Nucleophilic Substitution Reaction

Chapter







Mechanism of bimolecular (SN2) nucleophilic substitution [Mechanism & Kinetics]





An SN2 reaction proceeds with complete stereo chemical inversion.
SN2 reaction decreases with stearic hinderance and increases by presence of nonprotic solvent for example DMF and DMSO. SN2
reaction decreases in the presence of protic solvent like CH3OH, C2H5OH, HF etc.



As the size of alkyl group increases than chemical reactivity towards SN2 decreases.













As the size of alkyl group increases sterichindrance comes into play so reactivit y decreases.
Features of SN2 Reaction :
(i) Features of SN2 Reaction :
1. Occurs mainly in 1o alkyl halide due to small size and little stericfactor.
2. Order of reaction is 2 but total step in the mechanism is one.
3. Speed of the reaction increases by nonprotic solvent example DMF and DMSO.
4. Back attack of the nucleophile is there so that stereo chemical inversion occurs.
5. Elemental effect so that RI is maximum reactive.
6. no carbocation, so no molecular rearrangement. Only transition state is formed.
(ii) Stereochemistry of SN2 reaction
Two stereochemical possibilities are present here. In the pathway the nucleophile simply assumes the position occupied by the
leaving group. It attacks the reactant at the same face (front side) from which the leaving group departs. This is called fr ont-attack
displacement, or substitution with retention of configuration.
Other option is attack of nucleophile from back side of the molecule where no heterolytic fission occurs, actually transtion state is
formed. From these two opposite stereochemical possibilities, the correct one was determined by carrying out nucleophilic
substitution reactions with optically active alkyl halides. If we determine by experiment that hydrolysis of


2-chloro octane in the presence of hydroxide ion gave 2-octanol having a configuration opposite to that of the starting alkyl halide.
(back attack)



Nucleophile substitution in this above case occurred with inversion of configuration by back attack of nucleophile consistent with
the following transition state representation :



Substitution reaction that proceed the SN2 mechanism are stereospecific in nature and proceed with inversion of configuration at
the carbon that bears the leaving group. There is a stereoelectronic requirement for the nucleophile to approach carbon from the
side opposite the bond to the leaving group. Organic chemists often speak of this as a Walden inversion. For such reaction, rate of
chemical reaction depends upon concentration of alkyl halide and nucleophile both so order of reaction is two with single step























process.
Mechanism unimolecular (SN1) nucleophilic substitution
Mechanism unimolecular (SN1) nucleophilic substitution










Now nucleophilic attack can takes place at any time after the heterolysis of slow step and thus can involve any species from the
initially formed ion pair to the free carbocation, attack on the free carbocation is random and yields the racemic modificati on.
Actually the anion surrounds the planar carbocation and thus shields this side from front attack ; as a result, back side att ack is
preferred to the extent. Front side attack occurs before the ion pair has completely separated, inversion of configurati on competes
with racemization.




(i) Features of SN1 Reaction
1. Rate of reaction = K [RX], order of reaction is one which depends only upon alkylhalide concentration but it is a two step
process.

2. Carbocation formation takes place so that molecular rearrangement may occur.

3. Racemization takes place by both back side and front side attack.

4. Chemical reactivity 3o > 2o > 1o becasue ter. alkyl halide forms maximum stable carbocation.

5. Elemental effect, so that reactivity of differant halide is RI > RBr > RCl >> RF











Mechanism and stereochemistry

(ii) Mechanism and stereochemistry
Tertiary alkyl halides are practically inert to substitution by the SN2 mechanism because of hindrance, they forms highly stable
carbocation so undergo substition by heterolytic fission.
The hydrolysis of tert-butyl chloride, a first-order rate law known as SN1 reaction.


They found that the rate of hydrolysis depends only on the concentration of tert -butyl chloride. Adding the stronger nucleophile
hydroxide ion, moreover, causes no change on rate of reaction.


The overall reaction :




Step A: The alkyl halide break down into a carbocation and a halide ion.





Step B: The carbocation formed in step 1, rapidly reacts with a water molecule (lewis base). Water is a nucleophile. This step
completes the nucleophilic substitution stage of the mechanism and yields an oxonium ion (acid base complex).



Step C : This step is a fast acid-base reaction with nucleophilic substitution. Water acts as a base to remove a proton from the
oxonium ion to give the final product of the reaction.



The proposed mechanism is called SN1, standing for substitution nucleophilic unimolecular. The first step, a unimolecular
dissociation of the alkyl halide to form a carbocation as the key intermediate, is rate -determining step.



