John E.

McMurry

http://www.cengage.com/chemistry/mcmurry

Chapter 6
An Overview of Organic
Reactions

Richard Morrison • University of Georgia, Athens

Organic Chemical Reactions
Organic chemical reactions broadly organized in two
ways:

1. What kinds of reactions occur

2. How those reactions occur

6.1 Kinds of Organic Reactions
Addition reactions
• Occur when two reactants add together to form a single product
with no atoms “left over”
• Reaction of fumarate with water to yield malate (a step in the
citric acid cycle of food metabolism)
Kinds of Organic Reactions
Elimination reactions
• Occur when a single reactant splits into two products
(usually with the formation of a small molecule such as
water)
• Reaction of hydroxybutyryl ACP to yield trans-crotonyl
ACP and water (a step in the biosynthesis of fat
molecules)
Kinds of Organic Reactions
Substitution reactions
• Occur when two reactants exchange parts to give two new
products
• Reaction of an ester such as methyl acetate with water to
yield a carboxylic acid and an alcohol

• In biological pathways this type of reaction occurs in the

metabolism of dietary fats
Kinds of Organic Reactions
Rearrangement reactions
• Occur when a single reactant undergoes a reorganization
of bonds and atoms to yield an isomeric product
• Rearrangement of dihydroxyacetone phosphate into its
constitutional isomer glyceraldehyde 3-phosphate (a step
in the metabolism of carbohydrates)
6.2 How Organic Reactions Occur:
Mechanisms
Reaction Mechanism
• An overall description of how a reaction occurs at each
stage of a chemical transformation
• Which bonds are broken and in what order
• Which bonds are formed and in what order
• What is the relative rate of each step
• A complete mechanism accounts for all reactants consumed
and all products formed
How Organic Reactions Occur: Mechanisms

All chemical reactions involve bond breaking and bond making

Two ways a covalent two-electron bond can break:

1. Symmetrical
• One electron remains
with each product
fragment Half-headed arrow, “fishhook”,
indicates movement of one
2. Unsymmetrical electron
• Both bonding electrons
remain with one
product fragment,
Full-headed arrow indicates
leaving the other with movement of two electrons
a vacant orbital
How Organic Reactions Occur: Mechanisms
Two ways a covalent two-electron bond can form:

1. Symmetrical
• One electron is donated
to the new bond by each reactant (radical)

2. Unsymmetrical
• Both bonding electrons
are donated by one reactant (polar)
How Organic Reactions Occur: Mechanisms

Radical reaction
• Process that involves symmetrical bond breaking and
bond making
• Radical (free radical)
• A neutral chemical species that contains an odd

number of electrons and has a single, unpaired

electron in one of its orbitals
Polar reactions
• Process that involves unsymmetrical bond breaking and
bond making
• Involve species that have an even number of electrons
(have only electron pairs in their orbitals)
• Common in both organic and biological chemistry
6.3 Radical Reactions
Radical
• Highly reactive because it contains an atom with an odd
number of electrons (usually seven) in a valence shell
• Can achieve a valence shell octet through:
• Radical substitution reaction
• Radical abstracts an atom and one bonding electron
from another reactant
Radical Reactions
• Radical addition reaction
• A reactant radical adds to a double bond, taking one

electron from double bond and leaving one behind to

form a new radical
Radical Reactions
Industrial radical reaction
• The chlorination of methane to yield chloromethane
• A substitution reaction
• First step in the preparation of the solvents dichloromethane
(CH2Cl2) and chloroform (CHCl3)
Radical Reactions
Radical chlorination of methane requires three kinds of
steps: initiation, propagation, and termination

