Dha.

Ilangeswaran 1

Aliphatic Nucleophilic Substitution Reactions

1. SN2 Reactions
Here the term SN2 stands for bimolecular nucleophilic substitution. These
reactions can be completed in a single step with the formation of no intermediates.
Since both the substrate and reagent are involved in the same step it must follow the
second order kinetics. The nucleophile attacks the substrate carbon 180o away from
the leaving group, which is regarded as rear side or backside attack resulting in the
inversion of configuration. The mechanism of these reactions can be denoted as
follows.
Rear side attack

C X + Y- Y C X Y C + X-
Nucleophile Leaving
group
Substrate Product with
Transition state
inverted
configuration
During the formation of transition state the substrate carbon loses the sp3
hybridized state and attains the sp2 hybridized state with one unhybridized p orbital in
a perpendicular direction to the trigonal plane containing the carbon with the non
reacting groups. One lobe of this p orbital overlaps to the leaving group and its
opposite lobe may overlap to the nucleophile. Therefore the nucleophile can undergo
rear side attack in these reactions. In the transition state the carbon and non reacting
groups are almost coplanar. If the leaving group and nucleophile are identical then the
geometry of thr transition state should be perfectly planar. The energy required to
break the C – X bond had been supplied due to the creation of C – Y bond.
Kinetic Evidences
Here both the substrate and nucleophile take part in the rate determining step,
the reaction should follow 2nd order kinetics. Hence it would satisfy the rate
expression,
Rate = k [RX] [Y]
This law was found to apply for many reactions. But for reactions involving
excess of nucleophile (solvent), though the mechanism is bimolecular, experimentally
determined rate will be 1st order as
Rate = k [RX]
This kinetics is refered to as pseudo first oredr.
Other Evidences
This mechanism cannot be operated for the substrate containing the leaving
group at bridgehead C atom of polycyclic systems since the back side of this carbon
cannot be free to allow the nucleophile from that side during the formation of
transition state. For example, [2.2.2] system with ethoxide ion and [3.3.1] system with

Aliphatic Nucleophilic Substitution Reactions

 Dha. Ilangeswaran 2

NaI in acetone yield no products. But their open chain analogues underwent the
reactions readily.

C2H5O-
No Reaction

Br

[2.2.2]

NaI
No Reaction
Acetone
Br

Another evidence for this reaction is that between optically active 2-octyl
iodide and radioactive iodide ion as shown below.
H13 C6 H13 C6

H C I + I* H C I* + I-
H3 C H3 C
2-Octyl iodide
Here, the final product is actually a racemic mixture. If the reaction is started
with pure R isomer, initially S isomer of radio active 2-octyl iodide is formed due to
the exchange of I- ion by SN2 mechanism. Once a significant quantity of S isomer is
produced the same kind of iodide exchange with this isomer yields again the R
isomer. Due to the establishment of equilibrium on later stages of this reaction the
racemic mixture was obtained.
The rate of inversion and the rate of exchange of radioactive I*- are almost identical.
Rate of inversion = 2.88 X 10-5
Rate of exchange = 3.00 x 10-5

Aliphatic Nucleophilic Substitution Reactions

 Dha. Ilangeswaran 3

Evidences for the Linearity of Transition State

Eschenmoser and co-workers provided strong evidence that the transition state
in SN2 reactions should be linear. The base treatment of methyl-α-tosyl-o-toluene
sulfonate yielded o-(1-tosylethyl)benzene sulfonate.
SO2 SO2 SO2
OH- -
O O O
CH3 - CH3
CH2 CH CH CH3
Ts Ts Ts
Methyl-α-tosyl-o-toluene o-(1-tosylethyl)benzene
sulfonate sulfonate

In this reaction base is used to remove α – proton to give the anion. The
carbanion produced was believed to act as an internal nucleophile and attacks the
methyl carbon of sulfonate ester by intramolecular mechanism. If it is so linear
transition state can not be possible. But latter the cross over experiments of this
reaction showed that this is an intermolecular reaction confirms the linear transition
state. In intra molecular reactions linearity of transition state can be very difficult.
Stereochemical Factors
When a substitution takes place in a chiral carbon inversion of configuration
occurs and this is known as Walden inversion. This is observed a long time before
Hughes and Ingold formulated the SN2 mechanism. A few examples for Walden
inversion is given below.
COOH COOH COOH
SOCl2 PCl5
CHCl CHOH CHCl