Effect of solvent on the rate of nucleophilic substitution
To understand effect of the solvent at the rate of nucleophilic substitution reaction, following points must be considered.
1. Properties of the solvent which are responsible to effect the rate.
2. How does the activation energy of the rate-determining step respond to this property of the solvent?

(i) Effects of solvent on the SN1 reaction













Solvent effect on SN1 reaction is mainly based on its polarity and polarity of solvent is measured by its dielectric constant. Ability
of solvent to attract solute particles and minimize the force of attraction between them. The standard dielectric is a vacuum, which
has a value of e of exactly 1. Higher the value of dielectric constant, higher the ability to support separation of charged ions so
solvents with high DEC are known as polar solvents. As the value of DEC increases the rate of solvolysis also increases.
According to the S
N
1 mechanism, a neutral alkyl halide molecule ionizes to a positively charged carbocation and a negatively
charged halide ion in the rate-determining step. As the alkyl halide approaches the transition state for this step, a partial positive
charge develops on carbon and a partial negative charge on the halogen. Polar and nonpolar solvents are similar in their interaction
with the starting alkyl halide, but differ markedly in how they affect the energy of the transition state. A solvent with a low
dielectric constant has little effect on the energy of the transition state, while one with a high dielectric constant stabilizes the
charge - separated transition state, lowers the activation energy, and increase the rate of reaction.


Effects of solvent on the SN2 Mechanism
(ii) Effects of solvent on the SN2 Mechanism
Solvent on SN2 reactions are required in polar form because ionic substances, such as sodium, potassium, Rubidium salts are not
fully soluble in nonpolar solvents, so they cannot give enough amount of nucleophile to allow the reaction to occur at rapid speed.
But remember, effect of solvent polarity on the rate of bimolecular substitution is small. Primary factor that effect the rate of SN2
reactions is whether or not the polar solvent is protic or aprotic.
In polar protic solvents like HOH, ROH and RCOOH they all have OH groups that allow them to form hydrogen bonding with
anionic nucleophiles. Solvation forces such as these stabilize the anion and suppress its nucleophilicity. Aprotic solvent does not
contain OH group so they do not involve in solvation of anion, leaving them nekdly to express their better nucleophilic character.
The second order kinetics constants of 1-chloropropane by azide ion in polar protic solvent is very low for example in methanol
and water.


The large rate enhancements observed for SN2 in polar aprotic solvents. An example can be seen in the preparation of alkyl



cyanides (nitriles) by the reaction of potassium cyanide with alkyl halides :



When the reaction was carried our in aqueous methanol as the solvent, pentyl bromide was converted to pentyl cyanide in 70
percent yield by heating with sodium cyanide. While this is a perfectly acceptable synthetic reaction, a period of over 20 hours was
required. Changing the solvent to dimethyl sulfoxide brought about an increase in the reaction rate sufficient to allow the less
reactive substrate pentyl chloride to be used instead, and the reaction was complete (90 percent yield) in only few minutes.












Elimination Reactions
Elimination reactions, in which two groups are removed from a molecule, not being replaced
by another group, are the reverse of addition reactions. Usually they involve the loss of two
substituents from vicinal atoms resulting in the formation of a double or triple bond. Most
commonly a proton is lost from one carbon whereas a nucleophile is lost from the adjacent
carbon; these two carbon atoms are usually referred to as - and -carbons, respectively.





This type of elimination reaction is known as -elimination or a 1,2-elimination reaction. The
most familiar examples of b-elimination reactions include dehydrohalogenation of alkyl
halides, dehydration of alcohols, pyrolysis of esters and the Hofmann degradation of
quaternary ammonium hydroxides.
There are a few reactions in which both the groups are lost from the same carbon atom. These
are called -elimination reactions and the most common example of this type is the generation
of dichlorocarbene from chloroform.
In analogy with substitution reaction,b-elimination reactions are divided into E1 (Elimination,
unimolecular) and E2 (Elimination, bimolecular) reactions.
(i) E2 reaction : The Bimolecular mechanism
Most of the elimination reactions are successful only when carried out in the presence of a
strong base. The formation of ethylene on the treatment of ethyl bromide with sodium
ethoxide is an example of this type. The rate of alkene formation is proportional to the
concentrations of ethyl bromide as well as that of sodium ethoxide.


Two types of mechanism are praposed which are in agreement with the kinetic data. In the
first mechanism the base abstracts a proton from the -carbon and simultaneously the leaving
group departs from the -carbon along with the pair of bonding electrons.



