names (formaldehyde, acetaldehyde, benzaldehyde, acetone).
3. Preparation
a. Oxidation of alcohols: primary alcohols > aldehydes; secondary alcohols
> ketones. The oxidation states of carbon in organic compounds
b. Dehydrogenation of alcohols
c. Hydrolysis of dihalides in which both halogens are attached to the same carbon
atom
d. Synthesis with carbon monoxide — Gatterman-Koch reaction (aromatic hydro-
carbon, carbon monoxide, and aluminum chloride catalyst); Oxo process
e. Special methods for formaldehyde, acetaldehyde, and acetone
4. Nature of the carbonyl group; planar, 5/7^ bonding, polarized with the oxygen end
negative, susceptible to attack mainly by electron-donating reagents (nucleophiles).
5. Reactions
a. Oxidation. Aldehydes easily oxidized (Tollens' test); ketones more difficult to

oxidize.
b. Addition reactions
/. Hydrogen cyanide > cyanohydrin
//. Alcohols > hemiacetal, acetal, ketal
Hi. Hydroxylamine > oximes
Phenylhydrazine > phenylhydrazones

Ammonia plus formaldehyde > hexamethylenetetramine

iv. Grignard reagent plus formaldehyde > primary alcohol

Plus other aldehyde * secondary alcohols

Plus ketones > tertiary alcohols

V. Sodium bisulfite, Schiff's test

vi. Hydrogen or lithium aluminum hydride > alcohols

c. Base-catalyzed reactions
/'.
Ionization of the a-hydrogen; keto-enol tautomerism
//. Aldol condensation
Hi. Halogen substitution on the a-carbon; the haloform reaction; the iodoform

test

d. Polymerization; Bakehte
e. The Cannizzaro reaction
/. Aromatic substitution; the carbonyl group is meta-directing
160 A Idehvdes and Ketones

EXERCISES AND PROBLEMS

f.
'\: jkaxnc each of the following compounds.

CH3(CH2)3CHO [e) CH3 C-CH3

^J CH3CH2COCH2CH2CH3
O
CHO
P rvo
A^- ^^ CHgCH^CHCHO
% (CH3)2CHCHO
CHO CH3CH=CH— CO— CH3
/g)
7s CH3CCI2CH2COCH2CH3
2? Write structural formulas for the foUowmg:
^ hexanal / jL^^ropenal
(^ 2-bromopentanal *\
(^ l-phenyl-2-butanone
@/7-bromobenzaldehyde v^^^
S//^ 2-ethyl-2-pentenal
)!

^C M
:i

^ 2-methylcyclopentanone / Qp 2,4-dinitroacetophenone
e.) 2,2,2-trichloroethanal vli^.y/j-bromocinframaldehyde
3. By'means of equations show the steps in the oxidation of each of the following alcohols.
a. isopropyl alcohol e. 2-butanol
b. «-butanol /. isoamyl alcohol
c.\ 2-phenylethanol g. benzyl alcohol
I

'

a. cyclohexanol h. methyl alcohol

4. Starting with materials indicated, give equations for preparing each of the following
compounds.
a. 2-butanone from 5-butyl alcohol
b. methyl «-hexyl ketone from CH3(CH2)5CH(OH)CH3 (capryl alcohol)
c. cyclohexanone from phenol
d. acetone from acetic acid
e. propionaldehyde from ethylene
/. /7-bromobenzaldehyde from toluene
Give equations for a simple, single chemical test that can distinguish between com-
pounds in the following pairs.
a. butanol and butanone /7-butyl alcohol and 5-butyl alcohol
d.

b. and 1 -butanol
ethyl alcohol methanol and ethanol
e.

c. benzaldehyde and acetophenone /. 2-pentanone and 3-pentanone

6. Oxidation of a compound C5H12O yields C5H10O which reacts with phenylhydrazine
and gives a positive iodoform test. The original substance can also be dehydrated with
sulfuric acid to a hydrocarbon C5H10 which, on oxidation, gives acetone. What is the
structure of the original compound?
Give equations for the best methods to prepare the following compounds from the
materials indicated:
a. acetone from propyne d. 2-butanone from 2-butene
b. acetaldehyde from acetylene e. acetophenone from styrene
c. ^-methylbenzaldehyde from toluene /. diethyl ketone from 3-pentanol

\
 Aldehydes and Ketones • 161
/ 8. .Write equationsshowing the reactions of the following reagents with propionaldehyde
^''^
and with acetophenone.
a. ammoniacal silver nitrate

b. hydrogen cyanide

c. methyl alcohol and acid

d. methylmagnesium bromide followed by water

e. hydrogen (one mole) catalyzed by nickel

/. hydroxylamine

g. sodium bisulfite

h. phenylhydrazine
9. Using a Grignard reagent and the appropriate aldehyde or ketone, show how each of
the following could be prepared.
a. «-propyl alcohol d. 1-methylcyclohexanol
b. 2-butanol e. 3-butene-2-ol
c. 2-methyl-2-butanol /. 1 -phenyl- 1-propanol
10. Show, by means of equations, that in the synthesis of an alcohol from a Grignard rea-
gent and an aldehyde or ketone, the following statements are true:
a. 1-butanol (a primary alcohol) can be made from only one combination of reagents
b. 2-butanol (a secondary alcohol) can be made from two different combinations of
reagents
c. 3-methyl-3-hexanol (a tertiary alcohol) can be made from three different combina-
tions of reagents
11. Give a specific example of (a) a secondary alcohol which can be made from only one
combination of Grignard reagent and aldehyde; (b) a tertiary alcohol from one com-
bination of Grignard reagent and ketone.
12. Write equations for the following reactions:
a. aldol condensation of butyraldehyde
b. Cannizzaro reaction with benzaldehyde
c. haloform reaction of /7-bromoacetophenone
d. Gatterman-Koch reaction on /^-xylene
e. reduction of propiophenone with Uthium aluminum hydride
13. Using the aldol condensation as the first step, followed by any other necessary reactions,
show with equations how the following compounds can be prepared.
a. 2-ethyl-l,3-hexanediol e. cinnamyl alcohol
b. 1-butanol /. 4-methyl-3-pentene-2-one
c. 2-butene-l-ol g. 4-methyl-2-pentanol
d. cinnamaldehyde h. pentaerythritol
14. A compound CsHeO on treatment with methylmagnesium bromide followed by hy-
drolysis yielded an alcohol C4H10O. This alcohol was not readily oxidized, but when
drastically oxidized it yielded only acetic acid and carbon dioxide. What is the struc-
ture of the original compound? Write equations for each reaction.
15. Using acetylene and benzene as the only organic materials, write equations which could
be used for the industrial preparation of DDT.
16. Draw out in detail the mechanism for the acid-catalyzed conversion of a hemiacetal to
an acetal (equation (8-27)).
17. Write out, in stepwise fashion, the mechanism for the aldol condensation of «-butyral-
dehyde (equation (8-49)).
18. Acetaldehyde reacts with 2-methylpentane-2,4-diol, in the presence of a Uttle acid, to
1 62 'A Idehydes and Ketones
yield a cyclic product, C8H16O2. Suggest a possible structure for this substance, and
give equations which explain its formation.
19. When a mixture of benzaldehyde and crotonaldehyde (CHaCH^CH — CH=0) is

treated with a strong base, a good yield of the aldehyde C6H5CH=CH — CH^CH
CH=0 can be obtained. Suggest a mechanism for this reaction.
20. Acetone reacts with lithium acetylide to form (A) which on hydrolysis gives (B), CsHgO.
Partial reduction of (B) gives (C), C5H10O which, on dehydration, gives a product (D)
which can be polymerized to a rubbery product. Give formulas for (A-D) and equa-
tions for each reaction.
 // was known to the ancients that a sour taste devel-

oped in wine left exposed to the air, and this process is still
used in the manufacture of vinegar. Ethyl alcohol in the 0-Na
wine is oxidized by bacteria to a dilute solution of acetic acid.
This is one of the simplest members of a series of organic
compounds known as the carboxylic acids. Many occur in

nature, either free or in combination with other organic sub-

stances. Combined with alcohols, the acids occur in fruit
flavors, perfumes,and vegetable and animal fats and oils.
Modification of the carboxyl group leads to related com-
pounds known as acid derivatives, many of which have im-
portant uses.

Carboxylic Acids and Their

Derivatives

Substances which contain the carboxyl group (the name is derived from
carbonyX and hydroxy/)

O
_-^
—
OH
make up the important class of compounds known as carboxylic acids. The
reasons for the acidity of these compounds are discussed in some detail below.
In the aliphatic series, the carboxyhc acids are sometimes called fatty acids,
because many of them can readily be obtained from natural fats. In aromatic
acids the carboxyl group is directly attached to the aromatic ring.

163
164 • Carboxvlic Acids and Their Derivatives

Figure 9-1. Models of acetic acid.

H O O
_-^ _^
H— C—
H
I

O— O- c;
'\,
O—
acetic acid benzoic acid
(an aliphatic acid) (an aromatic acid)

The general formula for an acid is

o
_-^
R— c;
O—
which may be abbreviated to RCOOH or RCO2H. More than one carboxyl
group may be present in a molecule.

/^
C— OH
^ C— OH
C-OH C— OH
^O
oxalic acid phthciic acid

Figure 9-2. Model of benzoic acid.

 Carboxylic Acids and Their Derivatives 165

Nomenclature
Because of their wide distribution and abundance in natural products, the
carboxyhc acids were among the first organic compounds studied. Conse-
quently, many of them are known by common names, often derived from a
Latin or Greek name indicating the original source of the acid. Formic acid
(L., formica, ant) was obtained by distillation of ants. Others are acetic acid
(L., (L., butyrum, butter), and stearic acid (Gr.,
acetwn, vinegar), butyric acid
stear, beef The common names should be memorized by the student,
suet).
because they often provide the root names of other compounds.
The I.U.P.A.C. system employs the suffix -oic acid, and appHes all the other
rules. Because of its group (analogous to the aldehyde
structure, the carboxyl
group) must come at theend of a carbon chain; consequently, no number is
used to locate this group. Table 9-1 indicates the names of the first few members
in the ahphatic series:

TABLE 9-1 Aliphatic Carboxylic Acids

FORMULA
1 66 • Carboxylic Acids and Their Derivatives

Aromatic acids are given eithercommon names or ones derived from the
parent compound, benzoic acid. The following are a few examples; others will
be named as we meet them.

o
 Carboxylic Acids and Their Derivatives 167
The extent to which this equihbrium is shifted toward the right is a measure of
the strength of the acid. The equilibrium constant

Kn = [H3O+KRC-O-]
[RCOOH]
is therefore a measure of the strength of the acid: the greater its numerical value,
the stronger the acid.*

The determination of Ka is outlined briefly for acetic acid.

[H30+][CH3COO-
K,=
[CH3COOH]
The concentration of hydrogen ions, determined experimentally, in a 0. 1 M aqueous
solution of acetic acid is 0.00135 gram-ions per liter. Since one CHaCOO" is formed
every time an H3O+ formed, the concentration of acetate ions must also be 0.00135
is

gram-ions per Uter. The amount of undissociated acetic acid is 0.1 — 0.00135 moles
per liter. Substitution of these values in the equation gives the numerical value oiK^
for acetic acid.

[0.00135][0.00135]
K,^ - 1.8 X 10-
[0.1 0.00135]

Most carboxylic acids are relatively weak when compared with hydrochloric,
sulfuric, or nitric acid. They have approximately the same strength, regardless
of the length of the chain. Their strength may be increased markedly by the
presence of strongly electronegative substituents on the a-carbon. Note the
large increase in the ionization constant of acetic acid when the a-hydrogens are
successively replaced by chlorine (see Table 9-3). There will be a strong with-

TABLE 9-3 Ionization Constants of Some Carboxylic Acids

NAME
168 • Carboxylic Acids and Their Derivatives

drawal of electrons from the carboxyl end of the molecule owing to the elec-
tronegativity of chlorine. This facilitates the removal of the hydrogen as H+
(without electrons) or, in other words, increases the acidity of the molecule.

ci»-c— CI— c— C!_

I^
O-H
< h
Ij
We
Looked another way, the carbon-chlorine dipole places a positive charge near
at
the negative charge on the carboxylate group in the chloroacetate ion. This
partial neutralization of charge stabilizes the anion. Removal of the chlorine
to the )S-carbon (compare 2- and 3-chlorobutyric acids. Table 9-3) decreases the
effect. Electron-withdrawing substituents on the aromatic ring increase the
strengths of benzoic acids (compare /7-nitrobenzoic acid. Table 9-3).
As indicated by its ionization constant, formic about ten times as strong
acid is

as the other carboxylic acids in the series. one piece of experimental

This is

evidence upon which the notion that alkyl groups are electron-releasing com-
pared with hydrogen is based (see page 51). Whereas electron-withdrawing
groups increase the acidity of a carboxyhc acid, electron-releasing groups
decrease their acidity.

Resonance in the Carboxylate Ion

One wonders why the — OH of the carboxyl group

should give up protons
more easily — OH
of alcohols or phenols. The relative strengths of
than the
ethyl alcohol, phenol, and acetic acid are given in Table 9-3. Acetic acid is
about one hundred thousand times as strong as phenol, and the latter is lO^o
or ten thousand million times as strong an acid as alcohol. The increased
acidity of phenol over the alcohols has been discussed in terms of the stabiliza-
tion of the phenolate ion by resonance (page 104). A similar explanation may
be offered for the carboxylate ion.
X-ray studies on salts of carboxyhc acids show that the carbon-oxygen dis-
tance in the carboxylate ion is the same for both oxygen atoms, and Ues inter-
mediate between the usual distances separating the atoms in the and C=0
C — O bonds. This indicates that the two oxygen atoms in the ion are equivalent.

^9-- }0~ P--

R— < > R— C, or R—
: :
01/2-

The two structures differ only in the positions of the electrons. The true struc-
ture is a resonance hybrid of these extremes, possessing greater stabihty than
either. In molecular orbital terms, the carboxyl carbon is trigonal, using sp^
bonding attachment to R and the two oxygens (a planar system with 120°
for
angles). The remaining p orbital, perpendicular to this plane, overlaps with
similar orbitals on each oxygen, forming two molecular orbitals which accom-
modate the four remaining electrons.
 Carboxylic Acids and Their Derivatives 169

n o

There can be no doubt that resonance stabilization of the anion is a major

factor in the acidity of the carboxyl group. Another is the presence of the
strongly electronegative oxygen of the carbonyl, which attracts electrons and
therefore facihtates removal of the hydrogen ion. The alkoxide ion, RO~, which
would be formed from the ionization of an alcohol, cannot be stabilized by
resonance analogous to that which is important in the carboxylate anion.

Physical Properties

The lower aliphatic acids are liquids with sharp or unpleasant odors. Butyric
acid responsible for the disagreeable odor of rancid butter; the Ce, Cg, and
is

Cio straight-chain acids have the unpleasant odor associated with goats. Higher
fatty acids (greater than ten carbons) are waxlike soUds. Stearic acid, for
example, is mixed with paraffin in the manufacture of wax candles. The dicar-
boxylic and aromatic acids are crystalline soUds.
Molecular weight determination shows that formic acid and acetic acid con-
sist largely of dimers (two formula weights per molecule) even in the vapor
state.

_^
O H— \
CH,— C— CH,
^
O— O
The two units are probably held together by hydrogen bonds as indicated in the
above formula. This explains the high boiling points of the carboxylic acids in
comparison with their formula weights. The solubiUty of the lower molecular
weight acids in water is probably due to hydrogen bonding with the solvent.

TABLE 9-4 Physical Properties of Some Acids

SOLUBILITY,
NAME B.P. M.P.
GRAMS/1 OOg. HgO
FORMULA
OF ACID °C. °C.
AT 25°

Formic HCOOH 101 8

Acetic CH3COOH 118 17
miscible
Propionic CH3CH2COOH 141 -22
n-Butyric CH3CH2CH2COOH 164 -8
Coproic CH3(CH2)4COOH 202 -1.. 0.4
Capric CHalCHaJsCOOH 268 31
Palmitic CH3(CH2)i4COOH 356 64 almost insoluble
Stearic CH3(CH2)i6COOH 383 69
Benzoic C6H5COOH 249 122 about 0.4
Oxalic (COOH)2 189 about 15
170 • Carboxylic Acids and Their Derivatives

Preparation of Acids

Oxidation

The carbon atom in the carboxyl group is in a highly oxidized state (page
140). One would therefore expect it to be possible to prepare acids by oxidizing
other organic compounds (alkanes, alcohols, aldehydes).
Oxidation of alkanes to acids not readily controlled.
is However, under
special conditions higher alkanes from high-boihng petroleum fractions have
been successfully air-oxidized to carboxyhc acids similar to those derived from
fats. Such products were used in Germany during war time to make synthetic
edible fats.
When an alkyl group is a side chain on an aromatic ring (page 84), oxidation
occurs readily:

^ (j (9-1)

toluene benzoic acid

The oxidizing agent may be dilute nitric acid or potassium permanganate.

There may be more than one side chain, or the two side chains may be joined in
the form of a ring as in the case of naphthalene.

J"
,C— OH
(9-2)
vanadium
pentoxide
catalyst
"'^^i-^
~^C — OH
^/-^

naphthalene phthalic acid

Primary alcohols and aldehydes, when oxidized, give acids with the same
number of carbon atoms per molecule.
3 RCH2OH + 2 Na2+Cr207= + 8 H2+S04= ^

3 RCOOH -I- 2 Na2+S04= + 2 Cr2+++(S04)3= + 1 1 H2O (9-3)

Succinic acid, important in some living cell reactions, may be prepared from
1,4-butanediol (obtained indirectly from oat hulls).

CH2— CH2OH ,^,

101. r
^ C— OH
CH2—
(9-4)
i H2— CH2OH CH2— C— OH
1,4-butanediol O
succinic acic

Acetic acid is made commercially by the catalytic oxidation of ethanol or acetal-

dehyde. The acetaldehyde is usually prepared from acetylene (page 143).
 Carboxylic Acids and Their Derivatives 171
O
II

CH3CH MnO
CH,C— OH (9-5)
acetaldehyde acetic acid

Oxidation occasionally may be accomplished indirectly, as in the chlorination

of toluene to benzotrichloride, followed by its hydrolysis to benzoic acid (cf.
page 142).

CH,
1 72 • Carboxylic Acids and Their Derivatives

The acid formed has one more carbon atom per molecule than the alkyl halide.
Succinic acid may be prepared from ethylene by the following reaction
sequence.

CH2
^^ CH,C1 ^,.,,,^
CH^CN _^^ CH2C-OH
^
CH2 ^ CH2CI CH2CN H^ CH2C;:^OH '

The Grignard Method

Grignard reagents (page 127) react with carbon dioxide to form an addition
product which, upon hydrolysis, yields a carboxylic acid.

0=C=0 + RMgX > R— C— OMgX " ^'

> RC— OH + Mg+^XCl-
T' I'

(9-12)

This another method which may be used to increase the length of a carbon
is

chain, since the acid has one more carbon atom per molecule than the alkyl
halide from which the Grignard reagent was prepared.

CH3CH2CI —^^
dry ether
CH3CH2MgCl
^
-^^
ethyl chloride ethylmagnesium
chloride

o o
CH3CH2C-OMgCl -^^^^ CH3CH2C— OH (9-13)
propionic acid

In a similar manner, /7-bromo toluene may be converted to /7-toluic acid.

CH3 CH,

(9-14)

Br MgBr C\- + COOH

p-bromotoluene OMgBr p-toluic acid

Reactions of Acids and Their Derivatives

General Remarks

The carboxyl group, composed as it is of carbonyl and hydroxyl, displays

some properties of each. For example, the hydroxylic hydrogen can be replaced
by metals. Most reactions of acids and their derivatives, however, involve
attack by a nucleophile on the carbonyl carbon atom in reactions similar to
those of aldehydes and ketones (page 146). The net result of such reactions is
 Carboxylic Acids and Their Derivatives • 173
usually replacement of the hydroxyl group (or other group A in the case of acid
derivatives) by the nucleophile, usually through a tetrahedral intermediate as
shown.
R N R
^^ C ^=^ C=0: + :A (9-15)

The reactions are equilibria which may be driven to the right by using excess
reagent, removing some product from the reaction mixture, or a similar device.
They usually proceed more slowly than additions to aldehydes or ketones be-
cause the positive charge on the carbonyl carbon can in part be satisfied by un-
shared electron pairs on the group A.

O: :0: :0:

R— C— A < > R— C^
+
< > R— C=A
The reactions may be catalyzed by acid (a proton adds to the carbonyl oxygen)
or by base (a proton may be removed from a nucleophile, as in conversion of

HOH to :OH~, making it more nucleophilic).

Formation of Salts

Carboxylic acids dissolve in aqueous alkah to form salts.

R— + Na+OH- ^=± R— C^ + H2O (9-16)

OH 0-Na+

The crystalline salt may be obtained by using equivalent amounts of acid and
base and evaporating the water. Salts are named by changing the -ic ending of
the acid to -ate and preceding this with the name of the metal.

O — /O / ^O
CHsC^ (
^=^
Vc^ CHsCHsC^' I Ca-^+

^O-Na^ 0-K+ ^0-/2

\
sodium acetate potassium benzoate calcium propionate

The sodium and potassium salts are usually water-soluble, giving solutions
which are good conductors of an electric current. Their aqueous solutions are
alkaline because, being salts of strong bases and weak acids, they are appreciably
hydrolyzed. The sodium or potassium sahs of long-chain fatty acids are known
as soaps. Their chemistry will be discussed in detail in the following chapter.

CH3CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2C
> .
sodium pclmitate
1
0"Na+
(a soap)
174 Carboxylic Acids and Their Derivatives

The calcium, magnesium, and iron salts of the long-chain acids are insoluble in
water. Automotive greases are made by mixing lubricating oil with salts (es-
pecially lithium salts) of long-chain fatty acids.

Reactions of Salts

The free acids may be liberated from their salts by treatment with a stronger
acid. Thus, a soap solution will form a precipitate of the organic acid when it is
treated with a strong mineral acid. This is the final step in the manufacture of
stearic acid from fats (for use in wax candles).

CH3(CH2)i6C;^ + H+Cl- > CH3(CH2)i6C^ | + Na+Q- (9-17)

0-Na+ OH
sodium stearate stearic acid

The thermal decomposition of salts gives rise to several classes of compounds,

the exact nature ofwhich depends upon the positive ion of the salt. Sodium
salts of acids, when heated with soda lime (NaOH — CaO), give hydrocarbons
with the accompanying loss of carbon dioxide. This reaction is known as
decarboxylation or removal of the carboxyl group. Although methane can be
prepared in fair yields by heating a mixture of sodium acetate and soda Ume
(see page 31), the decarboxylation process is more important in the aromatic
series.

C^ + Na+Oi H- + Na2+C03= (9-18)

0-Na+
I

sodium benzene
benzoate

When the salt of a divalent metal, such as calcium, is heated, an inorganic

carbonate is again formed, but the organic product is a ketone.

O
J"
CH, c
o CHs
Ca^ -i^^ C=0 -h Ca++C03= (9-19)

X o-
CHs-C

calcium acetate

The calcium or barium salt of a dibasic acid gives rise to a cyclic ketone.
 Carboxyiic A cids and Their Derivatives 175

^CHs-
CH2 o
Ba^
heat
^ CH2 C=0 + Ba++C03= (9-20)
CH. X O- \
CH2- CH2
o
barium adipate cyclopentanone

The reactionis sometimes conveniently carried out by passing the acid (not the

salt) through a hot tube (300-400°) packed with CaO, BaO, or MnO.

MnO
R— C^OH HO— C- -R
300-
> R— C— R + H2O + CO2 (9-21)
II II

O o O
Acetone is made commercially from acetic acid in this way (see page 143).
Ammonium salts of carboxyUc acids, when heated, lose water to form amides.
O
_-^
R— heat
> R— c^ + H2O (9-22)
O-NH4+ NH2
amide

O
CH3C -h NH3 ^ CHsC i^^^ CHsCf^ -hH20 (9-23)
OH O-NH4+ NH2
ammonium acetate acetcmide

Formation of Acyl Halides

Just as with the alcohols, the hydroxyl group of acids may be replaced by
halogens. The products obtained are acyl halides. The most common reagents
used for this purpose are the phosphorus halides (PCI3, PCI5) and thionyl
chloride (SOCI2). The latter is particularly useful for higher boiUng acyl
haUdes, because the other two products are gases (excess thionyl chloride, a low-
boiling liquid, can be removed by distillation).

J" J"
R—C— OH -h PClj R-C— Cl + HClt + POCI3 (9-24)
phosphorus
oxychloride

o
J" J^
R— C— OH + SOCI2 > R— C— Cl + HClj + S02t (9-25)

Acyl bromides and iodides may be prepared by similar methods, although they
are less important than the chlorides.
1 76 • Carboxylic Acids and Their Derivatives

Figure 9-3. Models of acyl halide, acetyl chloride.

Acyl halides cannot be prepared by the action of a hydrohalic acid (HX) on

the carboxyUc acid. Although the hydroxyl group of alcohols can be replaced
by halogen in this way (page 104), the reaction, which is a reversible one in any
event, proceeds entirely in the opposite direction with acids. The acyl halides
are very rapidly hydrolyzed to the corresponding acid and HX.

Reactions of Acyl Halides

The presence of a halogen attached directly to the carbonyl carbon en-

hances its reactivity markedly. The effect is due to electron withdrawal by
the halogen, which increases the positive charge on the carbonyl carbon atom,

R— C—
H >

making it more by electron-supplying reagents (nucleo-

susceptible to attack
philes). For this reason the acid halides are highly reactive compounds which
are useful in the preparation of other acid derivatives. They fume in air, owing to
hydrolysis by the moisture in the atmosphere.

H
CH; CH3 0- H
C^: + HOH
CI
acetyl chloride

CH, CH,
Cl--h C=0: C=0 + H : (9-26)

H-^O
acetic acid
H
 Carboxylic Acids and Their Derivatives \77
Aromatic acid chlorides react somewhat more slowly, because the aromatic
ring can supply, through resonance, the electrons which the carbonyl carbon
needs.
.O .o
r\_y -C + r.^^^
.

HOH heat

slow
> ( \-c( +
\ /
H+Cl- (9-27)
CI OH
benzoyl chloride benzoic acid

Acid haUdes react with alcohols or ammonia in an analogous manner. These

known as alcoholysis and ammonolysis (similar to hydrolysis).
reactions are

R— C— CI + H— OR' > R— C— OR' + H+Cl" (9-28)

I I an ester

R—C— Cl + 2 H— NH2 » R—C— NH2 + NHi+Cl- (9-29)

t i an amide

Formation of Esters

When an organic acid is heated with an alcohol, especially in the presence of a

trace of mineral acid as a catalyst, equilibrium is established with the ester and

water.

.0<-
OH
R— C— OH + R'OH ^= R— C— OR' ^=± R— C— OR' + H2O (9-30)
t
acid alcohol
I

OH ester

^O ^o
CH3C— OH + CH3CH2OH ^^ CH3C— OCH2CH3 + H2O (9-31)
acetic acid ethyl alcohol ethyl acetate

Figure 9-4. Models of the ester, ethyl acetate.

178 Carboxylic Acids and Their Derivatives

The equilibrium may be toward the right by removal (by distillation or

shifted
other suitable means) of the water as it is formed.

Esters may also be prepared by the action of alcohols on acyl halides.

CH3CH2CH2C + CH3CH2OH >

\
CI
n-butyryl chloride

CH3CH2CH2C— OCH2CH3 + H+Cl- (9-32)

ethyl n-butyrate

Before proceeding with the chemistry of esters, let us consider their nomen-
clature. The esters are named in a manner analogous to the salts of acids, except
that the name of the alkyl group replaces the name of the metal.

CH3— C— 0-Na+ CH3-C^

sodium ocetate (salt) O-CH3
methyl acetate (ester)

o
CH,— CH3CH2C^ /^Hs
0CH2CH3 O— CH
ethyl acetate ^CH3
isopropyl propionate

o o
J"
CH3-C <OCH2CH3
°-o ethyl benzoate
phenyl acetate

Figure 9-5. Although the flavors and aromas of

fruits are often due to the combined effects of
several compounds, the principal esters present in

oranges, bananas, and apples ore octyl acetate,

amyl acetate, and isoamyl isovolerate, respec-
tively. (8/ack S\ar.)
 Carboxylic Acids and Their Derivatives 179
Esters are usually rather pleasant-smelling substances which are responsible
for the flavor and fragrance of many fruits and flowers. Some of the more com-
mon are ethyl formate (artificial rum flavor), «-amyl acetate (bananas), octyl
acetate (oranges), ethyl butyrate (pineapples), and amyl (C5) butyrate (apri-
cots). Artificial flavors of strawberry, cherry, raspberry, apple, etc., are made
largely from mixtures of esters.

Mechanism of Esterification

Reaction of benzoic acid with methanol enriched in the O^^ isotope of oxygen
gave labelled methyl benzoate and water containing no excess O^^. This tracer

rvc^oH+ HIOI8CH3 -i^ f Vc— 01 8CH3 + H20 (9-33)

experiment can be explained by a mechanism involving nucleophiUc attack by

the methanolic oxygen on the carbonyl carbon of the acid.

.0 OH
f VC— OH + H+ = rvcr
OH
CH3OI8H

OH OH
(9-34)

"CHaOiSH ~CH30i8H

O-pH O
H2O 4- C— OI8CH3 / VC— OI8CH3 + H+
This scheme of reversible reactions applies to most esterifications and also to the
reverse process, acid-catalyzed hydrolyses of esters.

Some Reactions of Esters

Esters may be converted to their component alcohols and acids by boiling

with aqueous sodium hydroxide. The reaction is known as saponification, since
it involves the same process as the making of soap from fats (see Chapter 11).

J" ^Q
R— C— OR' -h Na+OH
heat
R— \ + R'OH (9-35)

ester alkali 0-Na+ alcohol

sodium salt of acid

1 80 • Carboxylic Acids and Their Derivatives

CH3C-OCH2CH2CH3 + Na+OH- ^^^^ CHsC^ + CH3CH2CH2OH

n-propyl acetate 0~Na n-propyl alcohol

sodium acetate
(9-36)

For most esters, the reaction rate depends on the concentration of ester and
hydroxide ion; the rate-determining step is therefore probably nucleophiUc
attack by hydroxide ion on the carbonyl carbon of the ester.

*
'
slow /^ "

R— C— R— CA)R' R— C— OH
I

OR' -h/OH- ^^E^ ^=± + :OR'-

\ y •
OH
I

(9-37)

A rapid proton transfer to the strong base (alkoxide ion) completes the reaction.
Labelling experiments support this mechanism.

O O
•
R— C— OH R— C— O"
II II

+ :OR'- > + R'OH (9-38)

Esters react with alcohols or with ammonia in a manner analogous to saponi-

fication.
Alcoholysis:

J/ basic _ ^^
R— C— OR' + HOR" . ,

catalyst
^ R—C— OR" + R'OH (9-39)
^ '

Ammonolysis:

R— /P -h
,.
HNH2 >
_
R—
P + R'OH (9-40)

OR' NH2
Alcoholysis of esters which leads to the formation of another ester is sometimes
called ester interchange or transesterification. The reaction has been used
industrially in the manufacture of detergents. Ammonolysis occurs more
slowly with esters than with acid chlorides; the product is an amide.
Like many unsaturated molecules, esters can be reduced. This may be
accomphshed catalytically, or with a variety of chemical reducing agents. One
obtains not only the same alcohol as would be produced by saponification

//
R— C— OR'
P 2 H2
heat, pressure
^ RCH2OH R'OH
-h -F
copper chromite
catalyst

(9-41)
LiAlH4 or
Na in C2H5OH
 Carboxylic Acids and Their Derivatives 181

(R'OH), but also the alcohol corresponding to the acid portion of the ester.
Indeed acids may be reduced directly to alcohols with lithium aluminum hy-
dride (but not catalytically).

Formation of Anhydrides

Acid anhydrides are derived from acids by removal of the elements of water.
is shown below for two familiar inorganic acids.
This relationship

H2CO3 CO2 H2SO4 SO3

carbonic carbon dioxide sulfuric sulfur trioxide
acid (carbonic acid acid (sulfuric acid
anhydride) anhydride)

This same relationship is shown between organic acids and their anhydrides.

O
R— C— OH R— ,^
\
O
R- C— OH R—
two molecules of a
o
carboxylic acid carboxylic acid
anhydride

Figure 9-6. Models of acetic anhydride.

182 • Carboxylic Acids and Their Derivatives

Acid anhydrides are easily prepared by the action of an acid chloride on a salt.

/^ no
R— C— CI R— C— O— C— R
II II

Na+O—C—
II

+ solvent
> + Na+Cl" (9-42)
^

o o o o
CH3C— CI + Na+O— CCH3 -t^i^ CH3C— O— CCH3 + Na+Cl- (9-43)
acetyl chloride sodium acetate acetic anhydride

Acetic anhydride is produced in quantities approaching 100,000 tons per year

for use as a convenient source of acetyl groups in the manufacture of rayon (page
288) and aspirin (page 200). It is made by addition of acetic acid to the un-
usually reactive pyrolysis product of acetone, ketene.

o
I' 700° CIA C^Ct H
^"^^°^"
00
O—
I' II

CH3CCH3 — CH4 ' "

> CH2==C=0 > CH3C— C— CH3 (9-44)
ketene acetic anhydride
(a gas)

Phthalic anhydride is prepared by oxidation of naphthalene (page 170) or

o-xylene.

CH3
[Ol
or
13

naphthalene o-xylene f\ O
phthalic anhydride

(9-45)

It is used in making synthetic resins for surface coatings and plasticizers (page
190).

Reactions of Anhydrides

The reactions of acid anhydrides are analogous to those of acid chlorides but
are not so vigorous. Since they are easier to control, anhydrides lend them-
selves better to large-scale industrial reactions than do the acid halides. Hy-
drolysis, alcoholysis, and ammonolysis of anhydrides are illustrated in the
following equations.
Hydrolysis:

CH3CH2C / O
/ O + HOH > 2 CH3CH2C— OH (9-46)

CH3CH2C propionic acid

^O
propionic anhydride
 Carboxylic Acids and Their Derivatives • 1 83
Alcoholysis:

CHs-Q/' O
K .^
X
O + CH3CH2OH > CH3C— OCH2CH3 + CH3COOH (9-47)

CH3-C ethyl acetate

o
acetic anhydride

The acetylation of an alcohol with acetic anhydride is a useful reaction in the

study of carbohydrates (Chapter 14).

Ammonolysis

CH2-C
—
.-

CH2-C-NH2
/ p + HNH2 > I

CH2-COOH
(9-48)
CH2-c(
^/^ succinamic acid

succinic anhydride

Amides

Amides have the general formula

yO
R — C — NH2. They are named from the
corresponding acids.

o o
H—
NH2
CHsC^
NH2 o-< NH.
formamide acetamide benzamide

Figure 9-7. Models of the amide, ocetomide.

184 • Carboxylic Acids and Their Derivatives

Amides may be prepared by the action of heat on an ammonium salt (page

175), or by the ammonolysis of acid halides (page 177), esters (page 180), or
acid anhydrides (page 183). They are intermediates in the hydrolysis of a
cyanide to an acid (page 171). With the exception of formamide (b.p. 210°),
the simple amides are white crystalline solids which, because of their character-
istic melting points, may be used to identify the corresponding acid (by deter-
mining the melting point of its amide).
—
Rotation about the C N bond in amides is restricted, even though the bond
is formally single. This is due primarily to contributions from resonance struc-
tures in which the carbon-nitrogen bond is double. The C —
N bond distance
^6; ;o;.-

N— ^N—
I I

H H
in amides is appreciably shorter than the usual C—N single bond distance
( 1 .32 A, cf1 .47 A). Further, the four atoms attached to the carbon and nitrogen
tend to lie in one plane. This geometric restriction has important consequences
for the structures of proteins (Chapter 15) and other polyamides.
Amides hydrolyze slowly even in boiling water. In the presence of moderately
concentrated acid or alkali, however, hydrolysis to the acid does occur.

R— C— NH2 + HOH -^ R—C— OH + NH4+

heat
(9-49)

^o
R— C— NH2 + HOH -^ R— C-O- + NHst
heat
+ H2O (9-50)

If the hydrolysis is carried out in acid solution, the free organic acid and an
ammonium salt are formed, whereas in a solution of a base, the anion of the
acid and ammonia gas are the products.
Amides may be dehydrated to the corresponding cyanides.

/)
R—C— NH2 -^^ R— C=N
heat
+ H2O
1
^
(9-51)
V /

Urea
The diamide of carbonic acid, urea, is the normal end-product of human
metaboHsm of nitrogen-containing foods (proteins). About 30 grams are
excreted daily in the urine of an average adult. The laboratory synthesis of

O O
HO— C— OH H2N— C— NH2
carbonic acid urea
 Carboxylic Acids and Their Derivatives • 185

urea by Wohler (1828) was instrumental in the overthrow of the "vital force"
theory of organic chemistry.
Urea is now prepared and in the manu-
in large quantities for use as a fertiUzer
facture of urea-formaldehyde plastics. A
commercial synthesis involves the
reaction of ammonia with carbon dioxide under pressure.

I
/OH O-NH4+
^^ 0=C
1

0=C=0 + HNH2 r^^^^^ 0=C^

"^
1
NH2 NH2
carbamic acid ammonium carbamate

NH2
0=C(^ -KHsO (9-52)

NH2
urea

HO
Drugs (barbiturates) prepared from urea and the ester of malonic or a substi-
tuted malonic acid are used as sedatives or sleeping powders.