CH2COOH CH2COOH CH2COOH

(+)-chlorosuccinic (+)-malic acid (-)-chlorosuccinic
acid acid
Similarly
COOH COOH COOH

Ag2O KOH
CHOH CHCl CHOH
H2 O
CH2COOH CH2COOH CH2COOH

(+)-chlorosuccinic (-)-malic acid

(+)-malic acid
acid
In the above reactions one must be an inversion while the other must be
retention of configuration. But the exact point of inversion cannot be predicted. Hence

Aliphatic Nucleophilic Substitution Reactions

 Dha. Ilangeswaran 4

Philips, Kenyon and co-workers carried out the reaction using (+)-1-phenyl-2-
propanol as a substrate to predict the exact position of inversion.
EtOH,
CH2 Ph CH2 Ph K2CO3 CH2 Ph
TsCl

H3C CH OH A H3 C CH OTs B H3 C CH OEt

(+)-1-phenyl-2-propanol
α = +31.0
α = + 33.0 α = - 19.9

K
C
CH 2Ph
CH 2Ph EtBr
H3 C CH OEt
H3 C CH OK D
α = +23.5
Here (+)-1-phenyl-2-propanol can be converted into its ethyl ether by two
routes. In path A & B we get (-) – ether while in paths C & D we get (+)- ether. In
these four steps A, B, C & D one must be an inversion. There is no possibilty for the
inversion in steps A, C or D, since in all these steps the C – O bond is not broken at al.
Therefore there is a high probability that these steps may proceed with retention of
configuration. But in step B the C – O bond is broken and the oxygen of the new C-O
bond could have come from the reagent, EtOH. Therefore the step B should follow the
inversion of configuration.
2. SN1 Reactions
The unimolecular nucleophilic substitution (SN1) reactions consist of two steps.
These are slow ionization to form a carbonium ion intermediate and fast attack of
nucleophile on the intermediate and denoted as follows.
Step 1:
Slow
R-X R+ + X-

Step 2:
Fast
R+ + Y R-Y
The 1st step involves the slow ionization is the rate determining step and the 2nd step
involves a rapid reaction between carbocation and nucleophile. The ionization of 1st
step is assisted by solvent molecules and this solvation effect supplies energy required
for breaking the bond between carbon and leaving group. For example, the ionization
of t-BuCl in the gas phase, i.e. in the solvent free condition is 150 K. Cal/mole. In

Aliphatic Nucleophilic Substitution Reactions

 Dha. Ilangeswaran 5

water the ionization energy for the same substrate is 20 K. Cal/mole. The difference
between these two values is known as solvation energy.
H OH

R-X R+
H OH
It is evident from the above illustration that the role of solvent is to assist the
departure of leaving group alone from the front side.
Kinetic Evidences
The SN1reactions should follow 1st order kinetics since the substrate molecule
alone takes part in the rate determining step. Even though the solvent molecules assist
the ionization of substrate, their concentration term not involved in the rate expression
since their presence is large excess in the reaction. Therefore for most SN1 reactions
the following 1st order rate law can be followed.
Rate = k [RX] --------------------------------- (1)
st
In case of reversibility of the 1 step the above rate law can be obeyed initially.
But on later stages, once a significant quantity of leaving group(X-) is formed and if
the carbonium ion intermediate(R+) is less selective (and also less stable) there should
be a possibilty for the reversibility as shown below.
k1
R-X R+ + X-
k -1

k2
R+ + Y R-Y

k1 k2 [RX] [Y]
Rate = -------------------------------------------- (2)
k-1 [X] + k2 [Y]
Hence a new rate law was developed as shown in equation (2) for later stages of the
reaction if there is a competition between the leaving group and nucleophile(Y) for the
carbonium ion intermediate. At the beginning of the reaction the value of [X] is being
very small the term k-1 [X] is negligible as compared to k2 [Y] in (2) and the rate law
is reduced to equation (1). In fact SN1 reactions strictly follow 1st order kinetics in
their initial stages and latter the complicated law may be obeyed.
For example t-butyl cation is more stable & more selective and can react only
with nucleophile so that the equation (1) is obeyed for entire reaction. But diaryl
methyl cation is less selective with shorter life time and can not withstand collisions
with leaving group so that the equation (2) followed on later stages. These facts are
confirmed by the addition of halide (X-) ion to the reaction mixture which decreases

