Aliphatic Electrophilic Substitution Reactions

Aliphatic Electrophilic Substitution Reactions

SE2 and SEi Mechanisms
Both SE2 and SEi mechanisms are bimolecular and analogous to the SN2 mechanism,
i.e., the new bond forms at the same time when the old bond breaks. In the SN2 mechanism,
the attacking group brings with it a pair of electrons and the leaving group takes away its
electrons. These things are happening simultaneously. Therefore, the incoming attacking
group attacks backside at a position 180o away from the leaving group, resulting in inversion
of configuration.
But in SE2 mechanism the attacking group is an electrophile. This brings to the
substrate only a vacant orbital. Therefore we cannot predict from which direction the attack
must come. We can imagine two main possibilities. They are attack from the front, i.e., SE2
(front) and attack from the rear, i.e., SE2 (back). These can be represented as follows,

Y Y
SE2 (front)
C C + X
X

SE2 (back)
Y C X Y C + X

The SE2 (front) mechanism should result in retention of configuration and SE2 (back)
mechanism in inversion of configuration.
The SEi Mechanism
When an electrophile attacks from the front, there is a possibility for a portion of the
electrophile to assist in the removal of leaving group, forming a bond with it at the same time
a new C-Y bind is formed.

Y Y
SEi Z
C Z C +
X X

This mechanism also results in retention of configuration, where a second order kinetics
involves internal assistance that prevents the backside attack of an electrophile.

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 Aliphatic Electrophilic Substitution Reactions

The SE2 (front), SE2 (back) and SEi mechanisms are not easy to distinguish. All three
give second order kinetics, and SE2 (front) and SEi results in retention of configuration. The
study of stereochemistry can distinguish between SE2 (back) results in inversion of
configuration on the one hand and SE2 (front) and SEi on the other.
In the majority of second order electrophilic substitution reactions, the results have
been retention of configuration due to the front side attack of electrophile following either
SE2 (front) or SEi mechanism. For example, when the cis-isomer of compound 1 was treated
with labeled mercury the product was 100 % cis – isomer.
O CH3 O CH3
CH3 H
H *Hg Cl
Cl
CH3
Hg
+ *Hg Cl + Cl * Hg
H
H CH3
CH3
1

This indicates the bonds between the Hg atom and the ring on the one side, and the
carbon (Hg – C ) on the other side have been broken, which facilitate the front side attack of
the electrophile on the substrate carbon to produce the cis – isomer.
Another indication of front side attack is that second order electrophilic substitutions
proceed very easily at bridgehead carbons, where backside attack is impossible. Neopentyl
substrate is another example where SN2 reactions are extremely slow because attack from the
rear side is blocked.
CH3
H
H3C Br
H
CH3
1-bromo-2,2-dimethylpropane

But the above neopentyl system undergoes electrophilic substitutions slightly more due to the
front side attack of electrophiles.
However, inversion of configuration has been found in certain cases, indicating that
SE2 (back) mechanism can also takes place. For example, the reaction of optically active sec
– butyltrineopentyl tin with bromine gives inverted sec – butyl bromide.

Sec-BuSnR3 + Br2 Sec-BuBr

(R = neopentyl)

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 Aliphatic Electrophilic Substitution Reactions

A number of organo metallic compounds have also been shown to give inversion when
treated with halogens, thus confirming the SE2 (back) mechanism.
Thus the stereochemical investigations cannot distinguish between the SE2 (front) and
SEi mechanisms. The study of salt effect on the rate helps in distinguishing these two
mechanisms. The reactions in which the neutral starting molecules acquire charge in the
transition state are aided by an increase in concentrations of added ions. Hence SE2
mechanism would be more influenced by salt effects than the SEi mechanism, which acquires
no charge in the transition state.
On the basis Abraham and co – workers concluded that the following kind of
reactions,
R4Sn + HgX2 RHgX + R3SnX

takes place by SE2 and not by SEi mechanism.