1. Initiation
• Ultraviolet light breaks Cl-Cl bond to generate chlorine
radicals
Radical Reactions
2. Propagation
• Reaction with CH4 to generate new radicals and propagate
the chain reaction
Radical Reactions
3. Termination
• Two radicals combine to end the chain reaction
• No new radical species is formed
Radical Reactions
Biological radical reaction
• Prostaglandin synthesis initiated by abstraction of a
hydrogen atom from arachidonic acid.
Radical Reactions
• The carbon radical reacts with O2 to give an oxygen
radical
• Oxygen radical reacts with C=C bond (several steps)
• Prostaglandin H2 produced
6.4 Polar Reactions
Polar reactions
• Occur because of electrical attraction between
positive and negative centers on functional groups in
molecules
• Most organic compounds are electrically neutral, they
have no net charge
Bond polarity
• Certain bonds within a molecule are polar
• Consequence of an unsymmetrical electron distribution in a
bond
• Due to the difference in electronegativity of the bonded
atoms.
Polar Reactions
Certain bonds within molecules, particularly those in
functional groups, are polar
• Oxygen, nitrogen, fluorine, and chlorine are more
electronegative than carbon
• Carbon is always positively polarized () when bonded to
more electronegative elements
• Carbon is negatively polarized () when bonded to metals
Polar Reactions
Polar Reactions
Polar Reactions
Polar bonds
• Can also result from interactions of functional groups with acids or
bases
• Methanol
• In neutral methanol the carbon atom is somewhat electron-poor
• Protonation of the methanol oxygen by an acid makes carbon much
more electron-poor
Polar Reactions
Polarizability of the atom
• The measure of change in electron distribution around the atom to an
external electrical influence
• Larger atoms (more, loosely held electrons) – more polarizable
• Smaller atoms (fewer, tightly held electrons) – less polarizable
Effects of polarizability on bonds
• Although carbon-sulfur and carbon-iodine bonds are nonpolar according
to electronegativity values, they usually react as if
they are polar because sulfur and iodine are highly polarizable
Polar Reactions
Electron-rich sites react with electron-poor sites
• Bonds made when electron-rich atom donates a pair of
electrons to an electron-poor atom
• Bonds broken when one atom leaves with both electrons from
the former bond
A curved arrow shows electron movement
• Electron pair moves from the atom (or bond) at tail of arrow to
atom at head of arrow during reaction
Polar Reactions
Nucleophile
• Substance that is “nucleus-loving”
• Has a negatively polarized electron-rich atom
• Can form a bond by donating a pair of electrons to a
positively polarized, electron-poor atom
• May be either neutral or negatively charged

Electrophile
• Substance that is “electron-loving”
• Has a positively polarized, electron-poor atom
• Can form a bond by accepting a pair of electrons from a
nucleophile
• May be either neutral or positively charged
Polar Reactions
Electrostatic potential maps identify:
• Nucleophilic atoms (red; negative)
• Electrophilic atoms (blue; positive)
Polar Reactions
Neutral Compounds
• React either as nucleophiles or electrophiles (depending on
circumstances)
• Water
• Nucleophile when it donates a nonbonding pair of electrons
• Electrophile when it donates H+
• Carbonyl compound
• Nucleophile when it reacts at its negatively polarized oxygen
atom
• Electrophile when it reacts at its positively polarized carbon
atom
• A compound that is neutral but has as electron-rich nucleophilic
site must also have a corresponding electron-poor electrophilic
site
Polar Reactions

Nucleophiles and Electrophiles

• Similar to Lewis acids and Lewis bases
• Lewis bases
• Electron donor
• Behave as nucleophiles
• Lewis acids
• Electron acceptors
• Behave as electrophiles

• Terms nucleophile and electrophile used primarily

when bonds to carbon are involved
Worked Example 6.1
Identifying Electrophiles and Nucleophiles
Which of the following species is likely to behave as a
nucleophile and which as an electrophile?

