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ALIPHATIC NUCLEOPHILIC SUBSTITUTION REACTIONS

NUCLEOPHILE:
The word nucleophile comes from nucleus (the positive part of the atom) plus
phile from Greek word philein meaning to love. Thus nucleophile is a reagent that “loves
or seeks” a positive centre in an organic molecule. In fact, the nucleophile can be a
neutral (H2O:) or a negatively charged (HO:−) species but it must have an unshared pair
of electrons.
In an alkyl halide the positive centre is the δ−
δ+
carbon atom to which the halogen is attached. This C X
carbon atom bears a partial positive charge because
the electronegative halogen pulls the electrons of This is the positive The electronegative halogen
the carbon-halogen bond in its direction. When centret hat the polarizes the C X bond
nucleophile seeks
such a polarized molecule is treated with a nucleophile, it attacks on the electron deficient
carbon atom by the donation of its unshared pair of electron and the halogen molecule is
departed. The hydroxide ion, for example, is a nucleophile and it can react with alkyl
halide to form an alcohol.
HO + R X R OH + X

NUCLEOPHILIC SUBSTITUTION REACTIONS:

There are many reactions of the general type shown here.
Nu + R X R Nu + X
Nucleophile Substrate Product Leaving group
In this type of reaction a nucleophile reacts with the substrate by replacing the
leaving group. A substitution reaction takes place and the leaving group departs. Because
the substitution reaction is initiated by a nucleophile, it is called a nucleophilic
substitution reaction.
In the substrate the R group may be aliphatic or aromatic, so based upon the
nature of this R group, these nucleophilic substitution reactions can be divided into two
categories.
1) Aliphatic Nucleophilic Substitution Reactions
2) Aromatic Nucleophilic Substitution Reactions
First one is discussed in detail here.

™ ALIPHATIC NUCLEOPHILIC SUBSTITUTION REACTIONS

Following are some examples:
H2O + H3C I CH3 OH2 + I

CH3O + C2H5 Br C2H5 OCH3 + Br

+
H2O + CH3- S(CH3)2 CH3 OH2 + (CH3)2S

+
HO + CH3- S(CH3)2 CH3 OH + (CH3)2S

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As a result of these reactions the alkyl group is attached to the nucleophile,
therefore, the nucleophile is said to be alkylated. Sometimes, the solvent itself functions
as a nucleophile; the reaction is then called solvolysis. Thus, a reaction in which water is
used as a solvent and it also acts as a nuc1eophile, is called hydrolysis while a reaction
involving methanol as a solvent and also as a nucleophile is known as methanolysis.
In nucleophilic substitution reactions the R-X bond of the substrate undergoes
heterolysis, and the unshared pair of the nucleophile is used to form a new bond to the R
group.
Nu + R X Nu R + X

Heterolysis
occurs here
The question arises when does the R-X bond break? Does it break at the same time that
the new bond between the nucleophile and R forms? Or does the C-X bond breaks first?
The answer can be explained by the conditioned dependent mechanisms.

MECHANISMS:
The mechanism of a reaction is the actual pathway through which the reaction
proceeds, i.e., which bonds are broken, which are formed, and in what order; how many
steps are involved and what is the relative rate of each step, etc.

For an aliphatic nucleophilic substitution reaction several pathways are possible

depending on the nature of the substrate, the nucleophile and the leaving group, and the
reaction conditions including the solvent used. These mechanisms are
i) SN1 v) SN1'
ii) SN2 vi) SN2'
iii) SNi vii) SNi'
iv) Ion-pair mechanism.

A concise study of all these is given here.

i) SN1 (UNIMOLECULAR NUCLEOPHILIC SUBSTITUTION) MECHANISM:-

The SN1 mechanism consists of two steps. The first step involves slow ionization
of the substrate resulting in the formation of a carbocation that rapidly combines with the
nucleophile to form the product in the second step. Mostly the solvent itself acts as a
nucleophile, therefore the SN1 reaction is generally called as solvolysis.
In a reaction involving more than CH3 CH3
one step the slowest step Step 1 H3C C I Slow
H3C C + I
determines the rate of the (Ionization)
reaction and is therefore called CH3 CH3
the rate-determining step. So, CH3
CH3
in this reaction the first step, i.e., H2O
OH2
the ionization of the substrate, is Step 2 H3C C
Fast
H3C C

the rate-determining step. CH3

CH3

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Evidences:
There are some evidences that support this mechanism e.g.
a) Kinetic study
b) Stereochemistry
c) Rearrangement

a) Kinetic Study

This mechanism is supported by the kinetic study of the reaction. In a reaction

following the SN1 mechanism, only the substrate is involved in the rate-determining step.
The rate should therefore depend only on the concentration of the substrate, i.e., it should
be a first-order reaction with the following rate law:
Rate α [(Substrate] Rate = k1 [ (CH3)3C-I ]
Since only one molecule, i.e., the substrate, is involved in the CH3
δ δ
formation of the activated complex in the rate-determining step, this H3C C X
reaction is called a unimolecular reaction. The important transition state CH3
for the SN1 reaction is the transition state of the rate-determining step. In it
the C-X bond is largely broken and ions are beginning to develop. The solvent stabilizes
these developing ions by solvation.

b) Stereochemistry

Another strong evidence in favour of this mechanism also comes form the
stereochemical studies. This mechanism involves the formation of a carbocation as an
intermediate. Since the central carbon atom of the carbocation is sp2 hybridized, it is a
planar molecule. The unhybridized p orbital on carbon is perpendicular to the plane of the
molecule with one lobe on each side of the plane. The nucleophile can therefore attack
from either side (front or back) of the plane to form a bond with the carbocation. Since
the carbocation is a symmetrical molecule, the chances of attack form both sides are
almost equal, and if we start with an optically active substrate, we are expected to get a
racemic mixture of the product.
a a b
R1 R1
R1 R1
C X Y
C C Y + Y C
R3 R3 R3
R2 R2 R3 b -X R2 R2

Retention Inversion
(Predominates)
So, an aliphatic nucleophilic substitution is generally expected to be accompanied
by racemization if it proceeds by the SN1 mechanism. Anyhow the product is not
completely racemised because the inverted product predominates over its enantiomer.
The most probable answer to this question lies in the fact that attack of the nucleophile
occurs before the departing ion has completely left the neighbourhood of the carbonium
ion. Thus the departing ion shields the carbonium ion from the frontal attack (i.e. path a).
As a result back side (i.e. path b) is somewhat preferred.

