Substitution Reactions
and their
Mechanisms
Objectives
• 1. distinguish the general types
of organic reaction from given
chemical equations
• 2. illustrate the types of reactions
through examples
• 3. explain the mechanism of
each general type of organic
reaction
What is Substitution Reaction?
• The substitution reaction is defined as a reaction
in which the functional group of one chemical
compound is substituted by another group or it is
a reaction which involves the replacement of
one atom or a molecule of a compound with
another atom or molecule.
Substitution Reaction Example
• These type of reactions are said to possess
primary importance in the field of organic
chemistry. For example,
• CH3Cl is reacted with the hydroxyl ion (OH-),
it will lead to the formation of the original
molecule called methanol with that hydroxyl
ion.
CH3Cl + (OH−) → CH3OH( methanol) + Cl–
• Ethanol with the hydrogen iodide which
forms iodoethane along with water.
CH3CH2OH + HI → CH3CH2I + H2O
Substitution Reaction
Conditions
• In order to substitution reaction to occur there
are certain conditions that have to be used.
They are-
Maintaining low temperatures such as room
temperature
The strong base such as NaOH has to be in dilute
form. Suppose if the base is of a higher
concentration, there are chances of
dehydrohalogenation taking place
The solution needs to be in an aqueous state such
as water
Substitution Reactions – Types
• Substitution Reactions are of two types
nucleophilic reaction and
electrophilic reactions.
• These two types of reactions mainly differ in
the kind of atom which is attached to its
original molecule.
nucleophilic reactions the atom is said to be
electron-rich species, whereas, in the
electrophilic reaction, the atom is an electron-
deficient species.
Nucleophilic Substitution Reaction:
• a) What are nucleophiles?
Nucleophiles are those species in the form of an ion or a
molecule which are strongly attached to the region of a positive
charge. These are said to be fully charged or have negative
ions present on a molecule. The common examples of
nucleophiles are cyanide ions, water, hydroxide ions, and
ammonia.
• (b) What is Nucleophilic substitution reaction?
A Nucleophilic substitution reaction in organic chemistry is a
type of reaction where a nucleophile gets attached to the
positive charged atoms or molecules of the other substance.
• (c) Mechanism of Nucleophilic substitution reaction:
Two mechanisms of nucleophilic substitution reaction are S N1
reaction and the SN2 reaction, where S represents chemical
substitution, N represents nucleophilic, and the number stands
for the kinetic order of a reaction.
Nucleophilic Substitution
Nucleophilic Substitution
at saturated carbon centers
Example of Nucleophilic
Substitution Reaction:
• A good example of a nucleophilic substitution
reaction is the hydrolysis of alkyl bromide (R-Br),
under the basic conditions, wherein the nucleophile
is nothing but the base OH−, whereas the leaving
group is the Br−. The reaction for the following is as
given below R-Br + OH− → R-OH + Br−
• Nucleophilic reactions are as important in the field of
organic chemistry, and these reactions are broadly
classified as to occur at the place of a carbon atom
of a saturated aliphatic carbon compound.
Substitution reactions
• A substitution reaction occurs when an exchange
of elements in the reactants takes place. The initial
reactants are transformed or swapped around to
give a final product.
• The general equation for a substitution reaction:
AB+CD → AD+BC
•
Nucleophilic Substitution
at saturated carbon centers
• In SN2 Reaction, the addition of the nucleophile and
the elimination of leaving group take place
simultaneously
• SN2 occurs where the central carbon atom is easily
accessible to the nucleophile.
• By contrast the SN1 reaction involves two steps.
• SN1 reactions tend to be important when the central
carbon atom of the substrate is surrounded by bulky
groups, both because such group interfere sterically
with the SN2 reaction and because highly substituted
carbon forms a stable carbocation
Nucleophilic substitution at carbon atom
SN1 Mechanism
The step-in SN1 reaction that is a slow rate-
determining step is the formation of a transition
state
SN1 reaction favors a low concentration of
nucleophile
Nucleophilic substitution at carbon atom
SN1 Mechanism
SN1 Reaction Mechanism
• The reaction between tert-butylbromide and water
proceeds via the SN1 mechanism. Unlike SN2 that
is a single-step reaction,
• SN1 reaction involves multiple steps.