O
I . . II II

N-fH CsHsOf-C C2H5 /^"~^\ /^2H5

0=C

HO
"" + )c(
^N^H CaHsOl-C C2H5

ethyl diethylmalonate
-^^ 0=c( y^
^^"if
O
veronal (barbital)
^^^^
(9-53)

When urea is heated gently, ammonia is evolved and biuret is produced. An

alkaline solution of biuret gives a violet-pink color when copper sulfate solution
isadded, due to the formation of a complex ion. Since proteins and peptides
(Chapter 15) contain a similar geometric arrangement of amide groups, they also
give the biuret color test.

o
gentle
00
II I'

2NH2CNH2 healing
> NH2CNHCNH2 + NH3T (9-54)
biuret

Summary of Acid Derivatives

The hydrolysis, alcoholysis, and ammonolysis reactions of some acid deriva-

tives are summarized in the following table.
1 86 • Carboxylic Acids and Their Derivatives

TABLE 9-5 Summary of Some Reactions of Acid Derivatives

 Carboxylic Acids and Their Derivatives • 1 87

C— OH C— OH

FeBra
+ HBrt (9-57)

m-bromobenzoic acid

Friedel-Crafts Ketone Synthesis

Acyl halides and other acid derivatives react with aromatic compounds when
is used to form ketones.
a Friedel-Crafts catalyst

O O
R— C— CI + ( )
^^ R— C-^ \ -h HClt (9-58)

The reaction is an electrophilic aromatic substitution, the electrophile being an

acyl cation (acylium ion).

O
II

R— C— CI + AICI3 ^^ R— C=0 -h AICI4- (9-59a)

acylium ion

o
R-c=o + Q -^ ^-^^^ -^ '^-^^ + "^ '^-5^^>

H+ + AICI4- > HCl -h AICI3 (9-59c)

Acid anhydrides react in an analogous manner.

J ^^^ Y^
/^ ^ I
-"" CH3C
^ CH3COOH
CH3-C ^^ KJ
(9-60)

O acetophenone
(methyl phenyl ketone)

The First Members of the Series

Formic Acid
As the first member of the series of carboxyUc acids, formic acid exhibits sev-
eral distinctive chemical reactions. It is prepared by heating carbon monoxide
and alkali.
188 Carboxylic Acids and Their Derivatives

.O
200°
CO + Na+OH pressure
-> HC— 0-Na+ (9-61)
sodium formate

The free acid is liberated from the salt by careful warming with sulfuric acid.
The conditions must be well controlled, because sulfuric acid may dehydrate
formic acid according to the equation:

60-70°
HC— OH H2SO4
^ CO + H2O (9-62)

Formic acid may be decarboxylated more readily than other acids, and heating
to 160° is sufficient to bring about the reaction.

160°
H- C— H > H2 + CO2 (9-63)

Another striking property that contrasts formic acid with other members of
the series is its ease of oxidation. (Notice that there is a carbon-hydrogen bond
at the partially oxidized carbon atom of formic acid, whereas all other carboxylic
acids have a C — C bond at this point.)

O O
II

H— C— OH
II
[O]
HO— C— OH ^ CO2 + H2O (9-64)

Even such a mild agent as Tollens' reagent (page 145) can bring about the oxida-
tion. Thus formic acid gives a positive silver mirror test similar to aldehydes.
Because of its acidity and reducing properties, formic acid finds considerable
industrial use as a cheap organic acid, particularly in the textile industry.
Formic acid, which has a blistering action on the skin, is contained in the sting
of bees and ants.

Oxalic Acid

The first member of the dicarboxylic acid series also has certain distinctive
properties. It is prepared by heating sodium formate in the presence of alkaU.

HC— 0-Na+ he,, C— 0-Na+

-^^^^U
NaOH
-FH2 (9-65)
HC— 0-Na+
I

c-0-Na+
"^O ^o
sodiur slate

Oxalic acid occurs in the cell sap of many plants as the potassium or calcium
salt. The free acid is poisonous, but is usually removed from any foods which
Figure 9-8. At left, from tiny holes in a spinneret, fine filaments extrude which are twisted
together to make a single end of continuous-filament yarn. The principle applies to nylon, Orion
acrylic fiber, Dacron polyester fiber, and many other man-made yarns. The number of filaments in

a single thread of man-made yarn ranges from one, as in sheer hosiery, to 2,934 in tire cord. At
the right is shown a light-weight modern fire hose made from Dacron polyester fiber. (Both photos
courtesy of E.I. DuPont DeNemours & Company, Inc.)

contain it (such as rhubarb) by the cooking process, OxaHc acid decomposes

at its melting point.

C— OH 190=
> H2O + CO + CO2 (9-66)
C— OH
^O
Like formic acid, oxaUc acid is readily oxidized to carbon dioxide and water.
Use is frequently made of the reducing properties of oxalic acid in laundries for
the removal of stains and ink spots. It reduces the colored, insoluble ferric salts

of ink, etc., to the colorless, soluble ferrous salts. Rust stains may be removed
from porcelain in the same way. Oxahc acid is used in the bleaching of straw
and wood, and in the printing and dyeing of cloth.

Polyesters

When a dicarboxyhc acid reacts with a dihydric alcohol, ester linkages may
be formed at each end of each molecule, thus building up a large molecule con-
taining many ester linkages. The synthetic fiber Dacron is such a polyester,
prepared from terephthahc acid and ethylene glycol.

189
190 • Carboxylic Acids and Their Derivatives

O O
Q O
o o
. II

HO^C
II

-C-v-OH
,-

H OCH2CH2O H HOtC
I !
C^OH H1OCH2CH2O1H
glycol
terephthalic acid

o
HOCH2CH2O— C— OCH2CH2O- H (9-67)

polyethylene terephtholote
(Dacron)

The fiberproduced from this polyester has exceptional elastic recovery prop-
erties which contribute to its crease-resistance. It also absorbs little moisture,
its properties when wet being almost the same as when dry. The same polyester
can be converted to a film (Mylar) of unusual strength.
If a trihydroxy alcohol, such as glycerol, is employed, the possibility for cross-
finking appears. The glyptal resins which find applications chiefly as coatings
in the lacquer and paint industry are polyesters of glycerol and phthalic acid.

NEW CONCEPTS, FACTS. AND TERMS

1. The carboxyl group (from carborvyX and hydroxy/).
2. Nomenclature
a. I.U.P.A.C. -oic acid (pa§,e 165)
b. Mainly common names
c. Substituents frequently designated by a, yS, etc., and common name
d. The acyl group
3. Strength of acids; increased by electron-withdrawing groups.
4. Resonance of the carboxylate ion.
5. Preparation of acids
a. Oxidation of aromatic side chain, primary alcohols, aldehydes
b. Hydrolysis of cyanides
c.Grignard reagent and carbon dioxide
6. Reactions of acids and their derivatives; most reactions involve attack of a nucleophile
at the carbonyl carbon
a. Salts
/. Formed by neutralizing the acids
//. Thermal decomposition of salts; salts of alkaU metals, with alkaU, give
hydrocarbons; salts of divalent metals give ketones; ammonium salts give

amides
b. Acid haUdes
/. Formed from acids and PX3, PX5, or SOCI2
a. Hydrolysis gives acids, alcoholysis gives esters, ammonolysis gives amides
c. Esters
/. Formation from acids and alcohols, from acid chlorides and alcohols
//. Nomenclature (page 178)
 Carboxylic Acids and Their Derivatives • 191

///. Mechanism of esteriiication

iv. Saponification (hydrolysis with alkaU)
V. Alcoholysis, ammonolysis
vi.Hydrogenolysis yields two alcohols
d. Anhydrides
/. Formed from salts and acid hahdes
//. Hydrolysis, alcoholysis, ammonolysis
e. Amides
Formed from ammonium
/. salts by heating; from ammonolysis of anhy-
drides, acid hahdes, esters
/'/'.
Geometry of amides
///. Hydrolysis
iv. Urea, biuret
7. Substitution reactions of acids; halogen enters the a-carbon in ahphatic acids (HVZ
reaction), the meta position in aromatic acids.
8. Friedel-Crafts ketone synthesis (from acid hahdes or anhydrides, aromatic hydrocar-
bons and AICI3).
9. First members of the series; formic, oxahc.
10. Polyesters, Dacron.

EXERCISES AND PROBLEMS

1.1 Write structural formulas for the following compounds:

a. isobutyric acid /. a-naphthoic acid
b. 3-bromopentanoic acid g. a-chloropropionic acid
c. m-chlorobenzoic acid jk malonic acid
d. 2,4-dinitrobenzoic acid K a-chlorosuccinic acid
e. 3-chloro-2,3-dimethylbutanoic acid p. phthalic acid
Write the structural formula for each of the following compounds:
a. calcium acetate /. sodium benzoate
b. propionamide g. ethyl a-chloroacetate
c. isobutyryl chloride h. /7-bromobenzoyl chloride
d. ethyl butyrate /.

e.
 1 92 • Carboxylic Acids and Their Derivatives

Ur-^Name each of the following compounds:

^y a. (CH3(CH2)2C02)2-Ba++ /. (CeHsCOsO

Zj>% (CH3)2CHCH2C02C2H5 g. BrCH2CH2CONH2

^?T^C/'^."CH3(CH2)2COBr h. {(ZOtQ^^^)^ ^o^cX^xt^
^^ -
X02CH(CH3)2 n? •,^.^COO-K+
CI oc-i^^-
e. CH3CH2CH(CH3)CONH2 7. CH3CH2COCI cr ?. . ^ \^ '^^^ C^-*--
^ 5. In each of the following pairs of acids, which would be expected to be the stronger and
why?
a. CH2CICOOH and CH2ICOOH
h. CH3(CH2)2CHBrCOOH and CH3CHBr(CH2)2COOH
c. CH3COOH and CH2BrCOOH
d. CCI3COOH and CF3COOH
e. C6H5COOHand/7-CF3C6H4COOH
6. Two useful methods for extending the carbon chain of a molecule by a single carbon
atom involve the formation of carboxyUc acids. Write equations for these synthetic
methods,
w.j By means of equations indicate a good method for synthesizing each of the following
acids:

<@ propionic acid from «-propyl alcohol

{(^ propionic acid from ethyl alcohol
c. propionic acid from ethyl alcohol (by a method different from b)
i(^ o-chlorobenzoic acid from o-chlorotoluene
e. malonic acid from chloroacetic acid

succinic acid from ethylene

J.
(^g) a-methylbutyric acid from 2-butene
/^ ft. a-methoxyacetic acid from ethylene oxide
I
q8. jShow how the following compounds can be prepared starting with the appropriate acid:
potassium acetate ff) methyl benzoate
isobutyryl chloride ag!) benzoyl bromide
ethyl butyrate h. benzamide
succinic anhydride /. cyclopentanone
«-valeramide butyric anhydride
j.
9. Give the structural formulas of the parent members of the monobasic and dibasic
ahphatic acids. Write equations for two reactions of each which are not common to
other members of their respective homologous series.
10. Show how each of the following conversions could be accompUshed:
a. propionyl chloride to methyl propionate
b. acetic anhydride to acetamide
c. ethyl acetate to potassium acetate
d. «-valeric acid to 1-pentanol
e. «-butyryl bromide to «-butyramide
/. benzoyl chloride to ethyl benzoate
g. acetyl chloride to acetic anhydride
h. benzoic acid to benzene
/. acetic anhydride to acetone
j. propionyl chloride to a-bromopropionamide
 Carboxylic Acids and Their Derivatives • 193
11. What chemical tests can be used to distinguish the following compounds from each
other? Starting with benzene or toluene, show how each could be synthesized.
a. OCH3 b. COCl c. CHO d. COOH

CI
CI CI CI
12. Hydrolysis of anester, C4H8O2, gives an acid A and an alcohol B. Oxidation of B with
potassium dichromate and sulfuric acid yields A. Give the structure and name of the
original ester. Write equations for each reaction.
13. An ester C8H16O2 on hydrolysis gives an acid A and an alcohol B. Oxidation of B with
sodium dichromate gives a second acid C. Conversion of the acids A and C to their
sodium salts followed by fusion of each sodium salt with soUd sodium hydroxide yields
propane in each case. What is the structure of the original ester? Hint: Alcohol B, on
dehydration, yields isobutylene.
14. Write equations for the conversions indicated by the arrows:
tert-butyl alcohol ethyl acetate

isopropyl alcohol ^:^^ acetone ;^=i acetic acid ;?=^ acetic anhydride

I
propene ;;=^ 2-bromopropane > isobutyric acid

propane 2,2-dimethylbutane
15. Starting with acetylene as the only source of carbon, show by equations how the follow-
ing substances might be prepared. Use any inorganic materials that seem necessary.
a. acetic acid d. butyric acid
b. ethyl acetate e. 2-hydroxypropanoic acid
c. 1,3-butanediol /. propionic acid
16. Using general structural formulas, show what is meant by the terms: hydrolysis, am-
monolysis, and alcoholysis of acid halides, esters, and acid anhydrides.
17. Give the structural formula and where possible indicate an important use of each of
the following compounds:
a. urea d. terephthahc acid
b. biuret e. oxahc acid
c. carbamic acid /. phthaUc acid
18. The three carbon-oxygen bonds in potassium carbonate have the same length, 1.31 A,
and this is longer than the carbon-oxygen bond length found in potassium formate.
How do you account for this fact?
19. Based on equation (9-34), show the mechanism for the acid-catalyzed hydrolysis of an
ester RCOOR' in H2O18. Will the alcohol produced contain O^s?
20. Explain how the partial hydrolysis of methyl benzoate in aqueous alkali, in water con-
taining H20i^, could lead to the recovery of some methyl benzoate containing O^^ in
the carbonyl group (see equation (9-37)).
 Thus far we have concerned ourselves primarily
with the chemistry of compounds containing a singlefunctional
group. But many organic substances have two or more
groups within one molecule. In general,
different functional
the chemistry of these substances is the sum of the chemistry
of the individual functional groups, plus certain new prop-
erties due to the interaction of these groups when present in
the same molecule. In this chapter we shall consider the
chemistry of organic acids that contain a halogen, hydroxyI
group, a keto group, or a carbon-carbon double bond.

Substituted and Unsaturated

Acids

In substituted acids, the carboxyl group remains as such but the alkyl chain
or aromatic ring contains other substituents; the nature and position of these
substituents relative to the carboxyl group determine the properties of the
molecule. We will consider here halo-, hydroxy- and keto-acids, as well as un-
saturated acids, but will leave amino acids for a later chapter (see Chapter 15).

The Substituted Acids

Nomenclature
Many substituted acids are natural products of biological significance and are
usually known by their common names. Others may
be named by suitable
use of the I.U.P.A.C. system, or by location of the substituent on the chain with
the appropriate Greek letter (a, )S, y, 8, etc.). Several examples are given in
Table 10-1. Others will be named as we come to them.

194
 Substituted and Unsaturated Acids • 195
TABLE 10-1 Nomenclature of Some Substituted Acids

FORMULA
196 • Substituted and Unsaturated Acids

CH2=CH— C— OH + H+ ^=:^

JdH ^
OH
CH2=CH— C— OH < ^ CH2— CH=C (10-3)

an allylic carbonium ion OH

Br-

BrCHzCHjC— OH ^^ BrCH2CH=C— OH
enol form of the final product

Halogenated acids can often be converted to hydroxylated acids by treatment

with dilute alkali.

O O
CH3-CH-C^
\
Jilutebase^
Na2^C03-
CH3-CH-C''
\
^^ H+
OH
I I

^r l)H O-Na-

CH3-CH-C (10-4)

OH OH
lactic acid
(fl-hydroxypropionic acid)

Combination of two previously studied reactions affords another excellent

synthesis for a-hydroxylated acids. Cyanohydrins are readily prepared (page
146) from aldehydes or ketones. The cyano group may then be hydrolyzed to
a carboxyl group (page 171).

/O ?" ?" ^o
C''
R— + H+CN- » R-C— CN -S^S^ R—C— (10-5)

H i I^
OH
cyanohydrin a-hydroxyacid

CH3—
/> "'""
)
T
CH3-C-CN -!i^ CH3— C—
T /"
(10-6)

H I k OH
lactonitrile lactic acid

O OH OH Q
\=J \=/ \=/ \qj^
mandelonitriie mandelic acid (AC\ 1\
(occurs in almonds)
 Substituted and Unsaturated Acids 197
The Claisen condensation, a reaction in many ways analogous to the aldol
condensation (page 153), constitutes the most important synthetic route to
^-ketoesters. Treatment of ethyl acetate with a strong base (sodium ethoxide in
ethanol) furnishes ethyl acetoacetate according to the mechanism shown:

CH3C— 0C2H5 + -0C2H5 =^

ethyl acetate
^^ ^^_

-CH2-C-OC2H5 ^-^ CH2=C-OC2H5 + C2H5OH

v_

CH3C-OC2H5 (10-8)

O O O
^^'"\
P .0
CH3CCH2COC2H5 - CH3-C-CH2-C-OC2H5
ethyl acetoacetate d
'0C2H5
The net reaction is

o o 00
CHbCToCzHT + "h^ -^^^ CH3CCH2COC2H5 + C2H5OH
(10-9)

The corresponding ketoacid can be obtained by careful hydrolysis of the ester.

Alternatively, ketoesters can be prepared by oxidation of the corresponding
hydroxyesters.

.0
_^ ^o
CH3— CH— \
[O]
^ CH3— c— c (10-10)
\_
OH
I

OH o OH
lactic acid pyruvic acid
(a-ketopropionic acid)

Reactions of Substituted Acids

The reactions exhibited by the substituted acids reflect the previously studied
chemistry of the individual functional groups. As acids, they form all of the
normal acid derivatives (salts, acid haUdes, amides, etc.) discussed in Chapter 9.
The halogen of a substituted acid possesses properties characteristic of alkyl
halides. It may, in general, be replaced by a variety of other groups by simple
displacement (see page 126 for a summary of these groups). Dehydrohalogena-
tion with alcoholic alkali affords unsaturated acids (equation (10-1)).
Ketoesters show the common reactions of both functional groups. Thus they
react with the usual carbonyl reagents (hydrogen cyanide, hydroxylamine,
198 Substituted and Unsaturated Acids

phenylhydrazine, etc.) and can also be hydrolyzed (to ketoacids), ammonolyzed

(to ketoamides), etc. yS-Ketoesters show some special reactions. They are weak
hydrogens on the carbon between the two carbonyl groups being readily
acids,
removed by strong base because the resulting anion is resonance-stabilized.
The anion is a good nucleophile and can displace halide ion from primary or
secondary alkyl halides (p. 126), giving substituted acetoacetic esters.

o o o o o- o
II II K... 11-11 II

R— C— CH2— C— OEt
I
 Substituted and Unsaturated A cids • 1 99
When an a-hydroxyacid is heated, a bimolecular reaction occurs.

CHs-CH-C^ H /)
r-n >-_--_-_--i CH3-C-C\
OJH OH heat
+2H2O
^ O O (10-15)
[ho OiH
.C-C-CH3
\:-CH-CH3 o^ H
o
lactic acid a lactide

The product is a cyclic di-ester with a six-membered ring known as a lactide.

Phenolic Acids

The most important of the phenohc acids is the ortho isomer, salicylic acid.
manufactured industrially by heating the sodium salt of phenol with carbon
It is

dioxide under pressure.

pressure ^^^ ^(^ ^^^ Q

heat \ \
0-Na+ ^OH
salicylic acid

(o-hydroxybenzoic acid)

The reactions of phenolic acids are the same as those of the aromatic acids
(Chapter 9) and phenols (Chapter 5). Sahcyhc acid is used in the preparation
of several medicinals such as oil of wintergreen and aspirin. The carboxyl group
can be esterified in the usual manner.

OH ^ OH

^\
J^ + CH3OH ^^ K^J^ ^
^\
+ HOH (10-17)

OH OCH3
salicylic acid methyl salicylate
(oil of wintergreen)

The hydroxyl group may be esterified by reaction with acetyl chloride or acetic
anhydride.

O + >0 + CH3COOH
^^^^^O
>

// CH3-C
OH ^ OH
acetic anhydride acetylsalicylic acid
200 Substituted and Unsaturated Acids

The water-soluble sodium salt is aspirin. Annual production in the United

States, in the neighborhood of 30 million pounds, is sufficient to produce over
30 billion standard tablets, or more than 150 tablets per person per year.

O
Q— C— CH, OH
O
j^
c
O-Na^
phenyl salicylate
sodium acetylsalicylate (salol)
(aspirin)

Salol, the phenyl ester of salicylic acid, may be prepared by the action of phenol
on the acid chloride of salicylic acid. It is stable toward acids and may there-
fore pass through the stomach unchanged, but in the alkaline medium of the in-
testines it is hydrolyzed to salicyhc acid and phenol. Salol is used for coating
pills in order to permit their contents to pass into the intestines before acting.
This is desirable, for many drugs have an upsetting effect on the stomach or
would be destroyed by the normal acidity of the stomach.

Biologically Important Hydroxylated Acids

The most important of the simple hydroxylated acids is lactic acid.

o
^^
CHs— CH— C;
OH OH
lactic acid

It is present in sour milk and in many foods such as cheese, wine, and sauerkraut
which are fermented in processing or storage. It is prepared commercially

Figure 10-1. Models of lactic acid.

i
 Substituted and Unsaturated Acids • 201
(about 5 million pounds annually) from the action of certain bacteria on milk
sugar (lactose), glucose, or starch for use as a food-stuff additive. Lactic acid is

produced in muscle tissue by enzymatic reduction of pyruvic acid.

Citric acid is a hydroxylated acid, with three carboxyl groups, which
is found

and other citrus fruits. It is

in the juices of fruits, particularly lemon, lime,
added to many soft drinks and candies. Citric acid is an important intermediate
in carbohydrate metabohsm, and is a normal constituent of blood serum and
human urine.
Tartaric acid is a dihydroxylated succinic acid. It is prepared from grape juice

ferments, first being obtained in the form of its monopotassium salt, cream of
tartar. Tartar is a sludgy precipitate which forms during fermentation of grapes.

CH2— COOH COOH

HO— C— COOH H— C— OH
CH2— COOH H— C— OH
COOH
citric acid tartaric acid

Potassium hydrogen tartrate is used in medicine as a laxative. The sodium po-

tassium salt is baking powder. The acid itself is used in carbonated beverages
and effervescent tablets. Tartaric acid is interesting because of its role in the
study of an important type of isomerism which will be discussed in detail in
Chapter 13.

Unsaturated Acids
In the following chapter we will consider the important role of unsaturation in
the long-chain fatty acids. We wish here to discuss only the simpler, short-chain
fatty acids with one double bond in the a, y8 position relative to the carboxyl
group.

R—CH=CH— J^
H a

OH
a,;8-unsaturated acid

Nomenclature and Preparation

Many of these substances have common names. In Table 10-2 are hsted the
formulas and names of some of the more important a,)S-unsaturated acids. The
two common names for the last entry in the table are explained below.
The double bond is usually introduced into the molecule by any of the several
general methods for preparing olefins (pages 58-59). Dehydrohalogenation
with alkah is illustrated in the preparation of acrylic acid from a-bromopropionic
acid (equation (10-1)). )8-Hydroxylated acids give unsaturated acids when de-
202 • Substituted and Unsaturated Acids
TABLE 10-2 Some Common Unsaturated Acids

FORMULA
 w

Figure 10-2. Domes made of transparent Plexiglas acrylic plastic permit swimming all year
round. (Courtesy of Rohm & Haas Company.)

o o o
HO— CH— C— OH 1.0
H-C-C-OH H— C— C— OH
1^^^ +
H— CH— C— OH
II

H— C— C— OH
II

"=°
HO— C— C—
II II

O O O
malic acid maleic acid fumaric acid

H2, Ni (10-21)

O O
HO— C— CH2CH2— C— OH
succinic acid

geometric isomerism, and a few years later it was recognized that maleic and
fumaric acids were examples of such isomers. The cis structure was assigned to
maleic acid mainly because of the ease with which it forms an anhydride.
Fumaric acid must be heated to a much higher temperature before an anhydride
is formed; it then rearranges to maleic acid and forms maleic anhydride.

^O
HC— C— OH HC—
140°

/
;o + H20 (10-22)
HC— C—OH HC— %
^O O
203
204 • Substituted and Unsaturated Acids
TABLE 10-3 Physical Properties of Maleic and Fumaric Acids

PROPERTY
 Substituted and Unsaturated Acids • 205
O Q

+ O ^^^^ (10-24)

1 ,3-butadiene maleic C(s-1 ,2,3,4-tetrahydrophthalic

anhydride anhydride

NEW CONCEPTS. FACTS. AND TERMS

1. Substituted acids (halo, hydroxy, and keto acids).
2. Nomenclature (page 194).

3. Preparation
a. a-Halogenated acids (from the acid, phosphorus, and a halogen)
b. yS-Halogenated acids (from a-halogenated acids by dehydrohalogenation and
addition of HX)
c. Hydroxyacids (from the corresponding halogenated acid and dilute alkaU)
d. a-Hydroxyacids (from the cyanohydrin by hydrolysis)
e. /S-Ketoacids via the Claisen condensation of esters
4. Reactions of substituted acids: effect of heat on hydroxyacids
a. Alkylation and decarboxylation of /8-ketoesters and acids
b. y and 5-hydroxyacids give lactones (cycUc monoesters)
c. )3-Hydroxyacids give a,;S-unsaturated acids
d. a-Hydroxyacids give lactides (cyclic diesters)
5. Phenohc acids, salicylic acid, oil of wintergreen, aspirin, salol.
6. Biologically important hydroxylated acids; lactic, citric, tartaric.
7. Unsaturated acids; nomenclature (page 201) and preparation; maleic and fumaric
acids.

EXERCISES AND PROBLEMS

1. Write structural formulas for the following substituted acids:

a. )S-chloropropionic acid e. 4-hydroxypentanoic acid
b. chloroacetic acid /. lactic acid

c. a-bromovaleric acid g. )8-hydroxybutyric acid

d. saUcyhc acid h. 4-methyl-2-hydroxybenzoic acid

2. iName the following acids: hUo^cJa,!. e ,

s^ CH2FCOOH ^t^'-*-'^
^^J'
h6oCCH(OH)CH2COOH
<by (CH3)2CHCOOH2'''^^r^^'jB CH2BrCH2COOH ^ JU/w^-^
s^ CH3CHClCOOH^''''^i^^i'*^ CH3CHCICH2COOH ^--AiU^u^ ^
CH3CHBrCH2COOH3.^>—' /t.' CH3CHOH(CH2)2COOH «
C<f)

^ CH3CHOHCOOH.^;^r:X;: fi o
v^-vo*'-*'
V^^
c- c ,
»
loW^L^^uv^

/^ \VCHOHCOOH
-r^.'^M*-^
II

k. CH3CC(CH3)2COOH
f-

*^'
^uv^2--M_ f^^i^^^
206 • Substituted and Unsaturated A cids
3. Using general formulas, write a structural formula for each of the following
types of compounds:
a. a,^-unsaturated acid
b. a-hydroxyacid
c. lactide
d. lactone
e. phenoUc acid
/. ^-haloacid
g. a-ketoester
4. Using a-, ^-, and y-hydroxybutyric acids, illustrate with equations the effect of position
of the hydroxyl group on the types of products obtained when a hydroxyacid is dehy-
drated by heating.
5. Give equations showing a good method for preparing each of the following compounds:
a. acryUc acid from propionic acid

b. 3-bromobutyric acid from butyric acid

c. 2(/?-chlorophenyl)-2-hydroxyacetic acid from /7-chlorobenzaldehyde

d. salicyclic acid from phenol
e. cinnamic acid from benzaldehyde
/. 4-methylcyclohexanecarboxyhc acid from /;-bromotoluene
g. 4-phenyl-2-butanone from ethyl acetoacetate and benzyl bromide
h. 2-methyl-3-ketopentanoic acid from ethyl propionate
6. Write equations for the reactions of a-bromopropionic acid with each of the following
reagents and name each product.
a. cold dilute NaOH d. KCN followed by hydrolysis
b. hot dilute NaOH e. ethyl alcohol (plus H"*" catalyst)
c. excess NH4OH /. thionyl chloride (SOCI2)
7. How might lactic acid be converted to each of the following products?
a. n-butyl lactate d. a-aminopropionic acid (alanine)
b. acetic acid e. propylene glycol
c. methyl pyruvate
8. Write structural formulas for and show how to distinguish chemically between salicyhc
acid, oil of wintergreen, and aspirin.
9. Write equations for the following reactions:
a. acryhc acid + H2 and catalyst
b. methyl acrylate + H2 and catalyst
c. bromine and crotonic acid
d. hydrogen bromide and crotonic acid
e. oxidation of cinnamic acid with potassium permanganate
/. maleic acid + H2 and catalyst
10. A substance with the molecular formula C9H8O2 (A) is soluble in dilute sodium car-
bonate. It decolorizes Br2 rapidly to give C9H802Br2 (B). Catalytic hydrogenation of
A yields C9H10O2 (C) and treatment of A with hydrogen bromide produces C9H902Br
(D). Oxidation of the original material A with permanganate yields an acid C7H6O2
(E) which on bromination yields mainly a single derivative C7H502Br (F). What is
the structure of A? Write equations for aU reactions mentioned.
11. A compound with the molecular formula C5H902Br (A) is soluble in dilute sodium
hydroxide. When treated with alcoholic potassium hydroxide, A is converted to B,
which readily decolorizes bromine. When treated with hydrogen bromide, B gives a
compound isomeric with A. Catalytic hydrogenation of B gives «-valeric acid. Suggest
a structural formula for A, and write equations for all the reactions.
 Substituted and Unsaturated Acids • 207
12. Illustrate with formulas the structural features necessary in order that a molecule show
geometric {cis-trans) isomerism. Draw the cis and trans formulas for the products e
and /"prepared in Question 5.

13. Two isomeric acids have the molecular formula C4H8O3; both react with acetyl chloride,
but give no iodoform with NaOH and iodine. On dehydration with a mineral acid,
one of these acids forms a single substance C4H6O2 while the other gives two substances
with the same formula C4H6O2. There are no other products in either case. Deduce
structures for the original acids which fit these data.
14. A phenohc acid CgHgOa (A) exists in two isomeric forms. Both rapidly decolorize
permanganate and on moderate oxidation yield salicylic and oxalic acids as the only
organic products. One isomer of A easily loses water, when heated, to yield C9H6O2;
the other fails to dehydrate under the same conditions. Suggest structural formulas for
the isomers.
15. Using equation (10-8) as a guide, show how diethyl adipate,

C2H500C(CH2)4COOC2H5,
O
might be converted to 2-carboethoxy-cyclopentanone, r''^— CO2C2H5, by treat-

ment with sodium ethoxide in ethanol.

16. When 10-hydroxydecanoic acid is heated, a polymer, molecular weight 9,000-10,000,

is obtained. Suggest a possible structure for this polymer.
17. From what reagents could the following compounds be synthesized by the Diels- Alder
reaction?
O
CHO b. CH
 One of the oldest organic chemical reactions is the
conversion of animal fats, by heating with water and wood
ashes The phenomenal development of
(alkali), into soap.

time of the ancient Greeks into the im-

this reaction from the

portant chemical industry it is today has been climaxed in

recent years by the production of many new synthetic deter-
gents. The German chemist Liebig once stated that "of two
countries with an equal amount of population, we may
declare, with positive certainty, that the wealthiest and most
highly civilized is that which consumes the greatest weight of
soap." An understanding of the chemistry offats has also
led to important developments in the related drying oils and
waxes.

Fats, Oils, Waxes, and

Detergents

Fats, oils, and waxes belong to the group of naturally occurring organic
materials called lipids (from the Greek lipos,
fat). Lipids are those constituents
of plants or animals which are insoluble in water, but soluble in ether or other
relatively non-polar organic solvents. They are distinguished in this way from
the other two major classes of foodstuffs, the proteins and carbohydrates.
Lipids may be subdivided into two groups, depending on whether or not they
can be hydrolyzed with aqueous base (saponified). Fats, oils, and waxes are
saponifiable, whereas steroids (Chapter 16) are non-saponifiable hpids.
We are all familiar with the manifold uses of fats for frying, making pastries,
and for concocting salad dressings. The main sources of fat in our diet are milk,
cream, butter, lard, oleomargarine, bacon fat, solid vegetable fats, and liquid

208
 Fats, Oils, Waxes, and Detergents 209
vegetable oils. Fats and oils are also important chemical raw materials.
Closely related to fats and oils are the various waxes (beeswax, spermaceti,
camauba wax) and soaps.

Fats and Oils

Typical animal fats or vegetable oils such as beef tallow, com oil, or cotton-
seed oil are insoluble in water, but dissolve slowly in boihng aqueous alkali.
Analysis of these alkaline solutions leads to the isolation of glycerol and salts of
Some of the acids are saturated, some are un-
a mixture of carboxylic acids.
saturated,and most have an even number of carbon atoms (usually twelve to
twenty carbon atoms). TYms fats and oils are esters of glycerol with carboxylic
acids (glycerides).
O
II

CH2— O— C—
O
CH— O— C—
o
CH2— O— C—
a glyceride

The distinction between fats and oils is based primarily upon the differences
in melting points. Fats are solid esters of glycerol, whereas oils are liquid esieis

of glycerol. It is apparent that this distinction is not sharp since it depends upon
chmate. weather, and other physical variables. The melting point of a fat or oil

depends upon the nature of the R group of the fatty acid portion of the molecule.
When R is saturated, the glycerol esters are generally soUds. Double bonds in
the R groups tend to lower the melting point. Thus, the R groups in an oil are

usually highly unsaturated, whereas fewer double bonds are present in fats. The
more common saturated and unsaturated acids obtained from fats are hsted in
Table 11-1.

TABLE 11-1 Common Acids Derived from Fats

210 • Fats, Oils, Waxes, and Detergents

Glycerides

Triesters of glycerol are known as glycerides. Simple glycerides are esters in

which all three hydroxyl groups of glycerol are esterified with the same acid (that
is, all R groups are the same).

O o
CH20C(CH2)i4CH3 CH20C(CH2)i6CH3
O O
CHOC(CH2)i4CH3 CHOC(CH2)i6CH3
O O
CH20C(CH2)i4CH3 CH20C(CH2)i6CH3
glyceryl tripalmitate glyceryl tristearate
(palmitin) (stearin)

In mixed glycerides, glycerol is esterified with two or three different acids.

O o
II

°CH2-OC(CH2)i4CH3 CH2-OC(CH2)i4CH3
O O
II

^CH— OC(CH2)i6CH3 CH-OC(CH2)i6CH3

O O
II

" CH2-OC(CH2)i4CH3 CH2— OC(CH2)7CH=CH(CH2)7CH3

y8-stearo-a,a'-dipalmitin glyceryl palmitostearooleate

Both simple and mixed glycerides are present in natural fats and oils. In gen-
eral, does not consist of a pure glyceride, but rather of com-
a natural fat or oil

plex mixtures of glycerides. The composition of a fat is usually expressed in

Figure 11-1. Scale model of a long-chain fatty acid, stearic acid.

 Fats, Oils, Waxes, and Detergents 211
terms of the acids which may be obtained from it by hydrolysis. Certain fats
or oils give mainly one or two acids, as with oUve oil (83% oleic acid, 6% palmitic
acid, 4% stearic acid and 7% linoleic acid) or palm oil (437c palmitic acid, 43%
oleic acid, 10% linoleic acid, 4% stearic acid). Others are very complex: butter
fat contains esters of at least fourteen different acids.* Butter is different from
most other fats in that it contains appreciable amounts of glycerides of the lower
molecular weight fatty acids, including butyric acid.
The possibility for geometric isomerism exists for unsaturated fatty acids.
The arrangement in the more common unsaturated acids is cis.

CH3(CH2)6CH2 CH2(CH2)6C02H

/
c=c\
H H
oleic acid

Reactions of Fats
We shall consider three fundamental reactions of fats, each of which has been
discussed previously for simpler molecules.

Hydrolysis of Fats

Boihng with aqueous alkali hydrolyzes (saponifies) fats to glycerol and salts

of fatty acids.

O
CH2OCR CH2OH
O
II
heat
CHOCR + 3 Na+OH > CHOH + 3 RC' (11-1)

O ^0-Na+
soap
CH2OCR CH2OH
glycerol

This reaction is used to manufacture soaps industrially.

Hydrogenation of Fats and Oils

Glycerides that have unsaturated R groups in the acid portion of the fat mole-
cule can be converted to saturated glycerides by catalytic hydrogenation. This
is by the conversion of olein to stearin, wherein hydrogen adds to the
illustrated
carbon-carbon double bonds (page 48). The hydrogenation of vegetable oils
is carried out on a large commercial scale. By decreasing the amount of unsatu-
ration in the oil, the melting point is gradually raised until the material becomes

*3% butyric, 1.4% caproic, 1.5% caprylic, 2.7%capric, 0.7% lauric, 12.1% myrisitic, 25.3% palmitic,
9.2% stearic, 1.3% aracliidic, 0.4% lauroleic, 1.6% myristoleic, 4% palmitoleic, 29.6% oleic, and 3.6%
linoleic.
Figure 11-2. Fats can be obtained by hydrogenation of the olefmic double bonds in vegetable
oils. The beaker on the left contains clear oil before hydrogenation. On the right, the same oil is

shown hardened by hydrogenation. (Courtesy of The Procter & Gamble Company.)

a solid fat. These vegetable fats (Crisco, Spry, etc.) are sold for kitchen use.
This process of hydrogenation of oils to fats is sometimes called hardening.
Oleomargarine and various other butter substitutes are generally mixtures of
vegetable oils or animal fats which have been partially hydrogenated to a con-
sistency resembling that of butter. The most common starting materials are

o O
CH20C(CH2)7CH=CH(CH2)7CH3 CH20C(CH2)i6CH3
O O
3H2
CHOC(CH2)7CH=CH(CH2)7CH3 > CHOC(CH2)i6CH3 (11-2)
Ni catalyst

O heat
O
II II

CH20C(CH2)7CH=CH(CH2)7CH3 CH20C(CH2)i6CH3
olein stearin

cottonseed, soy bean, or peanut oil. The product is frequently churned with
milk and artificially colored to simulate the flavor and appearance of butter.
(Itshould be noted that during the winter months, butter itself is often artificially
colored to make it more attractive to the consumer.)

212
 Fats, Oils, Waxes, and Detergents 213

Hydrogenolysis of Fats

If the hydrogenation process is carried beyond the formation of a saturated

fat, hydrogenolysis of the ester hnkage may occur (page 1 80). This resuhs in
the formation of long-chain saturated alcohols which, as we shall see below, are
used in the manufacture of many synthetic detergents.

