Substitution and Elimination

Reaction of Alkyl Halides

SN1, SN2, E1 and E2 Reactions

Mahesh R. Borkar
Bombay College of Pharmacy, Mumbai

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 Organic compounds with an
electronegative atom or an electron-
withdrawing group bonded to a sp3
carbon undergo substitution or -
elimination reactions

Halide ions are good leaving

groups. Substitution reaction on
these compounds are easy and are
alkyl fluoride alkyl chloride alkyl bromide alkyl iodide
used to get a wide variety of
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compounds 2
 Nucleophilic Substitution Reactions
General Reaction

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Reaction Intermediates Leaving Groups
3 major types
• Relatively stable, weakly basic molecule or anion
Carbocation (C+)
Carbanion (C-) • Halogen atom of an alkyl halide is a good leaving group
Free radical (C·) because once departed it is a weak base and table anion

Reaction Site
• Nucleophiles (nucleus-loving) : any species containing electron pairs
❖Electrons are (-), so Nu: are attracted to (+) site
❖Charge Nu: are better than neutral one

• Electrophiles (electron-loving): any species or site in molecule

❖ that’s deficient in electron density because it’s near a electronegative
atom or lacking of e- altogether
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 SN2
Substitution Bimolecular

Nucleophilic

Bromomethane Methanol

Rate law:

rate = k [Bromoethane][OH-]

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Highlights of SN2 Reactions

Alkyl halide Relative rate

The rate of reaction depends on the
concentrations of both reactants.
1200

When the hydrogens of bromomethane

are replaced with methyl groups the 40
reaction rate slow down. Reaction is
sensitive to steric hindrance (bulky
groups slow down backside attack
1

The reaction of an alkyl halide in which

the halogen is bonded to an assymetric ≈0
center leads to the formation of only
one stereoisomer

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 Mechanism of SN2 Reactions

Hughes and Ingold proposed the following mechanism:

𝜹+

Transition state Inversion Configuration

 In the "backside attack", the nucleophile attacks the substrate from the backside in a
single step, resulting in inversion of configuration.
 Increasing the concentration of either of the reactant makes their collision more probable.
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• The nucleophile approaches the carbon bearing the leaving group from the back side
• Directly opposite the leaving group
• As the reaction progresses, the bond between nucleophile and the carbon strengthens, and the
bond between the carbon atom and the leaving group weakens
• Carbon atom has its configuration turned inside out  inversion

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 Mechanism of SN2 Reactions

Steric effect 𝜹+

𝜹+
activation
energy: DG2
Energy

activation
energy: DG1

reaction coordinate reaction coordinate

Stereochemistry: Inversion of configuration

(R)-2-bromobutane (S)-2-butanol
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 Factor Affecting SN2 Reactions

The leaving group

relative rates of reaction pKa HX
HO
- + RCH I RCH2OH + I
- 30 000 -10
2
HO
- + RCH2Br RCH2OH + Br
- 10 000 -9
HO
- + RCH2Cl RCH2OH + Cl
- 200 -7
HO
- + RCH2F RCH2OH + F
- 1 3.2

The nucleophile

In general, for halogen substitution the

strongest the base the better the
nucleophile.

pKa Nuclephilicity
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SN2 Reactions With Alkyl Halides
an alcohol

a thiol

an ether

a thioether

an amine

an alkyne

a nitrile

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 SN1
Substitution Unimolecular

Nucleophilic

1-bromo-1,1-dimethylethane 1,1-dimethylethanol

If concentration of (1) is If concentration of (2) is

doubled, the rate of the doubled, the rate of the
reaction is doubled. reaction is not doubled.
Rate law:

rate = k [1-bromo-1,1-dimethylethane]
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 Order of reactivity
Tertiary > secondary > primary
Highlights of SN1 Reactions
Alkyl halides shows Order of reactivity
The rate of reaction depends on the RI > RBr > RCl > RF
concentrations of the alkyl halide only.
1st order rate determination. Alkyl halide Relative rate
Rate is depends on the slowest step i.e.
formation of carbocation.
≈0*
When the methyl groups of 1-bromo-
1,1-dimethylethane are replaced with
hydrogens the reaction rate slow down. ≈0*

The reaction of an alkyl halide in which

12
the halogen is bonded to an asymetric
center leads to the formation of two
stereoisomers
1 200 000

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* a small rate is actually observed as a result of a SN2
 Mechanism of SN1 Reactions

nucleophile attacks the

carbocation

Step 1

Slow
Fast Step 2
C-Br bond breaks

Proton dissociation

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 Energy Profile Diagram of SN1