(a) (CH3)3S+

(b) CN

(c) CH3NH2
Worked Example 6.1
Identifying Electrophiles and Nucleophiles
Strategy
Nucleophiles have an electron-rich site because:
• They are negatively charged, or
• They have a functional group containing an atom that
has a lone pair of electrons
Electrophiles have an electron-poor site because:
• They are positively charged, or
• They have a functional group containing an atom that is
positively polarized
Worked Example 6.1
Identifying Electrophiles and Nucleophiles
Solution

(a) (CH3)3S+ (trimethylsulfonium ion) is likely to be an

electrophile because it is positively charged.

(b) CN (cyanide ion) is likely to be a nucleophile because it is

negatively charged.

(c) CH3NH2 (methylamine) might be either a nucleophile or an

electrophile depending on the circumstances. The lone
pair of electrons on the nitrogen atom makes methylamine
a potential nucleophile, while positively polarized N-H
hydrogens make methylamine a potential acid
(electrophile).
6.5 An Example of a Polar Reaction: Addition of
H2O to Ethylene
Addition of water to ethylene
• Typical polar process
• Acid catalyzed addition reaction (Electophilic addition reaction)

Polar Reaction
• All polar reactions take place between an electron-poor site and
an electron-rich site, and they involve the donation of an
electron pair from nucleophiles to electrophiles
An Example of a Polar Reaction: Addition of H2O
to Ethylene
Reactants of reaction
• Ethylene
• An alkene, contains a C=C double bond (overlapping orbitals
from two sp2-hybridized carbon atoms)
C=C double bond
• Has greater electron

density than single

bonds
• Electrons in  bond

are more accessible to

approaching reactants
• Nucleophilic and reacts

with electrophile
(Red indicates high
electron density)
An Example of a Polar Reaction: Addition of H2O
to Ethylene
• Water
• In presence of a strong
acid, it is protonated to give
the hydronium ion H3O+
(proton, H+, donor and
electrophile).

Polar reaction
• Electrophile-nucleophile
combination
An Example of a Polar Reaction: Addition of H2O
to Ethylene
Carbocation
• Formed in step two of the acid-catalyzed
electrophilic addition reaction of ethylene and
water
• Positively charged carbon species with only six
valence electrons
• Electrophile that can accept an electron pair from
a nucleophile
6.6 Using Curved Arrows in Polar Reaction
Mechanisms
Rule 1 – Electrons move from a nucleophilic source (Nu: or
Nu-) to an electrophilic sink (E or E+)

• Nucleophilic source must have an electron pair available

• Electrophilic site must be able to accept electron pair

Using Curved Arrows in Polar Reaction
Mechanisms
Rule 2 – The nucleophile can be either negatively
charged or neutral
• Negatively charged (the atom gives away an electron pair
and becomes neutral):

• Neutral (the atom gives away an electron pair to acquire a

positive charge):
Using Curved Arrows in Polar Reaction
Mechanisms
Rule 3 – The electrophile can be either positively charged
or neutral
• Positively charged (the atom bearing the charge becomes
neutral after accepting electron pair):

• Neutral (the atom acquires a negative charge after accepting

electron pair):
Using Curved Arrows in Polar Reaction
Mechanisms
Rule 4 – The octet rule must be followed
Worked Example 6.2
Using Curved Arrows in Reaction Mechanisms
Add curved arrows to the following polar reactions to
show the flow of electrons
Worked Example 6.2
Using Curved Arrows in Reaction Mechanisms
Strategy
1. Look at the reaction and identify the bonding changes
that have occurred
• C-C bond has formed (involves donation of an electron pair
from the nucleophilic carbon atom of the reactant to the
electrophilic carbon of CH3Br)
• C-Br has broken (octet rule)
2. Draw curved arrows
• Curved arrow originating from the lone pair on the
negatively charged C atom and pointing to the C atom of
CH3Br
• Curved arrow from the C-Br bond to Br (bromine is now a
stable bromide ion)
Worked Example 6.2
Using Curved Arrows in Reaction Mechanisms
Solution
6.7 Describing a Reaction: Equilibria, Rates,
and Energy Changes
Every chemical reaction can proceed in either the forward or
reverse direction

aA + bB  
 cC + dD

• The position of the resulting chemical equilibrium is expressed by the
equilibrium constant equation Keq