O
II

CH3(CH2)i4-C- pCH2
O
OCH + 6H2 '^'^^'P™
CH3(CH2)i4-C- copper chromite
>

catalyst
O
CH3(CH2)i4-C- OCH2 CH2OH
palmitin

3 CH3(CH2)i4CH20H + CHOH (11-3)

CH2OH
cetyl alcohol glycerol

Two moles of hydrogen are used per ester linkage hydrogenated.

Long-chain unsaturated alcohols may be obtained by hydrogenolysis of un-
saturated glycerides, employing a catalyst such as zinc chromite, which causes
hydrogenolysis of the ester linkage without hydrogenation of the carbon-carbon
double bonds. For example, olein yields oleyl alcohol

CH3(CH2)7CH=CH(CH2)7CH20H.

Detergents
For centuries, soap was the major useful cleansing agent or detergent. But
been a phenomenal upsurge in the manufacture of
since the late forties there has
a great variety of synthetic detergents. Sales of synthetic detergents have over-
taken and rapidly passed the annual sales of ordinary soap. Yet much is to be
learned from the chemistry of soap itself, and we can more easily understand
the requirements and advantages of synthetics if we have a background knowl-
edge of ordinary soaps.

Preparation of Soaps

Sodium salts of long-chain carboxylic acids are the most widely used soaps.
The potassium salts form soaps which are usually softer and more soluble; they
find limited use in Uquid soaps and shaving creams.
214 • Fats, Oils, Waxes, and Detergents

Soaps may be prepared by the saponification of natural or hardened fats with

a sHght excess of alkaU (caustic soda) in a heated open kettle. When the reaction
is complete, salt is added to precipitate the soap as thick curds. The water layer,
containing salt, glycerol, and excess alkali, is drawn off and the glycerol is
recovered by vacuum distillation.
The crude soap curds contain some salt, alkali, and glycerol as impurities.
These are removed by boiling with water and re-precipitation with salt several
times. Finally, the soap is boiled with sufficient water to form a smooth mixture
which, on standing, gives a homogeneous upper layer of soap. This may be sold
without further processing as an inexpensive industrial soap. Various fillers
such as sand, pumice, or sodium carbonate may be added to make scouring
soaps. Other treatments transform the crude soaps into toilet soaps, powdered
or flaked soaps, medicated soaps, laundry soaps, Uquid soaps, and, by blowing
air in, even floating soaps.

Mechanism of Soap Action

The cleansing action of soaps is a complex phenomenon for which many

theories have, at one time or another, been proposed. Here, we present a

simplified explanation.
The most important characteristic of a soap is that one end of the molecule
is highly polar or ionic, whereas the remainder of the molecule is nonpolar or

hydrocarbon-like.

nonpolar, lyophilic
0-Na+
polar,
hydrophilic
sodium stearate, an ordinary soap

The polar end of the molecule tends to make it water-soluble (hydrophUic or

attracted to water), whereas the nonpolar end of the molecule tends to make it
oil-soluble (lyophilic or attracted to fats). It has been shown that, if a droplet
of a fatty acid is placed upon the surface of water, it spreads out to form a thin
film with a thickness of one molecule. The molecules in this film are arranged so
that the carboxyl (polar) end dips into the water, and the molecules stand on end
(Figure 1 1-3). When soap molecules (salts which have a considerably more

Figure 11-3. Carboxylic acid film on water showing orientation of the polar end
toward the surface of the water.

hydrocarbon
chain
1: carboxyl
group
 Fats, Oils, Waxes, and Detergents • 215

Figure 1 1-4. A soap micelle.

polar end than the fatty acids) dissolve in water, they form opalescent or colloi-
dal rather than true solutions. These soap solutions contain aggregates of soap
molecules or micelles (Figure In order to form such solutions, the hydro-
1 1-4).

carbon part of the molecule should not be too long (generally twelve to eighteen
carbon atoms).
Oil and water do not mix. When a small amount of oil and a soap solution are
shaken, an emulsion of the oil in the soap solution is formed. The soap mole-
cules surround the fine oil droplets, their hydrocarbon "tails" being soluble in
the oil (Figure 11-5). The ionic or hydrophihc ends then stabilize the droplet
in the water solution, the surface charge of the droplets preventing coalescence.
Another striking property of soap solutions is their unusually low surface ten-
sion. This increases the "wetting" power of the soap solution over that of water.
It is a combination of the surface action and emulsifying power of soap solutions

which enables them to surround and carry away dirt, grease, and oil particles.

Chemistry of Soaps
Soaps, being the sodium or potassium salts of weak acids, are converted by
stronger mineral acids into the free fatty acids.

O
C17H35C, + H+Cl- > C17H35C i + Na+Cl- (11-4)
ONa- OH
sodium stearate stearic acid

Figure 11-5. An oil droplet becomes emulsified

when surrounded by soap molecules.
216 Fats, Oils, Waxes, and Detergents

Soaps cannot be used in acidic solutions, because a scum or precipitate of the

water-insoluble fatty acids will be formed.
The formation of a scum is also observed when ordinary soaps are used in hard
water, due to the presence of calcium, magnesium, or ferric ions. The salts of
these ions with fatty acids are insoluble, and form a precipitate when soap is
added to hard water.

2 C17H35C + Ca++ -. (Ci7H35COO)2-Ca++i + 2Na+ (11-5)

0-Na+ calcium stearate

Precipitation in this manner is undesirable not only because of the difficulty in

cleansing, but also because of the waste of soap.

Synthetic Detergents (Syndets) or Surface-Active Agents (Surfactants)

In recent years, detergents have been produced which have as good cleansing
power as ordinary soaps or better but which avoid some of their disadvantages.
Synthetic detergent molecules are designed according to the principles discussed

Figure 1 1-6. The suds in Sudbury, Massachusetts, looked like floating snowdrifts at the Old Grist

Mill on the grounds of famed Wayside Inn. The condition was blamed on detergents, used by house-
wives, draining into Hop Brook and then being aerated into suds by the grist mill and the waterfall.

Excessive use of detergents has created similar problems in septic tanks and sewage disposal
plants. (Wide World Photo.)
 Fats, Oils, Waxes, and Detergents • 217
above under the mechanism of soap action; that is, they have a long carbon
chain (twelve to eighteen atoms) and a highly polar group at one end of the
molecule. Their primary difference from ordinary soaps is that they do not
form precipitates with calcium, magnesium, or ferric ions. For this reason, they
may be used with essentially the same efficiency in hard or soft water.
Several hundred synthetic detergents are now marketed in this country.
Sodium salts of alkylsulfuric acids constitute one of the more important types.
They are manufactured from long-chain alcohols and sulfuric acid. The mix-
ture of alcohols obtained from the hydrogenolysis of coconut oil consists chiefly
of lauryl alcohol, CH3(CH2)ioCH20H, which reacts with suhuric acid to give an
alkyl hydrogen sulfate (page 106).

CH3(CH2)ioCH20H + HOSO2OH > CH3(CH2)ioCH20S020H + H2O

lauryl alcohol lauryl hydrogen sulfate

(11-6)
CH3(CH2)ioCH20S020H + Na+OH" >

CH3(CH2)ioCH20S020-Na+ + H2O
sodium lauryl sulfate

The physical resemblance (long nonpolar carbon chain with an ionic group on
the end) of the synthetic detergent molecule to that of ordinary soap is obvious.
Long-chain olefins (C12 to Cig) derived from polypropylene or polybutenes may
also be converted to synthetic detergents by addition of sulfuric acid to the
double bond, followed by neutralization.
The sodium salts of alkylarylsulfonic acids constitute another important type
of syndet. They are manufactured by alkylation (Friedel-Crafts) of benzene
with propylene tetramer (page 54) and subsequent sulfonation of the benzene
ring.

R-/^ S020-Na+

sodium alkylarylsulfonate (R = 12 C's)

Neutral and positive (cationic) syndets are also known; some will be men-
tioned in subsequent chapters.

Drying Oils

Certain fatty oils possess the property of forming a hard tough film when
exposed to the air in thin layers. The process is referred to as drying, although
it is not drying in the sense of evaporation, but rather a comphcated series of
reactions of the oil with the oxygen of the air which lead to the formation of a
dry film. The phenomenon seems to involve both oxidation and polymeriza-
tion and is particularly associated with highly unsaturated oils.
The most common drying oil is linseed oil (obtained from flax seed) although
218 • Fats, Oils, Waxes, and Detergents

many other oils (tung, soy bean, etc.) are used extensively. Linseed oil con-
tains large percentages of glycerides of linoleic and linolenic acids. Raw linseed
oil "drys" rather slowly, but the process may be hastened by boiling the raw oil
with soluble cobalt, manganese, or lead salts. Oil paints are suspensions of very
finely divided inorganic pigments in is made by applying
hnseed oil. Oilcloth
several coats of a linseed oil-paint to woven
Linoleum is made from a
fabric.
mixture of ground cork, boiled linseed oil, and rosin which has been pressed
together and "dried." Over a billion pounds of drying oils are used annually
in this country.
Because most drying oils are imported (from the Orient or South America),
research in this country has been directed to modifying available oils to increase
their drying power. Castor oil (from the castor bean), is about 85% the glyceride

of ricinoleic acid. Its double bond content can be increased by dehydration.

CH3(CH2)4CH2CHCH2CH=CH(CH2)7C
OH OH
ricmoieic acii

The drying ability of the product thus obtained compares favorably with that of
Unseed oil.

Analysis of Fats and Oils

It has been shown above that many properties of fats and oils are determined

by the carbon chain length and by the degree of unsaturation of the chains.
Since fats and oils are obtained from natural sources, their composition is
variable. In order to have some control over the raw materials used in the
manufacture of soaps, synthetic detergents, drying oils, and other products
derived from fats and oils, many analytical methods have been devised. Two
of the more important of these are described here.
Fats and oils may
be saponified quantitatively. The saponification number,
which is number of milligrams of potassium hydroxide required to
defined as the
hydrolyze I gram of a fat or oil, gives an indication of the average molecular
weight of the fat, or of the average length of the carbon chain of the fatty acid
portions. The higher the saponification number of a fat, the greater the percent-
age of short-chain, low-molecular weight glycerides it contains.
The degree of unsaturation of a fat or oil is expressed in terms of its iodine
number; that is, the number of grams of iodine which will combine with one
hundred grams of the fat or oil. Iodine in an alcoholic solution of mercuric
chloride adds to the carbon-carbon double bonds of the fatty acid portion of
the molecule. The more double bonds (greater unsaturation) in the fat, the
greater will be its iodine number.
The saponification and iodine numbers of several fats and oils are given in
Table 1 1 -2. Note the high saponification number of butter fat (which contains
 Fats, Oils, Waxes, and Detergents • 219
TABLE 1 1 -2 Analysis of Some Fats and Oils

FAT OR OIL
220 • Fats, Oils, Waxes, and Detergents

CH3(CH2)i4CH2CH2COOH + CoA— SH
stearic acid

o
II

CH3(CH2)i4CH2CH2C— S— CoA + HgO

stearic acid thioester

OH O -2H
I II

CH3(CH2)i4CH-CH2-C— S-CoA ^-^^^

O
-2H
CH3(CH2)i4CH=CH— C— S— CoA (11-7)

O o
CH3(CH2)i4C— CH2— C— S— CoA ^°^~^" >

|S-ketoester

o o
II II

CH3(CH2)i4C— S— CoA + CH3C— S— CoA

palmitic acid thioester acetyl — CoA

The coenzyme forms thioesters with fatty acids. In the scheme above, the
degradation of stearic acid to palmitic acid (loss of two carbons) is represented.
The thioester of CoA — SH, in a series of enzymatic reactions, is oxidized (dehy-
drogenated), hydrated, and oxidized again to a /S-ketoester which then breaks
down to acetyl —
CoA and an ester with two less carbon atoms. The process is
continued until the entire chain is degraded. The oxidation steps are exo-
thermic and furnish energy to the body.
In diabetes melhtus, certain steps in the degradation of fatty acids fail, and
acetoacetic acid and its decarboxylation product acetone accumulate in the
body.

O O o
II II II
normal
CH3CCH2C— S— CoA -> 2CH.C— S— CoA
CoA— SH
acetyl — CoA

abnormal (11-8)

o o O
CH3CCH2COH ^ CH3CCH3 + CO2
acetoacetic acid acetone

Synthesis of fatty acids from acetate units occurs according to scheme (11-9).
Acetyl — CoA is carboxylated enzymatically to malonyl — CoA by carbon
dioxide. Acetylation, followed by decarboxylation of the resulting )8-ketoacid,
 Fats. Oils, ^^'axes. and Deiergenis • 221
O o O O
''

ch,c-s-Coa
CH3C— S— CoA -^^ HOCCHoC— S— CoA
II 'I

^ j^qC— CH— C— S— CoA

acetyl CoA malonyl — CoA ~ —»_.

O (11-9)
O
I

'^"^^ ~^^^
CHsCH.CHX-S-CoA c
I CH3CCH.C-S-C0A < I

butyryl — CoA 3. 2 [H] ocetoocetyl — CoA

leads to acetoacetyl —
CoA. Reduction of the keto group, dehydration of the
and reduction of the unsaturated ester lead to butvn 1 CoA
resulting alcohol, —
which can again combine \Wth malonyl CoA to continue the cycle. —
The existence of separate processes for the synthesis and degradation of fatn"
acids permits automatic but essentially independent regulation of oxidation and
s\Tithesis rates bv the metabolizing cell.

Waxes
Waxes differ from fats and oils in that thev are not esters of glycerol, but rather
even-numbered fattv acids with long-chain,
are principallv esters of long-chain
even-numbered monohxdric alcohols. There is onlv one ester linkage in each
wax molecule.

R— C— OR'
a wax (R and R range from 16 to 36 carbons in length)

Waxes may be distinguished from fats in that they cannoi be transformed into
when boiled with alkah. They are saponified but. unlike
water-soluble products
glycerol, the long-chain alcohols are insoluble in water. Together with the esters,
waxes frequently contain small quantities of saturated hydrocarbons, free fatt)'
acids or alcohols, and sterols (page 318).
Beeswax is largely myricyl palmitate. C15H31CO2C30H61. Camauba wax
contains mvricyl cerotate. C25H51CO2C30H61. Spermaceti, obtained from the
head of the sperm whale, is mainly cetyl palmitate. C15H31CO2C16H33. Waxes
are generally more brittle, harder, and less greasv than fats. Thev are used in
making polishes, cosmetics, ointments and other pharmaceutical preparations,
and phonograph records.

NEW CONCEPTS. FACTS, AND TERMS

1. Fats and oils — esters of glvcerol with carbowlic acids. Chemically related, but difler

in amount of unsaturation.
2. Common acids derived from fats (page 209).
3. Glycerides. simple and mixed.
222 • Fats, Oils, Waxes, and Detergents

4. Reactions of fats
a. Hydrolysis to soap
b. Hydrogenation of oils to solid fats
c. Hydrogenolysis to long-chain alcohols
5. Detergents
a. Preparation of soaps
b. Mechanism of soap action
c. Chemistry of soaps
d. Synthetic detergents (syndets or surfactants)
6. Drying oils. Unseed oil, oilcloth, linoleum.
7. Analysis of fats and oils

a. Saponification number
b. Iodine number
8. MetaboUsm of fats; coenzyme A.
9. Waxes.

EXERCISES AND PROBLEMS

1. Write structural formulas for the following fats:

a. trilaurin c. glyceryl stearopalmitomyristate

b. glyceryl trioleate d. stearin
2. Name the following compounds (assume no branching of carbon chains):
a. CH2OCOC13H27 c. CH2OCOC15H31
CHOCOC13H27 CHOCOC15H31
CH2OCOC13H27 CH2OCOC15H31
b. CH2OCOC17H35 d CH2OCOC17H35
CHOCOC15H31 CHOCOC13H27
CH2OCOC17H35 CH2OCOC15H31
3. Write structural formulas for each of the following:
a. sodium stearate d. palmityl alcohol
b. calcium palmitate e. sodium /7-hexylbenzenesulfonate
c. sodium myristyl sulfate /. myricyl stearate
4. Write equations for the saponification, hydrogenation, and hydrogenolysis of glyceryl
linoleate.
5. What structural features are necessary to make a good detergent?
6. Explain (equations) why ordinary soaps do not work satisfactorily in hard water and
how synthetic detergents have overcome this defect.
7. Using specific examples, show by equations the synthesis of:
a. an ordinary soap

b. an alkyl hydrogen sulfate detergent

c. an alkylarylsulfonate detergent

8. What important structural feature is necessary to drying oils? How are drying oils
structurally related to fats? Give three practical uses of drying oils.

9. Show, with equations, how the drying properties of a drying oil could be destroyed and
how they could be increased.
 Fats, Oils, Waxes, and Detergents • 223
10. Calculate the saponification number of:

a. stearin b. palmitin
1 1 Calculate the iodine number of:

a. glyceryl trioleate b. glyceryl triUnoleate

12. Would a glyceride with a high iodine number be more hkely to be classified as a fat or
an oU? Explain the reason for your answer.
13. Butter has a saponification number of about 230 while that of oleomargarine is about
195. Suggest how the Pure Food and Drug Administration could make a practical
application of these data.
14. Illustrate with structural formulas the primary difference between a fat and a wax.

Using a specific example of a wax, show with equations how it might be converted into
a synthetic detergent.
15. How could one distinguish each member of the following pairs by simple chemical
tests?
a. mineral oil from cottonseed oil c. tributyrin from tristearin
b. palmitic acid from linoleic acid d. beeswax from beef taUow
16. Draw a general structural formula representing a thioester. What is the role of
thioesters in fat metabolism?
17. ester. In the diabetic patient, how does such a
Write a structural formula for a )S-keto
compound cause the production of acetone bodies in the blood?
18. Keeping in mind that three moles of KOH are needed to hydrolyze one mole of fat,
calculate the molecular weight of a fat whose saponification number is 210. What is
the average molecular weight of the R-groups in this fat?
19. has a molecular weight of 800 and an iodine number of 95.3, what
If a fat is the average
number of double bonds per fat molecule?
20. Draw a possible mechanism for the formation of acetoacetyl CoA from — its immediate
precursor in equation (11-9).
 The most typical organic bases are structurally
related to the inorganic base, ammonia. They contain
organic groups attached to a nitrogen atom and are known
as amines. Amines are widely distributed in nature both in
plants and animals. The odor of decaying fish is due to
simple amines. Amines are used to manufacture local
anesthetics, sulfa drugs, and many other medicinals. One of
the raw materials used to produce the synthetic fiber nylon
isan aliphatic diamine. Aromatic amines can be converted
to a wide variety of organic dyestuffs.

Organic Nitrogen Compounds

The element nitrogen occurs in many classes of organic compounds, some of

which have already been discussed. These include nitro compounds, nitriles,
amides, and certain nitrogen derivatives of aldehydes and ketones. In this
chapter we will consider several additional groups of nitrogen-containing com-
pounds, focusing particular attention on amines, organic derivatives of am-
monia.

Nomenclature of Amines
Amines are classified as primary, secondary, or tertiary depending upon
whether one, two, or three of the hydrogen atoms of ammonia have been re-
placed by organic groups. These groups may be aliphatic or aromatic, or the
nitrogen may be part of a cycUc system. AUphatic amines are named either
from the alkyl groups attached to the nitrogen or by using the prefix amino-.

224
 Organic Nitrogen Compounds • 225

Figure 12-1. Models of ammonia.

NH3 RNH2 R2NH R3N

H— N— H CH3— N— H CHs— N— CH3 CH3— N— CH3
H H H CH3
methylamine dimethylamine trimethylamine
(primary) (secondary) (tertiary)

CH3CH2— N— CH3 HOCH2CH2CH2NH2 CH3NHCHCH2CH2CH2CH3

H ICH3
ethylmethylamine 3-amino-l -propanol 2-(N-methylamino)hexane
(secondary) (primary) (secondary)

Figure 12-2. Models of methylamine.

Figure 12-3. Models of dimethylamine.

226 Organic Nitrogen Compounds

Figure 12-4. Models of trimethylamine.

The simplest aromatic amine is aniline, and certain amines are named as deriva-
tives of it.

O- NH, CH ^^™- o<l";

aniline p-toluidine dimethylaniline
(primary) (primary) (tertiary)

NH. ^NH^
2,4,6-tribromoaniline diphenylamine)
(primary) (secondary)

Heterocyclic amines are usually known by common names. A few of the more
important of these ring systems which occur in natural products are shown with
the numbering systems used for substituents.

1
H H
pyridine pyrrole quinolme indole
(tertiary) (secondary) (tertiary) (secondary)
 Organic Nitrogen Compounds • 227
6

8/
I J.
'

9N^^N^
1 H
pyrimidine purine

General Characteristics of Amines

The simple amines resemble ammonia. The lower members of the
aliphatic
series are gaseswhich are readily soluble in water to give basic solutions. The
more volatile amines have odors similar to ammonia, but less pungent and more
fishlike. Some properties of amines are given in Table 12-1.
Amines can form intramolecular hydrogen bonds, although the N H- -N — •

bond is not as strong as the O—H • • • O bond because nitrogen is less elec-
tronegative than oxygen (compare, for example, the boihng points of CH3NH2
( — 6.5°) and CH3OH (65°)). All three classes of amines form hydrogen bonds
with water (N • H — O); for this reason most of the amines listed in Table 12-1
•

are quite soluble in water.

Although only three groups are attached to nitrogen, the bond angles in
amines and ammonia are closer to the tetrahedral angle expected for sp^ bond-

unshared electron pair -

CH,

ing than to 90° which would be expected for pure p bonds. But at ordinary
temperatures, amines interconvert from one pyramidal form to the mirror image
many times per second as shown. This process is not possible when the central

R2
228 • Organic Nitrogen Compounds

TABLE 12-1 Some Properties of Amines

NAME
 Organic Nitrogen Compounds • 229
The basic dissociation constant Kb for ammonia is written as the equilibrium
constant of equation (12-1). It is a measure of the base strength of ammonia.

Kb = [NH4+KOH = 2 X 10-5
[NH3

Similar expressions may be written for the amines. The larger the Ki, (that is, the

[CHaNHa]^ + [OH] (12-4)

^' - [CH3NH2] " ^

smaller the integer in the negative exponent), the stronger the base.

The dissociation constants for a number of simple amines are listed in Table
12-1. In general, aliphatic amines are shghtly stronger bases than ammonia,
because alkyl groups can stabilize the positive charge on nitrogen in the corre-
sponding ammonium ions. But aromatic amines are much weaker, primarily
because of resonance which is possible in the free base, but not in the aryl am-
monium ion.

the positive charge in

resonance structures of aniline the cnilinium ion cannot

be delocalized by resonance

Quaternary Ammonium Compounds

Tertiary amines react with alkyl halides to form products in which all four hy-
drogens of the ammonium ion have been replaced by organic groups. Such
compounds are called quaternary ammonium compounds.

R R
R:N + (R):X: R:N:R + x- (12-5)

R ii

CH3 CH3
CH3-N: +CH3I CH3-N-CH3 + 1- (12-6)

CHs CH3
trimethylamine tetramethylammonium iodide
230 Organic Nitrogen Compounds

^^\ + CH3I - (12-7)

pyridine N-methylpyridinium iodide

These substances have true salt-Hke properties; they are usually water-soluble
and give solutions which conduct electric current. A quaternary salt in which
one of the R groups is a long alkyl chain has the structure necessary for a good
detergent (page 214). Detergents that are quaternary ammonium salts are
known as invert soaps, because the ionic part is a positive ion, whereas most
soaps involve negative ions (anions). Many invert soaps, such as cetyltrimethyl-
ammonium chloride, CH3(CH2)i5N(CH3)3+Cl~, are used to steriUze dishes, in-
struments, skin surfaces, etc.

Quaternary salts can be converted to quaternary bases by treatment in

aqueous solution with silver hydroxide.

CH3 CH3
CH3— N— CH3 I- + AeOH CH3— N— CH3 OH--FAgU (12-8)

CH3 CH3
tetramethylammonium hydroxide

The precipitate of silver hahde is removed by filtration. Upon evaporation of

the filtrate, white dehquescent crystals of the quaternary base remain. These
substances are strong bases, similar to sodium or potassium hydroxide.
Several quaternary ammonium compounds have physiological activity.

Choline, or trimethyl-^-hydroxyethylammonium hydroxide, exists in combina-

tion withphosphohpids which make up part of brain and spinal cord tissue.
These are known as lecithins, and they may also be isolated from egg yolks.
O
CH2— O— C—
CH3 O
GH— O— C—
II

CH3— N— CH2CH2OH OH-

CH3 CHc
,0
choline
CH2— O— P— OCH2CH2— N— CH.
%.
O CH?
an a-lecithin

CH3 o
CH3— N— CH2CH2— O— C— CH3 OH-
CH3
acetylcholine
 Organic Nitrogen Compounds • 231

Choline is a depressant, causing a fall in the blood pressure. Acetylcholine is in-

volved in the transmission of nerve impulses to ganglion cells, and also of motor
nerve impulses to the fibers of voluntary muscles, resulting in muscle con-
traction. The "nerve gases" developed during World War II get their lethal
punch by damaging chohnesterase, an enzyme that hydrolyzes acetylchoUne to
choline. An example is diisopropylfluorophosphate, [(CH3)2CHO]2PFO.

Preparation of Amines

There are no entirely general methods which may be used to prepare all types
of amines. A few procedures may be used to make most primary amines, but
often the synthesis of an amine involves special consideration of the particular
case at hand. A few of the more useful reactions are discussed here.

Alkylation of Ammonia and Amines

This is the oldest amine synthesis. Ammonia, and amines, react with primary
and some secondary alkyl halides to form alkylammonium halides. The reac-
tion is a nucleophihc displacement (Sn2; see page 95) of hahde ion by the
unshared electron pair on the nitrogen.

HaNi-hR—X ^ [H3N R X] > H3NR + -X: (12-9)

alkylammonium halide

Treatment of the product with aikah hberates the free amine.

H
H— N— X- + Na+OH- > RNH2 + Na+X- + H2O (12-10)
primary
H amine

The reaction does not stop at the primary amine stage, for, hke ammonia, the
primary amine may also be alkylated by the alkyl halide to give some secondary
amine.
^''^""
RNH2 + RX > R2NH2+X- > R2NH + Na+X + H2O (12-11)
diolkylommonium secondary
halide amine

The secondary amine is also subject to alkylation, as is the tertiary amine

formed from it. A
mixture of products results, therefore, consisting of am-
monia, primary, secondary, and tertiary amines, and the quaternary ammonium
compound. The three ethylamines are manufactured commercially in this way
and are separated by fractional distillation. Use of a large excess of ammonia
favors the formation of the primary amine in largest quantity.
Methylaniline and dimethylanihne can be made from aniline by using the
appropriate amounts of methyl chloride.
232 Organic Nitrogen Compounds

Figure 12-5. Scale model of aniline.

CH3
NH2 + CH3CI N— ci- (12-12)
I

CH3
N— NHCHa + Na+Cl- + H2O
CI- + Na+OH
H (12-13)
methylaniline

Industrially, methyl alcohol and hydrogen chloride are used, under pressure, to
form the methyl chloride first. Aniline, methylaniline, and dimethylaniline are
important starting materials in the manufacture of dyes.

Reduction of Certain Nitrogen Compounds

Many nitrogen-containing compounds can be reduced to amines. Among
these are nitro compounds, cyanides, amides, and the oximes and other unsatu-
rated nitrogen compounds which were prepared as derivatives of aldehydes or
ketones (page 149). Either chemical or catalytic hydrogenation may be used.
Among the common chemical reducing agents are iron and steam, tin and hydro-
Hthium aluminum hydride. Several specific examples will illus-
chloric acid, or
method.
trate the
One commercial method for the manufacture of aniUne involves the reduction
of nitrobenzene with iron and steam.

rvi
\_/
-NO. + 6[H]
Fe
^,_ ^rvNH2-h2H20 (12-14)

nitrobenzene aniline

In the laboratory, hydrochloric acid is frequently used in place of steam. Most

primary aromatic amines are prepared from the corresponding nitro com-
 Organic Nitrogen Compounds • 233
pounds, since these are readily available by nitration of the aromatic ring
(page 79).
Cyanides (nitriles) afford primary amines, as do the oximes.

R— C^N + 4[H]
*
"=
Ni. heat
) RCHoNHo
- (12-15)
pressure

CHs CHs
C=N— OH + 4[H] > CH— NHs + HOH (12-16)

CHg CHs
acetone oxime isopropylamine

A^-Substituted amides give secondan^ or tertiar>^ amines, depending on whether

one or both hydrogens on the nitrogen are substituted.

O
/"^K-NH-C-CHs ^^^^^ A~^NH-CH2CH3 (12-17)

acetanilide N-ethylaniline

The Hofmann Reaction (Rearrangement)

The German chemist A. W. Hofmann. who did much to unravel the early
chemistry- of amines, discovered in 1881 that amides (RCONH2). when treated
in alkaline solution with bromine, gave good yields of primary' amines (RNH2).
The over-all reaction is

O
R— C— NH2 + Bro + 4NaOH ^ RNH2 + 2NaBr + Na2C03 -¥ 2 H2O
(12-18)

O
CH3CH2CH2C— NH2 .^^^^
Bro
CH3CH2CH2NH2 (12-19)

The mechanism bv which the R group migrates from carbon to nitrogen has been
studied in detail.The first step invoh'es base-catalN-zed bromination of the amide on
nitrogen (equation (12-20)). The iV-bromoamide. in a base, forms a salt which de-
composes, losing bromide ion. The intermediate fragment, having only six electrons

O O
R-C-NH2 J^£^^^ R-C-NHBr + Na+OH" (12-20)

amide N-bromoatnide

on nitrogen, stabilizes itself by migration of R with its electron pair. This rearrange-
ment is similar to the rearrangement of carbonium ions where a group migrates with
its electrons to an electron-deficient carbon (page 53). The resulting isocyanate

subsequently hydrolyzes to the amine.

234 Organic Nitrogen Compounds

O
R— C— N— Br R— N=C=0 + Na+Br- + H2O
olkyl isocyanate
Na^ (12-21)
(con sometimes
hypothetical
intermediate
be isolated)

(only six electrons on N;

therefore R moves with
its electron pair from
carbon to nitrogen)

O
R— N=C=0 + HOH R— NH— C— OH RNH2 + CO2 (12-22)
a carbamic acid

Reactions of Amines

Salt Formation
The unshared electron pair on nitrogen is involved in the initiating step of
most reactions of amines. In the formation of salts (page 228), the electron
pair is donated to a proton. Amines which may be insoluble in water can be
extracted from an organic solvent by aqueous acid. Amines can be separated
from neutral or acidic materials this way.

CH3-/ V-NHa + H+Cl- -^^ CHs^ VNH3+CI- (12-23)

p-toluldine p-toluidine hydrochloride

(water-insoluble) (a water-soluble salt)

The free amine can then be liberated from the aqueous solution by making it

alkaline.

CH: NH3+CI- + Na+OH

CH. r\ NH2 + Na+Cl- + H2O (12-24)

Naturally occurring amines (i.e. strychnine, nicotine) may be extracted from

the plant source in this way.

Acylation (Amines to Amides)

Primary and secondary aniines react with acid haUdes or acid anhydrides to
form substituted amides. Reaction is initiated by attack of the unshared
Figure 12-6. A swarm of mosquitoes in this test glass enclosure shows no interest in the man's arm
above the black line where meta-Delphene repellent has been applied, although they feast on his

untreated wrist and hand. It is remarkable that if the methyl group is in either of the other isomeric
positions (ortho or para) the compound is ineffective as an insect repellent. [U.S.D.A. Photo. Cour-

tesy of the Hercules Powder Company.)

nitrogen electron pair on the carbonyl carbon, as illustrated in the prepara-

tion of acetanilide from aniline and acetic anhydride.

O :0^
IK
CH3COCCH3A HsN^
II /^. /r\ >
J
aniline

O :0: O
P
CHsCd^C— CH3 "^"^^°^"
> CH3C— NH-H^ \ (12-25)

acetanilide

Acetanilide, sometimes known as antifebrin, is used in medicine to treat head-

aches, neuralgia, and mild fevers.
iV;iV-Diethyl-m-toluamide, the active ingredient in insect repellents such as
"Off" (Figure 12-6), is the amide of a secondary amine.

235
236 • Organic Nitrogen Compounds

Ta ?
/ Vc-Cl + HN(CH2CH3)2
'^''°"'
>

m-toluoyi chloride diethylamine

CHs
°
/ \ -C— N(CH2CH3)2 + Na+Cl- + H2O (12-26)

N,N-diethyl-fr)-toluamide
(meta-Delphene)

Tertiary amines, not having a hydrogen attached to the nitrogen atom, can-
not be acylated.

Sulfonamides

Sulfonyl chlorides (related to sulfonic acids in the same way that acyl hahdes
are related to carboxylic acids) react with ammonia and primary and secondary
amines to form sulfonamides. The reaction is similar to acylation, being
initiated by attack of the nitrogen's unshared electron pair on the sulfur atom.
Sulfanilamide, the first of the sulfa drugs, can be prepared from acetanihde by a
series of steps which involve sulfonation, ammonolysis of the sulfonic acid
chloride, and hydrolysis of the acetanilide group.

O O
NH— C— CH3 NH— C— CH3
II II

CISO3H
(chlorosulfonic
fi ^ NH3

acid)

acetanilide
SO2CI

o
NH— C— CHs
II

NH5

(12-27)

SO2NH2 SO2NH2
sulfanilamide

The sulfonamides may also be used as a basis for distinguishing between

primary, secondary, and tertiary amines. The sulfonamides formed from
primary and secondary amines are usually crystalline soUds.
 Organic Nitrogen Compounds 2Z7

r^ SO2CI + RNH2
Na+OH
.rV:SO2NHR + Na+Cl- + H2O
(12-28)
benzenesulfonyl alkylsulfommide
chloride (soluble in base)

Na+OH
/ VSO2CI + R2NH -> / VSO2NR2 + Na+Cl- + H2O
(12-29)
dialkylsulfonamide
(insoluble in base)

O- SO2CI + R3N
Na+OH
^ no reaction (12-30)

Because of the remaining hydrogen atom on the nitrogen, the sulfonamide from
a primary amine is soluble in alkali, forming a salt.

/ ^S02NHR + Na+OH- i y-S02NR Na+ + H2O

(12-31)

In practice, the amine is shaken with benzenesulfonyl chloride and alkaU.

Primary amines yield a clear solution which, on acidification, precipitates the

alkylsulfonamide. Secondary amines yield an insoluble compound which is
unaffected by acid. Tertiary amines also give an insoluble compound (the un-
reacted amine) which, however, dissolves on acidification (forming a soluble
amine salt). This test for distinguishing between the three classes of amines is
known as the Hinsberg reaction.

Alkanolamines
Amines add to ethylene oxide in a manner similar to ammonia (page 1 19).

R— NH2 + CH2— CH2 > RNHCH2CH2OH (12-32)

O an ethanolamine

The products have been used as emulsifying agents. Choline (page 230) may
be prepared from trimethylamine in this way.

CH3 CH3
HOH
CH3-N:<rCH2-CH2 CH3— N+— CH2CH2— O-
CH3

CH3
CH3— N— CH2CH2OH OH (12-33)

CH3
choline
238 Organic Nitrogen Compounds

Reactions of Aliphatic Amines with Nitrous Acid

Reaction with nitrous acid, prepared in situ by action of a mineral acid on

sodium nitrite at 0°, provides a test to distinguish between primary, secondary,
and tertiary aliphatic amines.
Primary ahphatic amines liberate gaseous nitrogen, and the amino group is
replaced by a hydroxyl group.

RNH2 + HONO ^ ROH + Nat + H2O (12-34)

primary amine alcohol

The reaction must be used with caution as a synthetic tool, because rearrange-
ments frequently occur, as, for example:

CH3CH2CH2OH
and
"°^°) CH3-CH-CH3 +
CH3CH2CH2NH2 N2T + H2O (12-35)

OH
mixture of
products

Secondary amines form nitrosamines which separate from the aqueous solu-
tion as a yellow oily layer.

^\ ^\
/
nTh -I- ho no
I > N— N=0 + H2O (12-36)
R R
secondary amine nitrosamine

Tertiary amines simply dissolve in the aqueous acid without evolution of

nitrogen, usually giving complex products. The evolution of a gas, formation of
a yellow oily layer, or simply solution may be taken as criteria for the class of
amine tested.

Ring Substitution

With the unshared pair of electrons of nitrogen available for donation to the
aromatic ring (see page 229) one would expect anilines, like phenols, to be
reactive toward electrophiles, the amino group being ortho-para-directing.
Indeed, aniline reacts with bromine water much like phenol (page 107) to form
2,4,6-tribromoanihne.

NH. NH,

Br.,
(12-37)
H.O

2,4,6-tribromoaniiine
 Organic Nitrogen Compounds • 239
This reaction used in the commercial extraction of bromine from sea water.
is

One can moderate the reaction by first acylating the amine. The acetamido
group is also ring-activating and ortho-para-directing, but less so than the amino
group because of the competing amide resonance (see page 184). Thus,
/?-bromoaniline can be prepared as in equation (12-38),

O O
NH— C— CHs NH— C— CHa NH,

Br2 in f|
^ HoO
^ (12-38)
acetic acid k ^ heat

Br Br
acetanlllde p-bromoacetanllide p-bromoaniline

Electrophilic substitutions on sometimes complicated by the fact

anilines are
that the reagents are strong acidswhich form salts with the amino group. For
example, sulfonation of aniline first gives the salt which upon heating to 200°
furnishes sulfanilic acid (/?-aminobenzenesulfonic acid). This "acid" has the

NH2 NH3+OSO3H- NHc

+ H-OSO3H >
f\ ^^ II I
+ H2O (12-39)

anilinium hydrogen
sulfate

dipolar ion structure shown, the proton being attached to the amino nitrogen
rather than to theoxygen of the sulfonic acid group, because the former is more
basic. Dipolar ion structures are also important in the chemistry of amino
carboxylic acids and proteins and account for some of their salt-like properties.

The Benzidine Rearrangement

When nitrobenzene is reduced in alkaline solution, the product is hydrazo-
benzene.