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Mechanism of SN1 Reactions

Rate determining step

Carbocation
intermediate

DG R++ X-
+
Energy R-OH2

R-OH

Reaction Coordinates

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 Stereochemistry

Back side attack Front side attack

Inversion configuration Retention configuration

❖ The carbocation is sp2 hybridized and the groups attached to it lie in one plane.
❖ The ion is planar with an empty p-orbital perpendicular to the plane.
❖ The solvent molecule (Nu-) can thus attack from either side of the lobe of the empty orbital.
❖ The SN1 reaction of an optically active substance proceeds with essentially complete racemization i.e.
equal amount of d and l forms of the products are formed
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 Carbocation Rearrangement in SN1 Reaction

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 Comparing SN1 vs. SN2 reactions (Identification)

➢ The key skill to start with is identifying the leaving group.Look for halogens (Cl, Br, I) or tosylates/mesylates (OTs,
OMs) Alternatively, look for alcohols (OH) if acid is present
➢ Once you've identified the leaving group, instpect the carbon it is attached to. How many carbons is that carbon
connected to? That will tell you if the carbon is primary, secondary, or tertiary. If there are no attached carbons,
that's the special case of "methyl" (SN2 for sure!)
➢ If the carbon is tertiary, it's likely SN1. You can rule out SN2 due to sterichindrance.
➢ If the carbon is primary, it's likely SN2. You can rule out SN1 due to the fact that primary carbocations are
unstable [one exception: resonance stabilized carbocations].
➢ Next, examine the nucleophile. A negatively charged nucleophile generally indicates an SN2 reaction. A neutral
nucleophile (such as H2O or ROH) generally indicates an SN1 reaction.
➢ Finally, check the solvent. A polar aprotic solvent (such as DMSO, acetone, acetonitrile, or DMF) generally
indicates SN2, whereas a polar protic solvent such as H2O or ROH generally indicates SN1 conditions.

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 Rearrangement No Carbocation rearrangement
occurs
Steric hindrance No affect by branching Subject to steric hindrance of
groups at α and β-carbon atoms
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 Factors affecting SN1 and SN2 substitution reactions

The structure of the substrate

The concentration and reactivity of

the nucleophile

The effect of the solvent

The nature of the leaving group

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The effect of the structure of the substrate
• SN2 reaction shows the following general order of reactivity
• Methyl > primary > secondary >> (tertiary – unreactive)
• steric hindrance
• SN1 reaction
• Tertiary > secondary > methyl
• Hyperconjugation between p orbitals

Hammond-Leffler Postulate

The structure of a transition state resembles the stable species that is nearest it in free
energy.
The effect of the Concentration and Strength of the Nucleophile

• A negatively-charged nucleophile is always a more reactive nucleophile than its conjugated acid
• HO- is a better Nu: then H2O and RO- is better than ROH

• In a group of nucleophiles in which the nucleophilic atom is the same, nucleophilicities parallel to
basicities
• RO- > HO- >> RCO2- >> ROH > H2O
• equilibrium favors the side with weaker acid
Solvent Effects on SN2 Reactions: Polar Protic and Aprotic solvent

• The effect of hydrogen bonding with the nucleophile is to encumber

the Nu: and hinder its reactivity in a substitution reaction
Solvent Effects on SN2 Reactions: Polar Protic and Aprotic solvent

• Hydrogen bonds to a small nucleophile atom are more stronger than

those to larger nucleophilic atoms
• Halide Nucleophilic in Protic Solvent
I- > Br- > Cl- > F-

Larger atoms have greater polarizability  larger nucleophile atom can donate
a greater degree of electron density to substrate
SH- > CN- > I- > -OH > N3- > Br- > CH3CO2- > Cl- > F- > H2O
Solvent Effects on SN2 Reactions: Polar Protic and Aprotic solvent

• Aprotic solvents are those solvents whose molecules

do not have a hydrogen that is attached to an atom of
an electronegative element

• They do the same way as protic solvents solvate

cations; by orienting their negative ends around
cation and by donating unshared electron pairs to
vacant orbitals of the cation
Solvent Effects on SN2 Reactions: Polar Protic and Aprotic solvent

• They cannot form H-bond because their postive centers are well
shielded by the steric effects from any interaction with anions

• Rate of SN2 reaction generally increased when they are carried out in
a polar protic solvent
Solvent Effects on SN1 Reactions: The Ionizing Ability of the solvent

• The use of polar protic solvent will greatly increase the rate of
ionization of an alkyl halide in SN1 reaction
• Able to solvate cations and anions more affectively
• Stabilize transition state leading to the intermediate carbocation and halide
ion more than it does the reactant
• Lower activation energy
 The effect of the nature of leaving group

Leaving Group: I > Br > Cl > F for both SN1 and SN2
( the weaker the base after the group departs
the better the leaving group)

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 Elimination Reactions
Elimination happens when the nucleophile attacks hydrogen instead of carbon

Elimination reactions are important as a method for the preparation of alkenes.