Aliphatic Nucleophilic Substitution Reactions

 Dha. Ilangeswaran 6

the rate of reaction for diaryl methyl cation and not affecting the rate of reaction for t-
butyl cation by means of common ion effect. Addition of a common ion does not
affect the rate of an SN2 reaction whereas the most SN1 reactions show the common
ion effect.
If the nucleophile is not involved in the rate determining step of SN1 reactions,
then the rate should be the same for a given substrate under a given set of conditions
regardless of the identity of the nucleophile or its concentration. Bateman, Hughes and
Ingold proved this one by reacting benzhydril chloride substrate with the nucleophiles
such as fluoride, pyridine and triethylamine at several concentrations of each
nucleophile in SO2. In each case the initial rate of the reaction was found to be nearly
same.
Other Evidences
Like SN2 reactions SN1 reactions also failed or proceed very slowly at bridge
head C atoms since they can not assume planarity in order to give the carbocation. For
example 1-chloroapocamphane when boiled for 21 hours with 30% KOH in ethanol or
48 hours with aqueous ethanolic AgNO3 gave no product in both the cases. But the
respective open chain analogous compound reacts readily.
H3C CH3

Cl
1-Chloroapocamphane
If the rings are sufficiently larger SN1 reactions are possible due to the
possibility for the formation of near carbocation. For example the carbonium ion
formed on the bridgehead of 1-bicyclo[3.2.2]nonyl cation is very stable in the solution
of SbF5-SO2Cl at -50oC or below it.

+ -
C CSbF6

Single Electron Transfer (SET) Mechanism

Some cases of reactions which follow the SN1 mechanism involved free
radicals. In these cases the carbonium ion yielded may be a good electron acceptor
and the nucleophile a good electron donor. This kind of mechanism is referred to as

Aliphatic Nucleophilic Substitution Reactions

 Dha. Ilangeswaran 7

SET mechanism. For example, the reaction between triphenyl methyl cation and t-
butoxide ion proceeds in this way as mentioned follows.

     
  
   
    


Stereochemical Factors
Due to the formation of planar carbonium ions in the rate determining step of
SN1 reactions it is expected that nucleophile can attack this ion from either side with
equal facility, which leads to the formation of a racemic mixture of products with
optical inactivity. But the expected racemization is rarely observed with about 5 to
20% inversion of configuration. The relative proportion of the racemization and
inversion are found to depend on the following two factors.
i) The relative stability of carbonium ion
ii) The ability of solvent as a nucleophile
If the carbonium ion is more stable the racemization would be greater. If the solvent is
more nucleophilic the inversion would be more. This can be explained using the
following ion pair concept.
δ+ δ−
R - Br R+ Br
-
R+ Br- R+ Br-

Gegen ions Solvent separated Independently solvated ions

ion pair
Initially after ionization the two ions are tightly held by each other and this association
is called gegen ions. In this association there is no solvent molecule between these
ions. If the nucleophile present in the solvent attacks the carbonium ion in this case
only rear side attack is possible since the front side is blocked by its counter ion, Br-.
Hence inversion of configuration would result. If the carbonium ion is less stable and
the solvent is more nucleophilic in nature, then this kind of attack takes place in order
to give the product with inverted configuration.
If the carbonium ion is more stable and the solvent is less nucleophilic the
carbonium ion can withstand the collisions by the solvent molecule and wait till a
suitable nucleophile will be available and so it is separated from its counterion by the
solvent molecule as shown in the cases of either solvent separated ion pair or
independently solvated ion pairs. When the nucleophile attacks either of this
orientation of carbonium ion there is a possibility to attack from both side which
would result racemization.
Thus it is evident that the larger the life of carbonium ion, the greater the
proportion of racemization and shorter the life of this ion, the greater the proportion of
inversion. For example, the solvolysis of (+)-1-phenylchloroethane leads to 98%
racemization since it produces a carbonium ion stabilized by phenyl group. Whereas
(+)-2-octyl chloride has no comparable stable carbonium ion leads to only 34%
racemization.