• Reaction: (CH3)3CBr + H2O → (CH3)3COH + HBr
SN1 Reaction Mechanism
Stereochemistry
• Stereocenters are labeled R or S
• The "right hand" and "left hand"
nomenclature is used to name the
enantiomers of a chiral compound. The
stereocenters are labeled as R or S.
If the arrow points in a counterclockwise direction (left when leaving the 12 o' clock position), the
configuration at stereocenter is considered S ("Sinister" → Latin= "left").
If, however, the arrow points clockwise,(Right when leaving the 12 o' clock position) then the
stereocenter is labeled R ("Rectus" → Latin= "right").
The R or S is then added as a prefix, in parenthesis, to the name of the enantiomer of interest.
SN1 Reaction Mechanism
• The stereochemistry feature of the SN1 reaction is very
different to that of SN2, and of course can be explained well
with the SN1 mechanism.
Starting with (S)-3-bromo-3-methylhexane reactant, the SN1 reaction produces a 50:50
mixture of both R and S enantiomers of 3-methyl-3-hexanol, that is the racemic
mixture product.
This is because the carbocation formed in the first step of an S N1 reaction has the trigonal
planar shape, when it react with nucleophile, it may react from either the front side or the
back side, and each side gives one enantiomer.
There is equal possibility for reaction to occur from either side, so the two enantiomers are
formed with the same amount, and the product is a racemic mixture.
Nucleophilic substitution at carbon atom
SN2 Mechanism
Nucleophilic substitution at carbon atom
SN2 Mechanism
Primary alkyl halides undergo SN2 mechanisms
because 1∘ substrates have little steric hindrance to nucleophilic
attack and 1∘ carbocations are relatively unstable.
Since primary alkyl halide is least sterically hindered among primary,
secondary and tertiary alkyl halides therefore primary alkyl halides
undergo
Nucleophilic
substitution
at unsaturated carbon centers
Nucleophilic Aromatic
substitution
Substitution Reaction
• Some simple examples of substitution
reactions are shown below:
CH4+Cl2 → CH3Cl+HCl
•
A chlorine atom (from Cl2) and a hydrogen atom (from CH4) are exchanged to create new
products (CH3Cl and HCl).
Substitution Reaction
• 1. Formation of haloalkanes
• Haloalkanes can be formed when the hydroxyl (−OH) group of
an alcohol is replaced by a halogen atom (X = Cl, Br). This
reaction works best with tertiary alcohols where it can occur at
room temperature
The formation of a tertiary haloalkane from a tertiary alcohol by a substitution with HX (X = Cl, Br).
Substitution Reaction
• A tertiary carbon atom is attached to three other carbon atoms.
A secondary carbon atom is attached to two other carbon
atoms while a primary carbon atom is attached to one other
carbon atom.
• It is possible for a secondary or primary alcohol to form a
secondary or primary haloalkane, but this requires high
temperatures and the reaction is very slow.
The formation of a primary haloethane from ethanol by a substitution with HX (X = Cl, Br).
Substitution Reaction
• 2. Hydrolysis
• Alcohols can also be formed through a substitution reaction
with a haloalkane. In the example given, the haloalkane would
be dissolved in water.
The formation of ethanol from chloroethane through a substitution reaction with water.
Substitution Reaction
• Using a base (e.g. KOH, NaOH) dissolved in water and warming
the solution would increase the rate of the reaction
• However, in order for substitution to occur the following reaction
conditions must be used:
• low temperatures (around room temperature)
• a dilute solution of a strong base (e.g. NaOH)
• the solution must be aqueous (in water)
The formation of ethanol from bromoethane through a substitution reaction with potassium hydroxide (KOH)
If the concentration of the base is too high then the halogen atom and a hydrogen atom could be eliminated
(dehydrohalogenation).
Substitution Reaction
• Formation of haloalkanes from alkanes
• Another way of forming a haloalkane involves the removal of a
hydrogen atom from a saturated compound. The hydrogen
atom is replaced by a halogen (F,Cl,Br or I) to form a
haloalkane.
