Chapter:- Nucleophilic substitution reaction Department of Chemistry, Pratap College, Amalner.

Alkyl Halide:- Reactions Primary, secondary, and tertiary alkyl halides all undergo nucleophilic substitution reactions with
aqueous KOH or NaOH to form alcohols The mechanism of the substitution reaction depends on the structure of the alkyl halides .
 Primary alkyl halides undergo SN2 reactions with aqueous KOH or NaOH
 Tertiary alkyl halides undergo SN1 reactions with aqueous KOH or NaOH
 While Secondary alkyl halides undergo either SN1 or SN2 reactions with aqueous KOH or NaOH depends on reaction
condition
SN1 and SN2 mechanism of alkyl halides:-

“A reaction in which a nucleophile displaces another nucleophile and takes its position is called a nucleophilic substitution reaction.
" Nucleophilic substitution reaction are represented by the symbol "SN".
In alkyl halides, the C-X bond is polar because C-atom is attached to a highly electro-negative halogen atom. Therefore in alkyl
halides carbon atom is electrophilic and halogen has a nucleophilic character. In a substitution reaction, the electronegative atom
or group is replaced by another atom or group. This chapter focuses on the substitution reactions of alkyl halides—compounds in
which the leaving group is a halide ion ( F- , Cl-, Br- & I- )
R F R Cl R Br R I
an alkyl fluoride an alkyl chloride an alkyl bromide an alkyl iodide
A halogen is more electronegative than carbon. Consequently, the two atoms do not share their bonding electrons equally.
Because the more electronegative halogen has a larger share of the electrons, it has a partial negative charge and the carbon to
which it is bonded has a partial positive charge.
RCH2 X X= F, Cl, Br, I
There are two important mechanisms for the nucleophilic substitution reaction:
1. A nucleophile is attracted to the partially positively charged carbon (an electrophile). As the nucleophile approaches the carbon
and forms a new bond, the carbon–halogen bond breaks heterolytically (the halogen takes both of the bonding electrons).

R R

Nu + R C X Nu C R + X

R R

Where R = H or alkyl group

2. The carbon–halogen bond breaks heterolytically without any assistance from the nucleophile, forming a carbocation. The
carbocation (an electrophile) then reacts with the nucleophile to form the substitution product.
Step - I R R
+
R C X C + X
R R
R
Alkyl halide Carbocation

Step - II
R R

C+ + Nu R C Nu + X
R R Nucleophile
R
Where R = H or alkyl group

Mr.Milind S. Thakare (Organic Chemistry) SET 1

Chapter:- Nucleophilic substitution reaction Department of Chemistry, Pratap College, Amalner.

This is called a nucleophilic substitution reaction because a nucleophile substitutes for the halogen. The mechanism shown above
are depend upon following factors
• The structure of the alkyl halide
• The reactivity of the nucleophile
• The concentration of the nucleophile
• The solvent in which the reaction is carried out

The Mechanism of an SN2 Reaction

The reaction of methyl bromide with hydroxide ion is an example of an SN2 reaction, where “S” stands for substitution, “N” for
nucleophilic, and “2” for bimolecular. The rate of a nucleophilic substitution reaction such as the reaction of methyl bromide OR
ethyl bromide (i.e primary alkyl haide) with hydroxide ion depends on the concentrations of both reagents i.e alkyl halide &
nucleophile.
If the concentration of methyl bromide in the reaction mixture is doubled, the rate of the nucleophilic substitution reaction
doubles. If the concentration of hydroxide ion is doubled, the rate of the reaction also doubles. If the concentrations of both
reactants are doubled, the rate of the reaction quadruples.
CH3Br + HO− CH3OH + Br−
Rate law: - Thus the rate of the reaction of methyl bromide with hydroxide ion is dependent on the concentration of both
reactants, we can write a rate law for the reaction as given below.
rate α [alkyl halide] [nucleophile]
Proportionality sign in the rate law for the reaction can be replaced by an equals sign and a proportionality constant. The
proportionality constant, in this case k, is called the rate constant.
rate = k [alkyl halide][nucleophile]
The reaction is a second-order reaction because the rate of this reaction depends on the concentration of both alkyl halide &
nucleophile, Bimolecular means that two molecules are involved in the rate-determining step.

