Aliphatic Nucleophilic Substitution Reactions

Dha. Ilangeswaran 1

Aliphatic Nucleophilic Substitution ReactionsAliphatic Nucleophilic Substitution ReactionsAliphatic Nucleophilic Substitution ReactionsAliphatic Nucleophilic Substitution Reactions

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.

C X + Y-C XY CY + X-

Substrate

Nucleophile

Rear side attack

Transition stateProduct with inverted configuration

Leaving group

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

Dha. Ilangeswaran 2


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

reactions readily.

Br

C2H5O-

[2.2.2]

No Reaction

Br

O

No ReactionNaI

Acetone

Another evidence for this reaction is that between optically active 2-octyl

iodide and radioactive iodide ion as shown below.

C

H13C6

H

CH3

I + I* C

H13C6

H

CH3

I* + I-

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 SN

2 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

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

CH2

Ts

O

CH3

OH-SO2

CH-

Ts

O

CH3

SO2

CH

Ts

O-

CH3

Methyl-α-tosyl-o-toluenesulfonate

o-(1-tosylethyl)benzenesulfonate

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.

Similarly

COOH

CHOH

CH2COOH

COOH

CHCl

CH2COOH

COOH

CHCl

CH2COOH

PCl5SOCl

2

(+)-malic acid(+)-chlorosuccinicacid

COOH

CHCl

CH2COOH

COOH

CHOH

CH2COOH

COOH

CHOH

CH2COOH

KOHAg2O

H2O

(+)-chlorosuccinicacid

(+)-malic acid(-)-malic acid

(-)-chlorosuccinicacid

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

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.

CH3 CH

CH2Ph

OH

TsCl

A CH3 CH

CH2Ph

OTs

EtOH,

K2CO3

B CH3 CH

CH2Ph

OEt

C K

CH3 CH

CH2Ph

OK

EtBr

DCH3 CH

CH2Ph

OEt

(+)-1-phenyl-2-propanol

α = + 33.0α = +31.0

α = - 19.9

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:

R - X R+X-

Y R - Y

Slow

+

Step 2:

R+ +Fast

The 1

st step involves the slow ionization is the rate determining step and the 2

nd 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

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.

R - X

H OH

H OH

R+

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 1

st 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)

In case of reversibility of the 1st 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.

R - X R+X-

+k

1

k -1

Y R - YR+ +k

2

Rate =k1 k2 [RX] [Y]

k-1 [X] + k2 [Y] -------------------------------------------- (2)

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 1

st 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

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 SN

1 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 SN

1 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.

CH3CH3

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+

C-SbF6

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

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.

R - Br R+ Br- R+ Br- R+ Br-δ+ δ−

Gegen ions Solvent separated ion pair

Independently solvated ions

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.

Dha. Ilangeswaran 8


Cl

CH3CH

+

CH3

CH+

CH3

H13C6 CH3

Cl

H13C6

CH+CH3

(1-chloroethyl)benzene

2-chlorooctane

oct-2-ylium

phenylethylium

98% racemization

34% racemization

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 SN

1 reactions. Hence a different mechanism called SN

i

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.

C

CH3

H

H5C6

O

H

+ S

Cl

Cl

O-HCl

C

CH3

H

H5C6

O

S

Cl

O C

CH3

H

H5C6

Cl

-SO2

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

OH

COCl2

-HCl

octan-2-ol

H13C6 CH3

OCOCl

octan-2-yl carbonochloridate

-CO2

H13C6 CH3

Cl

2-chlorooctane

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.

C C

Z:

L

C C

Z+

+

C C

Z+

+

L-

Nu-

C C

Z:

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.

C

O

O-

C

HCH3

Br

- Br-

C C

HCH3

O

O

OH-

C

O

O-

C

HCH3

OH

(2R)-2-bromopropanoate

(3S)-3-methyloxiran-2-one

(2R)-2-hydroxypropanoate

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.

C

H

CH3

O-OC

Br

OH-

C

H

CH3

COO-

OH + - Br-

Another example of NGP is base catalyzed hydrolysis of mustard gas, which

obey 1st 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.

CH2 CH2 :S:Cl CH2

CH2 Cl

CH2 CH2 :S+

Cl

CH2

CH2

HOH

CH2 CH2 :S:Cl CH2

CH2 OH

slow

Mustard gas

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.



I

OBs

I+

I

OAc

- OBs

I

OBs

trans - 2 - iodocyclohexyl brosylate

AcOH

cis - 2 - iodocyclohexyl brosylate

No acetolysis

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.

CH2 CH2

Cl

OH

αβOH-

- H+CH2 CH2

Cl

O-

αβCH2 CH2

O

αβ- Cl-

2-chloroethanol

oxirane

OH

Cl

OH-

- H+

O-

Cl

- Cl-

O

OH

Cl OH-

- H+

O-

Cl

trans -2-chlorocyclohexanol

7-oxabicyclo[4.1.0]heptane

cis-2-chlorocyclohexanol

No epoxide

formed

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



absence of a double bond. Hence its rate of acetolysis is normal and takes place with

inverted configuration.

H OTs

SN1

C+H H

OAc-

H OAc

I IINon - Classical Carbocation

(+)

H OTs

III

No

Rean.

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.

Cl (+)

AcOH

AcO

Cl

AcOH

SN2

AcO

Cholesteryl chloride

Cholestanyl chloride

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Aliphatic Nucleophilic Substitution Reactions