Aliphatic Nucleophilic Substitution Reactions

 Dha. Ilangeswaran 8

CH3 CH3
CH3
+ +
CH HC 98%
Cl racemization
(1-chloroethyl)benzene
phenylethylium

H13C6 CH3
H13C6 CH3
+ 34%
CH
racemization
Cl oct-2-ylium
2-chlorooctane

Similarly the solvolysis of (+)-1-phenyl ethyl chloride in 80% acetone and 20% water
leads to 98% of racemization, but if more water is added due to more nucleophilic
nature the racemization decreases to 80%.
3. SNI Mechanism
The term SNI stands for internal nucleophilic substitution reactions. For
example alcohols react with thionyl chloride to produce chlorosulphites which further
decomposes to alky halides with retention of configuration as that of the starting
material. The stereochemistry of this reaction is inconsistent with the mechanisms
developed for either SN2 or SN1 reactions. Hence a different mechanism called SNi
has been proposed.
According to this mechanism an internal nucleophile, chloride ion comes from
the same molecule can attack on the front side of the substrate carbon through a cyclic
transition state leads to retention of configuration.

H 5C 6 H 5C 6 H 5C 6
H Cl O
-HCl -SO2
H C O + S O H C S O H C Cl
Cl Cl
H3C H3C H3C
Evidence: If this reaction is carried by the addition of pyridine to the reaction
mixture, the alkyl chloride if formed with inverted configuration. This is because as a
pyridine is a strong base it can substitute chlorine in the chlorosulphite, then the free
chloride ion acts as an external nucleophile attacks from the backside.
ROSOCl + C5H5N ROSON(+)C5H5 + Cl(-)
The SNi mechanism is occurring rarely and another example being the reaction of 2-
octanol with phosgene that proceeds with retention of configuration.
H13C6 CH3 H13C6 CH3 H13C6 CH3
COCl 2

-HCl -CO2
OH OCOCl Cl
octan-2-ol octan-2-yl carbonochloridate 2-chlorooctane

Aliphatic Nucleophilic Substitution Reactions

 Dha. Ilangeswaran 9

Neighbouring Group Participation (NGP)

It was observed that for many reactions of nucleophilic substitution on aliphatic
substrates the products obtained with complete retention of configuration. The rate of
reaction is also greater than the expected one. This is actually happening for the type
of reactions in which the substrate contains a second functional group (Z) with a pair
of electrons placed at a favourable distance from the first functional group.
These reactions consist of two consecutive SN2 reactions. In the first step the
neighboring group (2nd functionality) attacks as a nucleophile and pushes the leaving
group. In the 2nd step, the external nucleophile pushes out the neighboring group.

Z: +
Z
-
C C C C + L

+
Z Z:
-
C C + Nu C C

Nu

Since there are two consecutive inversions the net result is the retention of
configuration. As the 2nd nucleophile comes from the same molecule it helps for the
easy elimination of leaving group and thus such reactions occur thousands of time
faster than the comparable intermolecular reactions. This rate enhancement by the
neighboring group is called anchimeric assistance.
For example the neighboring group participation of the carboxylate anion in the
conversion of 2-bromopropanoate anion to lactate ion is the well known one.