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c) Rearrangemet

The formation of carbocation as an intermediate is also supported by the fact that

it can undergo rearrangement to a more stable carbocation, before it combines with the
nucleophile.
CH3 CH3 CH3
Rearr.
H3C C CH2 Br H3C C CH2 H3C C CH2CH3

CH3 CH3

CH3 CH3 H2O

-H
H3C C CH2CH3 H3C C CH2CH3

OH OH2

ii) SN2 (BIMOLECULAR NUCLEOPHILIC SUBSTITUTION) MECHANISM:-

The SN2 mechanism is involved in the substitution reactions that take place in one
step without the formation of any intermediate. In this mechanism the nucleophile attacks
the substrate from the side opposite to the leaving group, i.e., from the backside. The
bond formation between the nucleophile and the substrate and the bond cleavage
resulting in the removal of the leaving group occur simultaneously, i.e., the reaction is
concerted one.
Antibonding
orbital
δ δ
Nu + C L Nu C L

Transition state

Nu C + L

As the nucleophile starts making the bond with the central carbon atom of the
substrate, the leaving group starts leaving it and in the transition state both the
nucleophile and the leaving group are loosely bound to the carbon atom such that at no
time the carbon atom has more than eight electrons in its outer shell. The hybridization of
the central carbon atom changes from sp3 in the substrate to Sp2 in the transition state and
again to sp3 in the product. Thus, the central carbon atom and the three non-reacting
groups are approximately coplanar in the transition state, with the unhybridized p orbital
perpendicular to the plane and having one lobe on either side of the plane; one lobe of the
p orbital is engaged by the nucleophile and the other by the leaving group.
H
H H
δ δ
HO + C X HO C I HO C + I
H H
H H H
H

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Evidences:
Like SN1, this mechanism is also supported by some evidences e.g.
a) Kinetic study
b) Stereochemistry

a) Kinetic Study

The substitution reactions proceeding through the SN2 mechanism involve only
one step and that is the rate-determining step. In this step both the substrate and the
nucleophile are involved. The rate of the reaction should therefore depend on the
concentration of both, i.e., the reaction should follow the second-order kinetics with the
following rate law:
Rate α [(Substrate] [ Nucleophile ] Rate = k2 [ CH3-X ] [ OH ]

Since two molecules, i.e., the nucleophile and the substrate, are involved in the
formation of the transition state in the rate-determining step (the only step of the
reaction), this reaction is said to be bimolecular.
However, if the nucleophile is used in large excess, e.g., the solvent acts as a
nucleophile, the mechanism may still be bimolecular but the kinetics will appear as first-
order. This is because there will be no apparent change in the concentration of the
solvent, due to its large quantities, and the rate will depend only on the concentration of
the substrate. Such a reaction is said to be pseudo-first-order.

b) Stereochemistry

Much more convincing evidence for the SN2 mechanism comes from the
stereochemical study of the reaction. In this pathway since the nucleophile attacks the
substrate from the backside, inversion of configuration should take place. This has
actually been observed in the reaction of radioactive iodide ion with optically active 2-
octyl iodide. If we start with an optically pure R-2-octyl iodide, the substitution of I in the
substrate by *I will produce enantiomer of the substrate, i.e., S-2-octyl iodide.
One molecule of the product C6H13 C6H13
together with one molecule *I + C I *I C + I
CH3
of the starting substrate will H3C
H
form a racemate because H
they are enantiomers of each R-2-octyl iodide S-2-octyl iodide
other.
This means that the exchange of iodide in each molecule of the substrate will
result in a racemic mixture of two molecules. In other words the reaction is not only
accompanied by racemization but also the rate of racemization is twice the rate of
exchange. This is only possible when there is an inversion of configuration, i.e., the
nucleophile attacks the substrate from the backside.

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iii) SNi (INTERNAL NUCLEOPHILIC SUBSTITUTION) MECHANISM:-

In few reactions, nucleophilic substitution proceeds with retention of

configuration, even where there is no possibility of neighbouring-group participation. In
this mechanism part of the leaving group must be able to attack the substrate, detaching
itself from the rest of the leaving group in the process. The crucial difference with the
SN1 mechanism is that since the nucleophile resides at the same side as the original
leaving group, the stereochemistry is retention of configuration and not racemization.
A typical representative organic reaction displaying this mechanism is the
chlorination of alcohols with thionyl chloride.
R R
C OH + SOCl2 C Cl + SO2 + HCl
H H
R' R'
Mechanism:

O O O H
R R H R

C OH + S C O S C O S
H H H Cl Cl
Cl Cl R' Cl Cl R'
R'
O
O
- HCl
R R
SNi R S
S
C Cl C O Cl
H - SO2 H C O Cl
H
R' R'
R' Alkyl chloro sulfite
(Retention)

Thionyl chloride first reacts with the alcohol to form an alkyl chloro sulfite (these
alkyl chlorsulphites can be isolated). In the second step the sulfite group is lost and just
like in an SN1 reaction an alkyl carbocation is created. The actual nucleophile in the third
reaction step is the chlorine atom attached to the sulfite group which recombines with this
carbocation and results in the retention of stereochemical configuration.

The SNi mechanism is O

relatively rare. Another example C
is the decomposition of alkyl R O Cl
R Cl + O C O
chloroformate into alkyl chloride
and CO2.

Evidence:

This reaction mechanism is supported by the observation that the addition of

pyridine to the mixture of alchol and thionyl chloride results in the formation of alkyl
halide with inverted configuration. Inversion results because the the pyridine reacts with
ROSOCl (alkyl chlorosulphite) to give ROSONC5H5 before any thing can take place.The
Cl- freed in this process now attacks from the rear and consequently configuration is
inverted.