SE1 Mechanism
This mechanism is analogous to SN1, i.e., involves two steps via a slow ionization
and a fast combination.
slow
Step 1: R-X R(-) + X(+)

fast
Step 2: R(-) + Y(+) R-Y

The SN1 reactions do not proceed at bridgehead carbons in bicyclic systems because planar
carbocations cannot form at these carbon atoms. However carbanions not stabilized by
resonance are not probably planar. Hence SE1 reactions should readily occur with this type of
substrate.
If a carbanion is planar racemization should occur. If it is pyramidal and can hold its
structure, the result should be retention of configuration. However, even planar carbanions
need not give racemization. The nature of solvent plays an important role in deciding the
inversion or racemization.
In non-dissociating, non-polar solvents such as benzene or dioxane the intermediate
anion exists as an ion pair, solvated by the solvent BH,
- H- B
O H- B

R R R- + O R - H + B(-)

CR2
R

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 Aliphatic Electrophilic Substitution Reactions

In the above cleavage, the proton of the solvent moves into solvate the newly forming
carbanion (R-). When the carbanion actually bonds with the proton, the result is the retention
of the original configuration.
In protic solvents such as diethylene glycol, the solvent molecule solvates the
carbanion even before the elimination of leaving group and hence only the rear side attack is
possible in order to give the inversion of configuration.
-
O + H-B

R R B-H R- O B(-) + H - R

CR2
R
Racemization occurs in polar aprotic solvents such as dimethyl sulfoxide (DMSO). In
these solvents because of the absence of proton to donate, the carbanions are symmetrically
solvated.
The Factors Affecting the Reactivity of Aliphatic Electrophilic Substitution Reactions
1. Effect of Substrate Structure
For SE1 reactions electron donating groups decrease rates and electron with drawing
groups increase them. This is because of the formation of carbanion in the rate-determining
step. For SE2 (back) mechanism, the reactivity of alkyl groups is similar to that or the SN2
mechanism (i.e., Me > Et > Pr > iso-Pr > neopentyl) since both involve backside attack and
are equally affected by steric hindrance.
For SE2 (front) mechanism, the relative rates for the reaction,
catalyzed by Br(-) were given in the following
RHgBr + Br2 RBr + HgBr2
table.
R Relative Rate R Relative Rate
Me 1 Et 10.8
Et 10.8 iso-Bu 1.24
iso-Pr 780 Neopentyl 0.173
tert-Bu 3370
Here, - branching increased the rates due to electron donating effect of alkyl groups, which
stabilize the electron deficient transition state. But - branching decreased the rate due to
steric hindrance.

Dha. Ilangeswaran 4
 Aliphatic Electrophilic Substitution Reactions

2. Effect of Leaving Group

For both SE1 and second order mechanisms (SE2 & SEi), the more polar the C – X
bond, the easier, it is for the electrofuge (leaves without electron pair) to cleave. For example,
consider a series of organo-mercurials, RHgW. The more electro negative W decreases the
polarity of C – Hg bond and results in a less stable HgW(+), the electrofugal ability of HgW
decreases with increasing electro negativity of W. Thus HgR’ (from RHgR’) is a better
leaving group than HgCl (from RHgCl).
3. Effect of Solvent
The increase in solvent polarity increases the possibility of an ionizing mechanism,
i.e., the SE1 mechanism. The rates of SE2 (front or back) mechanisms should be increased by
an increase in solvent plarity, while SEi mechanisms are much less affected.

Electrophilic Substitution Reactions Accompanied by Migration of Double Bonds

When an electrophilic substitution is carried out at an allylic substrate, the products
obtained are usually a rearranged one.

C C C X + Y(+) C C C + X(+)

There are two principal pathways. The first one is analogous to the SE1 mechanism in that
the leaving group is first removed; giving a resonance stabilized allylic carbanion, and then
the electrophile attacks.

(-) (-) Y(+)

C C C X C C C: :C C C Y C C C

In the other pathway, the electrophile Y+ first attacks, giving a carbocation, which then loses
leaving group, X+.