2 /~Vn02 ^!l±il^^ ^VnH-NH^^ (12-40)

hydrazobenzene

When treated with strong acid, hydrazobenzene rearranges in a most unusual

fashion to benzidine, an important starting material for making azo dyes (page
247). Protonation of both nitrogens produces an unstable intermediate which
"folds" on itself, the benzene rings ultimately becomijig attached to one another
at the para positions. Repulsion between the two adjacent positively charged
nitrogens undoubtedly facihtates cleavage of the N N bond. —
240 Organic Nitrogen Compounds

^r ^
H H
fY^U-NH^f^ 2^ I

hydrazobenzene
H H
(12-41)

h,n^^V/Vnh. ^
benzidine

Aliphatic Diamines

The simplest aliphatic diamine, ethylenediamine, may be prepared by the

reaction of ammonia with ethylene dichloride.

CH2- -Cl CH2— NH2

+ 4NH3 + 2 NH4+CI- (12-42)
CH2- -CI CH2— NH2
ethylenediamine

It is a water-soluble basic hquid which, with long-chain acids, forms salts which
are useful emulsifying agents.
Two diamines, putrescine (1,4-diaminobutane) and cadaverine (1,5-diamino-
pentane), are formed when animal matter (meat or fish) decays. As the names
imply, their odors are disagreeable. Although not highly poisonous themselves,

H2NCH2CH2CH2CH2NH2 H2NCH2CH2CH2CH2CH2NH2
putrescine cade

putrescine and cadaverine belong to a group of compounds known as ptomaines,

nitrogen compounds formed from the decomposition of proteins by bacteria.
Hexamethylenediamine ( 1 ,6-diaminohexane) is one of the two major starting

materials in the manufacture of nylon, and is prepared in tonnage quantities for

this purpose. The other raw material is adipic acid, the straight-chain dicar-

O O
HO— C— (CH2)4— C— OH + H2N— (CH2)6— NH2
heat

H2O
adipic acid hexamethylenediamine

/o o \o
NH-\^C— (CH2)4— C— NH— (CH2)6-NH^C— (12-43)
polyamide

I
 Organic Nitrogen Compounds • 241
boxylic acid with six carbon atoms. When hexamethylenediamine and adipic
acid are heated together, they form a polyamide (analogous to polyesters, page
189).
The resulting polyamide, with molecular weights ranging from 10,000 to
25,000, becomes molten at 260-270°. The molten material can be drawn into
threads which, upon cooling to room temperature, can be further stretched to
about four times their original length. This "cold drawing" process orients the
polymer molecules so that their long axis is parallel to the fiber axis. Hydrogen
bonds of the N H —
O type, at regular intervals, cross-hnk nitrogen and
• • • •

oxygen atoms on adjacent chains and give the fiber strength. This variety of
nylon is known as Nylon 6-6, because the diamine and dicarboxyhc acid each
contain six carbon atoms. These raw materials can be made in many ways.
Hexamethylenediamine is prepared from butadiene by the steps shown.

CH2=CH— CH=CH2 -^ CH2— CH=CH— CHa

I
'^"^^
-2NaCl
>

CI CI

^"^
NCCH2CH=CHCH2CN metal
> H2N(CH2)6NH2 (12-44)
catalyst hexamethylenediamine

Adipic acid can be prepared from benzene (equation (12-45)).

O . O
^CH2 ^C ••
^C-OH^O
3„ CH2 CH2 „ CH2.-CH2 CH2 C-OH
^"^'
» I I
-^ I I
-^
o
I I
(12-45)
'"^'^'
CH2^CH2 CHs^CHa C^2 ^CH2
CH2 CH2 CH2
cyclohexane cyclohexonone adipic acid

Petroleum is the major ultimate source of these raw materials.

It isnot necessary to have a diamine and diacid to produce a polyamide; a

molecule with an amino group at one end and a carboxyl at the other might, by
reacting with itself in proper fashion, produce a polyamide. Caprolactam, the
cycUc amide of 6-aminocaproic acid, produces a polyamide known as Nylon-6.

O
c
/O O
HN ^CH2 I II II

heat
^ — NHVC— (CH2)5— NH— C— (CH2)
\CH2— / Nylon-6
(12-46)
CH2
caprolactam

Nylons are used to manufacture textile fabrics, carpets, rope, sweaters, hose,
and molded objects.
 Figure 12-7. The spinnakers of this sailboat are
mode of nylon, while the mainsails are of Dacron
polyester fiber. Among the advantages of these
fibers is the fact that mildew, which is the action of
fungi and bacteria, will not grow on sailcloth of
either fiber. (Courtesy of E. I. DuPont DeNemours &
Company.)

Heterocyclic Amines

Pyridine (page 226) is obtained commercially from coal tar. Like benzene, it

has six 77 electrons in a cyclic system and is aromatic. But, because the nitrogen
withdraws electrons from the ring carbons, and because the nitrogen becomes

©
e e
positively charged in acid solutions, electrophihc substitution is much more
difficult with pyridine than with benzene. Under severe reaction conditions,
substitution can occur in the 3-position.

NO2
HNO3, H2SO4
(12-47)
300°
N^
3-nitropyridine

But with nucleophilic reagents, pyridine readily undergoes substitution in the

2-position.

Na+NHo- NH,
liquid NH3
+ H2 + NaNHa (12-48)

^N^
2-aminopyridine

242
 Organic Nitrogen Compounds • 243
Complete reduction of pyridine gives piperidine; partial reduction can give
dihydropyridines which are easily oxidized again to pyridines. This reversible
oxidation-reduction is very important in many enzyme systems (see Chapter 16).

^^2 CH?
^^
^H
I I
(12-49)
XT- CH2 /CH2
N
H
piperidine

H H
-
2H >
(12-50)
~-2H

dihydropyridine

The pyrrole (page 226) ring system is present in chlorophyll, the green coloring
matter of plants, and in hemin, the red coloring matter of the blood. Again, the

^N-^ ^N^ -^N-^

H H H
ring has six 77 electrons and is aromatic. Despite the unshared electron pair on
nitrogen, pyrroles are exceedingly weak bases (Kb = 10"^^) because protonation
of the nitrogen would destroy the molecule's aromaticity.

Diazonium Compounds
Primary aromatic amines react with cold nitrous acid to form diazonium salts,

a class of compounds noted for their great versatility in aromatic synthesis. The
process is known as diazotization.

f^.NH2 + HONO+ ,..^.-

H+Cl-
0-5-
""'
water
solution
)
( y-N2+Cl- + 2 H2O
(12-51)
aniline (sulfuric acid benzenediazonium
may also be chloride
used)

Crystalline diazonium salts are sometimes explosive and are customarily not
isolated from their dilute acidic aqueous solutions. Rather, they are treated
directly with the particular reagent which will form the desired product (much as
in the procedure with a Grignard reaction). The diazonium ion is a resonance
hybrid of the following extreme structures
244 Organic Nitrogen Compounds

(3^N=N: ^^ ,^_NjN:
the diazonium ion

Replacement Reactions
The nitrogen of a diazonium ion is easily replaced by other groups. If warmed
in aqueous solution, a phenol is formed (displacement by OH). —

+ HOH .
(I 1 + Nat + H+Cl- (12-52)

phenol

This is analogous to the reaction of a primary aliphatic amine with nitrous acid

(equation (12-34)) and can be thought of as proceeding by an Sn mechanism,

with molecular nitrogen as the leaving group.

N=N: OH
-N, H2O
(12-53)
-H+

Fluorine can be introduced in an aromatic ring via the diazonium compounds,

using sodium fluoride and boron trifluoride (the Schiemann reaction).

N2+HSO4- N2+BF4-
NaF heat
(12-54)
BF, -N2, BF3

fluorobenzene

Cuprous cyanide gives benzonitrile. The use of cuprous salts (cyanide or

halide) is known as the Sandmeyer reaction.

N2+CI-
+ CU2(CN)2 -> +2N2t + CU2CI2
2II
J
(12-55)
cuprous benzonitrile
cyanide

CH? CH, CHc

NH, N2+CI- CI
HCl, NaNOo CU2CI2
(12-56)
0° HCl, 60°

o-chlorotoluene

Via diazonium salts, then, a primary aromatic amino group can readily be con-
verted to a hydroxyl, halogen, or cyano group.

I
 Organic Nitrogen Compounds • 245

Benzyne
When a carboxyl group is ortho to the amino group which is diazotized, the
diazonium salt which resuhs can undergo an unusual reaction. On heating,
both nitrogen and carbon dioxide are lost. The resulting fragment, callai
benzyne, is extremely reactive and will, in the absence of other reagents, dimerize
to biphenylene. If dienes are present, benzyne will add to them in a 1,4-fashion,
leading to new cyclic products.

Cn=n
heat

V ( .
o

O/
Nj. -COo

benzyne biphenylene
(12-57)

Reduction

The diazonium group may be replaced by hydrogen with a variety of reducing

agents. One of the more effective is hypophosphorous acid, H3PO2.
N2+CI-
+ H3PO2 + H2O >
^^ + "3PO3 + H+Cl- + N2T
f J
^^""^^
(12-58)
benzene

Certain reducing reagents (stannous chloride in hydrochloric acid) convert

diazonium salts to phenylhydrazine.

N=N : CI- j[H^ /^/NH-NH2 ^ ^^^^.

(12-59)

phenylhydrazine

Phenylhydrazine, it will be recalled, was important in aldehyde and ketone

chemistry and, as we shall see in Chapter 14, was an important reagent in eluci-
dating the structure of carbohydrates.

Coupling Reaction

The diazonium ion is a weak

and can attack strongly activated
electrophile
aromatic rings. If phenols or aromatic amines are added to alkaline or neutral
solutions of diazonium salts, a coupling reaction occurs, the nitrogen being
retained.

{~\-N=N CI- + ^^OH -^i^ fj T J\ ^

"^^^"

p-hydroxyazobenzene / 1
j f-ry^
246 • Organic Nitrogen Compounds

The products are azo compounds; they contain the

-N=N-
or azo group.
or amino group, unless that posi-
Coupling usually occurs para to the hydroxyl
in which case ortho coupling takes place.
tion is blocked by another substituent,
can be used for dyestuffs, particu-
Azo compounds are colored; many of them
if they are provided with other
functional groups which make it possible to
larly
fix them to fabrics.

Color and Dyes

of the light absorbed may be
Whena molecule absorbs light, the energy
an electron from one molecular orbital
transferred to the molecule by promoting
such an electron is held to the molec-
to a higher energy orbital. The
less firmly
easier will be to raise it to a liigher
ular framework in its initial state, the
it

have a higher energy (are less firmly

energy orbital. Since electrons in tt orbitals
not surprising that Ught absorp-
held by the nuclei) than those in a orbitals,
it is

with molecules that are highly unsaturated

tion in the visible region is associated
substance associated with vision)
(i e have many ir electrons). Thus retinene (a
hemoglobin), and many other colored
bUe' pigments (degradation products of
have extended conjugated
compounds of nature, as weU as most synthetic dyes,
systems.
CH3
CH3CH3 ^^3 ^^^

retinene

skeletal structure of bile pigments

In addition to the color-

Not colored substances may be useful as dyes.
all
dye must have groups which
bearmg portions of the molecules (chromophore) a
auxochromes.
fix it to the fabric. Such groups, usually salt-forming, are called
enhance, intensify or otherwise niodify the
In addition, certain groups which
color are often present. These groups,
which usuaUy have unshared electron

pairs (—OH, —NR2), are called bathochromes.

Application of Dyes
Those which dye a fiber
A dye may be appUed to textile fibers in many ways.
directly are called direct dyes. Many of these are known, particularly for use
Dyes capable of directly dyemg cotton are known as sub-
with wool and silk.

stantive dyes. Certain dyes may be

absorbed by a fabric in a colorless form, and
then take on the desired color by oxidation
on drying of the fabric in air. 1 hese
 Organic Nitrogen Compounds • 247
are known as vat dyes. Still other dyes require a mordant, or heavy metal salts
with which they form insoluble compounds which
impregnate the fabric. Thi^
ISknown as mordant dyeing. Ingrain dyeing involves formation
of the dyestuff
(by chemical reaction) directly on the fiber. For
example, a fabric may be im-
pregnated with an azo dye by carrying out the couphng
reaction on the fiber
The cloth IS first passed through an alkahne solution of the
phenol (or amine)
then through the solution of the diazonium salt.

Common Types of Dyes

LiteraUy thousands of dyestuffs are known, varying
widely in chemical con-
stitution as well as in color.
Only a very few typical examples may be cited here
Azo dyes form the largest single class, accounting for 36% of
all dyes produced.
They may be of the direct, substantive, ingrain, or mordant
type. Fara red,
made from /?-nitroaniline and yS-naphthol, has been used extensively as an in-
grain dye. Congo red is one of the simplest direct dyes for cotton.

NOc

para red

SO3H SO3H
Congo red

Many dyes are derived from the triphenylmethane structure. Malachite green,
which can be made from dimethylaniline and benzaldehyde, is an
intense bluish
green dye.

N(CH3)2 N(CH3)2 N(CH3)2

benzaldehyde

N(CH3)2 N(CH3)2 C1-+N(CH3)2

dimethylaniline malachite green
248 Organic Nitrogen Compounds

The structure of indigo, derived from the indigo plant, was first elucidated by
Adolph von Baeyer in 1883. At present, this vat dye is synthesized rather than
isolated from the natural source. Current production in the United States is
over 5 million pounds annually.

C=C
H II

O
indigo

The simplest of the phthalein dyes is phenolphthalein which, as the name

implies, may be synthesized from phenol and phthalic anhydride.

HO OH

o + O
/
cr
'%
b
rvon
\=/
c'

o
phthalic phenol phenolphthalein
anhydride (colorless)

(-H2O) Na+OH- (12-62)

Na+O JO

,0-Na

Note the similarity of the colored (alkaUne) form triphenylmethane dyes.

to the
In addition to its use as a dye and an indicator of acidity, phenolphthalein is
also the main ingredient of certain laxatives. Some other useful compounds in

this series are eosin, important in drugs, cosmetics, and the manufacture of red
ink, and mercurochrome, the well-known red-colored antiseptic.
Textiles are by far the biggest consumer of dyes, utilizing about 70% of total
United States production, but sizable quantities of dyes go into other outlets,
such as paper, leather, plastics, and foods.

1
^0-,
250 Organic Nitrogen Compounds

e. tetramethylenediamine /. trimethylamine
/. triethylmethylammonium bromide j. /7-aminobenzenesulfonic acid
g. m-toluidine (sulfanilic acid)
/;. ;8-naphthylamine A'. 4-methylpyridLne
Name the compounds given below:
,N02 CH3CHC1CH2CH(NH2)CH3
CH3NHCH2CH2OH
NHNH.
NH2
NH.
No+Br
h.
HO
c. (CH3)2CHN(CH3)2 /.(CH3)4N+OH-
d (C2H5)2NH2+C1- / (C2H5)3N
3. Write the structural formulas and names for (a) aU aUphatic amines with the formula
C4H11N, and (b) all aromatic amines with the formula CgHnN.
4. Explain in terms of the concepts of electronegativity or resonance why methylamine is

a stronger base than ammonia and why aniline is a weaker base than ammonia.
5. Suggest a good reason why dimethylamine has a higher boiling point than trimethyl-
amine (Table 12-1), although the latter has the higher formula weight.
6. Write equations for the synthesis of the following compounds:
tetramethylammonium bromide
a. c. choline from trimethylamine

from trimethylamine
b. triethylmethylammonium hydrox- d. acetylcholine

ide from triethylamine

7. Using alternatively the vapor phase nitration of an alkane, oxime formation from an
aldehyde, and the nitrile (cyanide) synthesis from an alkyl halide as the first step, write
equations for three different methods for preparing n-propylamine. In a similar
manner give equations for three different preparations of isopropylamine.
8. Write equations for the following syntheses:
a. A7-butyramide to w-propylamine d. sulfanilamide from aniline
b. /7-toluidinefrom toluene e. /7-bromoaniline from aniline
c. acetanilide from aniline /. sulfaniUc acid from aniline
9. Isopropylamine, methylethylamine, and trimethylamine are isomers. Show by means
of equations how they can be distinguished by their reactions with (a) nitrous acid, and
(b) benzenesulfonyl chloride.
10. Write the structural formula for the dyes obtained when the following organic com-
pounds interact:
a. C6H5N2+CI- + C6H5OH
b. /7-CH3C6H4N2+CI- + C6H5N(CH3)2
^
c. /;-CH3C6H4N2+Cl- + | |
T / /P
+ C6H5OH

d C6H5N(CH3)2 + C6H5CHO II

e. W-NO2C6H4N2+CI- -I- /7-CH3C6H4OH

11. Write equations for the reduction of w-nitrotoluene to the corresponding hydrazo
compound, and treatment of the latter with strong acid (compare equations (12-40,
12-41)).
 Organic Nitrogen Compounds • 25
12. Show how both raw materials for Nylon 6-6 might be synthesized from 1 ,4-dichlorobu-
tane.
13. Starting with phenol as the only organic material, and any necessary inorganic reagents,
write equations showing how nylon might be prepared.
14. Indicate with equations how each of the following conversions could be accomphshed.
Each conversion may require several steps.
a. isobutyric acid to isopropylamine
b. benzene to fluorobenzene
c. ethyl chloride to n-propylamine
d. «-butyl alcohol to 1-aminopentane
e. aniline to 1,3,5-tribromobenzene
/. ethylene to succinic acid
g. ethylamine to ethyl alcohol
h. methyl bromide to ethylamine hydrochloride
/. propene to isopropylamine
15. An unknown amine A on reaction with benzenesulfonyl chloride gave a derivative
which was aUcali-soluble. Treatment of A with nitrous acid gave an alcohol B which
underwent the haloform reaction. The amine A also formed a hydrochloride salt which
on analysis was found to contain 37.2% chlorine. Write structural formulas for A and B
and give equations for all reactions. (C = 12, H = 1, N = 14, CI = 35.5)
16. What volume of 0.5A'^ hydrochloric acid would be required to exactly neutrahze 36.5 g.
of diethylamine?
17. An impure sample of ^-propylamine weighing 0.60 g. is found to Uberate 224 ml. of
N2 (S.T.P.) on reaction with nitrous acid. Calculate the purity of the amine. (C = 12,

H= 1, N= 14, CI = 35.5)
18. Show the structure of the product to be expected when o-carboxybenzenediazonium
salt is heated in the presence of cyclopentadiene (see equation (12-57)).
19. Write equations showing the synthesis of Congo red (page 247) from benzidine and
4-aminonaphthalene-l -sulfonic acid. In the dye, which group is the auxochrome?
the bathochrome?
20. Explain why pyridine is much more basic than pyrrole.
21. Suggest a practical, simple method for separating a mixture of aniline (b.p. 184°),

«-butylbenzene (b.p. 183°), and valeric acid (b.p. 189°) into its pure components. All
three compounds are hquids at room temperature and are not very soluble in water.
22. Account for the fact that diphenylamine is a much weaker base (Kb = lO^i^) than
aniUne (Ki, = IQ-io).

23. Suggest a possible mechanism for the formation of isopropyl alcohol from n-propyl-
amine and nitrous acid (equation (12-35)).
 Some
molecules exist in isomeric forms because
of special features of their molecular geometry. One such
case is cis-trans isomerism, discussed in Chapter 3. Another
is optical isomerism, which results when a molecule and its
mirror image are not identical. Such isomerism iscom-
monly detected by the behavior of such molecules toward
plane-polarized light. Many naturally occurring substances,
among them carbohydrates, proteins, vitamins, hormones
and many others, show optical isomerism, and this may
markedly affect their biochemical behavior.

Optical Isomerism

Since optical isomerism is usually detected by determining whether a sub-

stance can alter the plane of vibration of plane-polarized light, it will be neces-
sary to consider first some of the properties of light.

Plane-Polarized Light

Ordinary hght may be thought of as rays of different wave length vibrating in

all possible planes perpendicular to the direction of their propagation. When
white light passes through a suitably colored filter, monochromatic light (light

of a uniform wavelength) is obtained. Such light may still vibrate in all possible
planes. This is indicated in Figure 13-1, in which a beam of monochromatic
light is directed out of the page toward the reader. A cross-section of the beam
would show waves with any from 0° to 360°. But each plane of vibration
axis
may be considered the resultant of two component waves vibrating in perpen-
dicular planes (Figure 13-2). If the light beam were to pass through a substance

252
 Optical Isomerism 253

Figure 13-1. Ordinary light beam vibrating in all

possible planes, coming toward the reader.

which would permit only one component (say, the vertical) to pass through it,
the resulting hght beam would have all waves vibrating in a single plane; it
would be described as plane-polarized light (Figure 13-3). Several rather special
substances [tourmaline crystals, polaroid (crystals properly oriented and em-
bedded in a transparent plastic), or a Nicol prism, especially constructed from
Iceland spar] can be used for this purpose. The phenomenon can readily be

Figure 1 3-2. Resolution of a light beam AB into its

vertical (CD) and horizontal (EF) components.

Figure 13-3. A monochromatic beam of light AB, initially vibrating in all directions,

passes through a polarizing substance v/hich "strains" the light so that only the ver-

tical component emerges.

254 Optical Isomerism

Figure 13-4. A beam of light as it passes through two tourmaline crystals with axes
parallel (left) or perpendicular (right).

demonstrated experimentally. A beam of light will pass through two tour-

maline crystals (or sheets of polaroid) only if the axes of the crystals are parallel.
If, however, one crystal is turned at right angles to the first, light will be pre-

vented from passing through the second crystal, and the latter will appear
opaque (Figures 13-4 and 13-5).

Figure 13-5. A beam of light cannot be seen through two sheets of linear polarizers unless their
axes are parallel. The region of overlap of these unaligned Polaroid polarizing discs appears
opaque although each disc alone is transparent. (Courtesy of Polaroid Corporafion.)
 Optical Isomerism 255

Optical Activity and the Polarimeter

A substance is optically active if it is capable of rotating the plane of plane-

polarized light. It has long been known that many products derived from nature
(carbohydrates, proteins, petroleum from certain sources, cell constituents)
rotate a beam of polarized light when it is passed through them (whether they are
in the pure state or in solution).The extent of the rotation may be measured
in a polarimeter. The principles of this instrument are illustrated in Figure 1 3-6.
Monochromatic light from some source (usually a sodium vapor lamp) is
polarized by passing through a polarizing prism. The beam of polarized light
then passes through a sample tube containing a solution of the substance to be
tested. Upon emerging from the sample tube, the light passes through an
analyzer, which is similar to the polarizing prism. If the test substance is

optically inactive, the polarizer be parallel for maximum trans-

and analyzer will
mission of Ught (that is, angle a will be 0°). If the substance being tested is
optically active (that is, if it rotates the plane of the polarized hght a degrees),
it will be necessary to rotate the analyzer an equal number of degrees in order to

obtain the maximum intensity of transmitted light. The angle a through which
the analyzer must be rotated is equivalent to the rotation of the light by the test
substance. This angle is measured by means of a calibrated circular scale.
The extent to which a given sample rotates polarized light depends upon the
length of the sample tube, and upon the concentration of the optically active
It also depends upon temperature and on the
substance in the inactive solvent.
wavelength of the These factors are usually standardized when it is
light used.
necessary to compare the activity of different substances. The specific rota-

tion (a) of an optically active substance in solution is expressed as [a\{ = —

(solvent), where t is the temperature, A the wavelength of light, a the observed
rotation, / the length of the tube in decimeters, c the concentration in grams of
solute per 100 ml. of solvent, and the solvent is indicated in brackets. Specific
rotation is as discrete a property of an optically active compound as is its melting
or boiUng point.
Some optically active substances rotate plane-polarized light to the left and

Figure 13-6. Diagrammatic model of a polarimeter

prism axes polarized

rotated polarized light
light

degree of
rotation

analyzer
prism
256 • Optical Isomerism

are called levorotatory or negative; others rotate plane-polarized light to the

right and are said to be dextrorotatory or positive. This is usually indicated by
a( — )or( + ) sign placed before the name of the compound. Sometimes a small /
or small dis used, but the algebraic signs are preferred.

Asymmetry and the Tetrahedral Carbon Atom

The question naturally arises as to why certain substances are optically active
and others are not. A precise explanation is complex, but briefly it can be stated
form of electromagnetic radiation, some interaction is to be
that, since light is a
expected between a light beam and the electrons in a molecule. The effect
produced by any one molecule will be small, but that of a collection of molecules
can be appreciable. If each molecule possesses reflective symmetry (that is, if
the molecule and its mirror image are identical), then the positive and negative
rotations caused by each molecule will, in a large aggregate, cancel to zero.
The molecules are said to be optically inactive. But if the molecules are asym-
metric with respect to a mirror plane, then there will be a net interaction, and
the plane of polarization will be rotated when plane-polarized light passes
through a collection of such molecules.
The need for molecular asymmetry in optically active molecules was clearly
recognized in the mid-nineteenth century by Louis Pasteur, who did pioneering
research in this field. But it was not until 1874 that the Dutch physical chemist,
van't Hoff", and former fellow student, the Frenchman Le Bel, simultaneously
his
but independently made a bold hypothesis concerning the structure of organic
molecules which would explain the optical activity of some and the inactivity
of other organic compounds.
It is a fact of soUd geometry that, if the four corners of a regular tetrahedron

have four different things attached to them, two arrangements are possible. These

Figure 13-7. The mirror image relationship of the right and left hands.
 Optical Isomerism • 257
W

Figure 1 3-8. Four different groups may be arranged at the corners of a tetrahedron
in two different ways.

arrangements are mirror images; they are related as are the right and left hands
(Figure 13-7); they are distinct and non-superimposable (Figure 13-8). If two
or more of the things at the corners of the tetrahedron are identical, the molecule
possesses a plane of symmetry, and only one arrangement is possible (see Figure
13-9).
Le Bel and van't Hoff suggested that the valences of carbon were directed
toward the corners of a regular tetrahedron. Any carbon, then, which has/owr
different groups attached to it would be a source of asymmetry in the molecule.
Such an asymmetric carbon atom would have two possible arrangements of the
groups around it. The two structures would be non-superimposable mirror
images (Figure 13-10). They would be expected to differ in some right-handed
or left-handed manner, such as the rotation of plane-polarized light to an equal
extent but in opposite directions. Such pairs of mirror images are called
enantiomers.

Figure 13-9. When two of the groups are identical, the molecule has a plane of
symmetry.

A
258 Optical Isomerism

Figure 13-10. When the four groups attached to

an asymmetric atom are arranged as mirror
images, they cannot be superimposed.

At the time the van't Hoff-Le Bel theory was proposed, thirteen optically
activecompounds of established structure were known, and all contained at
least one asymmetric carbon atom. Further experimentation confirmed the
correctness of their theory (the brilliance of which is better appreciated when
one and the nature of atomic structure and chemical bond-
recalls that electrons
ing were then unknown.) Carbohydrates (sugar, starch), proteins, natural
drugs (quinine, strychnine), and many other constituents of plants and animals
have at least one asymmetric carbon atom and are optically active.

Stereochemistry of Lactic Acid

One of the most thoroughly studied compounds showing optical activity is

lactic acid (page 200). In this compound, the carbon atom marked with an
asterisk is asymmetric; four different groups are attached to it. Two arrange-
ments of these groups are therefore possible, giving two different molecules;
they are mirror images and are represented in Figure 13-11.

H O
CH3-C*-C
y
6n OH
lactic acid

Because three-dimensional drawings of such molecules are cumbersome,

is more than one asymmetric carbon, a convention has been
particularly if there
adopted for their two-dimensional representation. These are the Fischer pro-
jection formulas (see page 259). The tetrahedral model is viewed as shown in
 Optical Isomerism 259

COOH HOOC
COOH HOOC
/^\ OH
H,C OH HO CH. HsC >H \/ CHs

Figure 13-11. Two different three-dimensional representations of the two enon-

tiomers (mirror images) of lactic acid.

Figure 13-12; groups which project toward the viewer are placed to the
left and

right of theasymmetric carbon, and groups which are furthest from the viewer
are placed above and below the asymmetric carbon.

COOH COOH
HO— C— H = HO^C^H
I
I

CHs in^
the three-dimensional models to the right of
the mirrors in Figure 13-1 1

Interchange of any two groups in a Fischer projection gives the mirror image.
This is easy to see if the H and OH in Figure 13-12 are interchanged. (It is not
so easy to see if other groups are interchanged, and
suggested that the reader
it is

try this with molecular models.) Rotation of a Fischer projection by 90° in the
plane of the paper gives the mirror image, but rotation by 180° leaves the model
unchanged.

Absolute and Relative Configuration

The structures represented above for lactic acid are mirror images, but the
absolute determination of which of these arrangements (configurations) repre-
sents the dextrorotatory form and which the levorotatory form is difficult. For
many years, to circumvent this difficulty, chemists chose the dextrorotatory
form of glyceraldehyde as a standard substance and arbitrarily assigned it the
configuration shown.

Figure 13-12. The formula at the right is the Fischer projection of the model at the
left (the same as the models to the left of the mirrors in Figure 1 3-1 1 ). Groups to the
left and right of the asymmetric carbon (H and OH) extend above the plane of the
paper; other groups (COOH and CH3) extend below the plane of the paper. The
asymmetric carbon atom lies in the plane of the paper.

COOH COOH COOH

H— C— OH
CH, CH CH3
260 • Optical Isomerism

£HO CHO CHO

OH = ^Cc-oH— H— C— OH
HOH2C H CH2OH
CH2OH
d( + )-glyceraldehyde

This configuration is said to be d (that is, with the carbon chain written vertically,
and the most oxidized carbon (CHO) at the top, the hydroxyl group is written to the
right of the asymmetric carbon). The symbol ( + ) indicates that it is also dextrorota-
tory.

CHO CO2H
H— C— OH
I
— — '%"-
steps
> H— C— OH
I
(13-1)

CH2OH CH3
d( + )-glyceraldehyde d( — )-lactic acid

When d( + )-glyceraldehyde is converted to lactic acid by a series of reactions which

converts the CHO to CO2H and the CH2OH to CH3 without breaking a carbon-
carbon bond, the lactic acid obtained is said to have the same relative configuration as

the starting aldehyde (i.e., with the carbon chain written vertically and the most
oxidized carbon at the top, the hydroxyl is on the right — hence d). But the lactic acid

thus obtained happens to be levorotatory. It is therefore referred to as d( — )-lactic

acid (equation (13-1)). It is seen that configuration (d or l) and sign of rotation
( + or — may
) vary independently.
In 1949 an ingenious application of X-ray analysis of certain optically active
crystals demonstrated that the formula of glyceraldehyde, arbitrarily designated as
the ( + ) isomer, was in fact the correct absolute configuration of the molecule.*

Enantiomers differ from one another only in a right- and left-handed manner.
They will be identical in all properties, both chemical and physical, which do
not depend on this distinction. They will have identical melting or boihng
points, wiU show identical chemical behavior toward optically inactive reagents,
and indeed will rotate plane-polarized light equal numbers of degrees (but in
opposite directions). Thus most physical and chemical properties of (-I-) and
( — ) lactic acids are identical; they differ only in the direction in which they rotate

plane-polarized light, and in the way they react with other asymmetric molecules.

Racemic Mixtures
In the laboratory, three lactic acids can be obtained. When isolated from
muscle, it is dextrorotatory (-I-) lactic acid;when obtained by the fermentation
of milk sugar, it is levorotatory ( — ) lactic acid; when synthesized in the labora-
tory, lactic acid is optically inactive and can be shown to be a mixture of equal
quantities of the ( -f ) and ( —) varieties. Such a mixture of equal amounts of
enantiomers is known as a racemic mixture (sometimes represented as it); it

* J. M. Bijvoet, most fittingly, Director of the van't Hoff Laboratories, University of Utrecht.
 Optical Isomerism • 261

is optically inactive (rotation of the ( + ) enantiomer is cancelled by the opposite

and equal rotation of the ( — ) enantiomer).
Most laboratory syntheses of compounds with an asymmetric carbon atom
lead to racemic mixtures. The reason for this is apparent if we consider as a
typical example the following synthesis of lactic acid from propionic acid.

/O ^O ^O
CHsCHaC^ -^
'
CHsCHC^ ^I^ CHgCHC^^ (13-2)
OH l^
OH \^^ OH
The step in this process involves the formation of an a-halogenated acid by
first

replacement of one of the a-hydrogen atoms with bromine (page 186). Because
the two hydrogen atoms on the a-carbon atom of propionic acid are equivalent,
the probabihty of substituting a bromine atom is the same for each of them. An
COOH COOH COOH HOOC
I
R I
^-—1—^ rotate |

CH3 H CH3 H CH3 ^Br H^ CH3

enantiomers

equimolar (racemic) mixture of ( + ) and ( — ) a-bromopropionic acids will there-

fore result. These, on hydrolysis, wiU give an equimolar (racemic) mixture of
( and ( — ) lactic acids.
+)
Whereas laboratory-synthesized compounds with an asymmetric carbon
atom are racemic, it is very striking that the chemical reactions that produce
such molecules in living cells almost always lead to optically active substances.
This because reactions in cells are catalyzed by enzymes which themselves are
is

optically active and can therefore differentiate between the dextro and levo
components of the racemate with which they react.

Molecules with Two Different Asymmetric Carbon Atoms

It can readily be shown that if a molecule has n different asymmetric carbon
atoms, there exists a total of 2^' possible isomers. This is known as the van't Hoff
rule. Because each asymmetric atom has two possible configurations for which
we wiU use the signs ( + ) or ( — ), a molecule with two such atoms would have
2 X 2 or four possible isomers (see Table 13-1). Remembering that (-I-) is the
mirror image of ( — ), it wiU be noted that A and B are mirror images of each
other or enantiomers. An equimolecular mixture of isomers A and B would
constitute a racemic mixture. Similarly, C and D are mirror images or enan-
tiomers. An equimolecular mixture of C and D constitutes another racemic
mixture. Thus, with four possible isomers, there are two possible racemic
mixtures.
262 • Optical Isomerism

TABLE 13-1 Configurations of o Molecule with Two

DifFerent Asymmetric Carbon Atoms

CARBON NO.
 Optical Isomerism 263
first rotating the rear asymmetric carbon 180° so that the carboxyl group is

down, as it is on the front asymmetric carbon; the model is then viewed from
above, or imagined to be pressed down on a flat surface. This is illustrated for
formula A of Figure 13-13.

COOH COOH
Cl- -H
H -OH
COOH
COOH COOH
As before (page 259) horizontal groups extend above the plane of the paper
toward the viewer, and vertical groups extend below the paper plane, with the
asymmetric carbon atoms lying in the plane of the paper. The formulas in
Figure 13-13 correspond to those indicated in Table 13-1. The pairs AB and
CD are enantiomers, whereas the other possible pairs are diastereoisomers.
Molecules with more than two different asymmetric carbons are best treated
using Fischer projection formulas (see Chapter 14).

Molecules with Two Similar Asymmetric Carbon Atoms

Similar asymmetric carbons are those surrounded by the same four different
groups. The most extensively studied compound of this type is tartaric acid.

H H
O% ^o
C— C*— C*— \
HO OH OH OH
tartaric acid

The asymmetric carbon atoms are marked with asterisks. Each has attached
to it the same four groups, H, OH, COOH, and —
CH(OH)COOH. The stereo-
isomers of tartaric acid can be derived from those of Figure 13-13 by replacing
the CI by OH. When this is done, it is seen that A and B remain distinct non-
superimposable mirror images (enantiomers) but that C and D become identical
(Figure 13-14). The identity of C and D is easily seen by rotating the Fischer
projection formula of D 180° in the plane of the paper, in which case it becomes
identical with C. It was stated earher (p. 259) that such a rotation does not
alter the configuration. A similar test apphed to A
and B will show that they
retain their separate identities.
There are, then, only three distinct isomers of tartaric acid represented by
A, B, and C of Figure 13-14. Form C has a center of symmetry in the confor-
mation shown at the top of Figure 13-14; it is the center of the bond joining the
two asymmetric carbons. In another conformation obtained by rotating one
264 • Optical Isomerism

COOH COOH COOH COOH

COOH COOH COOH COOH

enantiomers identical

COOH COOH COOH COOH

HO- -H H -OH H- -OH HO -H
H- -OH HO -H H -OH HO- -H
COOH COOH COOH COOH
meso form

B C

Figure 13-14. Stereoisomers of tartaric acid.

asymmetric carbon 180° with respect to the other, the molecule is seen to have
a plane of —
symmetry the plane perpendicular to and bisecting the bond be-
tween the two asymmetric carbons. Because of this symmetry, the molecule is
identical with its mirror image and is optically inactive. A molecule which is

meso-tartaric acid

an optically inactive isomer of a compound that can exist in other optically

activeforms is designated as a meso form. Some of the properties of the three
forms of tartaric acid are given in Table 13-2.

TABLE 1 3-2 Physical Properties of the Tartaric Acids

TARTARIC
ACID
 Optical Isomerism • 265

Resolution of Racemic Mixtures

The process of separating a racemic mixture into its components, ( + ) and

( — ), is called resolution. Since synthetic products that may be potentially
optically active are usually produced as racemic mixtures, it is necessary to
resolve such mixtures to obtain their dextro- and levorotatory components.
Since the physical properties of enantiomers are identical, they cannot be sepa-
rated by physical methods such as distillation or fractional crystalhzation. It
is only when they react with another optically active compound that two enan-

tiomers behave differently. Almost all methods of resolution are based on this
fact.

Conversion to Diastereoisomers

This is by far the most important method based upon the important principle,
cited above, that diastereoisomers have different physical properties. Let us
consider the resolution of a racemic acid. If the mixture of enantiomers is
allowed to react with an optically active base (say, ( + ) for illustrative purposes),
it will form a salt, as represented in equation (13-4).

(-h) acid I ,,,, ( + ) acid ( + ) base

., + +)base >
Ar.^u (1^-4)
( + ) base
/ X
(-) acid )
(-) acid

racemic diastereoisomeric
mixture salts

Although the ( + ) and ( — ) acids are mirror images and cannot be separated by
physical means, the salts are not mirror images but diastereoisomers. They
may therefore be separated by recrystallization from a suitable solvent. Each
salt may then be reconverted to the original acid now optically active.