Three experimental evidences for SN2 reation

1. The rate of the reaction depends on the concentration of the alkyl halide and on the concentration of the nucleophile. This
means that both reactants are involved in the rate-determining step.
2. When the hydrogens of methyl bromide are successively replaced with methyl groups, the rate of the reaction with a given
nucleophile becomes progressively slower (see table 1).
3. The reaction of an alkyl halide in which the halogen is bonded to an asymmetric carbon leads to the formation of only one
stereoisomer, and the configuration of the asymmetric carbon is inverted relative to its configuration in the reacting
alkyl halide.
Thus the mechanism of SN2 reaction is a concerted i.e. it takes place in a single step, so no intermediates are formed. The
nucleophile attacks the carbon bearing the leaving group and displaces the leaving group. The nucleophile attacks the carbon from
opposite the side of the leaving group, the carbon is said to undergo back-side attack. Why does the nucleophile attack from the
back side? The simplest explanation is that the leaving group blocks the approach of the nucleophile from front side of molecule.
Mechanism of the SN2 reaction

Mr.Milind S. Thakare (Organic Chemistry) SET 2

Chapter:- Nucleophilic substitution reaction Department of Chemistry, Pratap College, Amalner.

Reaction coordinates diagrams for the SN2 reaction of methyl bromide with hydroxide ion
2
Relative rate of alkyl halide towards SN reaction:-

2
Alkyl Halide Type of Alkyl Halide Relative rate of SN reaction

H3C Br Methyl 1200

H3C CH2 Br Primary 48

H3C CH2 CH2 Br Primary 18

CH3
Secondary 1
H3C CH Br

CH3

H3C C Br Tertiary too slow to measure

CH3

Table no.-1

Because the nucleophile attacks from back side of the carbon that is bonded to the halogen, therefore if bulky substituents
attached to this carbon it will make difficult for the nucleophile to get to attack from that side and will therefore decrease the rate
of the reaction & as generally, primary alkyl halides are less hindered than secondary alkyl halides, which, in turn, are less hindered
than tertiary alkyl halides:

Relative reactivities of alkyl halides in an SN2 reaction

most methyl halide > 1° alkyl halide > 2° alkyl halide > 3° alkyl halide l east
reactive reactive

Mr.Milind S. Thakare (Organic Chemistry) SET 3

Chapter:- Nucleophilic substitution reaction Department of Chemistry, Pratap College, Amalner.

The Mechanism of an SN1 Reaction

If we consider SN2 mechanism, we would expect the rate of reaction of tert butyl bromide with water to be relatively slow
because water is a poor nucleophile and tert -butyl bromide is sterically hindered to attack by a nucleophile. However it is
found that rate of the reaction is surprisingly fast. In fact, it is over one million times faster than the reaction of methyl
bromide, a compound with no steric hindrance—with water. This clearly indicate the reaction, the reaction must be taking
place by a mechanism different from that of an SN2 reaction.
Rate law:- By studying of rate of reaction it is found that, doubling the concentration of the alkyl halide doubles the rate of
the reaction. It also found that changing the concentration of the nucleophile has no effect on the rate of the reaction. Thus
the rate of this nucleophilic substitution reaction for above reaction depends only on the concentration of the alkyl halide &
not on the nucleophile, we can write the following rate law for the reaction.
rate = k [alkyl halide]
Because the rate of the reaction depends on the concentration of only one reactant, the reaction is a first-order reaction.
1
The reaction between tert-butyl bromide and water is an SN reaction, where “S” stands for substitution, “N” stands for
nucleophilic, and “1” stands for unimolecular. Unimolecular means that only one molecule is involved in the rate-
determining step.