In the second mechanism the base rapidly removes proton from the -carbon resulting in the
formation of carbanion which loses the leaving group in a rate-determining step. Since the
conditions of base-catalyzed elimination reactions do not allow the formation of an
unstabilized carbanion, it is reasonable to presume if some part is formed it must be either
rapidly reconverted to the substrate or converted to the product alkene.



In above mechanism the overall rate is limited to that of the slower second stage which
depends only on the concentration of the conjugate base of the reactant. This mechanism is
called as E1cB which means elimination, unimolecular, conjugate base. The distinction
between E2 and E1cB mechanism can be made very easily by means of labelling
experiments. Consider the reaction of 2-phenylethyl bromide (I) and ethoxide to yield styrene
(II) which follows second order kinetics. The reaction may follow either mechanism.



The first step of the E1cB mechanism is reversible and hence when the reaction is carried out
in C
2
H
5
OD instead of C
2
H
5
OH, the intermediate carbanion should pick up deuterium.















Nucleophilic Substitution Reaction
If the E1cB mechanism is correct we should be able to recover labelled 2-phenylethyl bromide after a partial transformation to
styrene. On the other hand, there should be no incorporation of deuterium if the E2 mechanism is operati ve. Actual experiments
have shown that there is no deuterium incorporation and hence the E1cB mechanism does not operate in this case. However, this
mechanism does operate under very special circumstances. 1,1,1 Trifluoro-2,2dichloroethane (III), due to strong CF bond which
take time to breakdown so partical negative charge develop on carbon atom, undergoes base-catalyzed exchange of -hydrogen
atom with the solvent deuterium faster than dehydrofluorination.



A strong carbon-fluorine bond (poor leaving ability of fluoride ion also) coupled with the electron withdrawing effect of the
halogens explain the formation of carbanion before elimination.
(ii) E1 Reaction : the unimolecular mechanism
The main feature of this mechanism is that under the influence of solvation forces, the electron-attracting group (leaving group)
breaks away along with the bonding electrons. The resultant carbonium ion subsequently loses a proton to the solvent or to some
other proton acceptor.



Acid-catalyzed dehydration of alcohols to alkenes provides another example of E1 reactions. The various steps can be written in
the following way. Synthesis of carbocation occurs so molecular rearrangement is possible in differant reactions.


(iii) Orientation in elimination reactions
The elimination reactions of unsymmetrical substrates usually yield mixtures of all possible products. There are two empirical rules
governing the orientation in these reactions.














R
2
C == CR
2
> RCH == CR
2
> RCH == CHR > RCH == CH
2
> CH
2
== CH
2

The greater stability of the more substituted alkene is sometimes explained on the basis of
hyperconjugation, more the number of hyperconjugative structure, more is the stability of
alkene.

a. The Saytzeff Rule
It states that neutral substrates (alkyl halides or sulphonates) capable of forming a double bond in either direction of the chain
preferably yield that alkene in which there is greater number of alkyl groups attached to the double bond. This rule applies to E1
reactions and to most of E2 reactions. The following examples are typical:



The preferential formation of more substituted alkenes in the above reactions can be correlated with the relative stability of various
alkenes. Calculations from heats of combustion and hydrogenation establish that the stability of a double bond is increased by alkyl
substitution on the double-bonded carbon atoms. Thus the stabilities of alkenes follow the order:







b. The Hoffmann Rule
It states that charged substrates (quaternary ammonium and sulphonium salts) yield
predominantly the least substituted alkene.
Let us first examine the mechanism of the elimination reaction of a quaternary ammonium
hydroxide. On heating, these compounds yield an alkene and a tertiary base.























Nucleophilic Substitution Reaction
It has been observed that quaternary ammonium hydroxides as well as sulphonium salts preferably yield less substituted alkenes.









For the same reason an isobutyl group shows still less tendency to lose a proton if either an n-propyl or an ethyl group is available
in the molecule.
Stearic factors also play a big role in Hoffmann eliminations. It is apparent that the groups eliminated in these reactions are bulkier
than those lost in the Saytzeff type of eliminations. So that, it has been found that E2 reactions of alkyl halides can be forced to
follow Hofmann type of elimination by sufficiently increasing the bulk of the attacking base or by increasing the degree of
branching in the substrate. Treatment of following bromoderivative with base, for instance, gives 1-alkene in preference to 2-
alkenes mainly due to stearic strain resulting from the interaction of methyl and tert-butyl groups in the latter alkene.



A similar stearic effect seems to operate when the size of the attacking base is increased, for example


This reaction is used for conversion of nonterminal into terminal derivatives for example