(-I-) acid ( + ) base + HCl > ( + ) acid -I- (-I-) base hydrochloride
separated by
recrystallization
(13-5)

( —) acid ( + ) base + HCl > ( — ) acid -I- ( +) base hydrochloride

The optically active base used in this resolution is usually some natural product,
such as quinine or brucine. It is recovered in the process and may be reused
indefinitely.
Similar resolutions of bases may
be accomplished using an optically active
acid. Alcohols may be resolved by forming the diastereoisomeric esters with an
optically active acid. By a judicious choice of reagents, the method is applicable
to many classes of organic compounds.

Biochemical Resolution

Certain bacteria or other microorganisms thrive more vigorously upon one

optical isomer than upon its enantiomer. This is because the enzymes involved
in metabolic processes are themselves optically active. As shown in Figure
266 • Optical Isomerism

a a
I

enantiomers

optically active sites

on an enzyme

Figure 13-15. Interaction of enantiomers with an enzyme. Only the enantiomer at

the left can form three effective bonds with its counterpart on the enzyme surface.

13-15, an between the enzyme and the substrate may be made

effective contact
with only one of the two enantiomers. In such cases, if the organism is allowed
to "feed" upon a racemic mixture, it will use up one isomer and leave the other
for the experimenter. This procedure has at least two important limitations;
it is applicable only to dUute solutions of nontoxic mixtures which may be

metabolized by an organism, and it results in loss of one isomer. Even so, the
method is occasionally useful. This type of interaction is also the basis for the
stereospecific reactions which occur in living cells.

Mechanical Separation of the Crystals

If one has the good fortune, as Pasteur had, to be working with optically active
materials which form crystals that are also mirror images, it may be possible to
separate them by the use of a magnifying lens and tweezers. Pasteur first sepa-
rated the racemic sodium ammonium salt of tartaric acid into its ( + ) and ( —
isomers in this way. The procedure is obviously laborious, possible only in
special cases, and primarily of historic interest.

NEW CONCEPTS. FACTS. AND TERMS

1. Plane-polarized light; optical activity; polarimeter; levorotatory ( — ); dextrorotatory

( + ); specific rotation.
2. Asymmetry and the tetrahedral carbon; asymmetric carbon atom— four different
groups attached to it, which may be arranged in two different ways (mirror images, or
enantiomers).
3. Stereochemistry of lactic acid; conventions for planar representation of the three-
dimensional models; Fischer projection formulas.
4. Absolute and relative configuration.
5. Racemic mixtures (half dextro and half levo); generally obtained from laboratory
syntheses.
 Optical Isomerism • 267
6. Molecules with two different asymmetric carbon atoms; the van't Hoff rule; diastereo-
isomers.
7. Molecules with two similar asymmetric carbon atoms; tartaric acid; meso form.
8. Resolution of racemic mixtures. Conversion to diastereoisomers. Interaction of
enantiomers with enzymes.

EXERCISES AND PROBLEMS

1. Define clearly the following terms:

a. monochromatic light /. racemic mixture
b. optically active compound g. diastereoisomers
c. levorotatory substance h. meso form
d. asymmetric carbon atom /. resolution
e. enantiomers j. polarized light
2. In the name d( — ) lactic acid, what do the capital d and the minus sign in parentheses
mean?
3. Explain why addition of hydrogen bromide to 1-butene gives a 50-50 mixture of ( + )

and ( — ) 2-bromobutane.
4. Illustrate each of the following with a specific example:
a. similar asymmetric carbon atoms d. meso structure
b. racemic mixture e. diastereoisomers
c. enantiomers
5. Which of the following might show optical activity?
a. 5-butyl chloride e. /S-aminopropionic acid
b. 2-pentene /. 1 -phenyl- 1-ethanol
c. bromochlorofluoromethane g. 2,2-dibromobutane
d. 3,4-dibromohexane h. cyclohexanol
6. How many optically active forms are possible for each of the following compounds?
a. CH3CH2CH(0H)CHC1CH3 d CH2ClCHClCH(OH)COOH
b. (CH3)2CHCH2CH(CH3)COOH e. CHsCHBrCHBrCHs

c. CH2(OH)[CH(OH)]4CHO
7. Might the fat, glyceryl stearopahnitooleate, be optically active? What effect would
catalytic addition of a mole of hydrogen to this glyceride have on its optical behavior?
8. Write structural formulas {a) for the simplest open-chain aUc ane, and {b) for the simplest
open-chain alkene, which might be optically active.
9. An unsubstituted monobasic ahphatic acid contained 58.8% carbon and 9.8% hydrogen.
The acid was resolvable into( -|- ) and ( — ) forms. Suggest a structural formula for the
acid.
10. Draw structural formulas for optically active compounds with the following molecular
formulas:
a. C5H12O b. C4H9Br c. C7H14O
1 1 Draw three-dimensional models, and their planar representations, for all the isomers
of methyl 2,3-dichlorobutanoate. Indicate which pairs are enantiomers and which
are diastereoisomers.
12. A derivative of one of the tartaric acids is optically active but yields optically inactive
products when esterified with methyl alcohol or when hydrolyzed. Deduce the stereo-
chemical formula which fits these data, and explain, using equations.
268 • Optical Isomerism

13. When the ( — ) isomer of A,

COOH
CH3-C-CH2CH,
CH2OH
is converted to its ethyl ester B, the latter can be oxidized to an acid C. Catalytic hy-
drogenolysis of C yields D, which is still optically active. Write equations, using planar
representations of the three-dimensional molecules, for the conversion of A to 5 to C
to D. How are A and D related?
14. How many stereoisomers, geometric, optical, or both, are possible for each of the
following?
a. (CH3)2CHCHBrCH2CH(CH3)2 c. CH3CH=CHCH(OH)CH3
b. CH3CH2C(CH3)=C(C2H5)2 d. CH2=CHCH2CH(NH2)C02CH3
15. Write structural formulas to fulfill the conditions indicated:
a. An open-chain compound which exhibits both geometrical and optical isomerism.
b. An open-chain compound which has two asymmetric carbon atoms, yet is

optically inactive.
c. A cychc compound which exists in cis and trans forms, neither of which is optically
active.
d. A cychc compound which exists in cis and trans forms, both of which are optically
active.
e. A cyclic compound which exists in cis and trans forms, with one of the geometrical
forms optically active and the other optically inactive.
16. When maleic acid is treated with bromine, the resulting addition product, 2,3-dibromo-
succinic acid, can be resolved into enantiomers. But addition of bromine to fumaric
acid gives a 2,3-dibromosuccinic acid which cannot be resolved. What do these ob-
servations indicate regarding the mechanism of bromine addition?
17. An optically active alcohol (1.2 g.) is dissolved in enough water to prepare 100 ml. of
solution. A portion of this solution, placed in a 5 cm. polarimeter tube, caused an
observed rotation of —1.8°. Calculate the specific rotation of the alcohol. What
would be the observed rotation if
{a) the same solution were placed in a 20 cm. tube? {b) 5 ml. of the solution were
diluted to 20 ml., then placed in a 10 cm. tube?
18. Would you predict that quaternary ammonium salts of the type RiR2R3R4N"'"X~ would
be capable of optical activity? Explain.
19. For each of the following, tell whether or not optical activity is possible; if so, draw the
remaining isomers.
CH3 CH3 CH3 CH3
d
\ / .

CHs
"^"^
CH3 CH3
20. Draw three-dimensional formulas for the compounds represented by the following
Fischer projection formulas.
CH3
CH3 CI
H -OH
a. H- -OH b. C6H5 CO2H c.
H- -CI
C2H5 H
CH3
 The carbohydrates include sugars, starches, cel-
lulose, and These compounds are found
related substances.
in the roots, stems, and leaf structures of all plant tissue.
They comprise one of our most important classes offood
products, being a major source of energy for the body. The
sugars ribose and deoxyribose are part of the backbone
structure of nucleic acids. Carbohydrates also are the
foundation of many of our important industries, including
clothing (cotton and rayon), fermentation (wines, liquors,
and alcohol), paper and allied products, confections, cello-
phane, and many Although their formulas may
others.
appear complex, carbohydrates exhibit the chemistry of
their several simple functional groups (primarily the car-
bony I and hydroxyl).

Carbohydrates

The name carbohydrate originated from the empirical formulas of compounds

in this class, many of which can be represented as C„i(H20)„* (hydrates
of carbon). Although these molecular formulas bear little relationship to
the structures of the molecules, the general name persists. Carbohydrates are
formed green plants as a result of photosynthesis, a process whereby carbon
in
dioxide and water are combined, using energy obtained by absorption of visible
light by chlorophyll.
Carbohydrates are poly hydroxy aldehydes or polyhydroxy ketones or substances
which, upon hydrolysis, give only polyhydroxyaldehydes and/or polyhydroxy-

* m and n are small whole numbers. Glucose is C6H12O6 or C6(H20)6 and sucrose (cane sugar) is

C12H22O11 or Ci2(H20)ii.

269
270 • Carbohydrates

ketones. The major portion of the chemistry of carbohydrates involves, there-

fore, thechemistry of aldehydes or ketones, of alcohols, and of the hemiacetals
and acetals which can be formed from them. The simplest carbohydrate units
are known as monosaccharides. These, in turn, may be divided into two sub-
groups, the aldoses and the ketoses, depending upon whether the carbonyl
group is aldehydic or ketonic, respectively. The aldoses and ketoses are named
according to the number of carbon atoms in the molecule. The most common
monosaccharides found in nature are pentoses and hexoses (five and six carbon
atoms, respectively). Disaccharides are composed of two monosaccharide units
and may be hydrolyzed to yield the constituent monosaccharides. Polysac-
charides containmany monosaccharide units. They are giant molecules or
polymers. They, too. on complete hydrolysis yield monosaccharides.
The names of the carbohydrates have the ending -ose. Common names are
generally used for carbohydrates.

Monosaccharides
The most important monosaccharide is glucose, C6H12O6. It is sometimes
known as dextrose and occurs free in fruits and honey, and is a normal and vital
constituent of blood. It is optically active and dextrorotatory. Glucose is
manufactured on a large scale by the hydrolysis of starch for use as a household
sweetening agent and for the manufacture of confections.

Structure of Glucose

The methods used to elucidate the structure of glucose are typical of those
used in carbohydrate chemistry. From the percentage composition, the empiri-
cal formula CH2O was deduced. Determination of the molecular weight
showed the molecular formula to be C6H12O6. One of the earliest experiments
performed on glucose was drastic reduction with hydrogen iodide. This led to a
mixture of 1-iodohexane and 2-iodohexane, indicating that the six carbon atoms
form a consecutive rather than a branched chain. The disposition of the oxygen
and hydrogen atoms remained to be discovered.
Mild oxidation of glucose with bromine water led to gluconic acid, with the
molecular formula C6H12O7. This implied an aldehyde group at the end of the
chain, since only an aldehyde can be oxidized to an acid by gaining one oxygen
atom (and losing no hydrogens). The aldehyde group was confirmed by posi-
tive reaction of glucose to the silver mirror test (page 145). Further oxidation
of gluconic acid with nitric acid gave glucaric acid, a dicarboxyhc acid with the
formula CeHioOg, indicating the presence of a primary alcohol function, since
these are oxidized to acids with the loss of two hydrogens and gain of one oxygen
( — CH2OH > — CO2H). Finally, reduction of glucose with sodium amal-
gam gave sorbitol, a hexahydric alcohol (C6H14O6).
Glucose itself reacts with acetic anhydride forming a pentaacetate
C6H70(CH3COO)5, indicating the presence of five alcoholic hydroxyls. Analo-
 Carbohydrates • 271
gously, sorbitol gives a hexaacetate, C6H8(CH3COO)6. All of these experi-
ments can be rationalized in terms of a structure for glucose with a six carbon
chain, an aldehyde function at the end of the chain, and a hydroxyl group
attached to each of the remaining carbon atoms as shown in the scheme (14-1).

CH2OH iCH=0 CO2P

CHOH 2CHOH CHOH
CHOH
I I

Na— Hg 3CHOH Bro.H.O

CHOH
I

CHOH 4CHOH CHOH

I

CHOH
I

5CHOH CHOH
I
I

CH2OH 6CH2OH CH2OH

sorbitol glucose gluconic acid

acetic acetic
anhydride anhydride
HNO3

O
(14-1)
(;h2— o— CCH3
II

CH=0 CO2H
o o
CH —O— oCCH3 CH— O— CCH3
O
CHOH

CH— O— CCH3
II II

CH— O— CCH3 CHOH

O O
CH — O— CCH3
II

CH— O— CCH3 CHOH

O O
CH — O— CCH3 CH— O— CCH3 CHOH
O O
CH2— O— CCH3
II

CH2 OCCH3 CO2H

sorbitol hexaacetate glucose pentoacetote glucaric acid

There are,however, several aspects of the glucose structure yet to be resolved.

For one thing, the substance is optically active. Examination of the postulated
formula discloses four possible centers of asymmetry (carbons 2, 3, 4, and 5).
All of these are different asymmetric carbon atoms. AppUcation of van't Hoff 's
rule (page 261) gives 2* or sixteen possible isomers or eight pairs of enan-
tiomers. Glucose is one of these sixteen isomers (all of which, incidentally, are
known and characterized). The methods used to determine the spatial con-
figuration about each asymmetric carbon atom in glucose and other sugars are
complex, and the interested reader should consult a more advanced text. The
correct two-dimensional Fischer projection for d( -|- )-glucose is
272 Carbohydrates

HO H
iCHO
H— 2C— OH
I

0=CH 3C^OH
HO— 3C—
I

H— 4C— OH HOH2C6 4C-- OH

H— 5C— OH
6CH2OH
d( + )-glucose Arc stereostructure
Fischer projection of D( + )-glucose
The Fischer projection is most easily visualized if the molecule is arranged so

that thecarbon chain forms an arc and is viewed from "outside" the arc. In this
case, whenever attention is focused on one of the asymmetric carbon atoms, the
two carbon atoms of the chain attached to it are vertically placed and go away
from the viewer, and horizontal groups come toward the viewer. Students are
advised to verify these points with models.
The capital d refers to the configuration of carbon 5 (the atom attached to the
primary alcohol grouping), which is configurationally related to d( + )-glyceral-
dehyde, the simplest monosaccharide.

CHO
H— C— OH
I

CH2OH
d( + j-glyceraldehyde

Figure 14-1. Structural model of on aldohexose.

 Carbohydrates 273

Mutarotation and the Cyclic Formula for Glucose

Although glucose undergoes certain typical aldehyde reactions, which include

the usual carbonyl reactions of oxime and cyanohydrin formation, a pecuhar
result was obtained when Emil Fischer attempted to convert glucose to its
methyl acetal by treatment with two moles of methyl alcohol and hydrogen

/OH /OCH3
H+CI CH3OH
C^ + CH3OH -CH CH + H2O (14-2)
H OCH3 ^OCHs
hemiacetal acetal

Two products were obtained, but surprisingly each

chloride (equation (14-2)).
contained only one methyl group, yet had acetal-like properties. This result
required that glucose itself must exist as a hemiacetal which, upon treatment
with alcohol, yields two acetals.
Examination of models, or the "arc" structure above, shows that thehydroxyl
group on carbon 5 (or 4) can easily be brought within bonding distance of the
carbonyl group at carbon 1. In glucose, it happens to be the hydroxyl on car-
bon 5 which is involved; this leads to a cychc hemiacetal with a six-membered
ring containing one oxygen and five carbons, as depicted in equation (14-3). In
the open-chain, or aldehyde structure, carbon 1 is not asymmetric, but it be-
comes so in the hemiacetal structure. Hence, there should be two optical
isomers. This idea was confirmed by the isolation of two different forms of
d( -I- )-glucose by crystallization from different solvents. One form in a fresh
solution had a specific rotation of -|- 113° (the a form); the other, -|- 19° (the ^
form.) Each of these, when dissolved in water gradually changed in rotation
until an equilibrium value of -|- 52° was reached (containing about 37% a and

Figure 14-2. Emil Fischer (1852-1919), the illus-

trious German organic chemist who is noted for his

pioneering work in the field of carbohydrates,

proteins, and dyestuffs. He received the Nobel
award in 1 902. (Bettmann Archives.)
274 Carbohydrates

o<
H— iC— OH HO— iC—
H— C— OH H— C— OH H— C— OH
I

HO— C— HO— C— HO— C—

I

(14-3)

H— C— OH H— C— OH H— C— OH
I

H— 5C— O— H— 5C— O'^^ H_5C— O—

CH2OH CH2OH CH2OH
a-D-glucose aldehyde form y8-D-glucose
(hemiacetal form) of D( + )-glucose (hemiacetal form)

63% 13 forms). is known as mutarotation and can be explained by

This process
the equiUbrium of the two hemiacetal forms with the aldehydic form, a- and
j8-D-glucose are not enantiomers; carbon atoms 1 in each form are mirror
images, but carbons 2-5 have the same configurations, a- and )S-D-glucose are
therefore diastereoisomers and can be separated by physical methods. The
amount of aldehyde form present at equihbrium in neutral solution is actually
less than 0.1%.
Now to and hydrogen
return to Fischer's experiment with glucose, methanol,
chloride. It is two products which he obtained must have been the
clear that the
acetals derived from a- and )S-D-glucose by replacement of the hydroxyl at car-
bon 1 by a methoxyl group. (Only the hydroxyl at carbon 1 is replaced, because

H— C— OCH3 CH3— O— C—
H— C— OH H— C— OH
HO— C— HO— C—
I I

H— C— OH
I

H— C— OH
H— C— O H— C— O—
I I

CH2OH CH2OH
methyl a-D-glucoside methyl /S-D-glucoside

it is a hemiacetal-type hydroxyl; the hydroxylson carbons 2,3,4, and 6 are simple

alcohols and require much more strenuous conditions for conversion to ethers;
review pages 147-148.) The glucosides cannot mutarotate because their
carbon 1 has an alkoxyl group which, unlike the hydroxyl in the free sugar, can-
not be converted to the aldehyde form.

Conformations of Glucose
The bonds in the cyclic structures are, of course, not long or bent, as they have
been depicted in the projection formulas used thus far. Rather, the six-mem-
bered ring resembles that of cyclohexane, in which the chair form is usually
preferred (see page 34). a-D-Glucose and ^-D-glucose have the configurations
 Carbohydrates 275
shown. The /8-isomer is more stable than the a-form (as shown by its predomi-
nance, sixty-three percent, at equilibrium), probably because all substituents,
including the hydroxyl at carbon 1, are equatorial. In a-D(-|-)-glucose the
hydroxyl at carbon 1 is axial.

H 6
CH2OH
HO HO
OH

a-D( + )-glucose /?-D(-4-)-glucose

(a-D-glucopyranose) (/S-D-glucopyranose)

Conventions for Expressing Ring Size of Carbohydrates

Two stable cyclic ethers with six- and five-membered rings respectively are
pyran and furan. The terms pyranose and furanose have therefore been
adopted to describe the appropriate ring size in the cychc forms of sugars. Thus

^CH2
CH CU CH CH
CH CH CH en
O
pyran furan

the two forms of glucose are more properly described as a-o-glucopyranose and
j8-D-glucopyranose. For an example of a furanose ring, see the formula of ribose
on the next page.

Other Important Aldoses

Two common stereoisomers of glucose are d( -|- )-mannose and D(-|-)-galac-

tose. d( -I- )-mannose differs from d( -|- )-glucose only in the stereochemistry of
carbon 2; D(-|-)-galactose, obtained by hydrolysis of milk sugar (lactose), differs
from D(-|-)-glucose only in the configuration of carbon 4.

CHO CHO
HO— C— H— C— OH
HO— C— HO— C—
H— C— OH HO— C—
H— C— OH H— C— OH
CH2OH CH2OH
D( + )-mannose D( + )-galactose
D-Ribose and 2-deoxy-D-ribose are pentoses on which much attention has
been focused because of their presence in RN A (ribosenucleic acids) and DNA
276 Carbohydrates

(deoxyribosenucleic acids), the polymers which are involved in protein synthesis

and in the transfer of genetic information. Both are shown in the furanose form,
as they occur in nucleic acids.

iCHO
H— 2C— OH CH
H— 3C— OH
H— 4C— OH OH
5CH2OH OH
D-ribose a-D-ribofuranose

ICHO
2CH2
CH2OH
H— 3C— OH
H— 4C— OH
OH
I

5CH2OH H
2-deoxyribose a-D-2-deoxyribofuranose

Fructose, a Ketohexose

The most common of the ketoses is d-(— )-fructose, sometimes called levulose
(due to its Together with glucose,
large negative or levorotation) or fruit sugar.
it is a product of cane sugar hydrolysis. There are only three asymmetric
carbon atoms in the keto form of fructose (see equation (14-4)) and these are
related directly to those in glucose.
Fructose can be obtained by hydrolysis of inulin, a polysaccharide obtained

1CH2OH
2C=0
HO— 3C— CH2OH
H— 4C— OH
H— 5C— OH
6CH2OH
D-( — )-fructose
keto form

(14-4)

OH
a-D-fructofuranose
 Carbohydrates • 277
from dahlia bulbs. It is difficult to crystallize for it tends to form syrups, but
from ethanol one can obtain pure crystals of the ^S-pyranose form. An aqueous
solution of the crystals mutarotates and contains pyranose and furanose forms,
two of which are shown.

Reactions of Monosaccharides
Reducing Action
Sugars which are a-hydroxyaldehydes or ketones, as for example glucose or
fructose, readily reduce various metalUc ions. The most common reagents for
thispurpose are Fehling's or Benedict's solutions, which consist of cupric ion,
Cu2+ complexed with tartrate or citrate ions, respectively. Such solutions are
deep blue. When they react with a reducing sugar, a brick-red precipitate of
cuprous oxide, CU2O, is produced.
Even though sugars are predominantly in the cyclic hemiacetal form, they can
reduce Cu2+ to CU2O because they are in equihbrium with the oxidizable
a-hydroxycarbonyl form. But if the hemiacetal is converted to an acetal, as for
example in the methyl glucosides, this equilibrium is no longer possible, and the
glucoside cannot reduce Fehling's or Benedict's solution. This distinction is
sometimes useful in determining structures of di- or polysaccharides, as will be
seen below with sucrose.

Osazones
The reaction of monosaccharides with phenylhydrazine, discovered by Emil
Fischer, was of fundamental importance in determining their structure. It is
possible to isolate the normal phenylhydrazone of an aldose or ketose. More
commonly, however, additional phenylhydrazine is consumed in oxidizing the
adjacent hydroxyl group to a carbonyl, which then forms a second phenyl-
hydrazone link. Such bis-phenylhydrazones are called osazones.

CH=0 CH=N— NHCeHs CH=N— NHCsHs

^'^"^^"'^"^
CHOH ^^"^"""^"S CHOH C=N-NHC6H5
(14-5)

sugar phenylhydrazone

Osazones have been shown to have the chelate structure

H. /CeHs
N

iCH H

%",N-C6H5
2.Q.

(CHOH),
CH2OH
278 Carbohydrates

It is perhaps for and their separation from the reaction solution as

this reason,
insoluble crystallinecompounds, that the reaction does not proceed further
down the carbon chain. Since the reaction involves only the carbonyl and hy-
droxyl groups on carbon atoms 1 and 2 of the monosaccharide, sugars with the
same configurations at carbons 3, 4, and 5 will give the same osazone, regardless
of the arrangements at carbons 1 and 2 (which become optically inactive in the
osazone). It was in this way that the configurations of carbons 3, 4, and 5 of
D-glucose, D-mannose, and D-fructose were shown to be identical. Each of
these sugars, when treated with phenylhydrazine, gave the identical osazone.
This implied that the only difference between these sugars must lie in the struc-
ture or stereochemistry of the first two carbon atoms.

CHO CHO CH2OH

H— C— OH HO— C—
I

c=o
^
+ 1

HO— C— HO— C— HO— C—

H— C— OH H— C— OH H— C— OH
I

H— C— OH
[
CH2OH
D-glucose
H— C— OH
[
CH2OH
/
D-mannose
—H— C— OH
^

CH2OH
D-fructose
(14-6)

HC=N— NHCeHs
C=N— NHC6H5
HO— C—
H— C— OH
H— C— OH
I

•
CH2OH
D-glucosozone

Sugars are sometimes they tend to form syrups,

difficult to crystallize, since
especially when impure.But the osazones are beautifully crystalline yellow
compounds, which are of great value in identifying monosaccharides.

Glycosides

Methyl glucosides, obtained from methanol and glucose, and already dis-
cussed in connection with the cyclic structures of monosaccharides (page 274),
are examples of a general class of compounds, glycosides, in which an alcohol (or
amine) becomes bonded to a sugar through the hemiacetal oxygen. These are
shown in equation (14-7) for the a-configuration at the hemiacetal carbon, but
)8-glycosides are equally common. Some sugars occur free in nature (glucose,
fructose), but these and many others are often found bound to a non-sugar
 Carbohydrates 279

H— C— OR
o
H— C— OH a-O-glycoside
(14-7)

a-sugar
H— C— NR.
o

a-N-glycoside

component in the form of glycosides (glucosides, fructosides, ribosides, etc.).

The pigments of flowers, the flavorings of vanilla beans or almonds, and many
steroids are among the natural products which occur as glycosides (most com-
monly, /8-D-glucosides). The many hydroxyl groups of the sugar portion of
glycosides are undoubtedly important in solubilizing these pigments, etc., in the
cellular protoplasm. Perhaps the most important A^-glycosides are the ribonu-
cleosides and deoxyribonucleosides which make up nucleic acids. Their struc-
ture and chemistry are discussed in Chapter 16.

Disaccharides

Disaccharides are glycosides in which one monosaccharide acts as the hemi-

acetal and a second monosaccharide furnishes the alcohol grouping. Disac-
charides are therefore acetals, formed from two monosaccharides by loss of
one mole of water. Conversely, hydrolysis of a disaccharide either by water in
the presence of a mineral acid catalyst or by an enzymatic method yields two
moles of monosaccharides. For two hexoses, the molecular equation is shown
(equation (14-8)). The structure determination of a particular disaccharide

C6H12O6 -l- C6H12O6 - C12H22O11 -\- H2O (14-8)

monosaccharide monosaccharide disaccharide

must therefore include {a) which monosaccharide functions as hemiacetal and

which as ROH, {b) which of the several hydroxyls in the monosaccharide func-
tioning as ROH is involved in the glycosidic linkage, (c) the configuration (a or
p) of the glycosidic linkage, and {d) the ring size (furanose or pyranose) in each
monosaccharide unit.
Among the most important disaccharides are sucrose, lactose, maltose, and
cellobiose.

Sucrose (Cane or Table Sugar)

Hydrolysis of sucrose gives equal quantities of D-glucose and D-fructose.

Since its molecular formula is C12H22O11, it must be made up of one unit of
280 Carbohydrates

each of these hexoses. Sucrose does not reduce FehHng's or Benedict's solution,
does not form an osazone (except on prolonged boiling, when glucosazone is
formed due to hydrolysis of the sucrose), and does not mutarotate. Since both
glucose and fructose are reducing sugars, they must be joined together in sucrose
in such a way as to destroy the possibihty for forming a free aldehyde or ketone
group. The glycosidic hnk therefore must involve splitting out a mole of
water between the hydroxyl groups on the No. 1 and No. 2 carbon atoms of the
cyclicforms of glucose and fructose, respectively.
The size of the rings in each monosaccharide portion was determined by first
converting all the hydroxyls in sucrose to methoxyls (with methyl sulfate and

Figure 14-3. The structure of sucrose and proof of the ring sizes.

^ CH2OH ^Q
HO

CH2OH
OH H
(fructose unit)
sucrose («-D-glucopyranosyl-
;8-D-fructofuranoside)

H CH2OCH3 o H CH20CH3^o
CH3O CH,0

2,3,4,6-tetramethyigiucose

+
.0.
CH2OCH CH9OCH..

CH2OCH.

OCH3 H OCH3 H
octamethylsucrose 1 ,3,4,6-tetramethyifructose
 Carbohydrates 281

base) and then hydrolyzing. The had methyls missing at car-

resulting glucose
bons 1 and 5; since carbon 1 was used
to attach the fructose unit, carbon 5 must
have been involved in ring formation. Similarly, the resulting fructose had
methyls missing at carbons 2 and 5, the latter of which must have been involved
in ring formation. These experiments and the structure of sucrose are sum-
marized in Figure 14-3.
The stereochemistry of the glycosidic link was estabhshed by experiments
with enzymes, certain of which hydrolyze a or ^ glycosidic linkages preferen-
tially. In sucrose, the link is a at glucose carbon 1 and ^ at fructose carbon 2,
as shown in Figure 14-3.
The structure of sucrose has been reasonably certain since about 1930, but it
was not until 1953 that it was synthesized by the Canadian chemists, Lemieux
and Huber, using purely chemical methods. Its two main commercial sources
are sugar cane and the sugar beet, each furnishing about half of the world's
supply. The juices, which contain about 14 to 20% of sucrose, are put through
a rather extensive purification process to remove odoriferous and colored im-
purities. Pure sucrose is obtained as white crystals by concentration of the
purified syrups by vacuum removal of the water. The principal use of sucrose
is for food.

Lactose

Lactose is the sugar present in milk; human milk contains 5 to 8%; cow's miUc,
4 to6%. On hydrolysis, lactose gives equal quantities of glucose and galactose.
Lactose is a reducing sugar, a fact which indicates that it still has a potential

aldehyde group. By methods analogous to those described above in more

detail for sucrose, it has been established that the hnkage of the two units is
between carbon 1 of galactose and carbon 4 of glucose. This leaves carbon 1 of

" CH2OH ^Q

XH H
H
D-galactose unit D-glucose unit

(14-9)
lactose (^ form)

responsible for
reducing action,
mutarotation, and
osazone formation

aldehyde form
282 • Carbohydrates

the glucose unit free to be in either the aor ^ form, in equiUbrium with the open-
chain aldehyde structure. Thus, lactose reduces FehUng's solution, undergoes
mutarotation, and forms an osazone.

Maltose and Cellobiose

Maltose is the sugar produced by the action of the enzyme diastase, from malt,
on starch. It consists of two glucose units joined by an a-linkage from carbon 1

of one unit to carbon 4 of Maltose is a reducing sugar and is

the other unit.
particularly important as an intermediate in the manufacture of ethyl alcohol
from starch. It is first fermented by yeast to glucose, then to ethyl alcohol and
carbon dioxide.

HO

may be a or /8

D-glucose unit D-glucose unit

maltose (a-form)

Cellobiose is the disaccharide which can be obtained by the careful hydrolysis

of cellulose. a reducing sugar consisting of two glucose units joined by a
It is

^-linkage from carbon 1 of one unit to carbon 4 of the other unit.

HO OH
may be a or /?

D-glucose unit D-glucose unit

cellobiose (yS-form)

The distinctions in structure between maltose and cellobiose give a clue to the
structural differences between the two polysaccharides from which they are
derived, i.e. starch and cellulose.

Polysaccharides

Polysaccharides contain many monosaccharide units joined in long chains.

The monosaccharide units are joined by oxygen linkages formed by the elimina-
 Carbohydrates 283
tion of water between the units, in much the same way as in disaccharides. The
most important polysaccharides are starch and cellulose. Others of interest are
glycogen, chitin, inulin, gums, and pectins.

Starch

Starch is the reserve carbohydrate in many plants and comprises large per-
centages of cereals, potatoes, corn, and rice. The granules of starch from these
different sources vary in appearance under the microscope both in shape and
size. Chemically, however, they are similar.
Complete hydrolysis of starch amount.
yields glucose in nearly the theoretical
Partial enzymatic hydrolysis gives maltose, showing that starch is made up
mainly of glucose units joined through carbons 1 and 4 by an a-glycosidic
linkage. Joined to these chains are branches containing glucose units hnked at
positions 1 and 6.
Many of the differences in the properties of starch samples can be accounted
for by variation in chain length and degree of branching. Starch can be sepa-
rated into two main fractions by treatment with hot water. The soluble com-
ponent (10-20%) is amylose; the insoluble component (80-90%) is amylopectin.
The molecular weight of amylose ranges from 10,000 to 50,000 (sixty to three
hundred glucose units). Amylopectin ranges from 50,000 to 1,000,000 in molec-
ular weight (300 to 6000 glucose units), but the chain lengths vary only from

Figure 14-4. Amylose starch from a new kind of corn is compared with amylopectin starch which
is found in ordinary corn. Scientists of the United States Department of Agriculture found that
amylose, when treated chemically, forms a fibrous material (right) that con be spun into fibers or

made into film. Given the same treatment, amylopectin (left) forms a powdery substance with no
film or fiber-forming properties. (United States Department of Agriculture.)
X o

0)

_o
>s
E
D
O

c
>o

9)
a
_o
>s
E
o

284
 Carbohydrates • 285
24 to 30 glucose units. Amylopectin is a highly branched polymer. Starch
granules swell in water, eventually forming a colloidal solution, probably owing
to this rather loose, highly branched structure. Partial hydrolysis of starch
transforms it into dextrins, polysaccharides of smaller molecular weight than
starch. They are more readily digested than starch and are used, mixed with
maltose, in infant foods (e.g. Dextrimaltose). A dried mixture of dextrins,
maltose, and milk is the preparation used for making malted milk. Dextrins are
sticky when wet and are used in manufacturing mucilage for postage stamps and
envelopes. In laundering, starched materials become stiff and shiny due to the
transformation of the starch to dextrins by the heat of the iron.

Glycogen
Glycogen is the reserve carbohydrate of animals, occurring mainly in the liver
and muscles. It resembles starch in appearance but has a smaller molecular
weight. Glycogen helps maintain the proper amount of glucose in the blood
by removing excess glucose and storing it when food is ingested or by supplying
it to the blood when it is needed by body cells for energy.

Cellulose

Cellulose is the main structural material of plant life, being the chief in-

gredient of cell walls, of cotton, wood pulp, linen, straw, corn cobs, and many
other materials. Its chemical constitution has been elucidated by hydrolysis

experiments. Complete hydrolysis gives glucose. More careful hydrolysis

gives cellobiose, a disaccharide of two glucose units joined through carbon
atoms 1 and 4 by a /S-linkage. Thus, the cellulose molecule is composed of long
chains of cellobiose molecules joined together by /8-linkages.
The molecular weight of cellulose is probably between 300,000 and 500,000
(or 1800 to 3000 glucose units per molecule). X-ray examination of cellulose
disclosed that it consists of hnear chains made up of cellobiose units in which
the ring oxygens alternate in being forward and back, as shown. Cellulose fibers
consist of bundles of such chains, about 70 to 80 A in diameter, held together by
hydrogen bonds between hydroxyls on adjacent chains. Thus cellulose is un-
affected by most solvents, in contrast to starch which swells under similar con-
ditions.
The digestive systems of man and most other animals do not contain the
necessary enzymes for hydrolyzing )S-glucosidic Hnkages. For this reason, they
cannot digest cellulose. Certain bacteria and other microorganisms in the
digestive tracts of ruminants and termites, however, can decompose cellulose
and use it as food. The striking abihty of the human body to digest starch (a-
glucoside) but not cellulose (yS-glucoside) once again emphasizes the stereo-
specificity of biochemical processes.
Cotton is about 95% cellulose, with impurities of fats and waxes. When the
impurities are removed by washing the cotton with ether, the fibers will take
up water. The product is then known as absorbent cotton. Linen, obtained
from flax, is a somewhat less pure form of cellulose than cotton.
 Carbohydrates 287
Cellulose for the manufacture of paper is obtained from wood pulp. Wood
contains fibers of cellulose and hemi-cellulose (which has a lower molecular
weight) bound by a high-molecular weight polymeric substance known as lignin.
The latter may
be removed from wood pulp with sodium hydroxide and sodium
sulfite. The more completely the lignin is removed, the better is the grade of
paper obtained. Better papers are treated with various sizing agents (rosin,
dextrins, glue) to prevent the soaking up or blotting of ink.

Cellulose Derivatives

The formula of cellulose (see p. 286) shows that each glucose unit contains
three hydroxyl groups. Cellulose, therefore, has chemical properties similar to
those of a trihydric alcohol; forms esters with acids, ethers with other alcohols,
it

and in general exhibits the chemistry of alcohols. Several important cellulose

derivatives are prepared in this way.
Cellulose reacts with nitric acid to form cellulose nitrates much as does glycerol
(page 106). The number of hydroxyl groups nitrated per glucose unit deter-
mines the nature of the product obtained. When most of the hydroxyl groups
are nitrated, the product is guncotton. Highly nitrated cotton is, like nitrated
glycerol, an efficient explosive and is used in the manufacture of smokeless
powders. The lower nitrates of cotton are called pyroxylin. Celluloid, made
from pyroxyhn, camphor, and alcohol, is highly combustible but not explosive.
Collodion is a solution of pyroxylin in a mixture of ether and alcohol. When
spread over a surface (such as a wound), the solvents evaporate, leaving a thin
protective film.

Figure 14-5. At left shown the beaming of cellulose acetate fibers which can be spun and
is

woven. At right, fruit wrapped in cellophane made from cellulose regenerated from cellulose
xanthate. (Photo at nghi by Stanley Rice from Monkmeyer.)
288 • Carbohydrates

Cellulose acetate is prepared from cellulose and acetic anhydride, the latter
reacting with the hydroxyl groups to form ester linkages. Cellulose acetate
rayon is made by forcing a viscous solution of cellulose acetate in acetone
through fine openings, in a current of warm air which evaporates the acetone.
The cellulose acetate is obtained in the form of long fibers which can be spun
and woven. Cellulose acetate does not burn readily and is used in making
motion-picture film.
Most of the rayon that is marketed is manufactured by the viscose process,
which depends upon the reaction of the alcohol groups with carbon disulfide and
alkali to form xanthates.

R— OH + CS2 + Na+OH- > R— O— C— SNa* + H2O (14-10)

cellulose a sodium xanthate

The cellulose xanthate is soluble in water to give a viscous solution (hence the
name viscose), which, when forced through small openings into aqueous acid,
regenerates the cellulose in fine threads. These threads are spun into yam.