The mechanism of an SN1 reaction is based on the following experimental evidence:

1. The rate law shows that the rate of the SN1 reaction depends only on the concentration of the alkyl halide. This means
that we must be observing a reaction whose rate-determining step involves only the alkyl halide.
2. When the methyl groups of tert-butyl bromide are successively replaced by hydrogens, the rate of the SN1 reaction
decreases progressively(See Table 2 ). .This is opposite to the order of reactivity exhibited by alkyl halides in SN2
reactions (See Table 1).
3. The reaction of an alkyl halide in which the halogen is bonded to an asymmetric carbon forms two stereoisomers: one
with the same relative configuration at the asymmetric carbon as the reacting alkyl halide, the other with the inverted
configuration.

Thus the mechanism of SN1 reaction is a stepwise i.e. it takes place in a two step (first is slow & second is fast), first step
involve formation of carbocation intermediates while second step involve attack of nucleophile from both side due to
planner structure of carbocation intermediates as shown below.

Step - 1
CH3 CH3

H3 C C Br C+ + Br
H3 C CH3
CH3
Carbocation
t- butyl bromide
CH3
Step - 2
H3 C C OH
CH3 CH3
.. ..
H2O + C+ + OH2 And
.. .. + Br
H3C CH3
CH3

HO C CH3

CH3

Mr.Milind S. Thakare (Organic Chemistry) SET 4

Chapter:- Nucleophilic substitution reaction Department of Chemistry, Pratap College, Amalner.

1
Relative rate of alkyl halide towards SN reaction:-

1
Because in the SN reaction the carbon–halogen bond breaks heterolytically without any assistance from the nucleophile, forming
a carbocation. The carbocation (an electrophile) then reacts with the nucleophile to form the substitution product.
The relative stability of carbocation is

30 > Benzylic ≅ Allylic > 20 > 10 > methyl

Mr.Milind S. Thakare (Organic Chemistry) SET 5

Chapter:- Nucleophilic substitution reaction Department of Chemistry, Pratap College, Amalner.

Comparision between SN2 & SN1

Sr.No. SN2 reaction SN1 reaction

1. SN2 reaction is a one step process. SN1 reaction is a two step process
2. SN2 reactions follow 2nd order kinetics SN1 reactions follow 1st order kinetics.
3. It is a bimolecular reaction. It is a unimolecular reaction.
4. Rate is doubled on doubling [RX] Rate is doubled on doubling [RX]
5. Rate is doubled on doubling [ Nu- ] Rate is unaffected on doubling [ Nu- ]
6. In SN2 reaction one transition state is formed. In SN1 reaction two transition states are formed.
7. The nucleophile attacks carbon of substrate from The nucleophile attacks the carbocation of substrate
back side from both side, front side as well as back side
8. In SN2 reaction complete inversion of In SN1 reaction racemisation (inversion as well as
configuration take place retension) take place.
9. Reactivity order of R-X is Reactivity order of R-X is
0 0 0 0 0 0
Methyl > 1 > 2 > 3 alkyl halide 3 > 2 > 1 > methyl halide.
10. Relative rates RI > RBr > RCl > RF Relative rates RI > RBr > RCl > RF
11. No intermediate is formed. Intermediate carbocation is formed.
12. It is favoured by Polar Aprotic solvent It is favoured by polar protic solvent.
13. It is favoured by strong nucleophiles. It is favoured by mild nucleophiles.
14. There is no possibility of rearranged products. Rearranged products can be formed.
15. For example For example
aq. NaOH CH3 CH3
CH3 Br CH3 OH H2O
NaBr CH3 C Br CH3 C OH
Methyl bromide Methyl alcohol
CH3 CH3
tert-Butyl bromide tert-Butyl alcohol