 C  D 
c d

K eq =
 A  B 
a b

[C]c= equilibrium concentration of C raised to the power of its coefficient in the balanced
equation
[D]d= equilibrium concentration of D raised to the power of its coefficient in the balanced
equation
[A]a= equilibrium concentration of A raised to the power of its coefficient in the balanced
equation
[B] = equilibrium concentration of B raised to the power of its coefficient in the balanced
b

equation
Describing a Reaction: Equilibria, Rates, and
Energy Changes
The value of Keq tells which side of the reaction arrow is
energetically favored
• Keq > 1
•Product concentration term [C]c[D]d is much larger than
reactant concentration term [A]a[B]b
• Reaction proceeds from left to right

• Keq≈ 1 Comparable amounts of both products and reactants are

present at equilibrium
• Keq < 1
• Product Concentration [C]c [D]d is much smaller than reactant
concentration [A]a [B]b
• Reaction proceeds from left to right
Describing a Reaction: Equilibria, Rates, and
Energy Changes

Equilibrium Expression (Keq)

• Reaction of ethylene with H2O

 


H2C=CH2 + H2O CH3CH2OH

K eq =
 CH CH OH  H O 25
3 2 2

 H C=CH 
2 2

Because Keq > 1

• the reaction proceeds as written (left to
right)
• some unreacted ethylene remains at
equilibrium
Describing a Reaction: Equilibria, Rates, and
Energy Changes
For a reaction to have a favorable equilibrium
constant and proceed from left to right
• the energy of products must be lower than the
energy of the reactants (energy must be released)

Gibbs free-energy change (∆G)

• the energy change that occurs during a chemical
reaction (energy difference between reactants
and products)

∆G = Gproducts – Greactant
Describing a Reaction: Equilibria, Rates, and
Energy Changes
Gibbs Free-Energy Change, ∆Gº
• ∆Gº is negative
• Reaction is exergonic (energy lost
by system and released to
surroundings)
• Has favorable equilibrium constant
• Can occur spontaneously
• ∆Gº is positive
• Reaction is endergonic (energy
absorbed into system from
surroundings)
• Unfavorable equilibrium constant
• Cannot occur spontaneously
Describing a Reaction: Equilibria, Rates, and
Energy Changes
∆Gº denotes standard free-energy change for a reaction
• (º) means that the reaction is carried out under standard conditions

Keq and ∆Gº are mathematically related because they both measure whether a
reaction is favored

∆Gº = -RT ln Keq or Keq = e-∆Gº / RT

where
R = 8.314 J/(K . mol) = 1.987 cal/ (K . mol)
T = Kelvin temperature
e = 2.718
ln Keq = natural logarithm of Keq

Keq = 25 for the reaction of ethylene with H 2O

ln Keq = ln 25 = 3.2

∆Gº = -RT ln Keq = -[8.314 J/(K . mol)] (298 K) (3.2)

= -7900 J/mol = -7.9 kJ/ mol
Describing a Reaction: Equilibria, Rates, and
Energy Changes
The free-energy change ∆G made up of two terms:
1. Enthalpy ∆H
2. Entropy T∆S (temperature depended)

∆Gº = ∆Hº - T∆Sº (standard conditions)

Reaction of ethylene with H2O at 298 K

Describing a Reaction: Equilibria, Rates, and
Energy Changes
Change in Enthalpy, ∆H
• The heat of reaction
• Calculated as the difference in strength between the bonds
broken and the bonds formed under standard conditions
∆Ho = Hoproducts – Horeactants (standard conditions)
• Negative ∆Hº
• The reaction releases heat, exothermic
• Products are more stable than reactants
• Have less energy than reactants