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O O
N N
R S R S R
C O Cl C O N Cl C
H - Cl H H
R' R' R'
Alkyl chloro sulfite (Inversion)

The reaction between alcohol and thionyl chloride is second order, which is
predicted by this mechanism, but the decomposition by simple heating of ROSOCl is first
order.

iv) ION-PAIR (MIXED SN1 & SN2) MECHANISM:-

Some reactions of a given substrate under a given set of conditions display all the
characteristics of SN2 mechanism; other reactions seem to proceed by SN1 mechanism,
but cases are found that can not be characterized so easily. There seem to be some thing
in between, a mechanistic “borderline” region. At least two broad theories have been
devised to explain these phenomena. One theory holds that an intermediate mechanism is
caused by a mechanism that is neither pure SN1 nor pure SN2, but some “in between”
type. According to second theory there is no intermediate at all, and borderline behaviour
is caused by simultaneous operation, in the same flask, of both SN1 and SN2 mechanism;
that is, some molecules react by SN1, while others react by the SN2 mechanism.
Sneen et al., formulated an intermediate theory. According to it all SN1 and SN2
reactions can be accommodated by one basic mechanism i.e. the ion-pair mechanism.
The substrate first ionizes to an intermediate ion pair that is then converted into product.
An intimate ion pair is an ionic intermediate in which the cation and anion are in close
proximity and are not separated by solvent molecules.

k1 k2
RX R X Products
(Ion-pair)
The difference between the SN1 and SN2 mechanisms is that in the former case the
formation of the ion-pair (k1) is the rate determining, while in the SN2 mechanism its
destruction (k2) is rate determining. Borderline behaviour is found where the rates of
formation and destruction of the ion-pair are of the same magnitude.

Evidence:

One of the experiments that support the ion-pair mechanism is the hydrolysis of
4-methoxybenzyl chloride in 70 % aqueous acetone. In this solvent, hydrolysis (i.e.
conversion to 4-methoxybenzyl alcohol) occurs by an SN1 mechanism. When azide ions
are added, the alcohol is still a product, but now 4-methoxybenzyl azide is another
product. Addition of azide ions increases the rate of ionization (by the salt effect) but
decreases the rate of hydrolysis. If more carbocations are produced but fewer go to the
alcohol, then some azide must be formed by reaction with carbocations – an SN1 process.
However, rate of ionization is always less than the total rate of reaction, so some azide
must also form by an SN2 mechanism.

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Thus, the conclusion is that an intermediate ion-pair is involved and SN1 & SN2
mechanisms operate simultaneously.

H2O
MeO CH2Cl MeO CH2 Cl MeO CH2OH
70 %
(Ion-pair) aq. acet.

H2O NaN3

MeO CH2OH + MeO CH2N3

v) SN1' MECHANISM:-

Allylic substrates undergo nucleophilic substitution reactions especially rapidly,

but they are usually accompanied by a certain kind of rearrangement known as an allylic
rearrangement. When allylic substrates are treated with nucleophiles under SN1
conditions, two products are usually obtained: the normal one and a rearranged one.
3 2 1 Y 3 2 1 3 2 1
R CH CH CH2-X R CH CH CH2-Y + R CH CH CH2
(Normal) (Rearranged)
Y
Two products are formed because an allylic type of carbocation is a resonance hybrid so
that C-1 and C-3 each carry a partial positive charge and both are attacked by Y.

R CH CH CH2 R CH CH CH2
Of course, an allylic rearrangement is undetectable in the case of symmetrical allylic
cations, as in the case where R=H, unless isotopic labeling is used. This mechanism for
the rearranged product has been called the SN1' mechanism.

Evidences:

a) As with other SN1 reactions, there is clear evidence that SN1' reactions can
involve ion pairs. If the intermediate attacked by the nucleophile is a completely free
carbocation, then, (1) and (2) should give the same mixture of alcohols when reacting
with hydroxide ion, since the carbocation from each should be the same.

0.8 M aq. NaOH

H3C CH CH CH2-Cl H3C CH CH CH2-OH + H3C CH CH CH2
25 oC 40 %
(1) 60 % OH
0.8 M aq. NaOH
H3C CH CH CH2 H3C CH CH CH2-OH + H3C CH CH CH2
25 oC
Cl (2) OH 62 %
38 %

When treated with 0.8 M aqueous NaOH at 25 oC, (1) gave 60 %

CH3CH=CHCH2OH and 40 % CH3CHOHCH=CH2, while (2) gave the products in yields
of 38 and 62 %, respectively. This phenomenon is called the product spread. In this case,

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and in most others, the product spread is in the direction of the starting compound. With
increasing polarity of solvent, the product spread decreases and in some cases is entirely
absent. It is evident that in such cases the high polarity of the solvent stabilizes
completely free carbocations.
b) There is other evidence for the intervention of ion pairs in many of these
reactions. When CH2=CHCMe2Cl was treated with acetic acid, both acetates were
obtained, but also some ClCH2CH=CMe2, and the isomerization was faster than the
acetate formation. This could not have arisen from a completely free Cl - returning to the
carbon, since the rate of formation of the rearranged chloride was unaffected by the
addition of external Cl - ion. All these facts indicate that the first step in these reactions is
the formation of an unsymmetrical intimate ion pair that undergoes a considerable
amount of internal return and in which the counterion remains close to the carbon from
which it departed.
Thus, (1) and (2), for example, give rise to two different intimate ion pairs. The
field of the anion polarizes the allylic cation, making the nearby carbon atom more
electrophilic, so that it has a greater chance of attracting the nucleophile.

vi) SN2' MECHANISM:-

Nucleophilic substitution at any allylic carbon can also take place by an SN2
mechanism, in which case no allylic rearrangement usually takes place. However, allylic
rearrangements can also take place under SN2 conditions, by the SN2' mechanism, in
which the nucleophile attacks at the γ carbon rather than the usual position:

R R" R
R"
SN2' mechanism R C C C X R C C C + X
R"
R' R" Y R'
Y

This mechanism is a second-order allylic rearrangement; it usually comes about

where SN2 conditions hold but where a substitution sterically retards the normal SN2
mechanism. There are thus few well established cases of SN2' mechanism on substrates of
the type C=C−CH2X, while compounds of the form C=C−CR2X give the SN2'
rearrangement almost exclusively when they give bimolecular reactions at all. Increasing
the size of the nucleophile can also increase the extent of the SN2' reaction at the expense
of the SN2. In certain cases, the leaving group can also have an effect on whether the
rearrangement occurs. Thus PhCH=CHCH2X, treated with LiAlH4, gave 100 % SN2
reaction (no rearrangement) when X = Br or Cl, but 100 % SN2' when X = PPh3+ Br−.
The SN2' mechanism as shown above involves the simultaneous movement of
three pairs of electrons. However, Bordwell and co-workers contended that there is no
evidence requiring that this bond making and bond breaking be in fact concerted, and that
a true SN2' mechanism is a myth. There is evidence both for and against this proposal.