1. Nucleophilicity
The rate of an SN2 process is dependent on the concentration of the nucleophile. For the same reason, SN2 processes are
also dependent on the strength of the nucleophile. A strong nucleophile will speed up the rate of an SN2 reaction, while a
weak nucleophile will slow down the rate of an SN2 reaction. In contrast, an SN1 process is not affected by the concentration
or strength of the nucleophile because the nucleophile does not participate in the rate-determining step. In summary, the
nucleophile has the following effect on the competition between SN2 and SN1:
2
• A strong nucleophile favors SN .
A weak nucleophile disfavors SN2 (and thereby allows SN1 to compete successfully).
• We must therefore learn to identify nucleophiles as strong or weak***
2
• Small, strong nucleophiles that favor SN reactions are shown below. Most of them have a localized negative
charge. It is also better if they are weak bases, such as bromide and iodide ions, but they can be strong bases
such as hydroxide and alkoxide ions (conjugate bases of alcohols).
• Weak, small nucleophiles that favor SN1 reactions. Notice that several are the conjugate acids of strong
nucleophiles. They are also typically neutral, but some have a delocalized negative charge.
• Large nucleophiles, especially if they are strong, have a tendency to act as Bronsted bases rather than as
nucleophiles. They should be avoided if a nucleophilic reaction is desired.
(i) For a given element, negatively charged species are more nucleophilic (and basic) than are equivalent neutral species.
(ii) For a given period of the periodic table, nucleophilicity (and basicity) decreases on moving from left to right.
(iii) For a given group of the periodic table, nucleophilicity increases from top to bottom (i.e. with increasing size), although
there is a solvent dependence due to hydrogen bonding. Basicity varies in the opposite manner.

Mr.Milind S. Thakare (Organic Chemistry) SET 6

Chapter:- Nucleophilic substitution reaction Department of Chemistry, Pratap College, Amalner.

 Within a period, nucleophilicity parallels basicity: CH3- > NH2- > OH- > F-
 Within a family, larger atoms are better nucleophiles (polarizability)
I- > Br- > Cl- >F- or R2Se > R2S > R2O or R3P > R3N
- -
 With the same nucleophilic atom but different charge type, nucleophilicity parallels basicity : OH > H2O or SH > H2S
 With the same nucleophilic atom, same charge type, nucleophilicity parallels basicity
OH- > CH3COO-

2. The Leaving Group

Both SN1 and SN2 mechanisms are sensitive to the identity of the leaving group. If the leaving group is bad, then neither
1 2
mechanism can operate, but SN reactions are generally more sensitive to the leaving group than SN reactions. Why?
1
Recall that the rate-determining step of an SN process is loss of a leaving group to form a carbocation and a leaving group:
The most important thing to remember in this regard is that good leaving groups are weak bases. (Refer table)
a) All halogens, except for fluorine, are good leaving groups
b) Groups that leave as resonance stabilized ions are also weak bases and therefore good leaving groups.
c) Water is a good leaving group frequently used to prepare alkyl chlorides and bromides from alcohols.
The OH group in alcohols is not a good leaving group because it leaves as hydroxide ion, which is a strong base. However, if
the hydroxyl group is protonated first with strong acid, it can leave as a water molecule, which is a good leaving group.

Mr.Milind S. Thakare (Organic Chemistry) SET 7

Chapter:- Nucleophilic substitution reaction Department of Chemistry, Pratap College, Amalner.

3. Solvent Effects
The choice of solvent can have a profound effect on the rates of SN1 and SN2 reactions. We will focus specifically on the
effects of polar protic and polar aprotic solvents. Polar protic solvents contain at least one hydrogen atom connected
directly to an electronegative atom. Polar aprotic solvents contain no hydrogen atoms connected directly to an
1 2
electronegative atom. These two different kinds of solvents have different effects on the rates of SN and SN processes.
In short polar protic solvents are used for SN1 reactions, while polar aprotic solvents are used to favor SN2 reactions.
The effect of polar aprotic solvents on the rate of SN2 reactions is significant. For example,consider the reaction between
bromobutane and an azide ion:
Br + N3 N3 + Br

+ +
NaN3 = Na N N N
2
The rate of this reaction is highly dependent on the choice of solvent. Relative rates of this SN reaction in various solvents.
From these data, we see that SN2 reactions are significantly faster in polar aprotic solvents than in polar protic solvents.

Solvent CH3OH H2O DMSO DMF CH3CN

Relative rates 1 7 1300 2800 5000

*Polar protic solvents contain at least one hydrogen atom connected directly to an electronegative atom.
Function Polar protic solvents stabilize cations and anions. Cations are stabilized by lone pairs from the solvent, while anions
are stabilized by H-bonding interactions with the solvent. As a result, anions and cations are both solvated and surrounded
by a solvent shell.

