6.

Aromatic Nucleophilic Substitution T he ArS N I ArS N 2 , b enzy ne a nd

S R N 1 m echa nism, r eactivity-effect of substrate structure, leaving group and
attacking nucleophile.

Chemical reactions of benzene.

The principal types of reactions of benzene are:

(a) Electrophilic substitution reactions : (Halogenation, Nitration, Sulphonation,

Alkylation, Acylation)

(b) Addition reaction (addition of hydrogen and halogen):

(c) Oxidation reactions (ozonolysis reaction and vapour phase oxidation):

(d) Nucleophilic displacement reaction:

Electrophilic Substitution reactions: Benzene undergoes substitution reactions. The

benzene ring with its delocalization  electrons is an electron-rich system. It is attacked by
electrophiles, giving substitution reaction products. For example,

Catalyst
H + E-Nu E + H-Nu

Benzene Substitution products

Where E+ is any electrophile and Nu- is a nucleophile. Such reactions in which

hydrogen atom of the aromatic ring is replaced by an electrophile are called electrophilic
aromatic substitution reaction.

Example: Halogenation of benzene

Cl
FeCl3
+ HCl
+ Cl2

Benzene Chlorobenzene

General Mechanism: All electrophilic aromatic substitution reactions follow the same three
steps mechanism.

Dr Md Ranzu Ahmed, Associate Professor, Dept of Chemistry, BUHS 1

Step 1: Formation of an Electrophile.

Catalyst
E Nu E+ + Nu - catalyst

Step 2: The electrophile attacks the aromatic ring to form a carbonium ion

+ H

+ E+ E

Benzene Carbonium ion

The intermediate ion is stabilized by the following resonance structures

H H H
+

E E E
+ +
Carbonium ion Carbonium ion Carbonium ion

Step 3: Loss of proton gives the substitution product.

+ H
E

Nu-Catalyst
E + H- Nu + Catalyst

Carbonium ion Substitution product

Nucleophilic aromatic substitution (ArSN1) or Nucleophilic displacement reaction

Unlike alkyl halides, aryl halides do not undergo nucleophilic displacement reaction
readily. The halogen bonded to the ring cannot be replaced by -OH, -NH2, -CN by
reaction with aqueous sodium hydroxide, ethanolic ammonia or potassium cyanide.
The reason is that the C-X in aryl halides is short (double bond like) and strong
compared to that in alkyl halides. Another reason is that the low reactivity of aryl
halides in nucleophilic displacement reactions because the aromatic ring itself is

Dr Md Ranzu Ahmed, Associate Professor, Dept of Chemistry, BUHS 2

center of high electron density due to π electrons. Hence a nucleophile is
discouraged from attacking the ring carbon bearing halogen.
Nucleophilic displacement reaction of halogen of aryl halides can take place either
under drastic conditions or by the presence of electron withdrawing groups on the
aromatic ring.
(a) Under drastic conditions. The halogen of aryl halides can be displaced by
-OH, -NH2, or -CN with appropriate nucleophilic reagents at high temperature and
pressure.
With strong bases such as NaNH2 or KNH2. Aryl halides react with sodium amide
or Potassium amide in liquid ammonia to form the respective anilines.

Br NH2
Liq. NH3
+ KNH2 + KBr
0
-33 C

Bromobenzene Aniline

Mechanism: Following elimination –addition mechanism is involved.

Step 1: Elimination step: A benzyne is formed through removal of H+ by NH2- and loss of Br-
.

Br
-
:NH2
+ :Br-

H
Bromobenzene
Benzyne
(Unstable)
Step 2: Addition step. a carbanion is formed by nucleophilic addition of NH2- to benzyne.
The carbanion abstract a proton from the solvent (NH3) to give the substitution product.

Dr Md Ranzu Ahmed, Associate Professor, Dept of Chemistry, BUHS 3

 NH2
NH2
-
:NH2 NH3
+ -:NH2
:-
H
Benzyne Aniline
(Unstable)

The above elimination-addition reaction mechanism is known as the Benzyne Mechanism

A nucleophilic aromatic substitution is a substitution reaction in organic chemistry in

which the nucleophile is places a good leaving group, such as a halide, on an aromatic ring.
There are nucleophilic substitution mechanisms encountered with aromatic systems:

 the SNAr (addition-elimination) mechanism

 the aromatic SN1 mechanism encountered with diazonium salts

The benzyne mechanism

Dr Md Ranzu Ahmed, Associate Professor, Dept of Chemistry, BUHS 4

 .

The most important of these is the SNAr mechanism, where electron withdrawing group
activate the ring towards nucleophilic attack, for example if there are nitro functional group
positioned ortho or para to the halide leaving group.