C C C X C C
(+)
C X C C C + X(+)
Y(+)
Y Y

Crotylmercuric bromide reacts with HCl about 107 times faster than n-butylmercuric
bromide. This is because of the double bond shift in the former compound.

Dha. Ilangeswaran 5
 Aliphatic Electrophilic Substitution Reactions

crotyl mercuric bromide

H3C
H H3C H

Cl Hg Br
+
H H CH2
H

H but-1-ene
Hg Br
Cl

The double bonds of many unsaturated compounds are shifted on treatment with strong bases.
Example,

KNH2
C5H11 - CH2 - CH - CH2 C5H11 - CH - CH - CH3
Me2SO

The mechanism involves abstraction of proton by the base to give a resonance stabilized
carbanion, which then combines with a proton at the position that will give the more stable
olefin.
Step-1:
(-) (-)
.. ..
R CH2 CH CH2 + B R CH CH CH2 R CH CH CH2 +BH+

Step-2:
(-) (-)
R CH CH CH2 BH+
R CH CH CH2 R CH CH CH3 + B

Later it has been shown that base catalyzed double bond shifts are partially intra
molecular in which the base leads the proton from one carbanionic site to other.

H B H B
.. .....
.....

R CH2 CH CH2 + B R CH CH2 R CH . CH2

. ....
..

....
...
...

CH CH

R CH CH CH3 + B

Triple bonds can also migrate in the presence of bases through the allene intermediate.

R CH2 C CH R CH C CH2 R C C CH3

Dha. Ilangeswaran 6
 Aliphatic Electrophilic Substitution Reactions

Double bond rearrangements can also take place on treatment with acids. Both proton
and Lewis acids can be used. The mechanism is the reverse of base catalyzed one. First step
involves the gain of proton to give a carbocation; the second step loses another proton to give
the final product.
Step-1:
(+)
CH3 CH2 CH CH2 + H +
CH3 CH2 CH CH3

Step-2:
(+)
CH3 CH2 CH CH3 CH3 CH CH CH3+ H+

Double bond migrations have also been accomplished photo-chemically by means of

metallic ions or metal carbonyl catalysts. Here two kinds of mechanisms are possible. One of
these mechanisms requires external hydrogen is called the metal hydride addition –
elimination mechanism.
M
MH MH
R CH2 CH CH2 R CH2 CH CH3 R CH CH CH3

The other mechanism does not require external hydrogen is called the - allyl
complex mechanism.

M M
M H
R CH2 CH CH2 R CH2 CH CH2 R CH...
... ... CH2
...
CH

M
-M
R CH CH CH3 R CH CH CH3

The metal hydride addition – elimination mechanism involves 1, 2 shifts and - allyl
complex mechanism involves 1, 3 shifts. For example, the isomerization of 1-butene by
rhodium (I) involves 1, 2 shifts.
+
Rh
CH2
MH -MH CH3
H3C H3C CH3
H3C
but-1-ene
(2E)-but-2-ene

Dha. Ilangeswaran 7
 Aliphatic Electrophilic Substitution Reactions

The isomerisation of 3-ethyl-1-pentene involves 1,3 shifts.

CH2CH3 CH2CH3
Fe3(CO)12
CH3 CH2 CH CH CH2 CH3 CH2 CH CH CH2
3-ethylpent-1-ene
M

CH2CH3 M

CH3 CH2 C .....H ... CH2

CH3 CH2 C CH CH2 . ...
H3CH2C CH
M

CH2CH3

CH3 CH2 C CH CH3

3-ethylpent-2-ene
The metal catalysts are used for the preparation of enols by isomerization of allylic
alcohols. Whatever may be the method of double bond shifting, the thermo dynamically most

OH
stable olefin is
CH3 formed in large
Rh complex H3C amounts. Usually
the migration is
H2C CH3
OH taking place toward
but-3-en-2-ol cis & trans but-2-en-2-ol
the end of chain.
Decarboxylation of Aliphatic Acids
Many carboxylic acids can be successfully decarboxylated and aliphatic acids having
certain functional groups or double bonds or triple bonds in the or positions readily
undergo successful decarboxylation.