*Polar aprotic solvents contain no hydrogen atoms connected directly to an electronegative atom.
Polar aprotic solvents stabilize cations, but not anions. Cations are stabilized by lone pairs from the solvent, while anions are
not stabilized by the solvent. Cations are solvated and surrounded by a solvent shell, but anions are not. As a result,
nucleophiles are higher in energy when placed in a polar aprotic solvent.

Mr.Milind S. Thakare (Organic Chemistry) SET 8

Chapter:- Nucleophilic substitution reaction Department of Chemistry, Pratap College, Amalner.

Nucleophilicity vs. Basicity

Nucleophilicity refers to the rate at which a particular nucleophile will attack an electrophile. There are many factors that
contribute to nucleophilicity. One such factor is charge, which can be illustrated by comparing a hydroxide ion and water.
Hydroxide is a strong nucleophile, while water is a weak nucleophile.
Another factor that impacts nucleophilicity is polarizability, which is often even more important than charge.
Polarizability describes the ability of an atom to distribute its electron density unevenly as a result of external influences.
Polarizability is directly related to the size of the atom and, more specifically, to the number of electrons that are distant
from the nucleus. A sulfur atom is very large and has many electrons that are distant from the nucleus, and it is therefore
highly polarizable. Most halogens share this same feature. For this reason, H2S is a much stronger nucleophile than H2O.
Unlike nucleophilicity, basicity is not a kinetic phenomenon and does not refer to the rate of a process. Rather, basicity
is a thermodynamic phenomenon and refers to the position of equilibrium.

Benzylic Halides, Allylic Halides, Vinylic Halides, and Aryl Halides:-

X
CH2 X X X

Benzyl halide Allylic halide Aryl halide Vinyl halide

*Allylic halides and benzylic halides can react either via SN2 or via SN1 processes:
These substrates can react via an SN2 mechanism because they are relatively unhindered, and they can react via an SN1
mechanism because loss of a leaving group generates a resonance stabilized carbocation.

*In contrast, vinyl halides and aryl halides are unreactive towards substitution reactions:
SN2 reactions are generally not observed at sp2-hybridized centers, because back-side attack of nucleophile is sterically
hindered & it is repelled by the electron cloud of the double bond or the aromatic ring. There are two reasons that vinylic
halides and aryl halides do not undergo SN1 reactions. First, vinylic and aryl cations are even more unstable than primary
carbocations because the positive charge is on an sp carbon. Since sp carbons are more electronegative than sp2 the carbons
that carry the positive charge of alkyl carbocations, sp carbons are more resistant to becoming positively charged. Second,
we have seen that carbons form stronger bonds than do sp3carbons. As a result, it is harder to break the carbon–halogen
bond when the halogen is bonded to an sp2 carbon.

2
Stereospecificity of SN Reactions
There is another crucial piece of evidence that led Ingold and Hughes to propose the concerted mechanism. When the
α position is a chirality center, a change in configuration is generally observed.
The reactant exhibits the S/R configuration, while the product exhibits the R/S configuration. That is, this reaction is said to
proceed with inversion of configuration. This stereochemical outcome is often called a Walden inversion, named after
Paul Walden, the German chemist who first observed it.
In 1896, German chemist Paul Walden reported the conversion of enantiopure (+)-(R)-malic acid into the enantiomer (-)-(S)-
malic acid, although he did not know at which step inversion was occurring. In the 1920s Kenyon and Philips investigated a
similar process with 1-phenyl-2-propanol:
The requirement for inversion of configuration means that the nucleophile can only attack from the back side (the
side opposite the leaving group), and never from the front side.
There are two ways to explain why the reaction proceeds through back-side attack:
1. The lone pairs of the leaving group create regions of high electron density that effectively block the front side of the
substrate, so the nucleophile can only approach from the back side.

Mr.Milind S. Thakare (Organic Chemistry) SET 9

Chapter:- Nucleophilic substitution reaction Department of Chemistry, Pratap College, Amalner.