The term "elimination" describes the fact that a small molecule is lost during the process. A 1,2 elimination indicates
that the atoms that are lost come from adjacent C atoms.
The two most important methods are:
 Dehydration (- H2O) of alcohols, and
 Dehydrohalogenation (- HX) of alkyl halides
.
There are three fundamental events in these elimination reactions:
 removal of a proton
 formation of the CC π bond
 breaking of the bond to the leaving group

Depending on the relative timing of these events, different mechanisms are possible:
 Loss of the LG to form a carbocation then removal of H+ with formation of C=C bond (two steps) : E1 reaction
 Simultaneous H+ removal, C=C bond formation and loss of the LG (one step) : E2 reaction
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 Removal of H+ to form a carbanion then formation of C=C bond with loss of the LG (two steps) : E1cb reaction
 E2 Reaction
The elimination reaction of t-butyl bromide happens because the nucleophile is basic.

The hydroxide is behaving as a base because it is attacking the hydrogen atom, instead of the carbon atom it
would attack in a substitution reaction.
The hydrogen atom is acidic, but proton removal can occur because bromide is a good leaving group. As the
hydroxide attacks, the bromide is forced to leave, taking with it the negative charge. Two molecules—t-butyl
bromide and hydroxide—are involved in the rate-determining step of the reaction. This means that the
concentrations of both appear in the rate equation, which is therefore second-order
Rate = k2[t-BuBr][HO–]
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and this mechanism for elimination is termed E2, for elimination, bimolecular
Because the E2 mechanism results in the formation of a pi bond, the two leaving groups (often a hydrogen

and a halogen) need to be antiperiplanar. An antiperiplanar transition state has staggered conformation with

lower energy than a synperiplanar transition state which is in eclipsed conformation with higher energy. The

reaction mechanism involving staggered conformation is more favorable for E2 reactions (unlike E1

reactions).

Eliminations often favour the more stable trans-product over the cis-product (stereoselectivity)

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 Mechanism of E2 Reaction

The above reation depicts an E2 elimination reaction between methoxide (H3CO -) and 2-chlorobutane
to form methanol, 2-butene, and a chloride anion . In the E2 reaction, a new bond is formed between
the base, H3CO-, and a proton from the 2-chlorobutane, while simultaneously the carbon-chlorine
bond is broken and a new pi bond is being formed on the butane species. The departing chloride anion
is referred to as the leaving group.
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Influence of alkyl halide structure on reactivity Secondary alkyl halides such as 2-bromobutane can react by
either the E2 or SN2 reaction pathways to varying degrees depending on the nature of the nucleophile/base
being used. If a strong base such as methoxide is used, the proton transfer step is favored and the E2 mechanism
predominates. If a weak base/strong nucleophile is used such as another halide or the azide (N3-) anion is used,
then substitution according to the SN2 reaction pathway is favored.
Effects of Substrate
Reactivity order : (CH3)3C- > (CH3)2CH- > CH3CH2- > CH3-
In an E2 reaction, the reaction transforms 2 sp3 C atoms into sp2 C atoms. This moves the substituents further
apart decreasing any steric interactions. So more highly substituted systems undergo E2 eliminations more
rapidly. This is the same reactivity trend as seen in E1 reactions.
LG (Leaving group)
The C-LG bond is broken during the rate determining step, so the rate does depend on the nature of the leaving
group.
However, if a leaving group is too good, then an E1 reaction may result.
B-Base
Since the base is involved in the rate determining step, the nature of the base is very important in an E2
reaction.
22-11-2018 More reactive bases will favour an E2 reaction
Stereochemistry

E2 reactions occur most rapidly when the H-C bond and C-LG bonds involved are co-planar, most often at 180o with
respect to each other. This is described as an antiperiplanar conformation. This conformation positions the σ
bonds that are being broken in the correct alignment to become the π bond.

The staggered,
antiperiplanar alignment is
preferred because it aligns
the two σ bonds that
become the π bond.
The JMOL image to the left
allows you to highlight the H
that is antiperiplanar to the Br
atom and look at this from
different view points. Newman
projection on the right above.
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Synperiplanar arrangments where the angle between the H-C bond and C-LG is 0o are also known,
usually in systems that are either inflexible rings or intramolecular eliminations

The eclipsed, synperiplanar alignment also aligns the

two σ bonds that become the π bond, but is less
favourable than the antiperiplanar arrangement.