• Have stronger bonds than the reactants

• Positive ∆Hº
• The reaction absorbs heat, endothermic
• Products are less stable than reactants
• Have more energy than reactants

• Have weaker bonds than reactants

Describing a Reaction: Equilibria, Rates, and
Energy Changes
Entropy change, ∆Sº
∆So = Soproducts – Soreactants
• The change in molecular disorder during a reaction at standard
conditions
• Negative ∆Sº
• Disorder decreases during reaction
• Addition reaction
• reaction allows more freedom of movement in products
than reactants by splitting one molecule into two
A+B→C
• Positive ∆Sº
• Disorder increases during reaction
• Elimination reaction
• reaction restricts freedom of movement of two molecules
by joining them together
A→B+C
Describing a Reaction: Equilibria, Rates, and
Energy Changes
Keq
• Tells position of equilibrium
• Tells how much product is theoretically possible
• Does not tell the rate of reaction
• Does not tell how fast equilibrium is established

Rate → Is the reaction fast or slow?

Equilibrium → In what direction does the reaction
proceed?
Describing a Reaction: Equilibria, Rates, and
Energy Changes
6.8 Describing a Reaction: Bond
Dissociation Energies
Bond strength is a measure of the heat change that
occurs on breaking a bond, formally defined as bond
dissociation energy
• Each bond has its own characteristic strength
Bond Dissociation Energy (D)
• The amount of energy required to break a given bond to
produce two radical fragments when the molecule is in the
gas phase at 25ºC
Describing a Reaction: Bond Dissociation
Energies
Describing a Reaction: Bond Dissociation
Energies
Describing a Reaction: Bond Dissociation
Energies
Connections between bond strengths and
chemical reactivity
• Exothermic reactions are favored by products with
stronger bonds and reactants with weaker bonds
• Bond formation in products releases heat
• Bond breaking in reactants requires heat
Reactive substances that undergo highly exothermic
reactions such as ATP (adenosine triphosphate)
are referred to as “energy-rich” or high energy
compounds
• ATP has relatively weak bonds (bonds require only a
small amount of heat to break)
Describing a Reaction: Bond Dissociation
Energies
Glycerol vs. ATP reaction with water
• Bond broken in ATP is substantially weaker than the bond broken
in glycerol-3-phosphate
6.9 Describing a Reaction: Energy Diagrams
and Transition States
For a reaction to take place
• Reactant molecules must collide
• Reorganization of atoms and bonds must occur
Describing a Reaction: Energy Diagrams and
Transition States
Chemists use energy diagrams to graphically depict
the energy changes that occur during a chemical
reaction
Addition of water to ethylene
• Vertical axis
• the total energy

of all reactants
• Horizontal axis
• “reaction coordinate”

the progress of the

reaction from
beginning to end
Describing a Reaction: Energy Diagrams and
Transition States
Activation Energy (∆G‡)
• The energy difference between reactants and
transition state
• Determines how rapidly the reaction occurs at a given
temperature
• Large activation energy results in a slow reaction
• Small activation energy results in a rapid reaction
• Many organic reactions have activation energies in the
range of 40 – 150 kJ/mol (10 – 35 kcal/mol)
• If ∆G‡ less than 80 kJ/mol the reaction takes place at or
below room temperature
• If ∆G‡ more than 80 kJ/mol the reaction requires heating
above room temperature
Describing a Reaction: Energy Diagrams and
Transition States
Activation energy leads to transition state
The Transition State
• Represents the highest-energy structure involved
in the reaction
• Unstable and cannot be isolated