Stereochemistry:
The stereochemistry of SN2` reactions has been investigated. It has been found
that both syn (the nucleophile enters on the side from which the leaving group departs)

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and anti reactions can take place, depending on the nature of X and Y, though the syn
pathway predominates in most cases.

Syn Y R X Anti R X
R" R"
R C C C R C C C
R" R"
R' R'
Y

vii) SNi' MECHANISM:-

When a molecule in an allylic position has a nucleofuge capable of giving the SNi
reaction, it is possible for the nucleophile to attack at the γ position instead of the α
position. This is called the SNi' mechanism and has been demonstrated on 2-buten-1-ol
and 3-buten-2-ol, both of which gave 100 % allylic rearrangement when treated with
thionyl chloride in ether.

SOCl2
H3C CH CH CH2-OH H3C CH CH CH2 H3C CH CH CH2 + SO2
- HCl
2-buten-1-ol Cl O
Cl
S

Ordinary allylic rearrangements (SN1') or SN2' mechanisms could not be expected

to give 100 % rearrangement in both cases. In the case shown, the nucleophile is only
part of the leaving group, not the whole. But it is also possible to have reactions in which
a simple leaving group, such as Cl, comes off to form an ion pair and then returns not to
the position, whence it came but to the allylic position:

R CH CH CH2-Cl R CH CH CH2 Cl R CH CH CH2

Cl

Most SNi' reactions are of this type.

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™ NEIGHBOURING GROUP PARTICIPATION:-

A properly placed group in a molecule can assist in the departure of the leaving
group. This results in a decrease in the energy of activation and the resultant increase in
the rate of reaction. The group that accelerates the rate is said to provide anchimeric
assistance and this act is called Neighbouring Group Participation.
There are many evidences for this participation e.g.
1) Kinetic studies 3) Molecular rearrangement
2) Stereochemistry 4) Spectroscopic studies
These are discussed one by one.

1) KINETIC STUDIES:-
Hydrolysis
H3C H2C O CH2 CH2 Cl H3C H2C O CH2 CH2 OH
(in aq. dioxane)
Hydrolysis
H3C H2C S CH2 CH2 Cl H3C H2C S CH2 CH2 OH
(in aq. dioxane)
The hydrolysis of the sulfide (latter) is over 10,000 times faster than the ether
(former). This rate difference is far too great to be attributed to differences in inductive,
conjugative, or steric effects, but suggests rather that the hydrolysis of the sulfide (but not
the ether) proceeds through a cyclic onium ion (in this case, sulfonium ion).
Actually, oxygen being more electronegative can not donate its lone pair to
carbon but sulphur can easily donate its lone pair to carbon and thus assists in the
departure of the leaving group by forming a cyclic intermediate, consequently increasing
the rate of reaction over 10,000 times faster as compared to first.

very fast
CH2 Cl S CH2
S Et S CH2 CH2 OH + H
CH2 Cl Et CH2 H2O
Et

The intermediate, because of the strained three-membered ring is readily

hydrolyzed to the observed products.

2) STEREOCHEMISTRY:-
The stereochemistry of a reaction might suggest that neighbouring groups become
involved. For example, the hydrolysis of the α-bromopropionate ion in water or dilute
base yields lactate with retention of configuration about the α-carbon.
H3C H3C
Hydrolysis
O Br O OH
C C
O H O H
Since nucleophilic substitutions at secondary carbon atoms almost invariably
result in partial or complete inversion of configuration, it was assumed that two
displacements were actually involved; the first a displacement of bromide by the
neighbouring –COO- to form the nonisolable α-lactone (A), and the second a very rapid
cleavage of the lactone by water. Inversion presumably occurred in both displacements,
the second inversion “nullifying” the first; hence we get retention of configuration.

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H3C H3C (A) CH3 H3C
H2O
O C Br O C Br C
O O C OH2
C Br very fast
C C H C
O H O H O H
O

3) MOLECULAR REARRANGEMENT:-
The neighbouring group participation may lead to molecular rearrangement when
the neighbouring group remains bonded to the reaction center but breaks away from the
atom to which it was originally attached in the substrate. Thus, the chlorinated amine (B)
yields, upon basic hydrolysis, the rearranged aminohydrin (D), presumably because the
intermediate imonium ion (C) is attacked preferentially at the primary α-carbon atom
rather than the secondary β-carbon atom.

(B) Et
Et (C) Et
Et (D) Et
Et
CH Cl N CH
N N CH
CH2 Cl Et CH2 OH
Et Et CH2OH

4) SPECTROSCOPIC STUDIES:-
In intermediate 1 the hydrogens on two OCH3

methylene carbons will behave differently 1

and there will be two peaks in NMR. In OCH3

intermediate 2, these hydrogens are identical SbF5/SO2

CH2 CH2
and therefore, will give one peak. In actual o
60 C
OCH3
practice, one peak is obtained, which shows CH2 CH2 Cl
the presence of intermediate 2, which in turn 2

is formed by participation.
Thus NMR also serves as an evidence
CH2 CH2
for neighbouring participation.
OCH3 OCH3 OCH3 OCH3 OCH3 OCH3

Cl

CH2 CH2 Cl
H2C CH2 H2C CH2 CH2 CH2 H2C CH2 CH2 CH2

¾ INTRAMOLECULAR DISPLACEMENT BY NEIGHBOURING OXYGEN:-

The nature of neighbouring-group reactions was first elucidated through
experiments involving participation of the carboxylate ion (-COO-). Particularly through
studies of the hydrolysis and alcoholysis of the anions derived from α-halocarboxlic
acids, as exemplified on page 11. As the distance between the halogen atom and the
carboxylate group is increased, the cyclic structure involved in direct displacement
becomes much less strained. Reaction by displacement becomes favoured, and solvolysis
is no longer facilitated by branching at the halogen bearing carbon by the addition of Ag+.