These alignments are example of a stereoelectronic effect because they

involve the specific spatial postioning of the bonds (electrons) in order for
the process to occur

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 E1 Elimination Reaction

loss of the leaving group, LG, to

generate a carbocation
intermediate, then

loss of a proton, H+, from the

carbocation to form the π-bond

1 indicates a elimination, unimolecular reaction, where

rate = k [R-LG].

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 E1 MECHANISM FOR ALCOHOLS

Step 1:
An acid/base reaction. Protonation of the alcoholic oxygen to make a better
leaving group. This step is very fast and reversible. The lone pairs on the
oxygen make it a Lewis base.

Step 2:
Cleavage of the C-O bond allows the loss of the good leaving group, a neutral
water molecule, to give a carbocation intermediate. This is the rate
determining step (bond breaking is endothermic)

Step 3:
An acid/base reaction. Deprotonation by a base (a water molecule) from
a C atom adjacent to the carbocation center leads to the creation of the C=C

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 E1 MECHANISM FOR ALKYL HALIDES

Step 1:
Cleavage of the polarised C-X bond allows the loss of the good leaving
group, a halide ion, to give a carbocation intermediate. This is the rate
determining step (bond breaking is endothermic)

Step 2:
An acid/base reaction. Deprotonation by a base (here an alkoxide ion)
from a C atom adjacent to the carbocation center leads to the creation of
the C=C

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 The various components of the reaction influence the reaction pathway

R-
Reactivity order : (CH3)3C- > (CH3)2CH- > CH3CH2- > CH3-
In an E1 reaction, the rate determining step is the loss of the leaving group to form the intermediate
carbocation. The more stable the carbocation is, the easier it is to form, and the faster the E1 reaction will be.
Since carbocation intermediates are formed during an E1, there is always the possibility of rearrangements
(e.g. 1,2-hydride or 1,2-alkyl shifts) to generate a more stable carbocation. This is usually indicated by a
change in the position of the alkene or a change in the carbon skeleton of the product when compared to the
starting material.

-LG
The only event in the rate determining step of the E1 is breaking the C-LG bond. Therefore, there is a very
strong dependence on the nature of the leaving group, the better the leaving group, the faster the E1
reaction will be. In the acid catalysed reactions of alcohols, the -OH is protonated first to give an oxonium
ion, providing the much better leaving group, a water molecule
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B
Since the base is not involved in the rate determining step, the nature of the base is unimportant in an E1 reaction.
However, the more reactive the base, the more likely an E2 reaction becomes.

Selectivity
E1 reactions usually favour the more stable alkene as the major product : i.e. more highly alkyl substituted and trans- >
cis-

This E1 mechanistic pathway is most common with:

•good leaving groups
•stable carbocations
•weak base

Solvent
Polar solvents also favour E1 reactions because they stabilize the intermediate carbocation. E1
eliminations from alcohols in aqueous or alcohol solution are particularly common, and very useful.
An acid catalyst is used to promote loss of water, and in dilute H2SO4 or HCl the absence of good
nucleophiles ensures that substitution does not compete.
Under these conditions, the secondary alcohol cyclohexanol gives cyclohexene.

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Zaitsev’s or Saytzev’s rule is an empirical rule used to predict regioselectivity of 1,2-elimination
reactions occurring via E1 mechanism or via E2 mechanism. It states that in a regioselective E1 or E2
reaction the major product is the more stable alkene, i.e., the alkene with the more highly substituted
double bond.

E1 reaction always follow Zaitsev’s rule; with E2 reactions, there are exceptions (see antiperiplanar).

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 How the nucleophile affects elimination versus substitution
Basicity
❖ Molecules bearing leaving groups being attacked at two distinct electrophilic sites: the carbon to which the
leaving group is attached, and the hydrogen atoms on the carbon adjacent to the leaving group.
❖ Attack at carbon leads to substitution; attack at hydrogen leads to elimination.
❖ Since strong bases attack protons, it is generally true that, the more basic the nucleophile, the more likely
that elimination is going to replace substitution as the main reaction of an alkyl halide.