A hypothetical transition–state
structure for the first step of
the reaction of ethylene with
H3O+
• the C=C bond about to break
• the C-H bond is beginning to form
Describing a Reaction: Energy Diagrams and
Transition States
Once transition-state is reached the reaction either:
• Continues on to give carbocation product
• New C-H bond forms fully
• Amount of energy corresponding to difference between
transition-state (∆G‡) and carbocation product is released
• Since carbocation is higher in energy than the starting alkene,
the step is endergonic (+∆Gº, absorbs energy)
• Reverts back to reactants
• Transition-state structure comes apart
• Amount of free-energy (-∆G‡) is released
Describing a Reaction: Energy Diagrams
and Transition States
Each reaction has its
own profile
(a) a fast exergonic
reaction (small G‡,
negative G°);

(b) a slow exergonic

reaction (large G‡,
negative G°);

(c) a fast endergonic

reaction (small G‡,
small positive G°);

(d) a slow endergonic

reaction (large G‡,
positive G°).
6.10 Describing a Reaction: Intermediates
Reaction Intermediate
• A species that is formed during the course of a multi-step
reaction but is not final product
• More stable than transition states
• May or may not be stable enough to isolate
• The hydration of ethylene proceeds through two reaction
intermediates, a carbocation intermediate and a
protonated alcohol intermediate
Describing a Reaction: Intermediates
Each step in a multi-step process can be considered separately
(each step has ∆G‡ and ∆Gº)

Overall ∆Gº of
reaction is the
energy difference
between initial
reactants and
final products

Overall energy diagram for the

reaction of ethylene with water
Describing a Reaction: Intermediates
Biological reactions occur at physiological conditions
• Must have low activation energy
• Must release energy in relatively small amounts

Enzyme catalyst
changes the
mechanism of reaction
to an alternative
pathway which proceeds
through a series of
smaller steps rather
than one or two large
steps
Worked Example 6.3
Drawing Energy Diagram for Reactions
Sketch an energy diagram for a one-step reaction that
is fast and highly exergonic
Worked Example 6.3
Drawing Energy Diagram for Reactions
Strategy
A fast reaction has a small ∆G‡, and a highly exergonic
reaction has a large negative ∆Gº
Worked Example 6.3
Drawing Energy Diagram for Reactions
Solution
6.11 A Comparison between Biological
Reactions and Laboratory Reactions
Solvent
• Laboratory reaction
• Organic liquid, such as ether or dichloromethane
• Used to dissolve reactants
• Used to bring reactants into contact with each other
• Biological reaction
• Aqueous medium inside cell

Temperature
• Laboratory reaction
• Takes place over wide range of temperatures (typically 80-
150ºC)
• Biological reaction
• Takes place at the temperature of the organism
A Comparison between Biological Reactions and
Laboratory Reactions
Catalyst
• Laboratory reactions
• Either none or very simple
• Biological reactions
• Catalyzed by enzymes

Enzyme
• A large, globular protein molecule that contains a
protected pocket called an active site
Active site
• The pocket in an enzyme where a substrate is bound and
undergoes reaction
• Lined by acidic or basic groups
• Has precisely the right shape to bind and hold substrate
molecule
A Comparison between Biological Reactions and
Laboratory Reactions
Models of hexokinase in space-filling and wire-frame formats, showing the
cleft that contains the active site where substrate binding and catalysis
occur
A Comparison between Biological Reactions and
Laboratory Reactions
Reagent size
• Laboratory reactions
• Usually small and simple (such as Br2, HCl, NaBH4, CrO3)
• Biological reactions
• Relatively complex reagents called coenzymes
• ATP is the coenzyme in the hexokinase-catalyzed phosphorylation
of glucose
• Reduced NADH is the coenzyme that effects hydrogenation in
many biological pathways
A Comparison between Biological Reactions and
Laboratory Reactions
Specificity
• Laboratory reactions
• Little specificity for substrate (a catalyst such as sulfuric acid
might be used to catalyze the addition of water to thousands
of different alkenes)
• Biological reactions
• Very high specificity for substrate (an enzyme will catalyze
only a very specific reaction)
A Comparison between Biological Reactions and
Laboratory Reactions