2. Molecular orbital (MO) theory provides a more sophisticated answer. Recall that molecular orbitals are associated with
the entire molecule (as opposed to atomic orbitals, which are associated with individual atoms). According to MO theory, the
electron density flows from the HOMO of the nucleophile into the LUMO of the electrophile. As an example let’s focus our
attention on the LUMO of methyl bromide. If a nucleophile attacks methyl bromide from the front side, the nucleophile will
encounter a node, and as a result, no net bonding will result from the overlap between the HOMO of the nucleophile and
the LUMO of the electrophile. In contrast, nucleophilic attack from the back side allows for efficient overlap between the
HOMO of the nucleophile and the LUMO of the electrophile.
The observed stereochemical outcome for an SN2 process (inversion of configuration) is consistent with a concerted
mechanism. The nucleophile attacks with simultaneous loss of the leaving group. This causes the chirality center to behave
like an umbrella flipping in the wind:
This reaction is said to be stereospecific, because the configuration of the product is dependent on the configuration of the
starting material.

1
Stereospecificity of SN Reactions
In SN1 reactions involve formation of an intermediate carbocation, which can then be attacked from either side, leading to
both inversion of configuration and retention of configuration.
As carbocation is planar, and either side of the plane can be attacked by the nucleophile with equal possibility & we should
1 1
expect SN reactions to produce a racemic mixture (equal mixture of inversion and retention). In practice, though, SN
reactions rarely produce exactly equal amounts of inversion and retention products. There is usually a slight preference for
the inversion product because loss of a leaving group initially forms an ion pair, which hinders attack on one face of the
carbocation. As a result, the nucleophile will attack more often on the side opposite the leaving group, leading to a slight
preference for inversion over retention. i.e. Inversion of configuration is greater than >50% & Retention of configuration
Is less than 50%

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Chapter:- Nucleophilic substitution reaction Department of Chemistry, Pratap College, Amalner.

An ambident nucleophile

An ambident nucleophile is a nucleophile with two nucleophilic sites (“two teeth”). The ambident nucleophile shows two
− − −
electron-rich sites: (ambi is Latin for “both”; dent is Latin for “teeth”). E.g. CN , SCN , NO2 , Enolate ion, etc. E.g.
CH3
NaCN
H3C CH C N
CH3 Isopropyl cyanide

H 3C CH Br
CH 3
AgCN +
H3C CH N C
Isopropyl isocyanide

CH3
NaSCN
H3C CH SCN
CH3 Isopropyl thiocyanate

H3C CH Br
CH3
AgSCN
H3C CH NCS
Isopropyl isothiocyanate

i
Mechanism & stereochemistry of SN reaction

H O H
Non polar solvent Me Me
O S Cl Cl + SO2
O
Et Et
H S H O Concerted mech.
Me Cl Cl Me
OH O S Cl
Et HCl
Et
H
Polar solvent H SO2 Me
+ Cl
Me Et Cl Et
Ion pair
SNi mechanism with retension in configuration

Step I
O
H S H O
Me Cl Cl Me
OH +
O S Cl + N
Pyridine Cl
Et Et
H

Step II
H O 2 H
Cl Me SN Mechanism Me
O S Cl + Cl Cl
Et Et

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Chapter:- Nucleophilic substitution reaction Department of Chemistry, Pratap College, Amalner.
Examples
I OH
NaOH
2
SN

I SH
NaSH
2
SN
O
I
CH3COO CH3
2
SN

CH3COO
Cl 1 OH
SN

Cl H2O, OH
1
SN

Br
OH HO
H2O,

SN
1 +

Br
H2O,
+ 1,2 Methyl shift H2 O,
SN1
+
OH
secondary carbocation
Tertiary carbocation

HCl + 1,2 Hydride shift Cl

+
OH 1
H2O, SN Cl
H
secondary carbocation Tertiary carbocation

Br
+
CH3OH 1,2 Methyl shift CH3OH
+ OMe

secondary carbocation Tertiary carbocation

O
1) S Cl
O
OH O O Nu Nu
S
2) Nu 2
O SN
Nu
OH is a bad leaving group

Mr.Milind S. Thakare (Organic Chemistry) SET 12