• As alkanes are not very reactive light is needed for this
reaction to take place.
The formation of bromoethane from ethane through a substitution reaction with Br 2.
Alkynes Are Unusually Acidic. Deprotonation of
Alkynes Gives “Acetylides”
• Alkynes are unusually acidic hydrocarbons.
• In an alkyne, where the carbon is sp hybridized,
the lone pair resides in an orbital with 50% s
character [the 2s orbital is closer to the positively-
charged nucleus than the 2p orbital, increasing
stability].
• Compare that to alkenes (sp2, 33% s-character)
and alkanes (sp3, 25% s character)
Less acidic most acidic
Deprotonation of Alkynes Gives
“Acetylides”
• Deprotonation of alkynes with a strong base yields the
conjugate base, often referred to as an “acetylide” :
Alkylation of Acetylides With Alkyl
Halides via Substitution
• The conjugate base is a stronger nucleophile.
• SN2 reaction, in which a nucleophile attacks a carbon with a
good leaving group (alkyl halides or sulfonates)
• Here’s an example of how the SN2 can be applied to alkynes.
•
Acidity of Terminal Alkynes: Formation
of Acetylide Anions
• Terminal alkynes are much more acidic than most other
hydrocarbons.
• Removal of the proton leads to the formation of an acetylide anion.
• Consequently, acetylide anions can be readily formed by
deprotonation using a sufficiently strong base.
• Amide anion (NH2-), in the form of NaNH2 is commonly used for the
formation of acetylide anions.
Nucleophilic Substitution Reactions of
Acetylides
• Acetylide anions are strong bases and strong
nucleophiles.
• Therefore, they are able to displace halides and other
leaving groups in substitution reactions.
• The product is a substituted alkyne.
Nucleophilic Substitution Reactions of
Acetylides
• Because the ion is a very strong base, the
substitution reaction is most efficient with methyl
or primary halides without substitution near the
reaction center,
Nucleophilic Substitution Reactions of
Acetylides
• Secondary, tertiary or even bulky primary
substrates will give elimination by the E2
mechanism.
Nucleophilic Addition of Acetylides to
Carbonyls
• Acetylide anions will add to aldehydes and ketones to
form alkoxides, which, upon protonation, give
propargyl alcohols.
Nucleophilic Addition
• With aldehydes and non-symmetric ketones, in the absence of chiral
catalyst, the product will be a racemic mixture of the two enantiomers.
• The triple bond in the propargyl alcohol can be modified by using the
reactivity of the alkyne.
• For example, Markovnikov and anti-Markovnikov hydration of the triple
bond leads to formation of the hydroxy-substituted ketone and
aldehyde, respectively, after enol-keto tautomerization.
Nitration
SUBSTITUTION REACTIONS OF
BENZENE AND OTHER
AROMATIC COMPOUNDS
Electrophilic Substitution
Reactions:
• (a) What are electrophiles?
The electrophilic substitution reaction involves the
electrophiles.
Electrophiles are those which donate a pair of
electrons in the formation of a covalent bond.
The Electrophilic reactions occur mostly with the
aromatic compounds.
These compounds have about an excess of
electrons that can be shared throughout the system
of reaction.
Electrophilic Substitution
Reactions:
• (b) What is Electrophilic substitution reaction?
The Electrophilic substitution reactions are basically
defined as those chemical reactions where the
electrophile replaces the functional group in a
compound but not the hydrogen atom. Some
examples of species of electrophiles include
hydronium ion (H3O+), halides of hydrogen such as
HCl, HBr, HI, sulphur trioxide (SO3), the nitronium ion
(NO2+), etc.
• (c) Types of Electrophilic substitution reaction:
Two types of electrophilic substitution reactions are
discussed here. Aromatic electrophilic
substitution reaction and aliphatic electrophilic
substitution reaction.
Electrophilic Substitution
Reactions:
• (c) Types of Electrophilic substitution
reaction:
Two types of electrophilic substitution
reactions are discussed here.
Aromatic electrophilic substitution reaction
Aliphatic electrophilic substitution reaction.