SNAr reaction mechanism

Aryl halides having electron-withdrawing group such as NO2 or CN in ortho or para
position to the halogen, undergo nucleophilic substitution reaction relatively easily.
Cl OH

NO2 NO2
aq. NaOH

1600C

NO2 NO2

o-,p-Dinitrobenzene o-,p-Dinitrophenol

Aryl halides cannot undergo SN2 reaction. The C–Br bond is in the plane of the ring as the
carbon atom is trigonal. To attack from the back, the nucleophile would have to appear inside
the benzene ring and invert the carbon atom in an absurd way. This reaction is not possible. SN1
reaction is possible but very unfavourable. It would involve the unaided loss of the leaving
group and the formation of an aryl cation.

The following is the reaction mechanism of a nucleophilic aromatic substitution of 2,4-

dinitrochlorobenzene in a basic aqueous solution.

Dr Md Ranzu Ahmed, Associate Professor, Dept of Chemistry, BUHS 5

In this sequence the carbons are numbered clockwise from 1–6 starting with the 1 carbon at 12
o'clock, which is bonded to the chloride. Since the nitro group is an activator toward nucleophilic
substitution, and a meta director, it allows the benzene carbon to which it is bonded to have a
negative charge. In the Meisenheimer complex, the nonbonded electrons of
the carbanion become bonded to the aromatic pi system which allows the ipso carbon to
temporarily bond with the hydroxyl group (-OH). In order to return to a lower energy state,
either the hydroxyl group leaves, or the chloride leaves. In solution both processes happen. A
small percentage of the intermediate loses the chloride to become the product (2,4-
dinitrophenol), while the rest return to the reactant. Since 2,4-dinitrophenol is in a lower energy
state it will not return to form the reactant, so after some time has passed, the reaction
reaches chemical equilibrium that favors the 2,4-dinitrophenol.

The formation of the resonance-stabilized Meisenheimer complex is slow because it is in a

higher energy state than the aromatic reactant. The loss of the chloride is fast, because the ring
becomes aromatic again.

Short note on Radical-nucleophilic aromatic substitution or SRN1

Radical-nucleophilic aromatic substitution or SRN1 is a type of of substitution

reaction in which a certain substituent on an aromatic compound is replaced by
a nucleophile through an intermediary free radical species:

Dr Md Ranzu Ahmed, Associate Professor, Dept of Chemistry, BUHS 6

The substituent X is a halide and nucleophiles can be sodium amide, an alkoxide or a
carbon nucleophiles such as an enolate.
This reaction type was discovered in 1970 by Bunnett and Kim and the abbreviation SRN1
stands for substitution radical-nucleophilic unimolecular as it shares properties with
an aliphatic SN1 reaction.

Reaction mechanism:

The involvement of a radical intermediate in a new type of nucleophilic aromatic

substitution was invoked when the product distribution was compared between a certain
aromatic chloride and an aromatic iodide in reaction with potassium amide. The chloride
reaction proceeds through a classical aryne intermediate:

Dr Md Ranzu Ahmed, Associate Professor, Dept of Chemistry, BUHS 7

The isomers 1a and 1b form the same aryne 2 which continues to react to
the anilines 3a and 3b in a 1 to 1.5 ratio.

Substrate
Four Factors to Consider in Determining the Relative Ease at which SN2
Displacement Occurs

 The nature of the leaving group

 The reactivity of the nucleophile
 The solvent
 The structure of the alkyl portion of the substrate

Sterically Hindered Substrates will Reduce the SN2 Reaction Rate

The reaction rate of biomolecular nucleophilic substitution (SN2) reactions depends

on the leaving group, nucleophile, and solvent.

The Kinetics of Nucleophilic Substitution Reactions in SN2 transition state is very

crowded. There are a total of five groups around the electrophilic center, thse are
nucleophile, leaving group, and three substituents.

Dr Md Ranzu Ahmed, Associate Professor, Dept of Chemistry, BUHS 8

If each of the three substituents in this transition state were small hydrogen atoms,
there would be little steric repulsion between the incoming nucleophile and the
electrophilic center, thereby increasing the ease attack of the nucleophile, resulting
in the expulsion of the leaving group.

If one of the hydrogens, however, were replaced with an R group, such as a methyl
or ethyl group, there would be an increase in steric repulsion with the incoming
nucleophile.

If two of the hydrogens were replaced by R groups, there would be an even greater
increase in steric repulsion with the incoming nucleophile.

The diagram below illustrates this concept, showing that electrophilic carbons
attached to three hydrogen atoms results in faster nucleophilic substitution
reactions, in comparison to primary and secondary haloalkanes, which result in
nucleophilic substitution reactions that occur at slower or much slower rates,
respectively. Notice that a tertiary haloalkane, that which has three R groups
attached, does not undergo nucleophilic substitution reactions at all. The addition of
a third R group to this molecule creates a carbon that is entirely blocked.