RCOOH RH + CO2

HOOC CH2 COOH HOOC CH3 + CO2

malonic acid

NC CH2 COOH NC CH3+ CO2

cyano acetic acid

Dha. Ilangeswaran 8
 Aliphatic Electrophilic Substitution Reactions

Glycidic acids give aldehydes on decarboxylation with the following mechanism.

COO(-) H+ (+)
R2C CH R2C CH COO(-) R2C CH COO(-)
O O (+) OH

H - CO2

tautomerization R2C CH
R2C H C H
O OH

Here the direct product is an enol that tautomerizes to give the aldehyde. This is usually the
last step in the Darzene’s reaction. When the carboxylate ion is decarboxylated, the
mechanism can be either SE1 or SE2. In the case of SE1 mechanism, the reaction is aided by
the presence of electron withdrawing groups, which can stabilize the carbanion.
Some acids can be decarboxylated directly by the mechanism involving a cyclic six –
centered intermediate. For example, - keto acids, malonic acids, - cyano acids, - nitro
acids and , - unsaturated acids follow this kind of mechanism.

CH2 CH2
1
R C C O R
1
C C O
+
O
O

O O
carbon dioxide
H H
- keto acid enol

Evidences for this mechanism is that the following bicyclic - keto acid resists
decarboxylation. This is because the formation of enol would violate the Bredt’s rule.

COOH

CH3
CH3

- keto esters can also be readily decarboxylated directly without the formation of
corresponding acids by hydrolysis. This direct decarboxylation is carried out under acidic,
neutral or slightly basic conditions to yield ketone.

Dha. Ilangeswaran 9
 Aliphatic Electrophilic Substitution Reactions

R R

R C C COOR' HOH R C C H + CO2 + R'OH

O R R
O

In some cases decarboxylation can give organometallic compounds.

RCOOM RM + CO2

Keto – enol Tautomerization

For most ketones and aldehydes, only the keto form is detectable, though the
following equilibrium is present.

acid or
1 1
R CH2 C R R CH C R
base
keto form O enol form OH

But aldehydes and ketones often react through their enol forms. The forward or backward
reaction cannot take place without a trace of acid or base. This behavior rules out the direct
shift of hydrogen from carbon to oxygen or vice versa. The mechanisms are given below.
Acid catalyzed

acid (fast) (+) - H+ (slow) 1

1 1
R CH2 C R R CH2 C R R CH C R
(slow) H+ (fast)
keto form O OH enol form OH

Base catalyzed
B, slow (-)
1 1 1
R CH2 C R R CH C R R CH C R
fast
keto form O O O
(-)
enolate ion
B, slow fast
1
R CH C R

O H enol form

For each catalyst the mechanism for one direction is the exact reverse of the other by the
principle of microscopic reversibility. If the reaction is reversible, the position of nucleus and
electrons must be the same in the reverse process too. This means that the forward and

Dha. Ilangeswaran 10
 Aliphatic Electrophilic Substitution Reactions

reverse reactions must proceed by the same mechanism and this is called the principle of
microscopic reversibility.
From the above mechanism it is clear that the C – H bond is broken in the rate –
determining step. Hence the substrate of type RCD2COR’ shows deuterium isotope effect,
kH/kD = 5 in both acid and base catalyzed processes. The enolate ion can be isolated if a full
mole of base per mole of ketone is used.
Halogenation of Aldehydes and Ketones
Aldehydes and ketones can be halogenated in position with Br2, Cl2, or I2.
Normally, the reaction cannot be performed with fluorine, but active compounds such as -
keto esters and - diketones can be fluorinated with the following reagents.
XeF2 in presence of a resin, N – fluoro –N – alkylsulfonamide, acetylhypofluorite, etc., the
chlorinating agents are sulfuryl chloride, hexachlolro – 2, 4 – cyclohexadiene and CuCl2. The
brominating agents are N – bromosuccinamide and pyrrolidine hydrotribromide is a reagent
that can - brominates a ketone without affecting a double bond.
For unsymmetrical ketones during halogenation the halogen prefers a carbon
containing more substituents or less hydrogen atoms. The halogenation reaction will be
taking place only in presence of a trace of acid or base, since the enol or enolate ion will
actually undergoes halogenation and not the aldehydes or ketones.
The acid catalyzed mechanism is