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O
Br 3 O H2O 4
H3C CH CH2 C O O
H3C

Br 5 O O
H2O 6
H3C CH (CH2)2 C O
O
H3C
O
7 O O
Ag2O 9
8 O +
Br (CH2)5 C OH HO (CH2)5 C O
H2O

10 O O
11
Br (CH2)6 C O HO (CH2)5 C O (no lactone)
H2O
Thus the conversion of γ-bromovalerate (5) in water to a five-membered ring
lactone, 6, proceeds by direct displacement, and same is probably true for the formation
of β-butyrolactone (4). But as is the case with other types of cyclization, formation of
rings of seven or more membered entails some difficulty, due to the low probability for
collision between opposite ends of a long chainlike molecule. When ε-bromocaproic acid
(7) is treated with Ag2O in water, ordinary solvolysis to give the ε-hydroxycaproic acid
competes with neighbouring-group participation (which gives the seven-membered ring
lactone, 8. Anion 10, yields only a hydroxyl acid (no eight-membered lactone).
When the carboxylate group is converted by protonation to the carboxyl group, -
COOH, it becomes very much less nucleophilic and loses a great deal of its effectiveness
as a participant. The substitution of carboxyl group for an α-methyl in (CH3)2CHBr
lowers the rate of solvolysis in water about a hundred-fold, whereas a similar substitution
in PhCHMeBr retards solvolysis by a factor of about 105. If any anchimeric assistance
effects are present, they are completely overshadowed by the strongly negative inductive
effect of the –COOH group. It has been found that the “deaminations” of α-amino acids
proceed with retention of configuration but in this case it is not clear whether paricipation
by the –COOH or the –COO- HNO 2 D-R CH COOH + N2
group is involved, since the D-R CH COOH OH
D-R CH COOH NO
NH2 C D-R CH COOH + N2
N N intermediate is a l
Cl
strong acid.
Whether or not an ester linkage functions as a neighbouring-group depends
largely upon how it is situated with respect to the reaction center in the substrate. The
solvolyses of CH3CHBrCOOEt and the deamination of CH3CH(NH2)-COOEt result in
inversion of configuration about the α-carbon, suggesting that there is negligible
participation by the –COOEt group when the reaction center lies alpha to the C=O bond
of the ester. This is what we might expect, for such participation would require the form-
ation of a strained three-membered ring X

without any compensating charge H3C CH C OEt H3C CH C OEt

neutralization. O
X
O
On the other hand, ester participation has been observed in a number of
substitutions in which the reaction center is located in the alkyl rather than the acyl,

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CHEM-2201 ORGANIC SECTION
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section of the ester molecule; in each of these, the anchimeric intermediate contains a
five-membered ring.
The conversion of H3C
C O 12
trans-2-acetoxycyclohe-
O
xyl brosylate (12) to H3C
C O
trans-1,2-diacetoxycyl- 15
O
ohexane (15) proceeds O HO Acetoxonium ion
Ac
through the symmetric -B 14

Ac
O S O sO -
intermediate acetoxoni- O

O-
H3 C
C OAc
um ion 14, and similar
evidence points to the O OAc 17
same intermediate in the Br +

reaction of trans-2-ace- Ag H2O

A c HO
toxycylohexyl bromide H3C HO
C O 13 CH3
(13) with silver acetate. H O O H
+
O
As indicated, addition C
of small quantities of 16
O
water to either reaction Br
mixture diverts some of the intermediate 14 to the monoacetate of cis-1,2-
cyclohexanediol (15), presumably through intermediate 16.
The formation of 14 from brosylate 12 or bromide 13 almost certainly involves
direct displacement of the leaving group by the acetoxy lying trans to it, the neighbouring
group being in a position favourable for attack. In contrast, the solvolyses of the cis
isomers of 12 and 13 are governed by the rate at which these substrates lose brosylate or
bromide ion, such ionizations being, in these cases, anchimerically unassisted. Hence, it
should not surprise us that 12 and 13 are solvolyzed several hundred times more rapidly
than their respective cis isomers under the same conditions.
Alkoxy groups are only slightly more effective participators than the hydroxyl
group. Because of the –I effect of –OR groups, 2-alkoxyethyl halides undergo solvolysis
much more slowly than ethyl halides and anchimeric assistance, if rendered at all, is not
detectable. However, incorporation of a δ-methoxy group in n-butyl brosylate boosts its
rate of destruction in acetic acid almost one thousand fold, whereas incorporation of an ε-
methoxy group in n-amyl brosylate increases its rate of CH3 CH3

acetolysis by a factor of well over a hundred. In these O O

ε OBs
cases, anchimeric assistance involves formation of δ
α
OBs
δ β
α
γ β γ
five- and six-membered rings, respectively.
The stereochemistry of the acetolysis of β-bromoethers 18 and 19 in the presence
of AgOAc suggests methoxide participation. Here, once again, nucleophilic substitution
results in retention of relative configuration about the reaction center. The anchimeric
intermediate, as shown below for the acetolysis of trans-2-methoxycyclohexyl bromide
(19) is a bridged Br 18
OMe
19 20
OMe
21
methoxonium ion H C CH CH CH +
Ag H3C O
3 3
20. OAc
OMe
Br OAc

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¾ NEIGHBORING NITROGEN, SULFUR, AND HALOGEN:-

Without considering the possibility of neighboring-group interaction, we might
expect such halogenated amines as 4-bromobutyl amine (22) [Br(CH2)4NH2] and N,N-
dimethyl-2-chloroethyl amine (24) [Cl(CH2)2NMe2] to behave in substitution reactions in
much the same way as do ordinary alkyl halides. Specifically, we might predict that these
amines be hydrolyzed in aqueous base at about the same rates as are simple primary
halides (for the inductive effects of the –NH2 and –NMe2 groups are slight), and that
these hydrolyses be first order in hydroxide. It is found, however, that treatment of these
amines with aqueous base releases halide ion thousands of times as rapidly as the
hydrolyses of nonaminated alkyl chlorides, and that the formation of halide is zero order
in (OH-). Yet in spite of their kinetic character, these reactions are not ordinary SN1
solvolyses, for they are not accelerated by the addition of Ag-: moreover, there is no
obvious reason why the presence of a nitrogen atom in the substrate should greatly
facilitate the usual type of solvolytic ionization. Instead, the rapid release of halide ion in
these cases is due to internal attack by the nitrogen atom at the halogenated carbon,
forming a cyclic ammonium ion such as 23 or 25.
H H H H
22 Cyclic ammonium ion
N N
H2C δ H2C Br H2C CH2 + Br
α 23
γ β (Stable)
H2C CH2 H2C CH2