R— O— C— S-Na+ + H+Cl- > R— OH + CS2 + Na+Cl" (14-11)

regenerated
cellulose

Cellophane is produced in a similar manner, except that the xanthate is extruded

into the acid bath in thin sheets. These are made water-resistant by a coating
of a transparent cellulose nitrate lacquer.
Cellulose ethers are made by the action of ethyl chloride or ethyl sulfate on
alkaline cellulose. Ethyl cellulose is used in the manufacture of plastics.

Carbohydrates in the Cell

Photosynthesis

Green plants synthesize their complex organic constituents from carbon

dioxide as the only carbon source, together with water and inorganic salts as
other raw materials absorbed from the soil. Light is necessary for the process,
as well as some pigment which can absorb the light (in most plants, chlorophyll)
and transform energy into a form useful for chemical synthesis. The over-all
its

process is represented by equation (14-12), where (CH20)n stands for some

carbohydrate.

/7CO2 + «H20 J"^'',,

chlorophyll
> (CH20)„ + n02 (14-12)

The principle involved in research to determine which organic compounds

are produced 7?«/ in photosynthesis and what they are then transformed to on
 Carbohydrates • 289
the path to sugars, starch, and cellulose, is very simple, though the experimental
techniques are exacting and difficult. Plants are exposed to carbon dioxide in
which the carbon is radioactive (C14O2, carbon with a mass of 14 instead of the
usual 12) and illuminated for varying periods of time. With short exposures (a
few seconds, or less), presumably only the first compounds produced will have
had the opportunity to become labelled with radioactive carbon. Longer ex-
posures enable the process to go further, and more compounds will be produced
containing C^^, until ultimately the carbohydrate molecules become uniformly
labelled. In this way the sequence of chemical events can be worked out,
provided of course that one can isolate the various substances from plant cells
and degrade them chemically, one carbon at a time, to determine the position of
labelling.
Much progress has been made, particularly by a group of researchers at the
University of California at Berkeley under the direction of Professor Melvin
Calvin who received a Nobel prize for this work in 1963. The CO2 acceptor
appears to be the diphosphate of a 5-carbon sugar, which is transformed to two
units of three carbons each, 3-phosphoglyceric acid, where the label first appears.

CH20PO(OH)2 CH20PO(OH)2
C=0 HO— C— C1400H H
H— C— OH -^^ C=0 OH —
H— C— OH H— C— OH
CH20PO(OH)2 CH20PO(OH)2
ribulose diphosphate possible intermediate

CH2— OPO(OH)2
2H— C— OH (14-13)

Ci^OOH
phosphoglyceric acid

Two of these three-carbon units combine at the carboxyl carbons, through a

sequence of steps, to give glucose- or fructose-6-phosphate. This was proved
because both carbons 3 and 4 of the hexoses were labelled with C^^. The
process involves many enzymes at various stages of the sequence. The exact
mechanism by which chlorophyll functions is not completely known. It is

certainly associated with the absorption of sunhght, for plants irradiated with
light of a wavelength which chlorophyll absorbs photosynthesize at an optimum
rate.

t It would seem, from this sequence, that one would obtain one mole of labelled and one mole of
unlabelled 3-phosphoglyceric acid. Since these cannot be separated or distinguished, all of the acid
appears carboxyl-labelled but with half the expected activity.
290 • Carbohydrates

Metabolism
The photosynthetic process is endothermic; energy (from sunlight) is ab-
sorbed to transform carbon dioxide and water to carbohydrates and oxygen.
The reverse process in which animals ingest carbohydrates and convert them
(with the help of oxygen breathed from the air) to carbon dioxide (exhaled) and
water must be an exothermic process or a source of energy for the body.
Di- and polysaccharides are hydrolyzed, primarily by enzymes of the saliva
and small intestines, to the monosaccharides glucose, galactose, and fructose.
These, in the form of various phosphate esters (see page 106; the phosphate
groups are supplied by certain phosphate-containing enzymes), are converted
during muscular activity to pyruvic acid and lactic acids. These are then further
oxidized in muscle tissue to carbon dioxide and water. The scheme for ac-
complishing this involves a number of enzymes and a variety of hydroxy and
unsaturated acids, such as mahc, fumaric, succinic and citric acids. Various of
the intermediates in this scheme can be converted to or be obtained from amino
acids and fatty acids, so that the reactions involved are also important in the
metabolism of proteins and lipids.

NEW CONCEPTS. FACTS, AND TERMS

1. Carbohydrate — polyhydroxyaldehydes or polyhydroxyketones, or closely related sub-
stances. Monosaccharides, disaccharides, polysaccharides; aldose, ketose; pentose,
hexose.
2. Determination of the structure of glucose; Fischer projection formula.
3. Mutarotation; the hemiacetal structure of glucose; methyl a- and )S-D-glucosides.
4. Conformations of glucose; chair form.
5. Pyranose and furanose conventions for ring size.

6. Other Aldoses: mannose, galactose, ribose, deoxyribose.

7. Fructose, a ketohexose.
8. Reactions of monosaccharides; reducing action (Fehling's and Benedict's tests);

osazones; glycosides.
9. Disaccharides
a. Sucrose (glucose and fructose units); a nonreducing sugar
b. Lactose (glucose and galactose units)
c. Maltose (2 glucose units, a-linkage) from starch
d. Cellobiose (2 glucose units, /S-linkage) from cellulose
10. Polysaccharides
a. Starch; dextrins. Glucose chains with a-linkage
b. Glycogen
c. Cellulose. Cellobiose units with yS-linkage. Cotton, linen, paper
d. Cellulose derivatives; guncotton, pyroxylin, celluloid, collodion, cellulose acetate,
cellophane
11. Biochemistry
a. Photosynthesis
b. Metabolism
 Carbohydrates • 291

EXERCISES AND PROBLEMS

1. Define the term "carbohydrate" according to a historical conception and in terms of

present day concepts.
2. Give a structural formula for a:

a. monosaccharide /. disaccharide
b. polysaccharide g. osazone
c. ketohexose h. reducing sugar
d. aldopentose /. nonreducing sugar
e. glucoside j. cycUc structure of a monosaccharide
3. Explain, with formulas, what meant by the term d sugar.
is

4. How many asymmetric carbon atoms are there in the open-chain form of an al-

dotetrose? How many optically isomeric aldoses with this formula should exist? Of
what significance phenomenon of mutarotation with respect to the number of
is the
possible isomers of such a compound?
5. Write structural formulas to show what is meant by the a and fi forms of a D sugar.
Write equations that show how each may spontaneously change to the other.
6. Compound A has the formula C5H10O5. Upon vigorous reduction with hydrogen
iodide, 1-iodopentane is obtained. Mild oxidation gives an acidic substance C5H10O6.
Treatment of A with acetic anhydride gives a tetraacetate. Compound A gives a red
precipitate with Fehling's solution. Suggest a possible formula for A, and write equa-
tions for each reaction.
7. Using glucose as an example, illustrate the behavior of monosaccharides toward the
following reagents:
a. hydrogen cyanide d. phenylhydrazine
b. catalytic hydrogenation e. Tollens' reagent
c. acetic anhydride /. methyl alcohol (plus HCl catalyst)
8. Write the structural formula for the product that results when sucrose is treated with
an excess of acetic anhydride. Calculate how many grams of acetic anhydride would
be required to react completely with one gram of sucrose. (C = 12, H = 1, O= 16).

9. What monosaccharides are obtained by the hydrolysis of:

a. sucrose d. starch
b. lactose e. cellulose
c. maltose /. ceUobiose
10. Draw the structural formulas for all the aldotrioses. Would catalytic hydrogenation of
these yield optically active or inactive products? Explain.
1 1. Draw the formulas of three tetroses, each of which would give the same D-osazone.
12. Write formulas for
a. methyl a-D-mannopyranoside
b. ethyl a-D-ribofuranoside
c. the open-chain forms of the methylated hydrolysis products in Figure 14-3.
d. the products to be expected from the sequence

,
lactose
(CH3).S04
> —
H.O
—- >

13. D-Arabinose, a pentose, is converted by successive treatment with HCN, H3O+, and

reduction with sodium amalgam, to a mixture of D-glucose and D-mannose. Give the

structure of D-arabinose, and equations for the reactions.

292 • Carbohydrates

[CsHtOsCOH).^],., where n is a large number, may

be used to
14. The molecular formula
represent the cellulose molecule. Using this notation, write equations for the reaction
of cellulose with acetic anhydride and with nitric acid,
assuming that all three hydroxyl
groups react. Name the product in each case.
for the preparation of
15. Using the above formula to represent cellulose, write equations
rayon and ethyl cellulose.
 Proteins are perhaps the most complex organic
molecules produced in nature. Because they are vital to the
structure, function, and reproduction of plant and animal
tissue, they have been the subject of intensive research. Pro-
teins are widely distributed: hair, skin, muscles, nerve tissue,
tendons, nails, feathers, horns, and hoofs are made almost
entirely ofproteins. Hemoglobin (from blood), casein (from
milk), and albumin (from the white of egg) are otherfamiliar
proteins. Enzymes, which catalyze chemical reactions in
the body, and even viruses, which transmit certain diseases,
are proteins. The proteins serve as structural materials for
animals much as the polysaccharides do for plants.

Amino Acids and Proteins

When a protein is hydrolyzed either by heating with aqueous acid or by

treatment with a hydrolytic enzyme, it is converted to a mixture of a-amino

acids. Considering the great variety of proteins found in nature, it is certainly

remarkable that only about twenty-five different a-amino acids are
in common
protein hydrolysates. These amino acids, then, constitute the building blocks
of proteins.

Amino Acids
Only a-amino acids are common in protein hydrolysates; that is, the amino
group is on the carbon atom adjacent to the carboxyl group.

Q
R— CH— _^
NH, OH
an Q-amino acid

293
294 Amino Acids and Proteins

With the exception of glycine (R = H), each a-amino acid has at least one
asymmetric carbon atom; the amino acids derived from proteins are therefore
optically active and are all of the l configuration as shown. (See page 260 for
definitions of d and l configurations.)

CO2H CO2H

H2N ->C H2N- H

H R
R
Fischer projection formula,
L-amino acid

Nomenclature and Classification

Amino acids may be named in the same fashion as hydroxy acids (page 195).

O
ft ^^
CH3 -CH—
I

NH, OH
a-aminopropionic acid
(alanine)

Amino acids derived from proteins have common names which, unfortunately,
often give no clue to their structure. Abbreviations for these names are fre-

quently useful in describing the sequence of amino acids in a peptide or protein.

Most natural amino acids have one amino (basic) group and one carboxyl
(acidic) group. But some have more amino than carboxyl groups and are said
to be basic amino acids, whereas others have more carboxyl than amino groups
and are acidic. Several amino acids contain sulfur; one, thyroxine, contains
iodine.
Organisms differ in their abilities to synthesize amino acids. Certain amino
acids,which are necessary for proper metabolism and growth in humans and

Figure 15-1. Models of alanine.

 Amino Acids and Proteins • 295
yet cannot be synthesized by the body, must be ingested in food and are said to
be essential amino acids.
The names, abbreviations, and structures of the more common amino acids
are given in Table 15-1. Essential amino acids are marked with an asterisk.

TABLE 15-1 Some Important Amino Acids

NAME ABBREVIATION FORMULA

A. Equal Number of Basic and Acidic Groups

1. Glycine Gly CH2— COOH

NH2

2. Alanine Ala CH3— CH— COOH

NH2

3. Phenylalanine* Phe fV<

f
~
V-CH2— CH— COOH
NH2

4. Tyrosine Tyr HOf ^CH2— CH— COOH

NH2

5. Tryptophan* Try ril n— CH2— CH— COOH

N^ NH2
H

6. Thyroxine Thy
/~\ J~\
I I NH2

7. Serine Ser CHo— CH— COOH

OH NH2

8. Threonine* Thre CH3— CH— CH— COOH

OH NH2
9. Valine* Vol CH3— CH— CH— COOH
CH3 NH2

10. Leucine* Leu CH3— CH— CH2— CH— COOH

CH3 NH2

11. Isoleucine* lieu CH3— CH2— CH— CH— COOH

CH3 NH2
296 • Amino Acids and Proteins

TABLE 15-1 Some Important Amino Acids (continued)

NAME ABBREVIATION FORMULA

A. Equal Number of Basic and Acidic Groups

12. Proline Pro CH2 CH2

CH2 £H— COOH

N
H

13. Hydroxyproline HPro HO— CH CH2

CH2 CH— COOH

^N
H

14. Cysteine CySH HS— CH2— CH— COOH

NH2

15. Cystine CyS— SCy S— CHg— CH— COOH

I
NH2
S— CH2— CH— COOH
NH2

16. Methionine* Meth CH3— S— CHg—CHg- CH— COOH

NH2

B. Basic Amino Acids

NH2

17. HN=C— N— CH2— CH2—CH2— CH— COOH

H NH2

CH2— CH2— CH2—CH2— CH— COOH

NH2 NH2

CH ^=C— CH2— CH— COOH

N NH NH2
^CH
C. Acidic Amino Acids

20. Aspartic Acid Asp HOOC— CH2— CH— COOH

NH2

21. Glutamic Acid Glu HOOC— CH2—CH2—CH— COOH

NH2
 Amino Acids and Proteins • 297
Analysis of Amino Acids
In order to determine the kinds and amounts of amino acids present in a
protein, it is necessary to have methods for analyzing the mixtures of amino
acids obtained when a protein is hydrolyzed. This requires (a) a procedure for
separating the amino acids from one another, (b) a method for identifying each
amino acid, and (c) a method for determining the amount of each amino acid
present.
Several separation procedures have been devised; the most important involve
paper or column chromatography. In paper chromatography, a spot of the amino
acid mixture is placed at one end or corner of a strip of filter paper. This end is
then dipped into an organic (or aqueous organic) solvent such as butanol. The
solvent slowly migrates up the paper by capillary action, carrying the amino
acids with it. Acids having greatest solubility in the solvent move most rapidly;
those which are less soluble move more slowly, and a separation can be
achieved. In two-dimensional paper chromatography, the spot of amino acids
to be separated is placed in the corner of a rectangular sheet of filter paper.
After migration of the fastest moving amino acid to the far end of the paper has
been achieved along one edge, the paper is turned at right angles and immersed
in a second solvent. Double migration gives a better separation than a single
migration, and results in concentration of the different amino acids in well-
defined spots or zones. The paper is then dried and the spots located by spraying
with ninhydrin, a reagent which gives a blue color with amino acids (see below).
The spots can be identified by comparison with the location of known, pure
amino acids with the same solvents.
In column chromatography, a solution of the mixture to be analyzed is
allowed to pass down a column packed with a material known to absorb amino
acids selectively; this is usually an ion-exchange resin which behaves similarly.

Figure 15-2. Diagram of apparatus used to develop a paper chromatogram. Paper is suspended
from its top edge within an air-tight container (here a glass box closed with a glass plate) having
an atmosphere saturated with solvent vapor; the lower edge of the paper dips into a trough con-
taining the liquid solvent. (John Roberts and Marjorie C. Caserio, Basic Principles of Organic
Chemistry, W. A. Benjamin, Inc., New York, 7 964.)
298 • Amino Acids and Proteins

used in water softeners. The effluent from the column

in principle, to materials
is mixed with ninhydrin reagent, and the intensity of blue color is plotted as a
function of time at constant flow rates. Machines which do this automatically
are now available. The time of appearance of an amino acid is used to identify
it by suitable calibration with known amino acids. The amount present is
determined by the intensity of the blue color.

The Ninhydrin Test

Ninhydrin, a triketone, reacts with amino acids to give a blue dye (equation
(15-1)).

O + RCHCOOH >

NH2

O
+ H3O+ + CO2 +RCH (15-1)

blue ion

The color of the dye is extremely intense, so that 10"^ to 10~^ moles of amino
acid can easily be determined quantitatively.

Synthesis of Amino Acids

For a study of the nutritional requirements of experimental animals, it is
often desirable to have pure amino acids available. Many of these can, of
course, be isolated from proteins more readily than they can be synthesized in
the laboratory. Synthesis generally leads to racemic acids which must then be
resolved to give the natural, optically active form. Nevertheless, many methods
of synthesizing amino acids have been devised and all the common amino acids
are commercially available. They are used as dietary supplements and in
nutritional and cUnical studies.
The halogen atom of a-halogenated acids (page 186) can be replaced by an
amino group if the compound is treated with an excess of ammonia.

/" yP
qHz— Q +2NH3 > CH2— + NHj+Cl- (15-2)

i:
1
OH I^H. OH
chloracetic acid glycine

The hydrolysis of a cyanohydrin has been employed as a method for making

a-hydroxy acids (page 196). This synthesis was modified by Strecker to prepare
 Amino Acids and Proteins • 299

a-amino acids. When hydrogen cyanide reacts with an aldehyde in the presence
of ammonia, the hydroxyl group of the cyanohydrin which is initially formed is
replaced by an amino group. Subsequent hydrolysis of the cyanide (nitrile) in
the usual fashion (page 171) yields the a-amino acid. Equation (15-3) repre-
sents the synthesis of alanine from acetaldehyde by the Strecker method.

O NH2 NH2
CH3— C— H -^^^
NH3
CH3— C— CN -^^ CH3— CH— COOH (15-3)
^ ^
I

H
acetaldehyde aminonitrile alanine
(a-aminopropionic acid)

Many other methods are available, for which the reader is referred to more
comprehensive texts.

Properties of Amino Acids

All of the amino acids in Table 15-1 are colorless, crystalline solids. They
have high melting points (well over 200°), at which they usually decompose.
Most amino acids are relatively insoluble in organic solvents (alcohol, ether,
benzene), but all are at least moderately soluble in water with the exception of
cystine and These properties are characteristic of an ionic rather than
tyrosine.
a covalent compound. The explanation is clear, if one recalls that the amino
nitrogen is expected to be appreciably more basic than a carboxylate anion.
A proton should preferentially add to the former, so that an amino acid is best
represented by the structure in which the proton is attached to nitrogen rather
than oxygen.

R— CH—
^'
+NH3
an amino acid
(dipolar ion structure)

Amino acids are dipolar ions, the positive and negative ends of which are not
free to migrate from one another as in ordinary salts. This type of structure
explains their high melting pointsand other ionic characteristics.
Amino acids are amphoteric; they can either accept a proton from a strong
acid or donate one to a strong base. The equihbria are expressed in equation
(15-4) for an amino acid with no other acidic or basic groups. The net charge
on the amino acid molecule is a function of the acidity of the solution. In an
acid solution, the molecule bears a positive charge (on the nitrogen atom); in an
alkahne solution it bears a negative charge (on the oxygen atoms). If an acidic
solution of an amino acid is electrolyzed, the organic ion will migrate toward the
cathode (negative electrode); if an alkahne solution is electrolyzed, the organic
ion will migrate toward the anode (positive electrode). Intermediate between
300 • Amino Acids and Proteins

amino
R— CH— C^ acid
in acid solution

^O^^^^- +NH3 ^"

R— CH— C^ (15-4)

, amino acid
^^"^ R— CH— \„
in alkaline
solution
+ H2O
NH2 ^

these two extremes, it is possible to attain a solution of the precise acidity (pH)
so that the organic ion will not migrate toward either electrode. This pH is

known as the isoelectric point and is characteristic for each amino acid. This
point may not come at neutrahty (pH = 7.0) because the basic part of the mole-
cule may not be as basic as the acid part is acidic, or vice versa. The basic amino
acids (Table 15-1, Nos. 17-19) have isoelectric points in basic solutions; the
acidic amino acids (Table 15-1, Nos. 20, 21) have isoelectric points in acidic
solutions; and the others have isoelectric points near neutrality but slightly on
the acid side.

Reactions of Amino Acids

Amino acids undergo numerous reactions which might be anticipated from
our previous study of the amino and carboxyl groups. The primary amino
group reacts with nitrous acid to liberate nitrogen gas (page 238). By measur-

CHs-C^ + HONO > CH2-C^ + Nst + H2O (15-5)

NH2 OH in OH
glycine glycollic acid

ing the volume of nitrogen evolved, one can determine the quantity of amino
acid present. This analytical method was developed by the American bio-
chemist, D. D. Van Slyke, and is particularly useful for determining the number
of free primary amino acid groups in a peptide or protein.
The carboxyl group forms esters by reaction with alcohols. The esters are
/O
R— CH— C;^ + HOCH2CH3 -^ R- CH-
NH2 OH
 Amino Acids and Proteins 301

o o
//
C— NH— CHo—
II

+ H-Cl-
KJ CI
.,-H.
OH amide OH
(15-7)
glycine hippuric acid
(benzoylglycine)

the detoxification of organic acids. Benzoates ingested by human beings are

eliminated as hippuric acid. \\'ith ammonia or amines, an amide is formed at

the carboxyl group.

O
R— CH— C'^^ - NH. -^ R— CH— 4- HoO (15-8)

NH-, OH NH2 _22l!

amide

Peptides and Proteins

.\lthough hvdrolvsis of proteins vields amino acids, there are relatively few
free amino or carboxyl groups in the protein itself. This suggested to Emil
Fischer many years ago that amino adds are present in proteins as long chains
joined together bv amide linkages formed betv^een the amino group of one acid
and the carboxyl group of another. Such linkages are known as peptide bonds
(Figure 15-3). X-rav studies, particularly by Linus Pauling (Figure 15-4) and

H !
O
j^ R
R— C*—
N* — *C— COOH
'C
\
NHz
I

H* i
H
the peptide bond

Figure 15-3. Models showing the peptide bond.

The atoms marked with an asterisk tend to lie in a
single plane.
302 • Amino Acids and Proteins

others at the California Institute of Technology, established the precise

geometry of such bonds. Proteins may therefore be represented by the partial
structure

H V,
OH

The amide group is flat (Figure 15-3), and the carbonyl-to-nitrogen bond is

appreciably shorter (1.32 A) than the usual (1.47 A) carbon-nitrogen single bond
distance. The structure is a hybrid of the two extremes shown. The structure
on the right requires a shortening of the carbon-nitrogen bond; it also makes
the nitrogen trigonal, similar to a carbonyl carbon, and is responsible for the
observed planarity.

po" vO
— C
V^N-
N-

By convention, the free amino group is written at the left end of the protein
chain and the free carboxyl group at the right. The amino acid which furnishes
the free amino group is called the "N -terminal acid" and that which furnishes
the free carboxyl is called the ''C -terminal acid." The distinction between
peptides and proteins is rather arbitrary. Chains of 2, 3, 4,etc. amino acids are
referred to as di-, tri-, tetra-, etc. peptides. When the molecular weight is over
10,000 (roughly 50-75 amino acid units), the substance is usually called a
protein.

Figure 1 5-4. Linus Pauling (Cal. Tech.) outstanding

tiieoretical chemist who has made many contribu-
tions to the knowledge of organic structures. He
did fundamental work on the theory of resonance
(page 66), measurement of bond lengths and
energies, and on the structure of proteins and the
mechanism of anti-body action. He received the
Nobel prize in chemistry in 1954 and the Nobel
Peace prize in 1962.
 Amino A cids and Proteins • 303

Sequence Determination
The number and kinds of amino acids present in a peptide or protein can be
determined by the chromatographic techniques abeady described. The prob-
lem of determining the sequence in which the amino acids are joined to form the
peptide chain is appreciably more difficult.
The general strategy is to hydrolyze partially the polypeptide or protein to
smaller peptides, perhaps containing from two to five amino acid residues each.
These smaller peptides are separated by column chromatography. If each of
these can be identified, then by piecing together overlapping sequences one can
establish the over-all sequence. For example, suppose a hexapeptide is known,
from complete hydrolysis, to contain one each of six diff'erent amino acids,
A,B,C,D,E and F. If partial hydrolysis led to the isolation and identification
of three tripeptides as C-B-F, E-C-B, and A-D-E, this would require that the
hexapeptide have the structure A-D-E-C-B-F. The isolation of the tripeptide
D-E-C or dipeptides such as C-B, A-D, E-C, etc., would confirm the structure.
The problem now resolves itself, in simplest terms, to determining the differ-
ence between a dipeptide A-B and its counterpart B-A. In the former, A is
N-terminal and in the latter it is C-terminal; i.e., in A-B, A has a free amino
group, whereas in B-A it has a free carboxyl group. The N-terminal amino acid
is usually determined by allowing the peptide to react with 2,4-dinitrofluoroben-
zene. This reagent readily undergoes nucleophilic aromatic substitution with
primary amino groups (review page 126). Complete hydrolysis leads to a mix-

R O
-HF
O2N F + H2N— CH— C— NH
peptide chain

R O
complete
O2N NH— CH— C— NH hydrolvsis

NO,
R
O2N NH— CH— COOH + other amino acids (15-9)

N-terminal amino acid

ture of amino acids, one of which has a 2,4-dinitrophenyl group attached to the
amino nitrogen. This alters its chromatographic behavior and allows its

identification.
The most successful procedure for determining the C-terminal amino acid
depends on use of the enzyme carboxypeptidase (from the pancreas), which
selectively hydrolyzes peptide bonds adjacent to free carboxyl groups. This
304 • Amino Acids and Proteins
allows the peptide chain to be degraded one amino acid residue at a time from
the carboxyl end. Use is also made of other highly specific proteolytic enzymes
in selectively degrading proteins.
Application of these methods has led to the complete sequence determination
of a number of physiologically important peptides. Oxytocin, a hormone which
regulates uterine contraction and was isolated from the posterior
lactation,
pituitary gland. It is a cychc octapeptide. V. du Vigneaud (Cornell) received
the Nobel prize in 1955 for determining its structure and synthesizing the
hormone.

H—CyS—Tyr— lieu— Glu— Asp— CyS— Pro— Leu— Gly

NH2 NH2 NH2
oxytocin

The terminal carboxyl groups of Glu, Asp, and Gly are present as simple amides
(-CONH2).
The complete amino acid sequence of the hormone insulin, a natural peptide
used to treat diabetes, was elucidated in 1954 by Frederick Sanger (Cambridge,
England, Nobel prize 1958). It has a molecular weight of 5,734 and contains
48 amino acid residues (counting sulfur amino acids as cystine rather than
cysteine) of 16 different kinds. The sequence is shown in Figure 15-5.
The adrenocorticotropic hormone, ACTH, which stimulates the hormone-
producing activity of the adrenal cortex, contains 39 amino acid units; the first
24 of these from the N-terminal end, and the last six units are independent of
the animal source of the hormone, but the sequences in the 25-33 region vary
somewhat with source. The fragment with the first 24 units retains essentially
all of the hormonal activity. Synthetic fragments with about half the chain,
from the N-terminal end, are physiologically active.
The determination of amino acid sequences in proteins is now solved in
principle, but the task is arduous and difficult. Among recent accompUshments
have been the sequence determination of certain cytochromes (enzymes im-
portant in cellular oxidation-reduction reactions; over 100 amino acid residues),
the a- and from human hemoglobin (141 and 146 amino acid
)8-peptides
and chymotrypsinogen-A (precursor of chymotrypsin,
residues, respectively)
an enzyme which hydrolyzes peptides and other acid derivatives, molecular
weight about 25,000; 246 amino acid residues).

Peptide Synthesis

Peptide synthesis is important for several reasons. The first is to verify a

particular peptide structure. But one might also want to study the effect of
exchanging one amino acid in a sequence for another on the physiological
properties of the peptide. Possibly fragments of a natural enzyme might show
activity (as with ACTH); one might wish to synthesize such fragments or
variants thereof. The need for methods of joining amino acids to form peptides
 Amino Acids and Proteins • 305
Gly

Figure 15-5. Amino acid sequence of beef insulin.

Gly and Phe are the N-terminal ends, Asp and Ala
are the C-termino! ends. — NH2 stands for carboxyl
groups present as primary amides.
306 • Amino Acids and Proteins

O O
H2N— CH2— C— CI + NH2— CH— C— OH ^^^^^ Gly— Ala (15-10)

CH3
the acid chloride might react with the amino group of another glycyl chloride
molecule (equation (5-11)) rather than the amino group of alanine, leading

O O
HoN— CH2— C— CI + NH2— CH2— C— CI HCl
-^

o o
II

NH2— CH2— C— NH— CH2— C— CI

II

> etc. (15-11)

ultimately to a polymer of glycine rather than to the desired dipeptide. It is

necessary, therefore, to protect the amino group of glycine in some way to avoid
this reaction. But the protecting group must be easily removed at the end of the
synthesis without destroying the peptide bond.
The carbobenzyloxy protecting group is the most generally used, although
numerous others are known. The reagent is benzyl chloroformate, prepared

O O
/^A-CH20H + Cl-C-Cl ^^ /^ VCH2-O-C-CI (15-12)

benzyl alcohol phosgene benzyl chloroformate

from benzyl alcohol and phosgene. It reacts with amino acids as shown for
glycine in equation (15-13).

O
/ VCH2— O— C— CI + H2N— CH2CO2H dilute

NaOH
>

o o
/ VCH2— O— C— NH— CH2C— OH (15-13)

carbobenzyloxyglycine

The amino acid, thus protected, is activated by conversion to an acid chloride,

000
anhydride, or other reactive form (many techniques are available for this step)
and allowed to react with the amino acid to follow in the sequence, in this case
alanine. The product will be the dipeptide, with the amino group protected.

f
r^VCH2— O— C—NH— CH2— C— NH— CH— C— OH
II II II

~
CH3
carbobenzyloxyglycylalanine
 Amino Acids and Proteins • 307
The protecting group must now be removed without hydrolyzing the peptide
bond. In this case it done by reduction, benzyl alcohol derivatives being
is

easily reduced to toluene. The carbamic acid thus produced ( 1 5- 1 4) is unstable,

loses CO2, and liberates the terminal amino group. If a tripeptide or higher
peptide is desired, the chain is built up stepwise, and the protecting group is
not removed until the last step.

O
/ V-CHg— O— C— NH> H., Pd

o
f~\ CH3 + H— O— C— NH^ (15-14)

carbamic acid

CO,

H2N
peptide, amino end

Classification of Proteins

Proteins may be divided into several general classes.

Fibrous proteins are the animal structural proteins of the hair, nails, hoofs, etc.

They have a fibrous structure, and are neither soluble nor dispersible in water.
Examples are fibroin (from silk), keratin (from hair, wool), and collagen (gelatin).
SUk fibroin consists primarily of glycine, alanine, serine, and tyrosine, with very
small percentages of seven or eight other amino acids. X-ray determinations

Figure 15-6. Silkworm cocoons shown in their

natural habitat of mulberry branches, the leaves

having been eaten by the silkworms. Each cocoon
contains between 500 and 1,300 yards of fiber,
a source of fibroin. (United States Department of
Agriculture.)
 Figure 1 5-7. Human blood showing red blood
cells, one white cell in the lower left corner of the
picture, and some platelets (magnified 1250x)-
c. The red cells contain large amounts of hemoglobin.

jty

*^

show considerable similarity between the structure of silk and nylon. Keratin
contains many amino acids, all in relatively small percentages. It is a good
source (14%) of the sulfur-containing amino acid cystine. Gelatin is nearly one-
third glycine and one-third proline and hydroxyprohne, with small percentages
of other amino acids. Since it contains no tryptophan (one of the essential
amino acids), it therefore cannot sustain life.
Globular proteins are more complex than the fibrous proteins. The edible
proteins of milk, eggs, meat, and similar foods are globular proteins. They are
soluble or dispersible in water and are far more sensitive to changes in tem-
perature, salt concentration, solvent, acids, and bases than are the fibrous pro-
teins. The globular proteins may be subdivided into several groups (albumins,

globuhns, glutelins, prolamines, histones, protamines), depending largely upon

their solubiUty in various solvents. For a detailed discussion of these sub-
may be made to any standard text in biochemistry.
classes, reference
Conjugated proteins have associated with them as an integral part of their
structure some nonproteinlike grouping called a prosthetic group. An example

CH=CH2

CH CH=CH2

CI-

CH CH,

H2CH2CO2H
 Amino Acids and Proteins • 309
is hemoglobin, the main protein in red blood corpuscles which functions to carry
oxygen from the lungs to the body tissue. It consists of a protein called globin
attached to a prosthetic group called heme. Acid hydrolysis of the protein
allows isolation of the prosthetic group as hemin, a complex ferric salt which
comprises about 4% of the protein.
The structures and function of other conjugated proteins, such as certain
enzymes and nucleoproteins (the proteins of cell nuclei), will be discussed in
Chapter 16.

Protein Structure

There are several of organization necessary to the understanding of

levels
protein structure, only one of which — —
amino acid sequence has been con-
sidered thus far. This may be referred to as the primary structure. The repeat-
ing unit in a protein chain consists of a nitrogen and two carbons, one of which
bears the particular R side-chain which distinguishes one unit from another (see
page 302). The secondary structure has to do with the preferred conformations
of the chain. Since many proteins can be crystallized, it follows that the
arrangement will be regular and not random. Much of what we know about
the secondary structures of proteins comes from X-ray studies of crystals.
The most common arrangement of the chain appears to be the alpha-helix
(Figure 15-8). This is amino acid residues per
a right-handed helix with 3.6
maintained by hydrogen bonds between amide
turn, the heUcal structure being
hydrogens and carbonyl groups four peptide bonds apart. The R groups of
the amino acid units lie outside the hehcal coil. Each amino acid contributes
1.5 A to the length of the long axis of the heUx; the spacing between turns of
the helix is about 5.4 A.
The a-hehx, suggested by PauUng for a-keratin, the protein of unstretched
wool, hair, horn, and nails, is known to be responsible for segments of the struc-
tures of many For example the globular conjugated
other proteins as well.
protein myoglobin, which is cells of tissues and acts as a
contained within the
temporary storehouse for the oxygen brought by the hemoglobin in the blood,
has about three-quarters of its amino acid residues in a-helical segments. Its
complete structure, as worked out by John Kendrew, Max Perutz, and their
associates (Nobel prize, 1963), consists of eight straight lengths of a-helix
varying in length from 7 to 24 amino acid units joined by irregular regions.
When a-keratin is stretched, it takes a new form called j8-keratin in which the
hehces become uncoiled and the chains stretch side by side to give a sheet-hke
structure. Adjacent chains head in opposite directions and are bound to one
another by inter-chain hydrogen bonds (see Figure 15-9). One reason why this
structure is not as common as the a-helix is that R groups on adjacent chains
come rather close to one another. This structure is only common when the R
groups are small, as for example in silk fibroin in which 46% of the amino acids
are glycine (R = H).
Least is known about the tertiary structures of proteins, the ways in which
coiled chains are folded and solvated (usually hydrated) in the natural state.
310 • Amino Acids and Proteins

Figure 1 5-8. The a-helix of a protein molecule. The

configuration is maintained by many N — H- • • -O
hydrogen bonds between amide and carbonyl
groups four peptide bonds apart in the primary
structure. (Sc/ent/fic American, December, ?96I.)
 Amino Acids and Proteins • 311
-7.0 A ^

region of
R — R repulsion
H R O H H R O
\f II I \/ II

C-terminal
unit ./
C\ /C\ /N\ /C\ /C\ / ,

N C C N C
I /\ II I
/\
H R H O H R H

Figure 15-9. Segment of ;8-keratin. Adjacent chains are held together by hydrogen
bonds. The sheets are slightly "pleated" to avoid serious R — R repulsions.

Chemical Behavior of Proteins

Like the amino acids, proteins are amphoteric in nature. They exhibit iso-
electric points in much
same way as do the amino acids. The acidity or
the
basicity of a protein depends upon the kind of amino acids of which it is com-
posed. Those proteins which contain large percentages of basic amino acids
(Type B, Table 15-1) form basic solutions, whereas those containing large per-

Figure 15-10. The beaker on the left shows a colloidal solution of egg white in water. After
boiling, the egg white separates out, as in the beaker on the right. This coagulation of a protein
by heat is called denaturation. (Courtesy of W/7bur Nelson, Michigan State University.)
312 • Amino Acids and Proteins

centages of acidic amino acids (Type C, Table 15-1) form acidic solutions. Zein
(from com), for example, which has a high glutamic acid content, will form salts
with bases but not with acids.
When proteins are heated or treated with concentrated acids, ultraviolet light,
alcohol, or other reagents, they may become denatured. Denaturation involves
profound and complex changes in the protein molecule. Thus the denatured
protein is always less soluble than the native protein. Enzymatic activity, if any,
is destroyed. Crystallinity is lost. The nature and mechanism of the changes
that accompany denaturation are still subjects of active research, but probably
are associated with uncoiling of the helical structures and with changes in the
degree of hydration. An everyday illustration of the denaturation of a protein
is the coagulation of the white of egg (albumin) when cooked (see Figure 15-10).

Metabolism of Proteins
Proteins are hydrolyzed by digestive enzymes to peptides and amino acids
which are absorbed and transported by the blood to various body tissues. Tissue
proteins are continually being broken down and resynthesized, ingested amino
acids being incorporated and those already present being ehminated. Certain
amino acids necessary for growth and maintenance must be included in the diet
(page 295), but others can be synthesized by the animal body.
One important process in biosynthesis is transamination, which allows inter-
conversion of a-keto acids and a-amino acids.

CO2H
c=o
I

NH2
^^^^ CH3-CH-CO2H + CH2 (15-15)
 Amino Acids and Proteins • 313

NEW CONCEPTS. FACTS. AND TERMS

1. Alpha amino acids — the building blocks of proteins. All amino acids in proteins have
the L configuration.
2. Table of important amino acids (pages 295-296); essential amino acids.
3. Analysis of amino acids; paper and column chromatography; the ninhydrin test.

4. Synthesis of amino acids

a. From a-chloroacids and ammonia
b. ammonia)
Strecker synthesis (aldehyde, hydrogen cyanide, and
5. Properties ofamino acids; dipolar ions; amphoteric; isoelectric point.
6. Reactions of amino acids
a. With nitrous acid (amino group converted to a hydroxyl, and nitrogen gas evolved)

b. With alcohols to form esters

c. With acid halides. anhydrides or ammonia to form amides at either function

7. Peptides and proteins; the peptide bond; N- and C-terminal amino acids.
8. Sequence determination; reaction of N-terminal acid with 2,4-dinitrofluorobenzene.
Insulin, ACTH.
9. Peptide synthesis; protecting groups (carbobenzyloxy).
10. Classification of proteins
a. Fibrous (fibroin, keratin, collagen)
b. Globular (albumins, globuhns)
c. Conjugated (hemoglobin, enzymes, nucleoproteins)
11. Protein structure; the a-hehx, a-keratin, myoglobin; the y8-sheet structure, silk fibroin.
12. Chemical behavior of proteins; isoelectric point, denaturation.
13. Metabohsm of proteins; transamination, deamination.