Step 1:
1
H+
1
R2 CH C R R2 C C R
slow
O OH
Step 2:
1 (+)
R2 C C R + Br Br R2 C C R
1
+ Br -
OH OH
Br
Step 3:
(+)
1 1
R2 C C R R2 C C R
- H+

Br OH Br O

The step 1 actually consists of two steps as seen in the acid catalyzed keto – enol
tautomerization. The second step is very similar to the first step in electrophilic addition to
double bonds. The evidences for this mechanism are

Dha. Ilangeswaran 11
 Aliphatic Electrophilic Substitution Reactions

1. The rate is first order with respect to substrate

2. Bromine does not appear in the rate expression
3. The reaction rate4 is same for bromination, chlorination, and iodination under the
same reaction conditions
4. The reaction shows isotope effect.
The base catalyzed mechanism is as follows

Step 1:
1
OH-
1
R2 CH C R R2 C C R

O O(-)
Step 2:
1 - Br - 1
R2 C C R + Br Br R2 C C R

O(-) Br O

Here the reaction may go readily through the enolate ion without the formation of the enol. It
is very difficult to distinguish the acid and base catalyzed halogenations. However, in the
base catalyzed reaction, if the substrate has two or more hydrogen atoms on the same side
of the C=O group, then it is not possible to stop the reaction after just one halogen atom has
entered. Because, the electron withdrawing field effect of the first halogen increases the
acidity of remaining hydrogen atoms, i.e., a CHX group is more acidic than a CH2 group.
Hence the initially formed halo ketone is converted to enolate ion and then halogenated more
rapidly than the original substrate.
Hell – Volhard – Zelinskii Reaction
The hydrogen atoms of carboxylic acids can be replaced by bromine or chlorine
with a phosphorous halide as catalyst. This reaction is known as Hell – Volhard – Zelinskii
reaction. This is not applicable to iodine or fluorine.

PBr3
RCH
2
COOH + Br Br RCH COOH

Br

The reaction actually takes place on the acyl halide formed from the acid and the catalyst.
Friedel – Crafts Acylation at Olefinic Carbons
Olefins can be acylated with an acyl halide and a Lewis – acid catalyst.

Dha. Ilangeswaran 12
 Aliphatic Electrophilic Substitution Reactions

H COR
AlCl3
C C + RCOCl C C

The products can arise by two paths. The initial attack is by the acyl cation RCO+ on the
olefin to give a carbocation.
COR
H
(+)
C C + RCO+ C C H

The carbocation formed may either lose a proton or combine with chloride ion.
Cl COR

C C H

COR Cl -

(+)
C C H - HCl
- H+
COR
C C

If it loses a proton, the product is an unsaturated ketone and the mechanism is similar to the
tetrahedral mechanism. If it combines with a chloride ion the product is a halo ketone,
which can be isolated so that the result is addition to the double bond.
On the other hand, the halo ketone may lose HCl to give the unsaturated ketone
under the reaction conditions. Here addition – elimination mechanism is followed. In the case
of unsymmetrical olefins, the attacking ion prefers the position at which there are more
hydrogens following Markonikov’s rule.