24
H3C H3C 26
Cl OH H3C
N H2C Cl CH2
N N H2C OH
H3C H3C or
C H3C
H2 25 CH2 H2O C
H2
As indicated, the five-membered ring ammonium ion 23 (the pyrrolidinium ion),
is stable. Ethyleneimonium ions, such as 25, are, as class, somewhat more reactive than
ethylene oxides, although nitrogen containing such ions can, with care, be isolated. As
might be expected, the rate at which the various cyclic ammonium ions are formed
depends markedly on the number of atoms in the ring. The five or six membered rings,
being stable, are readily formed.
These imonium ions undoubtedly also intercede in rearrangements, not only of
such aliphatic haloalkylamines as on page 12, but also such heterocyclic amines as N-
ethyl-2-chloromethylpyrolidine (27).
Et Et Et
27 CH2
N CH2 Cl N N
1 Cl Cl H2C CH2
H2C 5 2CH H2C CH
28 29
4 3
H2C CH2 H2C CH2 H2C CH
C Cl
H2
What has been said about neighboring-group participation by nitrogen may be
applied, with but slight modification, to sulfur. The hydorlyses of β- and δ-chlorosulfides
are thousands of times as rapid as those of the corresponding chloroethers and, when
carried out in the presence of base, are zero order in base. These reactions doubtless
proceed through cyclic sulfonium ions of the type 31 and 33, analogous to the cyclic
ammonium ions 25 and 23.

15
CHEM-2201 ORGANIC SECTION
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R R
30
32 S
S
R S H2C Cl H3C S CH2
H2C α H2C Cl H2C CH2
β 33
C α Cl 31 CH2 β γ δ Cl
H2 H2C CH2 H2C CH2
The most familiar (and the most extensively studied) chloroalkyl sulfide is
mustard gas (34) [β,β′-dichlorodiethyl sulfide], the hydrolysis of which involves the
formation of the ethylenesulfonium ion 35, followed by the much faster destruction of this
ion by water. As befits a reaction sequence of this type, the first-order rate constant for
the hydrolysis will “drift downward” as the reaction proceeds, due to the reversal of the
cyclization when intermediate 35 is attacked by Cl- accumulating in solution (the mass
law effect). Moreover, if the reaction is carried out in the presence of an additional
nucleophile, even one as weakly nucleophilic as formate or chloroacetate, much of
intermediate 35 may be converted to a substitution product (for example, formate 37)
rather than to the hydrolysis product, 36.
Starting material
Cl
CH2 34 CH2 CH2 OH
CH2 35 H2O
CH2 Cl S 36
S S CH2

HC
Cl CH2 CH2 Cl
CH2 CH2 Cl CH2 CH2 Cl _

OO
O
Mustard gas
Rate determining CH2 CH2 O C H
S 37
Product
determining CH2 CH2 Cl
The fact that such relatively weak nulceophiles as chloride and format may, even
at low concentration, compete with the solvent water for the cationic intermediate is
further evidence that this intermediate is indeed sulfonium ion, rather than the very much
more reactive primary carbonium ion, ClCH2–CH2-S-CH2CH2+. While the latter is not
excluded by the kinetics, its lifetime would be extremely short, and all but a very small
fraction of such ions would be converted to the hydrolysis product 36 (by action of a
solvent molecule from their solvent “cages”) before colliding with a nucleophilic species
present in small concentration in solution.
As we have noted, anchimeric assistance by negatively charged oxygen or by an
ester linkage requires that the assisting group and the leaving group lie trans to each
other. The fact that the trans forms of 2-chlorocyclohexyl phenyl sulfide (38) and the
corresponding cyclopentyl derivative are hydrolyzed 105 to 106 times as rapidly as their
respective cis isomers indicates that trans orientation is required for β-sulfur participation
also. But trans orientation, although necessary, is apparently not sufficient; for it has been

ArS
H

SPh Cl
40
38 39 H SAr
Ar = Me
H

Cl H
Cl

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CHEM-2201 ORGANIC SECTION
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found that the trans-chlorosulfide 39 is solvolyzed (in 85 percent aqueous ethanol at very
nearly the same (very low) rate as is its cis isomer, and that the trans-chlorosulfide 40 is
solvolyzed similarly slowly. The rigidity of the structure in compounds 39 and 40 will
prevent a coplanar arrangement of the four atoms involved in formation of the sulfonium
bridge (the sulfur atom, the chlorine atom, and the α– and β-carbons), it is reasonable to
infer that the stereochemical requirements for anchimeric assistance by β-sulfur (and
probably for assistance by β-nitrogen and β-halogen also) are similar in nature to those
for facile bimolecular elimination. In elimination, the same the rigidity of the ring
systems in these compounds prohibits the formation of the transition states necessary for
trans elimination, thus leading to very low rates of biomolecular dehydrochlorination,
even when hydrogen and chlorine atoms on adjacent carbons lay trans to each other.
Although more data are clearly needed, it may be tentatively assumed that
effective anchimeric assistance requires a transition state in which the α- and β-carbons,
the leaving group, and the “assisting atom” lie in or near a common plane.
Neighboring-group participation by a β-bromo or β-iodo group results in the
formation of a cyclic (three-membered ring) bromonium or iodonium ion. Although such
halogenonium ions are too reactive to be isolated, the stereochemistry of conversions of
the diastereomeric 3-bromo-2-butanols (41) to 2,3-dibromobutanes (44), and that of the
acetolyses of these dibromides in the presence of Ag+, point to the intervention of
bromonium ion 43 in the erythro-meso series, and to the intervention of the cis isomer of
43 in the threo-d, l series.
OH 42 OH2 43 H
Me 41 Me Me
+
H
H H H H
H2O H Me
Br Erythro Me Br Me Br trans
_
c Ag Br
OAc O A Me Br
Me 45
44
H H H H
Erythro Meso
Br Me Br Me

As shown, the conversion of the bromohydrin 41 to the dibromide 44 and the

conversion of the latter to the acetoxy bromide 45 involve retention of relative
configuration. Retention of configuration is also observed for the corresponding reactions
in the threo-d, l series.
Since chloride is considerably less nucleophilic than bromide, the β-chloro group
would be expected to be a less effective “participator” than the β-bromo group. Although
some reactions appear to proceed through a chloronium-ion bridge, there is no evidence
that a chloro group renders appreciable anchimeric assistance.
On the other hand, I
I
participation by the very 46
47 48
nucleophilic iodine atom I HOAc

may greatly accelerate a OBs

reaction. It has been found OBs OAc
for example, that the acetolysis of trans-2-iodocyclohexyl brosylate (46) is almost 3
million times as rapid as that of its cis isomer, quite obviously because the reaction of the
trans (but not that of the cis) compound may proceed through idonium ion 47. With the

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corresponding bromobrosylates the trans isomer is likewise solvolyzed more rapidly than
the cis, but here the effect (Ktrans/Kcis = 800) is much less striking.