EXERCISES AND PROBLEMS

Name and write the structural formulas for two naturally occurring amino acids which
fit each of the following descriptions:
a. monoamino monocarboxyhc acids
b. diamino monocarboxyhc acids
c. monoamino dicarboxyhc acids
d. amino acids containing ring structures
Write structural formulas for the following peptides:
a. alanylglycylleucine c. leucylglycylalanine
b. glycylglycine d. glycylglycylglycine
Define the following terms. Illustrate with formulas wherever possible.
a. denaturation g. dipolar ion
b. neutral amino acid h. peptide bond
c. basic amino acid /. dipeptide
d. acidic amino acid J. essential amino acid
e. isoelectric point k. fibrous protein
/. globular protein /. conjugated protein
314 • A mi no A cids and Proteins

4. State the number of possible optical isomers in the following compounds:

a. glycine d. cystine
b. alanine e. hydroxyproline
c. glutamic acid /. leucine
5. Which amino acids may form polypeptides with {a) free amino groups, {h) free carboxyl
groups? Illustrate with structural formulas showing the unit structure in such
polypeptides.
6. Draw the structure of alanylalanine, using the natural (l) configurations and showing
the stereochemistry clearly.
7. Illustrate with equations the reaction of a monoamino monocarboxyhc acid,
RCH(NH2)COOH. with hydrochloric acid and with sodium hydroxide.
8. The isoelectric point of lysine is 9.7. Will an aqueous solution of this ammo acid in
water be acidic or basic? Explain using the structural formula of lysine, and an equa-
tion representing its reaction with water.
9. Give equations for the preparation of:

a. alanine from propionic acid c. glycine from acetic acid

b. vaHne from isobutyraldehyde d. leucine from isobutyl chloride
10. Write equations for the following conversions:
a. acetylene to glycine c. ethylene to aspartic acid
b. isobutyl alcohol to leucine d. toluene to phenylalanine
11. Using glycine as an example, write equations for the reaction of an amino acid with
a. nitrous acid d. ethyl alcohol
b. benzoyl chloride e. ammonia
c. acetic anhydride /. ethylamine
12. Write the equation for the reaction of phenylalanine with ninhydrin.
13. Write the structures likely to be present as a strongly alkaUne solution of lysine is

gradually made strongly acidic.

14. In order to get a feeling for the complexity of peptides and proteins, write out the com-
plete structure of oxytocin, an abbreviated formula for which is given on page 304.
15. Work out the amino acid sequence of a peptide which contains one residue each of
alanine, arginine, glutamic acid, glycine, lysine, proline, threonine and tyrosine and two
of phenylalanine. The following peptides were identified from its hydrolysis:
Thr-Pro-Lys-Ala; Gly-Phe; Phe-Tyr-Thr; Phe-Phe; Glu-Arg-Gly. Draw the com-
plete structure.
16. A water-insoluble protein yields mainly diamino monocarboxyhc acids on hydrolysis.
Predict the solubility of this protein in dilute acid and dilute alkah. Would the iso-
electric point of this protein be at, above, or below 7?
17. Polysaccharides and proteins are both high-molecular-weight natural products. How
could one distinguish between them by simple chemical methods?
18. Proteins from widely different animal and vegetable sources have percentage composi-
tions which lie within a narrow range: C, 51-55%; H, 6.5-7.3%; and N, 15-18%. Using
a value of 16% for nitrogen, calculate the percentage of protein in a sample of food con-
taining 3.5% nitrogen. What is the percentage of combined fats and carbohydrates in
the food?
19. Illustrate the use of the carbobenzyloxy protecting group in the synthesis of alanyl-
glycine.
20. Write a detailed mechanism for the reaction of 2,4-dinitrofluorobenzene with valyl-
glycine. What products are obtained when the product from this reaction is hydrolyzed
with aqueous hydrochloric acid?
 c-c-c-c—
G

One major goal of the organic chemist is to deter-

mine the structures of compounds which occur in nature and
to understand their reactions. Often such compounds have
important and useful physiological effects. By being able to

synthesize variants of natural products, the chemist can often

modify these effects to advantage. Only through complete
understanding of the chemistry of natural products can life
processes be unravelled.

Natural Products

Most compounds which occur in nature have rather complex structures, often
with several functional groups. It is therefore difficult to classify them accord-
ing to one or two functional groups, as has been done with both natural and
unnatural compounds discussed up to this point. They can, however, be con-
sidered under several categories which, though a bit arbitrary, do point up cer-
tain gross structural features. In this chapter, natural products will be con-
sidered in three major groups: {a) terpenes and steroids, whose main skeleton
consists solely of carbon atoms either open-chain or cycHc, (b) heterocycUc
natural products, those compounds in which an atom other than carbon
—
usually oxygen or nitrogen is an important structural feature, and (c) nucleic
acids which, although they belong in group (Z>), will be considered separately and
in greater detail because of the intense current interest in these genetic materials.
Throughout the chapter compounds may be discussed which, although they do
not occur in nature, have an important effect on natural processes. Among
these are certain drugs and agricultural chemicals.

315
316 Natural Products

Terpenes and Steroids

The fragrance of many plants is due to the presence of volatile compounds,
usually with ten or fifteen carbon atoms, known as essential oils. Many of these,
such as those obtained from camphor, turpentine, citronella, cedar, sandalwood,
etc., are used as flavors, perfumes, medicinals, or solvents and thus are important
articlesof commerce. The structural feature which they have in common is

the branched five-carbon isoprene unit, so named because of its relation to

isoprene, the diene obtained from the pyrolysis of rubber.

C CH3
c— c—c— CH2=C— CH=CH,
an isoprene unit isoprene

Terpenes (from terpentin, an old form of the word turpentine) are unsaturated
hydrocarbons with the molecular formula CioHie, composed of two isoprene
units usually joined at carbons 1 and 4. Examples are myrcene (from bay or
verbena oils) and limonene (in oils of citrus fruits, pine leaves, and peppermint).
The faint dash Unes in the formulas show how the molecules can be considered
to have been derived from isoprene units. a-Pinene, a bicyclic terpene, is the
chief constituent of turpentine and is probably the most abundant hydrocarbon
in nature.

myrcene limonene a-pmene

Other natural hydrocarbons related to the terpenes but with three, four, or
more isoprene units are common. C15 compounds are known as sesquiterpenes,
C20 as diterpenes, and C30 as triterpenes. a-Famesene is an acyclic sesquiter-
pene obtained from oil of citronella. The sesquiterpenes caryophyllene (from
oil of cloves) and cedrene (from oil of cedar), with their unusual ring sizes and

junctures, illustrate some of the more intricate ways in which isoprene units may

a-far caryophyllene cedrene

be combined. (As an exercise, it is suggested that the reader supply the dash
lines, 3 and 5, respectively, in the last two formulas.) The unsaturated acyclic
 Natural Products 317
triterpene squalene, which occurs in high percentages in shark Hver oil. is a
precursor in the bios\nthesis of the steroids (p. 321).

squalene

Perhaps more common than the terpene hydrocarbons themselves are their
many oxygenated derivatives which contain the common oxygen functions
alcohols, aldehydes, ketones and acids. Geraniol occurs in oil of geranium,
whereas its partially reduced derivative citronellol occurs in rose oil. Geraniol
is a colorless liquid with a ver\' pleasant rose odor. Its esters more
are often
stable than the alcohol itself and are used in perfumes. The aldehydes corre-
sponding to these alcohols, geranial and citronellal, occur in lemon oil and oil
of citronella. respectively. Natural rose oil, extracted from rose petals, contains

CH9OH CH9OH CHO CHO

geraniol citronellol geraniol

40-60% geraniol and 20-40% citronellol. together with a mixture of odorless

hydrocarbons. Synthetic rose oil, manufactured by suitable reduction of oil of
citronella, is considerably less expensive.
Farnesol, a sesquiterpene acyclic alcohol with a lily-of-the-valley aroma, is an
important intermediate in the biosynthesis of triterpenes and steroids. Reduc-
tive couphng of two farnesol units (as pyrophosphate esters) gives squalene.
Vitamin A, a diterpene alcohol, is necessary for synthesis of certain pigments

CH2OH

vitamin A

essential to sight. Its deficiency m the diet results in improper growth, and the
disease xerophthalmia, or the inabihty to see properly in semidarkness.
Vitamin K. which is used in medicine to help prevent excessive bleeding at

childbirth or after operations, is largely but not entirely isoprenoid.

318 • Natural Products

vitamin Kj

Menthol, a saturated alcohol related structurally to limonene, is the chief con-

stituent of peppermint oil. The corresponding ketone, menthone, is also present
in the oil. Camphor is a particularly well-known bicyclic terpene ketone. It is
synthesized commercially from pinene at a price which competes favorably with

OH

menthol camphor

natural camphor isolated from the camphor tree grown almost exclusively in
the Orient. The synthetic material is racemic, whereas the natural product is

optically active; but both may be used equally well in medicine and in the manu-
facture of celluloid and other plastics.
The glassy residue, known as rosin, which remains after the removal of tur-
pentine from pine tree sap, iscomposed largely of abietic acid, a tricyclic
diterpene carboxylic acid. The sodium or potassium salts of abietic acid are

CO2H
abietic acid

sometimes used in inexpensive soaps. It is also used in the manufacture of

hnoleum, varnishes, sizing for paper, and sealing waxes. Rosin and turpentine,
which were essential articles on wooden sailing ships, are still known as "naval
stores."

Steroids

It has been known for many years that plant and animal fats contain a portion

which is nonsaponifiable (that is, which is not converted to fatty acid and glycerol
by boUing alkaU). These substances, which are primarily sohd alcohols, are
known as sterols. Common to the structure of all sterols is a system of four fused
carbon rings, three with six members and the fourth with five; seventeen carbon
 Natural Products 319
atoms comprise the rather The rings are generally not
rigid skeleton structure.
aromatic; the ring skeleton may be
modified by functional groups or carbon side
chains in order to complete the particular sterol molecule.
The fundamental carbon skeleton of the sterols persists through a variety of
interesting, biologically among which are the brain and
important materials,
spinal tissues, the constituents of bile, the sex hormones, compounds related to
vitamin D, and others. Compounds with this ring system (through they may
not be alcohols) are known as steroids.
The numbering of the shown in the formula below. The
steroid ring system is

rings are referred to as A, B, C, Most steroids have methyl groups

and D.
(called angular methyls) attached to carbons 10 and 13, and a side-chain or other
functionality at carbon 17. To give some idea of what such a complex molecule
might look like, the formula below shows the steroid ring system with rings A,

4 6

steroid ring system

B, and C as cyclohexane rings fused in a trans manner; note that the methyl
groups (Ci8 and C19) are axial and on the "top" side of the molecule. A group
which is up with respect to the molecular "plane" is called beta (^), whereas one
which extends down is called alpha (a). This is shown in the formula for sub-
stituents at C3.
Probably the most common steroid is cholesterol, a substance present in
rather large amounts in the brain and spinal cord and in smaller amounts in all
cells of animal organisms. Cholesterol was first isolated from and is the chief
constituent of gallstones. In recent years, it has received notoriety in connec-
tion with circulatory ailments, especially hardening of the arteries. The total
cholesterol extractable from body
all tissues, including blood, amounts to about
half a pound for the average man.

HO
cholesterol

Cholesterol has a ^-hydroxyl at C3, a double bond at Cs-Ce, and an eight-

carbon side-chain at C17. Because of its many asymmetric centers, cholesterol
320 • Natural Products

presented a formidable synthetic challenge, but, after considerable effort and

ingenuity, was synthesized in the laboratory in the 1950's (Figure 16-1). It is
it

a sobering and humbling thought that the cell synthesizes this complex molecule
in a matter of minutes from such a simple precursor as acetate ion! A study of
the biosynthesis of cholesterol by using radioactive-labelling in possible pre-
cursors has led to an understanding of the biogenetic relationship between the
terpenes and steroids.
All the carbon atoms of cholesterol, like those of the fatty acids (p. 219), are
derived from acetyl coenzyme A. The synthetic pathway is the same up to
acetoacetyl CoA, at which point, by means of an aldol-type condensation, a
branch is introduced.

O O O OH
11 II II I

CH3CCH2C— S— CoA -h CH3C— S— CoA ^ CH3CCH2CO2H

O
CH2C— S— CoA
reduction (16-1)

CHs^ ^H
^C— CH2CH2OH <^^^^
-H.O
CH3C— CH2CO2H
CH2 I

CH2CH2OH
isopentenol

The active isoprene unit, isopentenyl pyrophosphate, is obtained with label as

shown

<-H3 ^
.C— CH2-CH2— O-P-O— P-OH
II II

3CH3CO2H ^ (16-2)
acetyl-CoA y^
^^2
|

OH OH
isopentenyl pyrophosphate

Double bond isomerization and coupling of two such units can lead to geranyl
pyrophosphate; addition of a third unit gives famesyl pyrophosphate, reductive
coupUng of which gives squalene. Isotopic labelling experiments indicate that
cholesterol is derived from acetate via squalene and lanosterol. The evidence is
that homogenized liver tissue is able to convert labelled squalene to labelled
lanosterol and thence to labelled cholesterol. The last steps require loss of three
carbons, which tracer experiments show to be oxidized to carbon dioxide (the
methyls at C4 and C14). Konrad Bloch and Feodor Lynen received the Nobel
prize in medicine in 1963 for their elucidation of these biosynthetic schemes.
Although cholesterol occurs only in animals, a wide variety of steroids may be
obtained from plants. Among the more common is ergosterol, originally ob-
tained from ergot but also present in yeast. Ergosterol differs from cholesterol
 Natural Products 321

-> cholesterol

(16-3)

squalene lanosterol

by one methyl group and two double bonds. Irradiation of ergosterol with
ultraviolet light leads to calciferol (vitamin D2), a substance which can control
the amount and ratio of calcium and phosphorus in the blood.

irradiation

(16-4)

HO HO
ergosterol vitamin D2

Sex Hormones

The substances produced in the gonads (ovaries and testes) which control the
physiology of the reproductive process and the secondary sex characteristics are
known as sex hormones. Although primarily concerned with reproductive
mechanisms, sex hormones are also significant as growth substances of general
importance to body health and well-being.
Tht female sex hormones are of two types, the estrogens which are necessary
for the changes of estrus, the cycle of ovulation, and progesterone which is re-
quired for normal pregnancy. Estrone, one of the estrogens, has been found in
the urine of women, particularly during pregnancy. Comparison of estrone
with cholesterol shows that ring A is aromatic and that the side chain at carbon
17 is lacking. Certain synthetic materials, though not hormones because they
are not produced in the body, have been shown to possess estrogenic activity.
Stilbesterol is an example of-^uch a substance (its structure is only remotely
related to that of estrone). Progesterone is now produced synthetically and
used in treating certain unfavorable pregnancies. Progesterone differs from the
estrogens in that none of the rings is aromatic.
The male sex hormones, or androgens, may be obtained from testicular extracts
or from urine. Testosterone regulates the development of reproductive organs
322 Natural Products

HO

HO
stilbesterol

OH

HO'
testosterone androsterone

and secondary sex characteristics. Androsterone, which differs by one double

bond and reversal of the ketone and alcohol functions, has somewhat less
potency than testosterone.

Adrenal Cortical Hormones

Chemical studies of the extract of the adrenal cortex have resulted in the
hormones, closely related in structure
isolation of nearly thirty different to the

CH2OH

sex hormones. One of these is cortisone, particularly effective in the treatment

of rheumatoid arthritis and rheumatic fever. A unique feature of the cortisone
structure is the oxygen atom at carbon 1 1 Synthetic analogs, but with a fluorine
.

attached to carbon 6 or 9, are even more potent.

 Natural Products • 323

Heterocyclic Natural Products

Oxygen Heterocycles
Carbohydrates probably constitute the largest class of natural oxygen hetero-
cvcles. being related to either turan or pvran (5- or 6-menibered ring, respec-
tively: see p. 275). Their chemistry was discussed in detail in Chapter 14.

Two of the common \ itamins are owgen heterocycles. Ascorbic acid (vitamin
C) is a carboh\drate deri\ ative found in citrus fruits, tomatoes, and fresh vege-
tables. Its deticiencv in the diet causes scurv\ . and as long ago as the eighteenth
centur\ British sailors were required to eat fresh limes (hence, "limey'') to
pre\ ent outbreak of the disease. It is easilv and reversiblv oxidized, and its

biochemical function is in certain oxidation-reduction processes. It is related

stericallv to L-^lvceraldehyde.

HO OH CH
\^
c=o
H—
HO <^-H
CH.
^ HoOH
ascorbic acid rt-tocopherol

Vitamin E, a factor necessary to normal reproduction in rats, consists of a

group of substances known as tocopherols, one ot^ which is shown above.
Sources of the vitamin are lettuce, milk, and whole-grain cereals. It probablv
fimctions as an antioxidant in cells.
Couniarin. which occurs in clo\er and grasses, and is responsible for the
pleasant tragrance when these are freshlv cut. is widelv used as a perfume and
flavoring agent. Compounds with a similar structure, but with thecarbonvl
group in the 4-position. are called chromones. Derivatives of 2-phenyl-
chromone (flavones) are responsible for manv of the beautiful colors of flowers.
plant leaxes. truits. and berries.

Rings with One Nitrogen

Several important pigments with \ital biochemical functions contain four

pyrrole rings joined in the 2 and 5 positions by one-carbon bridges. The parent
compound, porphyrin, does not occur in nature, but with various side-chains,
difterent central metal ions, and other sliaht modifications one obtains several
324 Natural Products

CH=CH CH,

CH CH2CH3

CH CY\:

the same side-

RO2CCH2CH chain as in
H I O vitamin Ki
CO2CH3
porphyrin chlorophyll-a

very important natural products. Hemin, with a central iron atom, was dis-

cussed earlier (p. 308). Chlorophyll has the four pyrrole nitrogens coordinated
to the magnesium and is The determination of its
essential to photosynthesis.
structure required many work in Germany (R. Willstatter, H.
years of brilliant
Fischer) and the United States (J. B. Conant), and a total synthesis was elegantly
achieved by R. B. Woodward (Figure 16-1) and co-workers in 1960. Vitamin
B12, the antipernicious anemia vitamin, has a complexed cobalt and cyanide
group at the center. Its structure determination by X-ray diffraction in 1955
entitled Dorothy Crowfoot Hodgkins to become the second woman (Madame
Curie was the first) to win a Nobel prize in chemistry (1964). It is even more
complex than chlorophyll, containing sugar and other heterocyclic groups as
well as four pyrrole-type rings.

Figure 16-1. Robert B. Woodward (1917—)/ one

of the world's outstanding organic chemists. At
age 27, he, with W. Doering (Yale), synthesized

quinine. His synthesis of steroids and work on the

structure of strychnine and other natural products
hove been particularly noteworthy. Lysergic acid
(ergot), strychnine, reserpine (used to treat mental
disorders), and chlorophyll are on his list of
synthetic victims. ProfessorWoodward received
the Nobel prize in chemistry in 965 for his con-
1

tributions to the "art" of organic synthesis.

 Natural Products 325
The group of natural nitrogen-containing heterocyclic compounds are
largest
the alkaloids, basic substances isolatedfrom plants. Most alkaloids show
pronounced physiological activity, and their structures are often complex.
Several of the more common alkaloids will be described here, classified accord-
ing to the principal heterocycUc ring system Ln the structure.
Indole alkaloids have the indole (or benzopyrrole) ring as part of their struc-
ture; the same ring system is present in the essential amino acid tryptophan
HO / CH2CH2NH2
CH2CHCO2H
I

indole tryptophan

(p. 295). Serotonin, which occurs widely in plant and animal hfe, is among the
simpler indole alkaloids. It may have a function in mental activity, since a
disturbance in its normal concentration in the brain can induce schizophrenia.
Among the more complex alkaloids of this class are reserpine and strychnine.

/^N~
CH3O
OCHc
.H O
CH3C— O' A
H OCH3
O— OCHc

OCH3
strychnine reserpine

Strychnine, the exceptionally powerful poison, has found some use in

medicine as a stimulant of the central nervous system. This complex molecule
was synthesized by Woodward and his co-workers in 1954.
Rauwolfia serpentina (Indian snake root), which grows wild on the foothills

of the Himalayas, has been used for centuries to treat insanity, cholera, epilepsy,
and assorted other disorders. The active alkaloid
hysteria, snake-bite poisoning,
was isolated in pure and named reserpine or serpasil. Despite its
form in 1952,
stereochemical complexity, its structure was determined and total synthesis
(Woodward) accomphshed through intensive efforts of many workers in but 4
years. Reserpine is used to lower blood pressure and as a tranquilizer for the
emotionally disturbed.
The pyridine, quinoline (2,3-benzopyridine), and isoquinoUne (3,4-benzo-

W
pyridine quinoline isoquinoline
326 Natural Products

pyridine) ring systems are present in many natural products. Perhaps the
simplest and most widely known of the pyridine alkaloids is nicotine, which also
contains a saturated five-membered nitrogen heterocycle (the pyrrohdine ring).
Nicotine is the principal alkaloid in tobacco, constituting about 5% by weight of
the dry leaves. It is a violent poison and is used in high dihition as an insecticide.
Oxidation of nicotine gives nicotinic acid, a member of the vitamin B complex
which is an antipellagra factor. Nicotinic acid is manufactured commercially
by oxidation of 3-methylpyridine (yS-picohne), a constituent of coal tar; it is
used as a food supplement.

CH,
cone. HNO) fi I
oxidation
-* I
< (16-5)

N-

nicotine nicotinic acid |S-picoline

Vitamin Be is also a pyridine derivative; the group in the 4-position may be an

alcohol, aldehyde, or amine. As the phosphate of the primary alcohol group in
position 5, the aldehyde and amine function reversibly as coenzymes in the inter-
conversion of a-keto acids and a-amino acids.

R = CH2OH (pyridoxine)
= CH=0 (pyridoxal)
= CH2NH2 (pyridoxamine)
vitamin Be

Reduced pyridine (piperidine) and pyrrole (pyrrohdine) rings are present in

cocaine, isolated from the coca plant. Cocaine has been used in medicine;
small doses decrease fatigue, increase mental activity, and afford a feeUng of

N-CH3
rOsCHs CH3CH2. ^
N— CH2CH2OC / \ NHc
/
O— CH3CH2
novocaine
o

N— CHs

OC— CH—
O CH2OH
atropine
 Natural Products Z27
calm and happiness. But these benefits are short-Uved, being followed by
periods of strong depression which demand more of the drug. To avoid the
defects of cocaine, many have been synthesized, the most
local anesthetics
successful of which has been novocaine which bears some structural similarity
to cocaine. Novocaine is less toxic and not habit-forming. Atropine, an
alkaloid from the belladonna plant, is used (in dilute solution) to dilate the eye
pupil prior to ophthalmic examinations.
Quinine is the best known of the quinohne alkaloids. It occurs in cinchona
bark and is used to treat malaria. Morphine and codeine are two of the more
than twenty-five alkaloids isolated from the opium poppy; they have reduced
isoquinoline ring systems. Heroin is the diacetyl derivative of morphine.

CH2=CH^-^H
RO

CH,Q
HO
morphine (R = H)
codeine (R = CHj)
quinine

Rings With More Than One Heteroatom

The two most important ring systems with more than one nitrogen are
The heterocyclic nitrogen bases present in nucleic acids
pyrimidine and purine.
(DNA and RNA) are of this type and will be discussed separately in the final

W1

pyrimidine purine

section of this book. Two major vitamins, thiamin (Bi) and riboflavin (B2), con-
tain pyrimidine rings. Thiamin is essential to human nutrition, its deficiency
causing the disease beri-beri.The pyrophosphate of thiamin is the coenzyme of
carboxylase, the enzyme which catalyzes decarboxylation of a-ketoacids. The
NH2 CH3
e^^CH2CH20H
CH f< CHc
ci

thiamin
328 Natural Products

CH2(CHOH)3CH20H
CH
NH
CH

five-membered sulfur-containing ring is a thiazole. Riboflavin is involved in

biological oxidation-reductions; the reduced form involves 1,4-addition of hy-
drogen to the two nitrogens at the ends of the conjugated system. Both vitamins
are manufactured synthetically for use in food supplements.
Caffeine is the best known purine alkaloid. It occurs in the tea plant and
coffee bean and is the substance responsible for the physiological stimulation
derived from drinking the corresponding beverages.

CH,

caffeine

Figure 16-2. Trays at the bottom of the picture (left) contain the sodium salt of penicillin ready
for drying operations after extraction from Penicillium notatum mold. Flasks containing experi-
mental quantities of the crude mold are shown on the right. (Courtesy of Merck & Company, and
Corning Glass Works.)
 Natural Products 329
Antibiotics are chemicals which are antagonistic to the metabolic processes of
certain microorganisms and inhibit their growth or kill them. The best known,
and one of the first antibiotics to be used in medicine, is penicillin, a heterocycUc
compound in which one of the rings is a reduced thiazole. The substance is
obtained commercially by extraction from a mold which produces it. Various

o
CHc
O- CH2— C— NH— CH— CH
C N
C,
/

O^ "CH
CH,

CO2H
benzylpenicillin

other groups may replace the benzyl group, and the molecule still retains its

physiological activity. Other common antibiotics, such as streptomycin, Ter-

ramycin, Chloromycetin and the macrohdes, are not structurally related either
to penicillin or to each other.

Nucleic Acids

Without question, the development in fundamental science which has most

caught the pubhc eye during the decade is the unravelling of nucleic acid
last

chemistry, and its concomitant impUcations for understanding protein syn-

thesis and chemical genetics. In this final section, some of the organic chemistry
involved in these discoveries will be presented.

The Structure of DNA

Chemical analysis of chromosomes shows them to be composed of giant
molecules of deoxyribonucleic acids (DNA) bonded to proteins. The gross
structural features of DNA are independent of its source, though the detailed
structure does depend on the organism from which the is derived. DNA
Indi-
vidual DNA molecules are sufficiently large, with molecular weights of several
million, to enable them to be "seen" with the electron microscope. X-ray
diffraction studies show that DNA
is made up of two long-chain molecules
twisted around each other to form a double-stranded hehx with a diameter
about 20 A.
330 • Natural Products

Each of the strands in the double heUx is a polymer, the backbone of which
consists of repeating phosphate and sugar units, the sugar being present as an
A^-glycoside (p. 279) with certain heterocychc bases. The sugar is D-2-deoxy-

sugar I— phosphate
I
sugar phosphate sugar phosphate

base base base

ribofuranose,and the common bases are two pyrimidines, cytosine and thymine,
and two purines, guanine and adenine. The sugar and base are then combined

OH H
D-2-deoxyribofuranose

guanine adenine

at the hemi-acetal carbon of the sugar, as shown for adenine and cytosine. In
the latter case, necessary that the base tautomerize to the keto or amide
it is

form. These sugar-base units are called nucleosides. When the hydroxyl group
NH2
HOCH2 OH -H,0

OH
NHc

(16-6)

OH
adenine deoxyriboside
 Natural Products 331

NH
2-deoxvribose

-HoO

(enol) (keto)

HOCH2 (16-7)

OH
cytosine deoxyriboside

at carbon five is esterified with phosphoric acid, the substance is referred to as a

nucleotide.

O
HO— P— O— CH2
II

OH

OH
adenine deoxyribonucleotide

Nucleotides are the monomer units from which the nucleic acid polymers are
built; the units arelinked together by esterification of the hydroxyl group at
carbon three of one nucleotide with the phosphate group of another nucleotide.
The number of such units may vary from several thousand to several milhon.
The DNA strand is shown. The sequence of bases along the chain
structure of a
will vary, depending on the organism from which the DNA was isolated. When
this chapter was written, no natural DNA base sequence had yet been deter-
mined.
Finally we come to the problem of the double helix. Although the sequence
of purine and pyrimidine bases in the chain is not known, there is a striking re-
lation between certain of the bases. Analysis of DNA, regardless of source,
332 • Natural Products

O
HO— P— O— CH2^
I

II u
^ B
O

B = a nitrogen base, i.e. cytosine,

thymine, guanine, or adenine

structure of a DNA strand

usually shows that the number of cytosine (C) groups equals the number of
guanine (G) groups, and the number of thymine (T) groups equals the number
of adenine (A) groups. This base-pairing (i.e. C^G
and T=A) led to the sug-
gestion by Watson and Crick that the two strands of the double helix were held
together by hydrogen bonds between an adenine in one strand and a thymine in
the other or a guanine in one strand and a cytosine in the other.

CHc
O.
H H,

sugar
Y ^H 11

sugar
thymine-adenine pair cytosine-guanine pair

The double helix, then, consists of two intertwined deoxyribose-phosphate

chains; the base on each sugar unit of one strand is directed toward the center
of the helix where it is hydrogen-bonded to a corresponding base on the other
strand. There are ten pairs of bases for a complete 360° twist of the chain. The
protein moiety of nucleoproteins is probably wrapped around the helix.
The genetic information inherent in DNA depends on the base sequence; i.e.,
the sequence T-A-G at some point along the chain must convey a different
 Natural Products • 333
message from the sequence G-A-T. The idea of replication is also clear;
untwisting of the double helix leads to single strands, each of which can act as
the template for formation of its counterpart. The details of these processes,
however, are quite complex and are now being worked out.

The Structure of RNA

Although DN A is a storehouse of genetic information, including the codes for
protein and enzyme synthesis, it cannot be directly involved in these processes,
because they occur primarily outside the cell nucleus, in the cellular cytoplasm
which does not contain DNA. Clearly, information must be passed from DNA
to other substances which carry this information to the site of protein synthesis.
These sites are known as ribosomes, which consist of ribonucleoproteins. RNA,
or ribonucleic acids, differs from DNA
in several major respects, although the
gross features of the polymer strands are similar. The sugar of RNA is

D-ribofuranose, and the base thymine is replaced by uracil (the other three bases
are the same). Finally, the pairing of bases noted in DNA is not common with

HOCH2/' ^\ OH OH O

OH
OH OH
D-ribofuranose uracil

most RNA, suggesting that RNA is single-stranded (although some pairing of

bases in one part of the chain with others in another part of the chain can lead
to structural regularities by folding of the chain back on itself).

Besides ribosomal RNA, two other types of RNA are known. These are
messenger RNA, which conveys the information of what protein to make, and
transfer RNA, which seems to guide each amino acid into its proper place on the
surface of the ribosome. One of the most exciting research results of 1965 was
the elucidation of the complete structure (i.e. base sequence) of alanine transfra*
RNA, a nucleic acid isolated fromwhich transfers the amino acid alanine
yeast,
to its correct position for incorporation in a protein. Alanine transfer RNA
contains 77 nucleotides and has a molecular weight of 26,600; its structure was
worked out by R. W. Holley and co-workers at Cornell University by partial
hydrolysis and examination of the fragments for overlapping sequences in a
manner modelled after the techniques used in determining amino acid sequences
in proteins.
We have come a long way in this text — from the simplicity of methane, one of
which hold the
the earth's primordial gases, to the complexity of nucleic acids,
key to our understanding of hving processes. What we know of organic
chemistry is due to men whose curiosity, desire to understand the physical
world and to improve it for man's benefit, and courage led them to experiment
in the laboratory and to share their observations and ideas by publication in
international journals.
334 • Natural Products

NEW CONCEPTS. FACTS. AND TERMS

1. Terpenes; isoprene unit. Myrcene, limonene, pinene, squalene, geraniol, farnesol,
vitamins A and K. Mentliol, menthone, camphor, abietic acid.
2. Steroids; cholesterol, vitamin D2, sex hormones, cortisone.
3. Oxygen heterocycles; ascorbic acid, vitamin E, coumarin.
4. Rings with one nitrogen; pyrrole, porphyrins, chlorophyll. Indole alkaloids (serotonin,
strychnine), pyridine alkaloids (nicotine, vitamin Be, cocaine, novocaine, atropine).
Quinohne and isoquinoline alkaloids (quinine, morphine). Pyrimidines (thiamin,
riboflavin); purines (caffeine). Penicillin.
5. Nucleic acids; DNA, deoxyribose, cytosine, thymine, guanine, adenine, nucleoside,
nucleotide, base-pairing, RNA, uracil, alanine transfer RNA.

EXERCISES AND PROBLEMS

1. Explain briefly the meaning of the following terms:
a. essential oil e. sex hormone
b. terpene /. alkaloid
c. steroid g. vitamin
d. nucleic acid h. antibiotic
2. What structural unit occurs in the terpenes and their derivatives? Does natural rubber
(page 67) fit this pattern? Draw the appropriate dash hnes in the formulas of menthol,
caryophyllene and cedrene, to show these units.
3. Limonene can be prepared by heating isoprene to about 280° -300°. Write an equation
to show how the reaction might occur.
4. Write an equation for the catalytic hydrogenation of racemic limonene and name the
product. How many stereoisomers are possible for this product? Illustrate with suita-
ble formulas.
5. Limonene and menthol have the same carbon skeleton. Write equations for reactions
that would convert each of these compounds to the same dialkylcyclohexane, thus
proving the identity of their carbon skeletons.
6. In a manner analogous to question 5, how could one prove that the arrangement of
carbon atoms in geraniol and citronellol (page 317) is identical?
7. Camphor has a carbonyl group and undergoes reactions similar to simple ketones.
Write equations for the reactions of camphor with:
a. hydroxylamine c. an alkylmagnesium bromide

b. 2,4-dinitrophenylhydrazine d. hydrogen and a nickel catalyst

8. Estrone (page 322) contains two functional groups, a phenolic hydroxyl group and a
keto carbonyl group. Write equations for the following sequence of reactions: Solution
of estrone in sodium hydroxide followed by treatment with ethyl iodide yields A. Inter-

action of A with methylmagnesium bromide in ether followed by hydrolysis yields B.

9. Write equations showing what products might be expected if the following were warmed
with aqueous sodium hydroxide:
a. cocaine b. novocaine c. atropine
10. Geraniol, on treatment with acid, gives a tertiary alcohol a-terpineol which, on dehy-
dration, yields limonene. Give the formula for a-terpineol and suggest mechanisms
for both reactions.
 Natural Products • 335
11. How many stereoisomers of menthol are possible? Draw the formulas. Of these,
which is hkely to be the most stable?
12. Starting with isopentenyl pyrophosphate labelled as in equation (16-2), show the
labelling to be expected in (a) the geraniol, (b) the famesol, and (c) the squalenewhich
would be obtained from this precursor.