Y Y
(+) (+)
R C C H + Y+ R C C H R C C H
OR
H H H H H H
o o
2 cation, more stable 1 cation, less stable

Dha. Ilangeswaran 13
 Aliphatic Electrophilic Substitution Reactions

Anhydrides and carboxylic acids are sometimes used instead of acyl halides. Alkanes can be
acylated with acyl halides and a Friedel Craft’s catalyst if there is a trace of compound such
as an olefin is present, which can give rise to carbocation.
The Stork Enamine Reaction
When enamines are treated with acyl halides, an alkylation occurs. This is analogous
to the first step of F.C. acylation at an aliphatic carbon and the hydrolysis of the resultant
imine salt gives a ketone.
1 1 3
R R R
.. 2 .. 2
R2N C C R R2N C C R
(+)
3
H H R
hydrolysis 1 2
3 R R
+ R X C C
1
R 1 3 O H
(-) R R
(+) .. 2 ketone
R2N C C R (+)
2
R2N C C R
H
H

The net result is the alkylation of ketone at the position since the enamine is normally
formed from a ketone. This method is known as Stork enamine reaction.This method is an
alternative to the alkylation of ketone by the aliphatic nucleophilic substitution method. The
Stork method has an advantage that the reaction can be brought to an end with the
introduction of just one alkyl group. Alkylation usually takes place on the less substituted
side of the original ketone.
The most commonly used amines are the cyclic amines such as piperidine,
morpholine and pyrrolidine. This method is quite useful for active alkyl halides such as allyl,
benzyl and propargyl halides and also for - halo ethers and esters. This is not applicable for
ordinary primary, secondary and tertiary halides.
The reaction may also be applied to activated aryl halides (2,4 – dinitrichlorobenzene)
and to activated olefins such as acrylonitrile.

.. (+)
N + CH2 CH CN N

(-)
..
CH2 CH CN

CH2 CH2 CN

Dha. Ilangeswaran 14
 Aliphatic Electrophilic Substitution Reactions

Acylation can be accomplished with acyl halides or anhydrides.

1 1 2 2
R R R R
.. 2 3 (+) 3 hydrolysis 1 3
R2N C C R + R C X R2N C C C R R C C C R

H O H O O H O

A COOEt group can be introduced by treatment of enamine with ethylchloroformate,

ClCOOEt, a CN group by CNCl and a CHO group by using mixed anhydride of HCOOH &
CH3COOH or with DMF and phosgene. The enamine salts are prepared by treating an imine
with EtMgBrn in THF. The imines are prepared as follows

C + RNH2 C

O N-R

1 1 1 3
R H R R R
2 EtMgBr R3 - X 2
2
R-N C C R R-N C C R R-N C C R
THF (+)

H MgBr H MgBr H
lysis
1 3 hydro
R R
2
C C R

O H

Keteimines react with alkyllithium reagents to give lithioenamines, which may be hydrolyzed
to give alkylated ketones.
3 2
R C CH R
1 R4
(+)
H + O R
Li 3 2
3
R C C R
2 R Li 2
R-N C C R R-N C C R 1
(-) R4-X R4 H+ O R
1 3 1
R R R 2
R-N C C R
3 1
R R

The Chugaev (Tschugaev) Reaction

Methyl xanthates are prepared by treatment of alcohols with NaOH and CS2 to give
RO-CS-SNa, followed by treatment of this with methyl iodide.

Dha. Ilangeswaran 15
 Aliphatic Electrophilic Substitution Reactions

CH3I
C C C C
C C + CS2 + NaOH - H2O - NaI H
H H O C SNa O C SMe
OH
S S
methyl xanthate

100-250 °C

MeSH + COS + C C

Pyrolysis of xanthates to give the olefin, COS, and the thiol is called the Chugaev reaction.
Thus this reaction is like the pyrolysis of esters, and an indirect method of accompanying the
formation of olefins.

300 - 550 °C
C C C C + RCOOH
H O C R
O

The temperatures required with xanthates are lower than with ordinary esters and
hence the possible isomerization of olefins at higher temperature is minimized in case of
xanthates. The mechanism is infact an Ei, similar to that of pyrolysis of esters. The study of
34
S and 13C isotope effects, suggest the following mechanism.

C C C C
H O +
S C
H O
SR
S C RSH + COS
SR

Dha. Ilangeswaran 16