-
O H O H
CH3 - Br- CH3
C C O C C
O Br (3S)-3-methyloxiran-2-one
(2R)-2-bromopropanoate -
HO
-
O H
CH3
C C

O OH
(2R)-2-hydroxypropanoate

Aliphatic Nucleophilic Substitution Reactions

 Dha. Ilangeswaran 10

Treatment of 2-bromopropanoic acid with dilute alkali results in a substitution

product with complete retention of configuration. This is because, before the leaving
group (Br-) has completely dissociated from the carbon atom, the electron pair on the
carboxylate anion forms a weak bond with that carbon. This bond is formed on the
side opposite to that of the leaving group thus protecting that side from attack by the
nucleophile (OH-). Then the nucleophile attacks α- lactone intermediate from the front
side, liberating the carboxylate anion and effecting substitution with retention of
configuration.
The kinetic studies reveal that the formation of α- lactone intermediate is the
rate determining step. As this lactone is associated with high ring strain, it rapidly
reacts with hydroxide ion in order to relieve such a strain. However in presence of a
strong alkali, the hydroxide ion competes with carboxylate anion and succeeds in this
competition and so 2-bromopropanoate undergoes hydrolysis involving a single SN2
reaction to give the product with inverted configuration.
H H
H3 C CH3
C Br HO C + - Br-
- -
HO - COO
O OC
Another example of NGP is base catalyzed hydrolysis of mustard gas, which
st
obey 1 order kinetics. The rate of this reaction is independent of the concentration of
alkali. This reaction proceeds thousands of time faster than the reactions involving
analogous alkyl halides.
Cl CH2 CH2 :S: CH2 slow
CH2
+
Cl CH2 CH2 :S
H C Cl CH2
2
HOH
Mustard gas

Cl CH2 CH2 :S: CH2

H 2C OH
The rate of this begins to decrease with time thereby suggesting that the chloride ion
regenerates the starting material. Therefore the rate determining step is the reversible
formation of a cyclic sulfonium ion, which being highly strained, undergoes rapid
hydrolysis.
Properly situated halogen atom also offer anchimeric assistance. For example,
the rate of acetolysis of trans – 2 – iodo cyclohexyl brosylate is many times faster than
the acetolysis of cis – isomer.

Aliphatic Nucleophilic Substitution Reactions

 Dha. Ilangeswaran 11

I I
- OBs + AcOH
I

OBs OAc
trans - 2 - iodocyclohexyl I
brosylate
No acetolysis
OBs
cis - 2 - iodocyclohexyl
brosylate

In many cases of NGP, a stable bond is formed between neighboring group and
carbon atom undergoing displacement reaction. This results in the isolation of cyclic
products. For example, epoxide formed from the β-chlorohydrin in presence of base
has been isolated. Reactions of this type may be regarded as internal SN2 reactions
requiring a back side attack by the internal nucleophile. This geometric requirement is
well illustrated by the observation that cis – 2- chlorocyclohexanol forms epoxide far
more slowly than its trans- analog.

Cl Cl
-
OH
β α β α - Cl- β α
H 2C CH2 H2C CH2 H2 C CH2
- H+
O
- oxirane
OH O
2-chloroethanol

-
OH O
OH- - Cl-
O
- H+
Cl Cl 7-oxabicyclo[4.1.0]heptane
trans -2-chlorocyclohexanol

-
OH O

Cl OH- No epoxide
Cl
- H+ formed
cis-2-chlorocyclohexanol

The properly situated electrons of a double bond may also act like neighboring
group having unshared electrons. For example the acetolysis of compound I is 1011
times faster than that of compound III. Moreover, it proceeds with retention of
configuration. No such anchimeric assistance is available to compound III due to the

Aliphatic Nucleophilic Substitution Reactions

 Dha. Ilangeswaran 12

absence of a double bond. Hence its rate of acetolysis is normal and takes place with
inverted configuration.
H OTs H + H H
C OAc

SN1 (+) OAc-

I II
Non - Classical Carbocation
H OTs

No
Rean.
III
Similarly participation of a double bond has been invoked to explain the
acetolysis of cholesteryl chloride to give cholesteryl acetate with retention of
configuration, while it’s dehydro derivative, cholestanyl chloride undergoes normal
SN2 reaction with inversion of configuration.

AcOH

Cl (+) AcO
Cholesteryl chloride

AcOH

SN2
Cl AcO
Cholestanyl chloride

Aliphatic Nucleophilic Substitution Reactions