™ STRUCTURE AND REACTIVITY:-

The course (mechanism & rate) of a particular substitution reaction is influenced
by the following factors.
i) Structure of the substrate
ii) Concentration and strength of the nucleophile
iii) Nature of the leaving group
iv) Polarity and proticity of the solvent (medium)
All these are discussed in detail one by one.

i) STRUCTURE OF THE SUBSTRATE:-

The substrate structure is the major factor that controls the mechanism and the
rate of a substitution reaction. As we have seen, the SN1 mechanism involves the
intermediate formation of a carbocation in the rate-determining step. The ease of
formation of the carbocation depends on its stability. The greater the stability of the
carbocation, the more rapidly it is formed. The order of stability of the carbocations is:
tertiary > > secondary > primary > methyl. So, the SN1 reaction is more favourable for
the tertiary substrates than for the secondary or primary substrates.
The SN2 reactions proceed through a transition state that involves five groups
attached to the central carbon atom and becomes rather over-crowded. The alkyl groups
attached to the central carbon atom will make the transition state more over-crowded, and
thus more unfavourable, than would do the hydrogen atoms. Also, the approach of a
nucleophile from the backside to a tertiary carbon atom is sterically more hindered than
to a primary carbon atom. Thus, the SN2 reactions are more favourable for the primary
substrates and less favourable for the tertiary substrates. In fact, the tertiary substrates
seldom react by the SN2 mechanism; even the neopentyl systems in which substitution
occurs at primary carbon atom, react so slowly as to make it synthetically useless because
the approach of the nucleophile from the backside is severely hindered by three β-methyl
groups.
Generally, the primary substrates react by the SN2 mechanism, whereas the
tertiary substrates react by the SN1 mechanism. The secondary substrates could proceed
either by SN1 or SN2 or both mechanisms depending on the reaction conditions, though
mostly they also follow the SN2 mechanism. If the reaction conditions are not suitable for
SN1 mechanism in the case of tertiary substrates, elimination usually predominates.
Similarly, when the rate of the SN2 reaction is slowed down by the structural effects,
alternate side reactions (mostly elimination) begin to compete.
Comparison of rate constants (Table 1) for SN1 reactions shows an increase by a
factor of 106 in changing the substrate form primary to tertiary. Similarly, rate constants
for SN2 reactions decrease as the number of alkyl groups surrounding the central carbon
atom increases.

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CHEM-2201 ORGANIC SECTION
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Table 1: Effect of the Substrate Structure on the Relative Rates of SN1 and SN2 Reactions
R k1(SN1) k2(SN2)

H3C 1 30
CH3CH2 1 1
(CH3)2CH 12 0.02
(CH3)3C 1,200,000 0
(CH3)3CCH2 0.00001

ii) CONCENTRATION AND STRENGTH OF THE NUCLEOPHILE:-

Any species, whether neutral or negatively charged, that has an unshared pair of
electrons can function as a nucleophile. Nucleophile is not involved in the rate-
determining step of an SN1 reaction. It is only the second step when the nucleophile
comes into the picture and combines with the intermediate carbocation to form the
product. The rate of the SNI reaction is therefore not influenced by the nucleophile. For
example, the rate of hydrolysis of tert.butyl bromide which follows SN1 mechanism is not
affected by changing the nucleophile from H2O to HO-. On the other hand, the SN2
reaction requires a nucleophile to push off (displace) the leaving group in the rate-
determining step (the only step). The rate of this reaction therefore greatly depends on the
nucleophile. For example, the rate of hydrolysis of methyl bromide that proceeds by SN2
mechanism increases by more than 5000 times when the nucleophile is changed from
H2O to HO- because the latter is a better nucleophile than the former.

H2O + CH3Br CH3OH + HBr

NaOH + CH3Br CH3OH + NaBr (5000 times faster)

(aq.)

Similarly the rate in SN2 reaction is also dependent on the concentration of both
the substrate as well as the attacking nucleophile so if we double the concentration of the
nucleophile keeping the concentration of the substrate same, the rate in this case also
becomes double.

Nucleophilicity and basicity:-

We should expect a good electron-donor, i.e., a good Lewis base, to be a good

nucleophile. In fact, nucleophilicity does correlate with basicity in a series of compounds
having the same nucleophilic atom. For example, the order of nucleophilicity of RO− >
HO− > ArO− > H2O is the same as the order of their basicity. A similar correlation is
found for the nucleophiles whose attacking atom is in the same row of the periodic table.
For example, NH3 is a better nucleophile than H2O.
However, going down a family of atoms in the periodic table, as the atomic
number increases, the nucleophilicity increases, though the basicity decreases. For
example, the order of halide nucleophilicity is: I- > Br- > CI- > F- which is opposite to the
order of their basicity. Similarly, RS- is a better nucleophile than RO-, though the latter is

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CHEM-2201 ORGANIC SECTION
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a better base. The opposite order of nucleophilicity and basicity in this case can be
explained as follows:
The outer electrons of the larger atoms are spread over greater volume than are
those of smaller atoms. The less-localized electrons form weaker bonds to a proton. The
larger atoms are therefore less basic. The outer electrons of the larger atoms are also less
tightly held by the nucleus, i.e., they are more polarizable. In other words, they are more
available for forming bonds to a carbon atom. The larger atoms are therefore more
nucleophilic.
Steric considerations are also important in determining the nucleophilicity of a
nucleophile. When a Lewis base interacts with a proton, steric requirements are normally
important because proton is a small species. However, approach of the same reagent to a
tetracoordinate carbon atom can involve severe steric interactions. For example, whereas
methoxide ion can easily approach the carbon atom during a nucleophilic substitution
reaction, tert-butoxide ion, being very bulky, is sterically hindered to approach the central
carbon atom. Thus, the ability of tert-butoxide ion to function as a nucleophile is greatly
reduced, although its basicity is similar to that of the methoxdie ion.