Substitution Reactions of
Benzene
• Five most useful substitution reactions of
benzene
Reaction Type Typical Equation Electrophile E(+)
Halogenation: C6H6 + Cl2 & heat ——> C6H5Cl + HCl Cl(+) or Br(+)
FeCl3 catalyst Chlorobenzene
Nitration: C6H6 + HNO3 & heat ——> C6H5NO2 + H2O NO2(+)
H2SO4 catalyst Nitrobenzene
Sulfonation: C6H6 + H2SO4 + SO3 ——> C6H5SO3H + H2O SO3H(+)
& heat Benzenesulfonic
acid
Alkylation: C6H6 + R-Cl & heat ——> C6H5-R + HCl R(+)
Friedel-Crafts AlCl3 catalyst An Arene
Acylation: C6H6 + RCOCl & heat ——> C6H5COR + HCl RCO(+)
Friedel-Crafts AlCl3 catalyst An Aryl Ketone
Mechanism for electrophilic
Aromatic Substitution
• 1. The cation may bond to a nucleophile
to give a substitution or addition
product.
2. The cation may transfer a proton to a
base, giving a double bond product.
3. The cation may rearrange to a more
stable carbocation, and then react by
mode #1 or #2.
Bromination of Benzene - An Example of
Electrophilic Aromatic Substitution
1. A Mechanism for Electrophilic Substitution Reactions of
Benzene
Bromination of Benzene - An Example of
Electrophilic Aromatic Substitution
2. Ring Substitution Reactions of Benzene Derivatives
• When substituted benzene compounds undergo
electrophilic substitution reactions of the kind
discussed above, two related features must be
considered:
• I. The first is the relative reactivity of the compound
compared with benzene itself.
Experiments have shown that substituents on a benzene
ring can influence reactivity in a profound manner. For
example, a hydroxy or methoxy substituent increases the
rate of electrophilic substitution about ten thousand fold
Substitution Reactions of
Benzene
• Five most useful substitution reactions of
benzene
Nitration
Sulphonation
Mechanism for Sulfonation
of Benzene
Halogenation
Halogenation
Halogenation
Reaction Mechanism
Scope
Reaction Mechanism
Reaction Mechanism
Substitution Reactions of Benzene
and Other Aromatic Compounds
• The chemical reactivity of benzene contrasts with
that of the alkenes in that substitution reactions
occur in preference to addition reactions
Comparison Between SN1
and SN2 Reactions
Comparison Between SN1
and SN2 Reactions
Reaction Mechanism
Types of Reactions
Types of Reactions
Rearrangement Reactions
Types of Reactions
Organic Redox Reactions
Check your Understanding
• Which of the following reaction will go faster if the
concentration of the nucleophile is raised?
• Explanation:
• I & II reaction undergo via SN2 mechanism. III & IV reaction
undergo via SN1 mechanism. As we know the rate of
reaction in SN2 reaction is directly proportional to the
concentration of nucleophile.
Check your Understanding
• SN1 reaction undergoes through a
carbocation intermediate as follows:
[R = t-Bu, iso-Pr, Et, Me] (X = Cl, Br, I)
Explanation:
(1) Formation of carbocation is rate-determining
steps(RDS), more stable the cation more easily it will
form. Hence rate order is t-BuX > iso-PrX > EtX > MeX
(2) Formation of carbocation CH3 is most difficult hence
ionization energy is highest. Similarly, EtX has lesser
ionization energy than MeX and so on.
(3) Order of energy of activation is MeX > EtX > iso-
Check your Understanding
• Which one is an excellent substrate for
SN2 reaction?
Alpha-halo carbonyl undergoes fastest S N2
reaction due to the coupling of π* of CO
bond and π* of C–X bond.
Check your Understanding
3. Write down the mechanism for the following reaction and predict
which of the two possible products will be formed in the greatest
yield ( 2nd and 3rd carbocation). Write down the structures of the two
possible products and explain your answer.
CH3CH CHCH2 CH2 CH3 + HBr
2- hexene
4. Give the major product of each of the following
a. HC CCH3 HBr
excess HBr
b. HC CCH3