13. Chromones (p. 323) are exceptionally basic, being readily protonated on the carbonyl
—
oxygen much more readily than ordinary a,/S-unsaturated ketones. Can you suggest
an explanation?
14. Write a possible mechanism by which pyridoxamine (p. 326) might react with pyruvic
acid to convert it to alanine. What is the pyridoxamine transformed to in this reaction?
15. Write the formula for the reduced form of riboflavin (p. 328).
16. Draw the formula for the triphosphate ester, at position 5. of adenine riboside (cf p.
106). This substance, sometimes called adenosine triphosphate (ATP), is an extremely
ubiquitous compound in biochemical reactions.
17. Three important enzymes in biochemical reactions have modified nucleotide structures.
From the following descriptions, try to write out the correct formula of each. Nico-
tinamide adenine dinucleotide (NAD+) consists of adenine riboside and nicotinamide
riboside joined at the two 5-positions by a diphosphate bridge. Flavin adenine dinu-
cleotide (FAD) consists of adenine riboside joined at carbon 5 by a diphosphate bridge
to the terminal hydroxyl of riboflavin. Coenzyme A is the 3-phosphate of adenine
riboside joined by a diphosphate bridge at carbon 5 to the terminal hydroxyl group of
the /S-mercaptoethylamide of pantothenic acid; the formula of pantothenic acid, a
vitamin, is

HOCH2C(CH3)2CH(OH)CNHCH2CH2C02H.
O
18. Draw a segment of an RNA chain.
INDEX
Index

Acid anhydrides. 166. 181-183, 187.203-

205
Abietic acid. 3 1 Acid derivatives. 172-190
Absolute alcohol. 97 summar\' of reactions. 186
Acetaldehyde. 136. 196. 299 Acid hahdes. 166. 175-177. 187
acetal formation. 148 Acids. 30. 163-190, 194-204
aldol condensation. 153 amino, see Amino acids
halogenation of. 155 decarboxylation of, 31, 174-175
oxidation, 171 dicarboxylic, 164, 165
preparation. 143 from fats. 209
reaction with Grignard reagent. 150 halogenated. 195
trimer. 156 hvdroxylated. 196. 198-201
Acetals. 148. 149 ionization constants. 166-168
in sugar series, 273-274 keto. 197-198
Acetamide. 175. 183 nomenclature. 165-166
AcetaniUde. 233, 235. 236. 239 phenohc. 199-200
Acetic acid, 30, 136, 164, 165. 167, 169. 177 physical properties. 169
decarboxylation. 30. 143 preparation. 145. 170-172
preparation. 171. 176 reactions. 172-190
Acetic anhydride. 181. 182. 183. 199 salts of 173-175
Acetoacetic acid, 195. 197. 220 substituted. 186-187. 194-201
Acetone, 137. 220 substitution reactions of 186-187
preparation. 101. 140. 143. 174 unsaturated. 201-205. 209
uses. 143 Acr)hcacid. 195. 202
Acetone cyanohydrin. 146 Acr\lonitrile. 62
Acetophenone, 137, 187 ACTH, 304. 322
Acetyl chloride, 176, 182 Acyl group. 166
Acetyl group. 166 Acyl halides. 166. 175-177. 187
Acet\ichohne. 230-23 Acylation
Acetylene. 59-64, 68 of alcohols, 177, 179, 183
hydration of, 143 of amines, 234-236
Acetylenes, see Hydrocarbons, unsaturated Acyhum ion. 1 87
Acetyhdes. 62-63^ 126 Addition reactions. 44-52
Acetylsahcylic acid, 199 1,4-, 64-68

339
 340 Index

Adenine, 330 Alkyl halides, 123-129

Adipic acid, 165, 175, 240, 241 displacement reactions, 125-127, 171
Aerosols, 131 hydrolysis, 94-96
Alanine, 294, 295, 299, 307, 312 preparation, 123-125
Albumin, 308 Alkyl hydrogen sulfates, 106-217
Alcohols, 14, 91-111 Alkyl iodides, 125
acidity, 103-104 Alkyl isocyanate, 234
classification of, 92 Alkyl lithium compounds, 129
dehydration, 58, 113-114 Alkyl nitrates, 105
dehydrogenation, 141 Alkylation
displacement reactions, 104-105, 124 of alkenes, 53
long chain, 213, 217 of ammonia and amines, 231-232
nomenclature, 92-94 of aromatic hydrocarbons, 82-84
oxidation, 139-141 Alkylbenzenes, 81-84
physical properties, 101-103 Alkynes, see Hydrocarbons, unsaturated
polyhydric, 97-99 Allyl alcohol, 8, 98, 124
preparation, 94-99, 126, 128, 149-151 Allyl chloride, 98, 124
primary, 92, 149 AUyl sulfide, 117
reactions of, 103-107 Alpha carbon atom, 152-155
secondary, 92, 150 Aluminum chloride, 52, 82-84, 187
sulfur analogs, 107-108 Amides, 166, 183-186, 233, 234-237
tertiary, 92, 150 preparation, 175, 177, 180, 183
Alcoholysis, 177, 180, 183, 186 Amines, 224-243
Aldehydes, 135-162 acylation, 234-236
addition reactions, 145-152 base strength, 228-229
halogenation, 155 classification, 224
naturally occurring, 138-139 di-, see Diamines
nomenclature, 136-138 dissociation constants, 228-229
oxidation of, 144-145, 155, 202 nomenclature, 224-227
physical properties, 136, 138 physical properties, 227-229
polymerization of, 156-158 preparation, 126, 231-234
preparation, 139-143 primary, 224-225, 231-234, 237, 238
reactions, 144-159 reactions, 234-243
reduction of, 151 salts of, 234
tests for, 145, 151 secondary, 224-225, 231, 233, 237, 238
Aldol, 153 tertiary, 224-225, 231, 233, 237, 238
Aldol condensation, 153-154 238
tests for, 237,
Aldose, 270-272 Amino 293-314
acids,
Aliphatic, definition, 76 amphoterism of, 299-300
Alkadienes, see Hydrocarbons, unsaturated analysis, 297-298
Alkaloids, 325-327 essential, 295
Alkanes, 20, see Hydrocarbons, saturated nomenclature, 294-296
Alkanolamines, 119-237 optical activity, 294
Alkenes, 39, see Hydrocarbons, unsaturated preparation, 298-299
Alkoxides, 103, 126 properties, 299-300
Alkyl aryl sulfonates, 217 reactions, 300-301
Alkyl cyanides, 126 structure, 294, 299
Alkyl fluorides, 124 Ammonia, 148, 177, 225, 227, 228
Alkyl groups, 21, 22 alkylation of, 231-232
 Index 341

Ammonia continued Beeswax, 221

basicity, 228-229 Benedict's test, 277
Ammonolysis, 177, 180, 183, 186 Benzal chloride, 142
«-Amyl alcohol, 101 Benzaldehyde, 136, 138, 139
Amylopectin, 283-284 phenylhydrazone, 149
Amylose, 283 preparation, 142
Androgens, 321 reactions, 150, 154, 158, 196
Androsterone, 322 Benzamide, 183
Anethole, 116 Benzene, 73-77
AniHne, 226, 228, 232, 235, 239 acylation, 187
alkylation, 232 alkylation, 82-84
bromination, 238 deuteration, 80
diazotization, 243 halogenation, 74, 79, 81, 85, 87, 124
preparation, 232 nitration, 80, 85
resonance in, 229 oxidation, 204
Anisole, 112, 115, 116 preparation, 174
Anthracene, 77 resonance, 75-76
Antibiotics, 329 structure, 73-76
Antifebrin, 235 sulfonation, 80
Antifreeze, 98 Benzenediazonium chloride, 243-245
Antiknock fuels, 52 Benzenesulfonic acid, 80, 99
Antimalarials, 327 Benzenesulfonyl chloride, 237
Arginine, 296 Benzidine, 240
Aromatic compounds, definition, 76 rearrangement, 239-240
Aromatic hydrocarbons, see Hydrocarbons, Benzoic acid, 164, 166, 167, 169, 179
aromatic bromination, 187
Aromatization, 54 preparation, 84, 170, 171, 177
Aryl groups, 78 Benzonitrile, 244
Arylhalides, 79, 81, 124, 126 Benzophenone, 137
Ascorbic acid, 323 Benzotrichloride, 171
Aspartic acid, 296 Benzoyl chloride, 177, 301
Aspirin, 199-200 Benzoyl group, 166
Association Benzyl alcohol, 158, 306
of acids, 169 Benzyl chloride, 79
of alcohols, 102 Benzyne, 245
Asymmetry of carbon atoms, 256-258, Bicyclobutane, 34
262-263 BUe, 246
Atropine, 326, 327 Biphenyl, 77, 78
Auxochrome, 246 Biphenylene, 245
Axial bonds, 34 Bisulfite addition compounds, 150-151
Azo compounds, 245-246 Biuret, 185
Azo dyes, 247 Boat conformation, 35
Bond
axial, 34
B
covalent, 3
Baeyer test for double bonds, 57 double, 7, 40^4
BakeUte, 157-158 equatorial, 34
Barbital, 185 geometry, 9-12
Bathochromic group, 246 ionic, 2
342 Index

Bond continued Carbon, 1

multiple, 7 alpha, 152-155

polar, 3 asymmetric, 256-258, 262-263
sigma, 1 oxidation states, 139-140
triple, 7, 59-61 Carbon-carbon bonds
Bond distance, 8, 23, 44, 60, 75, 144, 184, double, 40-44
301 single, 11
Bromination, see Halogenation triple, 59-61
/7-Bromoaniline, 239 Carbon dioxide, 7, 31, 140, 172, 181
Bromobenzene, 81, 96, 124, 127 Carbon disulfide, 29 1

Bromoform, 155 Carbon monoxide, 29, 97, 142

Bromoniom ion, 46, 65, 80, 81 Carbon tetrachloride, 27, 129
Brucine, 265 Carbonic acid, 140
1,3-Butadiene, 64-66, 154, 205, 241 Carbonium ions, 13, 51, 53, 54, 65, 81, 82,
Butane, 19, 321, 59 86-87, 95, 147, 196
conformations of, 24 Carbonyl group, 144
Butanols, see Butyl alcohols Carboxyl group, 30, 163
Butenes, 44, 51, 57, 58 Carboxylate ion, 168
Butter fat, 211,219 Camauba wax, 22
Butyl alcohol Carotene, 68
iso-, 92 Caryophyllene, 3 1

normal, 92, 97, 101 Castor oil, 218

secondary, 58, 92, 95 Cedrene, 316
tertiary, 92, 95 Cellobiose, 282, 285-286
«-Butyl cyanide, 171 Cellophane, 288
rt-Butyl mercaptan, 108 Cellosolve, 119
«-Butylamine, 228 Celluloid, 287
Butyne, 61, 63 Cellulose, 285-288
A2-Butyraldehyde, 136, 154 acetate, 287-288
«-Butyric acid, 165, 167, 169 ethers, 288
nitrate, 287
• xanthate, 287-288
C
Cetyl alcohol, 213
Cadaverine, 240 Chain reaction, free radical, 26, 48, 56, 124
Caffeine, 328 Chair conformation, 34
Calcium carbide, 63 Chloral, 147, 155, 156
Calvin, M., 289 hydrate, 147
Camphor, 138, 318 Chlordane, 131
Cane sugar, see Sucrose Chlorination, see Halogenation
Carmizzaro reaction, 158 Chloroacetic acid, 167, 195, 298
Capric acid, 169 Chlorobenzene
/2-Caproic acid, 165, 169 DDT from, 156
Caprolactam, 241 preparation, 79, 85
Carbamic acid, 185, 234, 307 reactions, 85, 100
Carbanions, 4, 13, 52, 127 Chloroform, 27, 129, 130, 155
Carbenes, 130 Chlorohydrins, 50, 98, 118
Carbobenzyloxy group, 306 Chlorophyll, 288-289, 324
Carbohydrates, 269-292 Chloroprene, 68
Carbohc acid, 104 Chlorotoluenes, 79, 124, 244
 Index 343
Cholesterol, 319 Cyclobutanes, 33, 43
Choline, 230, 231,237 Cyclohexane, 33, 34, 74, 241
Chromatography, 297-298 Cyclohexanol, 107, 141
Chromone, 323 Cyclohexanone, 137, 141
Chromophore, 246 Cyclohexene, 44, 130
Cirmamaldehyde, 138, 154, 202 Cyclonite, 148
Ciimamic acid, 202, 204 Cyclopentane, 28, 33
Cis-trans isomerism, 41-43, 44, 202-204, Cyclopentanone, 175
211 1 ,2-CyclopropanedicarboxyUc acids, 204
Citric acid, 200 Cyclopropanes, 33, 123, 130, 131
Citronellal, 138, 139, 317 Cysteine, 296
Citronellol, 317 Cystine, 296
Claisen condensation, 197 Cytosine, 330
Cocaine, 326
Codeine, 327
Coenzyme A, 219-221, 320
D
CoUagen, 307 Dacron, 189-190, 242
Collodion, 287 DDT, 131, 156
Color, 246 Deamination, 238, 244, 300, 312
Combustion, 29 Decarboxylation, 31, 174-175, 198, 220
Configuration Dehydration
absolute and relative, 259 of acids, 181-182
in amino acids, 294 of alcohols, 58,59, 113-114
in sugars, 272 of amides, 184
Conformations Dehydrogenation of alcohols, 141
butane, 24 Dehydrohalogenation, 59, 64, 195
cyclohexane, 34 Delrin, 157
ethane, 23 Denaturation of proteins, 312
glucose, 274-275 Denatured alcohol, 99
Congo red, 247 2-Deoxyribose, 275-276, 330
Conjugated double bonds, 64 Detergents, 213-217, 230
Conjugated proteins, 308 Deuterium exchange, 80
Cortisone, 322 Dextrins, 285
Cotton, 285 Dextrorotatory substances, 256
Cottonseed oil, 219 Dextrose, see Glucose
Coumarin, 323 Diabetes melhtus, 220
Coupling of diazonium compounds, 245- Diamines, 240-242
246 Diastereoisomers, 262, 265, 274
Cracking, 29, 59, 64 Diazonium compounds, 1A2-1A6
Cresols, 94, 101 Diazonium ion, 243
Crotonaldehyde, 151 Diazotization, 243
Cro tonic acid, 198, 202 Diborane, 96
Crotyl alcohol, 151 Dichloroacetic acid, 167
Cubane, 34 /7-Dichlorobenzene, 87
Cumene, see Isopropylbenzene Dichlorocarbene, 130
Cumene hydroperoxide, 101 Dichlorodiethyl sulfide, 117
Cyanides, 126, 171-172, 184, 233, 244 Dichlorodifluoromethane, 131
Cyanohydrins, 146, 196, 299 Diels-Alder reaction, 204-205
Cycloalkanes, 33-35 Dienes, 64-68, 205
344 Index

Diethyl ether, 112, 113, 116 Esters continued

Diethylene glycol, 1 19 poly-, 189-190
Diisopropylfluorophosphate, 23 Estrogens, 321
Dimethyl ether, 6-7, 102, 1 16 Estrone, 321-322
Dimethyl sulfoxide, 117 Ethane, 18
Dimethylamine, 225, 228 chlorination of, 27
Dimethylaniline, 226, 228, 247 conformations of, 23
Dimethylbenzenes, see Xylenes preparation of, 31, 32, 48
Dinitrofluorobenzene, 126, 303 Ethanol, see Ethyl alcohol
Diolefins, 64-68, 205 Ethanolamine, 118, 237
Dipeptide, 305-307 Ether, see Diethyl ether
Diphenyl ether, 116 Ethers, 112-122
Diphenylamine, 226 nomenclature, 112
Dipolar ions, 299-300 preparation, 113-115, 118, 126
Disaccharides, 270, 279-282 reactions, 115-116
Displacement reactions, 94-96, 104-105, sulfur analogs of, 117
125-127, 244 Ethyl acetate, 177, 197
Dissociation Ethyl alcohol, 6-7, 92, 93
of acids, 167 preparation, 96, 97
of amines, 228-229 properties, 101-167
Disulfides, 108 reactions, 58, 59, 104, 177
Diterpenes, 316 Ethyl bromide, 32
DNA, 329-333 Ethyl chloride, 27, 49, 104, 172
Double bond, 7, 40-44 Ethyl ether, see Diethyl ether
location of, 57 Ethyl group, 22
tests for, 48, 57 Ethyl hydrogen sulfate, 49, 96, 113
Dow Process, 100 Ethylamine, 228
Drying oils, 217-218 Ethylbenzene, 76, 82, 83
Dyes, 246-249 Ethylene, 39, 43, 44
Dynamite, 106 preparation of, 58, 59
reactions, 44, 48, 55, 58, 96, 98, 118, 172
Ethylene chlorohydrin, 50, 98
Ethylene diamine, 228, 240
Eclipsed conformations, 23 Ethylene dibromide, 44, 48, 55
Electronegativity, 2, 4, 13, 168 Ethylene dichloride, 48, 172, 240
Electrophile, 45, 80-82, 187, 242 Ethylene glycol, 98, 118, 188-189
Elimination reaction, 58-59 Ethylene oxide, 117-120, 128, 237
Enantiomers, 257, 260, 262 Eugenol, 116
Enol, 153, 196 Explosives
Enolate anion, 152 cyclonite, 148
Enzymes, 219-221, 231, 265-266 dynamite, 106
Eosin, 249-250 nitroglycerine, 106
Epoxides, 120 picric acid, 104
Equatorial bonds, 34 RDX, 148
Ergosterol, 320-321 TNT, 87
Essential oils, 316
Esterification, 179-181
Esters, 107, 166, 177-181
inorganic, 105-106 Famesene, 316
of glycerol, 209-213 Famesol, 317
 Index 345
Fats, 208-223 Gluconic acid, 270-27
analysis,218-219 Glucose, 270-275
hydro genation, 211-212 a and ^8 forms, 273-274
hydrolysis, 2 1 mutarotation of, 274
iodine number, 218 osazone, 278
metabolism, 219-221 stereochemistry, 272
saponification number, 218 structure, 270-275
Fatty acids, see Acids Glucosides, 274
FehUng's test, 277 Glutamic acid, 296, 312
Fermentation, 97, 143 Glutaric acid, 165
Fibroin, 307, 309 Glutehns, 308
Fischer, E., 273, 300 Glyceraldehyde, 260, 272
Fischer projection formulas, 259, 272, 294 Glycerides, 209-213
Fittig reaction, 81-82 Glycerol
Fluorobenzene, 244 esters of, 209-213, 230
Formaldehyde, 135, 136, 140 from fats, 211, 213
hydration, 146 glyptal resins, 190
oxidation state, 140 nitration of, 106
polymers, 156-157, 158 preparation of, 98
preparation, 142 uses of, 98-99
reaction with ammonia, 148 Glyceryl trinitrate, 106
Tollens' test, 145 Glycine, 295, 301, 307
uses, 143 preparation, 298
Formalin, 143 reaction with nitrous acid, 300
Formamide, 183 Glycogen, 285
Formic acid, 136, 140, 165, 167, 169, 187- GlycoUic acid, 195, 300
188 Glycols, 98; see also Ethylene glycol
Free radicals, 13, 26, 52 Glycosides, 278-279
in chain reaction, 26, 48, 56, 124 Glyptal resins, 190
Freons, 131 Grain alcohol, see Ethyl alcohol
Friedel-Crafts reaction, 82-84 Grignard, V., 127
ketone synthesis, 187 Grignard reagent, 127-129
Fructose, 276, 278, 280 hydrolysis of, 128
Fuchsin, 151 reaction with sihcon tetrachloride, 128
Fumaric acid, 202-204 synthesis of acids, 172
Functional group, 13, 14 synthesis of alcohols, 128, 149-150
Furan, 275 synthesis of saturated hydrocarbons, 128
Guanine, 330
Guncotton, 287
G
Galactose, 275, 281
Gasoline, 52-55
H
Gatterman-Koch reaction, 142 Haloform reaction, 155
Gelatin, 308 Halogen compounds, 123-134
Geometrical isomerism, 41-43, 202-204, Halogenated acids, 195
211 Halogenation
Geranial, 317 acids, 186-187
Geraniol, 317 aldehydes, 155-156
GlobuUns, 308 alkanes, 25-28
Glucaric acid, 270-271 aromatic hydrocarbons, 74, 79, 81, 124
346 Index

Halogenation continued Hydrocarbons continued

ketones, 155-156 properties, 44
saturated hydrocarbons, 25-28, 123 reactions, 44-58
unsaturated hydrocarbons, 58, 98 Hydroforming, 54
Hell-Volhard-Zelinsky reaction, 186 Hydrogen bonding, 102-103, 144, 169,227,
Hemiacetal, 147, 148, 273-274 241, 309, 332
Hemin, 308, 324 Hydrogen chloride molecule, 3
Hemoglobin, 309 Hydrogen molecule, 3
Heptane, 20, 52, 54 Hydrogenation
Heroin, 327 apparatus, 49
Heterocyclic compounds, 76, 226, 242-243, aromatic compounds, 74, 107
323-329 carbonyl compounds, 151
Hexamethylenediamine, 228, 240-241 of fats and oils, 211-212
Hexamethylenetetramine, 148 of unsaturated hydrocarbons, 48, 49, 62
Hexane, 19 Hydrogenolysis, 180, 213
1-Hexene, 44 Hydrolysis
Hexose, 270, 272 acid derivatives, 176-177, 186
Hexylresorcinol, 101 alkyl hahdes, 94-96, 126
Hinsberg reaction, 237 cyanides, 171-172
Hippuric acid, 301 dihalides, 141
Histidine, 296 fats, 211
Hofmaim rearrangement, 233-234 Grignard reagents, 128
Homologous series, 20, 25 Hydroquinone, 94
Hormones Hydroxyl group, see Alcohols and Phenols
adrenal cortical, 304, 322 Hydroxylamine, 149
sex, 321-322 Hydroxylated acids, 196, 198-201
Hydration of acetylene, 143 Hydroxyproline, 296
Hydration of alkenes, 96 Hypohalous acids, addition to olefins, 50,
Hydrazine, 149 51
Hydrazobenzene, 239-240 Hypophosphorous acid, 245
Hydrazones, 149
Hydride transfer, 53
I
Hydrides, 2
Hydroboration, 96 I.U.P.A.C. system of nomenclature, 20
Hydrocarbons Indigo, 248
aromatic, 54, 73-90 Indole, 226, 325
saturated, 17-38 Infrared spectra, 8, 102, 144
cyclic, 33-35 Ingrain dye, 242
nomenclature, 20-22 Inorganic esters, 105-106
preparation, 30-32, 128 Insecticides, 131, 156
properties, 23-25 Insulin, 304, 305
reactions, 25-30 Invert soaps, 230
structure, 18-19 Iodine number, 218
unsaturated, 39-72 Iodoform, 156
acetylenic, 59-64, 126, 131 Ionization constants
diolefins, 64-68 acids, 167
olefins, 39-59 amines, 228-229
nomenclature, 39-40 Isobutane, 33, 53
preparation, 58-59 Isobutylene, 39, 53-54
 Index 347
Isobutyraldehyde, 136 Lanosterol, 321
Isoelectric point, 300, 3 1 Lard. 219
Isoleucine, 295 Laurie acid. 165, 209
Isomerism, 6-7 Lauryl alcohol. 217
geometric, 41-43, 202-204, 211 Lauryl hydrogen sulfate, 217
optical, 252-268 Le Bel, J. A., 256-258
Isomerization, 52 Lecithin, 230
Isooctane, 52-54 Leucine, 295
Isopentenyl pyrophosphate, 320 Levorotatory substances, 256
Isoprene, 66-68, 316 Levulose, see Fructose
unit, 316 Limonene. 316
Isopropyl Linen, 285
alcohol, 92, 93, 140 Linoleic acid, 209
bromide, 50 Linolenic acid, 209
chloride, 22, 28 Linoleum, 218
group, 22 Linseed oil. 217-219
hydrogen sulfate, 50 Lipids. 208
Isopropylamine, 233 Lipmann. F., 219
Isopropylbenzene, 84. 100-101, 124 Lithium. 129
Isoquinohne, 325 Lithium aluminum hydride, 151, 180, 233
Isotopic tracer, 179, 320 Lucite, 202
Lysine, 296

K
Kekule, 74-76
M
Keratin, 307, 308, 3 1 Malachite green, 247
Ketals, 148 Maleic acid, 202-205
Ketene, 182 Maleic anhydride, 203-205
Keto acids, 197-198, 312 Mahc acid, 203
Keto form, 153 Malonic acid, 165
Ketohexose, 276 Maltose, 282-284
Ketones, 135-162 MandeUc acid, 196
methyl, test for, 155 Mannose, 275, 278
nomenclature, 136-137 MarkownikoflTs Rule, 50-52
preparation, 139-143. 174-175, 187, 198 applied to acetylenes, 61-62
reactions, 144-159 appUed to olefins, 50-52, 96, 124
Ketose, 270, 276-277 exceptions, 195
Kolbe reaction, 3 Mechanisms, 12-13
of addition to carbonyl compounds, 145-
146
of addition to conjugated systems, 65-66
Lactic acid, 195, 200 of addition to unsaturated hydrocarbons,
oxidation, 197 45-48
preparation, 196, 261 of alkylation, 53
reaction of heat, 199 of aromatic substitution, 80-8 1 86-87 ,

stereochemistry, 258-261 of displacement reactions, 94-96

Lactide, 199 of electrophilic aromatic substitution,
Lactone, 198 80-81, 86-87
Lactose, 281-282 of esterification, 179-181
348 Index

Mechanisms continued Mordants, 247

of halogenation of saturated hydrocar- Morphine, 327
bons, 26 Muscone, 138
of Hofmann rearrangement, IZZ-HA Mustard gas, 117
of nucleophihc substitution, 95, 100 Mutarotation, 273-274
of polymerization, 56 Mylar, 190
of soap action, 214-215 Myoglobin, 309
Menthol, 318 Myrcene, 316
Mercaptans, 107-108, 126, 219-220 Myristic acid, 209
Mercaptides, 108, 117
Mercurochrome, 249-250
Mesitylene, 81
N
Meso form, 264 Naphthalene, 77, 78, 124, 170, 182
Meta, 78 Naphthols, 94
Metabolism Natural gas, 17
of fats, 219-221 Natural products, 315-335
of carbohydrates, 290 Neoprene, 68
of proteins, 312 Nerve gas, 231
Meta-Delphene, 235-236 Nicotine, 326
Meta-directing groups, 86 Nicotinic acid, 326
Methane, 17, 18, 21 Ninhydrin, 298
halogenation, 26. 27 Nitrates, 105-106
oxidation state, 140 Nitration
preparation, 31 alkanes, 28
reactions of, 26-29, 64 benzene, 80
Methanol, see Methyl alcohol cellulose, 287
Methionine, 296 chlorobenzene, 85
Methyl alcohol, 92, 93, 101, 199 methane, 28
catalytic dehydrogenation, 142 phenol, 107
industrial preparation, 97 pyridine, 242
reaction with sodium, 103 saturated hydrocarbons, 28
Methyl cellosolves, 119 toluene, 87
Methyl chloride, 26 vapor phase, 28
Methyl glucosides, 274 Nitriles, see Cyanides
Methyl group, 21, 22 Nitroalkanes, 28
Methyl iodide, 31, 115, 127 Nitrobenzene
Methyl methacrylate, 202 chlorination, 85
Methyl radical, 26, 31 preparation, 80, 85
Methyl salicylate, 199 reduction, 232, 239
Methyl sulfate, 115 Nitrochlorobenzenes, 85
Methylamine, 225, 228 Nitroethane, 29
Methylanihne, 228, 232 Nitrogen compounds, 224-25
Methylene chloride, 27, 130 Nitroglycerine, see Glyceryl trinitrate
Methylene group, 20 Nitromethane, 28
Methylene iodide, 130 Nitronium ion, 80
Methylsodium, 32 /;-Nitrophenol, 107
Micelle, 215 Nitropropanes, 29
Molecular models, 18 Nitrosamine, 238
Monosaccharides, 270-279 Nitrous acid, 238, 243, 300

\
 Index 349
Nomenclature Oil paints, 218
acetylenes, 61 Oilcloth, 218
acids, 165-166 Oils, 209-213, 217-219
alcohols, 92-93 analysis, 218-219
aldehydes, 136-138 drying, 217-218
alkanes, 20-22 essential, 316
alkenes, 39-40 hardening, 212
alkyl groups, 21,22 Olefins, see Hydrocarbons, unsaturated
amines, 224-227 Oleic acid, 209, 211
aromatic hydrocarbons, 78-79 Olein, 212
diolefins, 64 Oleomargarine, 212
ethers, 1 12 Oleyl alcohol, 213
glycerides, 210 Olive oil, 219
ketones, 136-137 Optical activity, 255-256
olefins, 39-40 Optical isomerism, 252-268
phenols, 93-94 Orbitals, 9, 10, 41, 42, 60, 76, 144, 168, 227
saturated hydrocarbons, 20-22 Organometallic compounds, 32, 56, 127-
substituted acids, 195 129, 131, 149-150
Novocaine, 326, 327 Orientation rules for aromatic substitution,
Nucleic acids, 329-333 85-87
Nucleophile, 45, 145-151, 173 Orion, 62
Nucleophilic substitution, 94-96, 126, 242, Ortho, 78
303 Ortho-para-directing groups, 86
Nucleoside, 330 Osazones, 277-278
Nucleotide, 331 Oxalic acid, 164, 165, 169, 188-189
Nylon, 240-242 Oxidation
alcohols, 139-141, 170
aldehydes, 144-145, 170
O alkanes, 29
Octane, 20 alkenes, 56-57
Octane number, 52 aromatic side-chain, 84, 170
OU hydroxylated acids, 197
aniseed, 116 saturated hydrocarbons, 29
bitter almonds, 138, 196 states of carbon compounds, 139-140
castor, 218 unsaturated hydrocarbons, 56-57
cedar, 316 Oximes, 149, 233
cinnamon, 138 Oxiranes, 120
citronella, 138, 316 Oxo process, 142
cloves, 116, 316 Oxytocin, 304
cottonseed, 219 Ozone, 57
garUc, 1 1 Ozonolysis, 57
geranium, 317
lemon, 317
linseed, 217-219
olive, 219 Pahnitic acid, 165, 169, 209
peppermint, 318 Pahnitin, 210, 213
pine, 316 Paper chromatography, 297-298
rose, 128 Para, 78
wintergreen, 199 Para red, 247
350 Index

Paraffins, see Hydrocarbons, saturated Polyhydric alcohols, 97-99; see Glycerol,

Paraldehyde, 156 Glycols
Pasteur, L., 256, 266 Polymer, definition of, 55
Pauling, L., 302 Polymerization
Penicillin, 328-329 free radical, 55

Pentaerythritol. 158 ionic, 54

Pentane, 19, 53 of aldehydes, 156-158
Pentanes. boiling points of, 25 of chloroprene, 68
1-Pentene, 44 of dienes, 66-68
Pentose, 270, 276 of ethylene, 55-56
2-Pentyne, 63 of isobutylene, 54, 55
Peptides, 301, 307 of isoprene, 67
Periodic table, 2 of methyl methacrylate, 202
Petroleum, 17, 18, 52-55 of tetrafluoroethylene, 131
Phenanthrene, 77 Polymers
Phenetole, 116 BakeUte, 157-158
Phenol, 91, 93, 94, 167 Dacron, 189-190, 242
coefficient, 101 Delrin, 157

formaldehyde resins, 157-158 ethylene, 55-56

preparation, 99-101, 116, 244 Lucite, 202

reactions, 103-104, 107. 249 natural, 66-68, 283-288, 301-312, 329-

Phenolphthalein, 248 333

Phenoxides, 100, 104 neoprene, 68
Phenyl group, 78 nylon, 240-242
Phenyl salicylate, 200 Orion, 62
Phenylalanine, 295 phenol-formaldehyde, 157-158
Phenylhydrazine, 149, 245, 277-278 Plexiglas, 202, 203

2,4-dinitro-, 149 polyamides, 240-242

Phenylhydrazones, 149, 277 polyesters, 189-190

Phosgene, 306 synthetic rubber, 68

Phosphates, 106, 230, 289 Teflon, 131

PhosphoUpids, 230 Polyoxymethylenes, 156

Photosynthesis, 288-289 Polypeptides, 301-307
Phthaleins, 248-249 Polysaccharides, 270, 282-288
Phthalic acid, 164, 170, 182, 190 Polystyrene, 83-84

Phthalic anhydride, 182, 249 Porphyrin, 323-324

Pi (tt) bond, 40, 42, 45, 246 Primary alcohols, 92, 101, 149, 170
Picric acid, 104 Primary amines, 224-225
Pinene, 316 preparation, 231-234
Piperidine, 243 test for, 237, 238
Plastics, see Polymers Progesterone, 321-322
Plexiglas, 202-203 Proline, 296

Polarimeter, 255 Proof, 97

Polarity of bonds, 3-4 Propane, 19, 28

Polarized light, 252-254 Propionaldehyde, 136, 140, 141
Polyamides, 240-242 Propionic acid, 165, 167, 169, 172, 182, 261
Polyesters, 189-190 Propyl
Polyethylene, 55 alcohol, 92, 94, 101, 115, 140, 141, 180

Polyhalogen compounds, 1 29- 1 3 bromide, 94, 114

 Index 351

Propyl continued Reduction, see Hydrogenation

chloride, 28 Replacement, see Substitution
groups, 22 Reserpine, 325
rt-Propylamine, 228, 233, 238 Resolution of racemic mixtures, 265-266
/j-Propylbenzene, 82, 84 Resonance, 66, 147, 196
Propylene, 39. 43, 44, 50, 51, 59 amides, 184, 302
tetramer, 54 229
aniline,
Propyne, 61 aromatic compounds, 75-76
Prosthetic group, 308 carbonyl group, 144
Proteins, 301-312 carboxylate ion, 168
biuret color test, 185 diazonium ion, 244
classification, 307-309 enolate anion, 152
conjugated, 308 phenoxide ion, 104, 157
denaturation, 312 pyrrole, 243
fibrous, 307 Resorcinol, 94, 100
globular, 308 Retinene, 246
metaboUsm, 312 Riboflavin, 327-328
structure, 309-311 Ribonucleic acids, 333
Ptomaines, 240 Ribose, 275-276
Purine, 227, 327 Ricinoleic acid, 218
Putrescine, 240 RNA, 333
Pyran, 275 Rosin, 318
Pyridine, 226, 228, 230, 242-243, 325 Rubber, 66-68
Pyridoxine, 326
Pyrimidine, 227, 327
Pyrofax, 29
Pyroxylin, 287 SaUcyUc acid, 195, 199
Pyrrole, 226, 243 Salol, 200
Pyruvic acid, 197, 312 Sandmeyer reaction, 244
Sanger, F., 304
Saponification, 179
Q number, 218
Quaternary ammonium compounds, 229- Saturated hydrocarbons, see Hydrocarbons,
231, 237 saturated
Quinine, 265, 327 Schiemann reaction, 244
Quinoline, 226, 325 Schiffs test for aldehydes, 151
Secondary alcohols, 92, 150
Secondary amines, 224-225, 231, 233, 237,
R 238
R-, definition, 22 Sequence determination, 303-304
Racemic mixtures, 260-261 Serine, 295, 307

resolution of, 265-266 Serotonin, 325

Radicals, 13 325
Serpasil,

Rayon, 288 Sex hormones, 321-322

RDX. 148 Sigma (a) bond, 11,40,42
Rearrangements Silicon tetrachloride, 128
benzidine, 239-240 SiUcones, 129
Hofmann, 233-234 SnI reaction, 95, 115
Reducing sugars, 277 Sn2 reaction, 95, 115, 124-126, 198
352 Index

Soap, 173, 213-217 Sugars continued

invert, 230 non-reducing, 279-281
Soda lime, 3 reducing, 277
Sodamide, 63 Sulfa drugs, 236
Sodium acetate, 31, 173 Sulfanilamide, 236
Sodium acetylide, 62, 126 Sulfanilic acid, 239
Sodium alkoxides, 103, 1 14 Sulfhydryl group, 107
Sodium bisulfite addition reactions, 150 Sulfides, 117, 126
Sodium borohydride, 96 Sulfonamides, 236-237
Sodium lauryl sulfate, 106 Sulfonation, 80
Sodium phenoxides, 99 Sulfone, 1 17
Sorbitol, 270-271 Sulfonic acids, 80, 99-100
Specific rotation, 255 Sulfoxide, 117
Spermaceti, 221 Sulfur monochloride, 117, 129
Spiropentane, 34 Surfactants, 216-217
Squalene, 68-69, 317,321 Syndets, 216-217
Staggered conformations, 23, 34
Starch, 283-285
Stearic acid, 165, 169, 174, 209, 210, 215,
220 TNT, 87
Stearin, 210, 212 Tallow, 219
Stereoisomerism Tartaric acid, 201, 263, 264
geometric, 41^4, 202-204, 211 Tautomerism, 153
optical, 252-268 Teflon, 131
Steroids, 208, 318-321 Terephthalic acid, 84, 188-189
Sterols, 318 Terpenes, 316-321
Stilbesterols, 321-322 Tertiary alcohols, 92, 150
Strecker synthesis of amino acids, 298-299 Tertiary amines, 224-225, 231, 233, 237,
Structural formulas, 5-6, 10-12 238
Strychnine, 325 Testosterone, 138, 321-322
Styrene, 76, 84, 124 Tetraethyl lead, 52
Substantive dyes, 246 Tetrafluoroethylene, 131
Substitution reactions Tetrahedral carbon, 9-10, 12, 256-258
in acids, 186-187 Tetramethylammonium hydroxide, 230
nucleophilic, 95-96, 114, 115, 118 Tetramethylammonium iodide, 229
nucleophilic aromatic, 100, 126 Thiamin, 327
of aromatic hydrocarbons, 74, 79-82, Thioalcohols, 107-108, 126,219-220
85-87, 107, 158, 187 Thioesters, 220-221
of saturated hydrocarbons, 25-29, 44 Thioethers, 117, 126
of unsaturated hydrocarbons, 57, 98 Thiols, 107-108, 126
rules for, in aromatic compounds, 85-87 Thionyl chloride, 105
Succinic acid, 165 Threonine, 295
dehydration, 183 Thymine, 330
preparation, 170, 172, 203 Thyroxine, 295
Succinic anhydride, 183 a-Tocopherol, 323
Sucrose, 279-281 Tollens' test, 145, 188, 270
Sugars, 270-282; see also Carbohydrates /7-Tolualdehyde, 142
fermentation of, 97 Toluene, 54, 76, 77
 Index 353

Toluene continued
nitration. 87
Valeric acid, 171
reaction with carbon monoxide. 142
Vahne, 295
ring chlorination. 79
Vanillin, 138
side chain chlorination. 79. 142, 171
Van Slyke detection of amino nitrogen. 300
side chain oxidation. 84. 170 256-258
van't Hoff. J. A.. 202,
/7-Toluic acid. 166. 172
rule, 261, 271
/7-Toluidine, 226. 234
Vat dye, 247
Trans, see Cis-trans isomerism Veronal, 185
Transamination, 312 304
du Vigneaud, V..
Transesterification. 180
Vinyl chloride, 58
TribromoaniUne. 226, 238
Vinylacetylene, 68
Tribromophenol, 93, 107
Viscose process for rayon, 288
Trichloroacetic acid, 167
Vitamin A, 317
Trichloroethylene, 131
Vitamin Bi. 327
Trichloromethane, 27
Vitamin B2, 328
Triethanolamine. 119
Vitamin Be, 326
Triethylbenzene, 82
Vitamin B12, 324
Trigonal carbon, 40-42
Vitamin C, 323
Trimethylamine. 225-229. 237
Vitamin D, 321
Trinitrotoluene, 87
Vitamin E, 323
Trioxane, 156
Vitamin K, 138, 139,317-318
Triphenylmethane, 77. 83
dyes. 247-248
Triple bond. 59-61 W
test for. 63
Waxes, 209, 221
Tryptophan, 295
Weizmann, C, 143
Turpentine. 316
Williamson synthesis of ethers, 114-115
Tyrosine, 295, 307
Wohler, F.. 185
Wood alcohol, see Methyl alcohol
Woodward, R. B., 324
U Wurtz reaction, 31-33
Unsaturated hydrocarbons, see Hydrocar- Wurtz-Fittig reaction, 81-82
bons, unsaturated
Unsaturation, test for, 48
X
UracU, 333
Urea, 184-185 Xanthates, 288
Urotropine, 148 Xylenes, 78, 84, 182
 Jhiles oj the J.IA.P.A.C. System

i
a) Use the longest continuous chain of carbon atoms (containing the functional

groups) as the basis for the name, and name the compound as a derivative

of this parent hydrocarbon.

b) Use the appropriate ending to indicate the functional groups present in

the molecule.

c) Number the longest continuous carbon chain, starting at the end which will

give the principal functional group the smallest number.

d) Locate the functional groups by the numbers of the carbon atoms to which

they are attached.

e) Name and locate by number any other atoms or groups attached to the

longest continuous chain.

oj CNomenclature Applied

4 - methyl - 2 - pentene - 1 - ol

Application

i
pent —
r (five carbon atoms in the longest chain)

pentene ol
"^ (-ene for the double bond; -ol for the alcohol group)

5-4321
C—C— C=C— C— OH

2 - pentene - I - ol

4 - methyl - 2 - pentene - I - ol
"^ (The methyl group is a substituent on the

fourth carbon atom of the main chain)