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Size
➢ SN2 is so slow on hindered alkyl halides—the
nucleophile has difficulty getting to the reactive
centre.
➢ Getting at a more exposed hydrogen atom in an
elimination reaction is much easier, so using hard,
basic nucleophiles that are also bulky, elimination
becomes preferred over substitution, even for
primary alkyl halides.
➢ One of the best bases for promoting elimination and
avoiding substiutution is potassium t-butoxide. The
large alkyl substituent makes it hard for the
negatively charged oxygen to attack carbon in a
substitution reaction, but it has no problem
attacking hydrogen.
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Temperature
Temperature has an important role to play in deciding whether a reaction is an elimination or a substitution.
In an elimination, two molecules become three.
In a substitution, two molecules form two new molecules.
The two reactions differ therefore in the change in entropy during the reaction: ΔS is greater for elimination
than for substitution. the equation
ΔG = ΔH – TΔS
This equation says that a reaction in which ΔS is positive is more exothermic at higher temperature.
Eliminations should therefore be favoured at high temperature.

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Substrate
structure may
allow E1

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The role of the leaving group

▪ Both E1 and E2 are possible, but in the first example, a stabilized cation cannot be formed (so E1 is
impossible), and a strong base is used, allowing E2.
▪ In the second, a stabilized tertiary cation could be formed (so either E1 or E2 might occur), but no strong base
is present, so the mechanism must be E1.

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Stereochemistry
E1 reactions can be stereoselective

➢ The factors that control the

stereochemistry (geometry) and
regiochemistry (that is, where the double
bond is) of the alkenes, starting with E1
reactions.

➢ For steric reasons, E-alkenes (and

transition states leading to E-alkenes)
are usually lower in energy than Z-
alkenes (and the transition states
leading to them) because the
substituents can get farther apart from
one another

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  A reaction that can choose which it forms is therefore likely to favour the formation of E-alkenes. For
alkenes formed by E1 elimination, this is exactly what happens: the less hindered E-alkene is
favoured. Here is an example.

 The geometry of the product is determined at the moment that the proton is lost from the intermediate
carbocation. The new p bond can only form if the vacant p orbital of the carbocation and the breaking C–H
bond are aligned parallel. In the example shown there are two possible conformations of the carbocation
with parallel orientations, but one is more stable than the other because it suffers less steric hindrance.
 The same is true of the transition states on the route to the alkenes—the one leading to the E-alkene is
lower in energy and more E-alkene than Z-alkene is formed. The process is steroselective, because the
reaction chooses to form predominantly one of two possible stereoisomeric products.

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 E1 reactions can be regioselective

1 eliminations that can give more than one regioisomeric alkene

More substituted alkenes are more stable.

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 Anion-stabilizing groups allow another mechanism—E1cB
The E1cB elimination reaction is a type of elimination reaction which occurs under basic conditions,
where a particularly poor leaving group (such as -OH or -OR) and an acidic hydrogen eliminate to form
an additional bond. E1cB is a three-step process.
First, a base abstracts the most acidic proton to generate a stabilized anion.
Second, the lone pair of electrons on the anion then moves to the neighbouring atom, thus expelling the leaving
group and forming double or triple bond.
The name of the mechanism - E1cB -
stands
for Elimination Unimolecular conjugate
Base.
Elimination refers to the fact that the
mechanism is an elimination
reaction and will lose two substituents.
Unimolecular refers to the fact that the
rate-determining step of this reaction
only involves one molecular entity.
Conjugate base refers to the formation
of the carbanion intermediate, which is
the conjugate base of the starting
material.
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 relatively poor leaving group

Requirements to have a reaction

proceed down an E1cB mechanistic
pathway.

acidic hydrogen

Example: The degradation of a hemiacetal under basic conditions.

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 The first step of an E1cB mechanism is the deprotonation of the β-carbon, resulting in the
formation of an anionic transition state, such as a carbanion

The greater the stability of this transition state, the more the mechanism will favor an E1cB
mechanism. This transition state can be stabilized through induction or delocalization of
the electron lone pair through resonance. In general it can be claimed that an electron
withdrawing group on the substrate, a strong base, a poor leaving group and a polar solvent
triggers the E1cB mechanism.

Example: Degradation of ethiofencarb illustrating the presence of a stable anion due to

resonance between the amide functional group and the carbonyl group.

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E.g. The preferential elimination of fluorine in an E1cB-elimination reaction.

The important point about substrates

that undergo E1cB is that there is
some form of anion-stabilizing group
next to the proton to be removed—it
doesn’t have to stabilize the anion
very well but, as long as it makes the
proton more acidic, an E1cB
mechanism has a chance. Here is an
important example with two phenyl
rings helping to stabilize the anion,
and a carbamate anion (R2N—CO2 -)
as the leaving group.
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The general pattern of reactivity expected from various structural classes of alkyl halides (or tosylates, mesylates) in
reactions with a representative range of nucleophiles (which may behave as bases).

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