iii) NATURE OF THE LEAVING GROUP:-

The best leaving groups are those which become the most stable molecules or
ions after they depart. This means, in general, that the best leaving groups are
molecules or ions that are weakest bases.
In most of the nucleophilic substitution reactions alkyl halides are used as
substrates in which halide ion acts as a leaving group. Thus, among the halides, iodide is
the best leaving group and fluoride the poorest; (iodide is also the best nucleophile of all
the halides): I− > Br− > Cl− >> F−. However, other groups can also act as good leaving
groups if these are the conjugate bases of strong acids. For example, bisulphate ion
(HSO4−), which is the conjugate base of sulfuric acid, is a good leaving group. Thus the
ability of a group to act as a leaving group is usually inverse of its basicity; the weakest
base is the best leaving group; (conjugate base of a strong acid is a weak base).
As in both SN1 and SN2 reactions, the leaving group comes off along with its
bonding electron pair. So, the groups that can better accommodate the electron pair (or
negative charge) are better leaving groups. For example, PhO - is a better leaving group
than RO− because the negative charge of phenoxide ion can be delocalized over to the
ring. This type of delocalization is not possible in alkoxide ion. However, a poor leaving
group like RO− (or HO−) may be converted to a good leaving group by protonation, e.g.,
H2O is a better leaving group than HO− because H2O is a weaker base than HO−. Thus,

I + R-OH No reaction

but I + R-OH2 R-I + H2O

Under the acidic conditions necessary to protonate the leaving group the
nucleophile would also be converted to its conjugate acid. It would therefore no more act
as a nucleophile. Since SN1 reactions do not require powerful nucleophiles but do require
good leaving groups, most of them take place under acidic (or neutral) conditions. On the
other hand, SN2 reactions which do require powerful nuclephiles, mostly take place under

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CHEM-2201 ORGANIC SECTION
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basic (or neutral) conditions.
Another way of converting –OH to a better leaving group is to convert it to a
reactive ester such as sulfonic ester. The sulfonic ester group like tosylate (p-
toluenesulfonate), is a better leaving group than halide and is frequently used in the
nucleophilic substitution reactions.
O O
PTSA
R-OH R O S CH3 R-I + O S CH3

O I
O Tosylate ion

The trifluoromethanesulfonate ion (CF3SO3−, O F

commonly called the triflate ion) is one of the best
leaving groups known to chemists. It is the anion Triflate ion O S C F
of CF3SO3H, an exceedingly strong acid - one that (a "super" leaving group)
is much stronger than sulfuric acid. O F

iv) POLARITY AND PROTICITY OF THE SOLVENT:-

The nucleophilic substitution reactions are heterolytic processes that usually take
place in solution. Each reaction involves either creation, dispersion or destruction of
charges. The reaction medium (solvent) can therefore play an important role in
determining the mechanism and the rate of these reactions through dipolar interactions
with the reactants, the intermediates and even the transition states.
The polarity of a solvent, usually determined from its dielectric constant (Table
2), is an indication of how well it can stabilize the charged species. The greater the
polarity of a solvent the greater its ability to stabilize a charged species, i.e., the greater
its ionizing power. The SN1 reactions, in which carbocations are formed in the rate-
determining step, are more favourable in polar solvents. For example, the rate of
hydrolysis of tert-butyl chloride increases more than 1000 times as the solvent is changed
from ethanol to water because water is more polar than ethanol.

Table 2. Dielectric Constant (at 25 oC) of Common Solvents

Protic solvent Dielectric constant Aprotic solvent Dielectric constant

H2O 81 (CH3)2SO 45
HCOOH 59 CH3CN 38
33
CH3OH HCON(CH3)2 37
24
C2H5OH CH3COCH3 23
6 C2H5OC2H5 4
CH3-COOH

In the SN2 reactions charges may be created, dispersed, or destroyed as the

reactions progress toward the rate-controlling transition state. The reactions in which the
charges are created in the transition state are favoured by increasing the polarity of the

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CHEM-2201 ORGANIC SECTION
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solvent, whereas the reactions in which the charges are either destroyed or dispersed in
the transition state are favoured by decreasing the solvent polarity. Generally, the
influence of a solvent is large when the charges are either created or destroyed; the
effects are small when there is a dispersal of charges.

A polar solvent may also decrease the nucleophilicity of a nucleophile through

solvation. However, the solvation is less in aprotic solvents, like dimethylsulfoxide
(DMSO) or dimethylformamide (DMF), than in protic solvents, like water or alcohol,
which solvate the nucleophile through hydrogen bonding.

SUMMARY. (SN1 versus SN2).

Reactions of alkyl halides by an SN1 mechanism are favoured by the use of

substrates that can form relatively stable carbocations, by the use of weak nucleophiles,
and by the use of highly ionizing solvents. SN1 mechanisms, therefore, are important in
solvolysis reaction of tertiary halides, especially when the solvent is highly polar. In a
solvolysis the nucleophile is weak because it is a neutral molecule (of the solvent) rather
than an anion.

If we want to favour the reaction of an alkyl halide by an SN2 mechanism, we should use
a relatively unhindered alkyl halide, a strong nucleophile, a polar aprotic solvent, and a
high concentration of the nucleophile. For substrates, the order of reactivity in SN2
reaction is

Methyl-X > Primary-X > Secondary-X

Tertiary halides do not react by an SN2 mechanism.

The effect of the leaving group is the same in both SN1 and SN2 reactions: alkyl
iodides react fastest; fluorides react slowest. (Because alkyl fluorides react so slowly,
they are seldom used in nucleophilic substitution reactions.)

R-I > R-Br > R-Cl SN1 or SN2

‡ Reference Books
1. M. Younas “A Text Book of Organic Chemistry”, 2nd edition 2005, Al-Hajaz
Printing Press, 18-A Darbar, Ilmi Kitab Khan, Urdu Bazar, Lahore, Pakistan.
2. Arun Bahl, B. S. Bahl, “A Text Book of Organic Chemistry (For B. Sc.
Students)”, 18th edition 2006, Rajendra Ravindra Printers (Pvt.) Ltd., S. Chand
and Company Ltd., New Delhi-110055, India.
3. Michael B. Smith and Jerry March, “March’s Advanced Organic Chemistry,
Reactions, Mechanisms, and Structure”, 5th edition, John Wiley and Sons, USA.

22