Dr Md Ranzu Ahmed, Associate Professor, Dept of Chemistry, BUHS 9

Substitutes on Neighboring Carbons Slow Nucleophilic
Substitution Reactions

Adding R groups to the electrophilic carbon results a slower reaction rate. The
addition of substitutes on neighboring carbons will slow nucleophilic substitution
reactions as well.

In the example below, 2-methyl-1-bromopropane differs from 1-bromopropane in

that it has a methyl group attached to the carbon that neighbors the electrophilic
carbon. The addition of this methyl group results in a significant decrease in the
rate of a nucleophilic substitution reaction.

If R groups were added to carbons farther away from the electrophilic carbon, we
would still see a decrease in the reaction rate. However, branching at carbons
farther away from the electrophilic carbon would have a much smaller effect.

The Nature of the Leaving Group

Weak base is the best leaving group. The factors that will determine whether a
species is weak base or not are electronegativity, size, and resonance.

As Electronegativity Increases:

As Electronegativity Increases, Basicity Decreases. The Ability of the

Leaving Group to Leave Increases

The following diagram illustrates -CH3 to be the worst leaving group and F- to be
the best leaving group. This particular example should only be used to facilitate
your understanding of this concept. In real reaction mechanisms, these groups are

Dr Md Ranzu Ahmed, Associate Professor, Dept of Chemistry, BUHS 10

not good leaving groups at all. For example, fluoride is such a poor leaving group
that SN2 reactions of fluoroalkanes are rarely observed.

As we know that from the left of the periodic table to the right of the periodic table
as shown in the diagram below, electronegative increases. As electronegativity
increases, basicity will decrease results leaving group will leave easily.

As Size Increases, Basicity Decreases, The Ability of the Leaving Group to

Leave Increases: If we move down the periodic table, size increases. With an
increase in size, basicity decreases, and the ability of the leaving group to leave
increases. For example,

Resonance Increases the Ability of the Leaving Group to Leave: As we

learned previously, resonance stabilized structures are weak bases. Therefore,
leaving groups that form resonance structures upon leaving are considered to be
excellent leaving groups. The following diagram shows sulfur derivatives of the type
ROSO3- and RSO3-. Alkyl sulfates and sulfonates like the ones shown make
excellent leaving groups. This is due to the formation of a resonance stabilized
structure upon leaving.

Dr Md Ranzu Ahmed, Associate Professor, Dept of Chemistry, BUHS 11

The Reactivity of the Nucleophile

Now that we have determined what will make a good leaving group, we will now
consider nucleophilicity. That is, the relative strength of the nucleophile.
Nucleophilicity depends on many factors, including charge, basicity, solvent,
polarizability, and the nature of the substituents.

Increasing the Negative Charge Increases Nucleophilicity

Nucleophiles can be neutral or negatively charged. In either case, it is important

that the nucleophile be a good Lewis base, meaning it has electrons it wants to
share. For example, the O in OH- is negatively charged, but the O in H2O is neutral.

Dr Md Ranzu Ahmed, Associate Professor, Dept of Chemistry, BUHS 12

Experimentally showed that a negatively charged nucleophile is better attacking
group than a neutral nucleophile. The O of -OH is a better nucleophile than the O of
H2O, and results in a faster reaction rate. Similarly, when nitrogen is part of NH2,
it bears a negative charge, and when it is part of NH3, it is neutral. The N of NH2 is
a better nucleophile than the N of NH3, and results in a faster reaction rate.

When Moving Across a Row, Nucleophilicity Follows basicity

Basicity increases from right to left on the periodic table, nucleophilicity also
increases. As basicity decreases from left to right on the periodic table,
nucleophilicity also decreases.

When it comes to nucleophilicity, do not assign this same rule when making
comparisons between the halogens located in a column. In this case of moving up
and down a column, nucleophilicity does not always follow basicity. It depends on
the type of solvent you are using.

Dr Md Ranzu Ahmed, Associate Professor, Dept of Chemistry, BUHS 13

In the section Nucleophilic Substitution, we assigned a relationship to leaving
groups containing C, N, O, and F, showing that the strength of the leaving group
follows electronegativity. This is based on the fact that the best leaving groups are
those that are weak bases that do not want to share their electrons. The best
nucleophiles however, are good bases that want to share their electrons with the
electrophilic carbon. The relationship shown below, therefore, is the exact opposite
of that shown for the strength of a leaving group.

Solvents and Nucleophilicity

We classified solvents as being either polar or nonpolar. Polar solvents can be

further subdivided into protic and aprotic solvents.

Protic Solvents

A protic solvent is a solvent that has a hydrogen atom bound to an oxygen or

nitrogen. A few examples of protic solvents include H2O, ROH, RNH2, and R2NH,
where water is an example of an inorganic protic solvent, and alcohols and amides
are examples of organic solvents. The diagram below shows a few examples of protic
solvents we will see.

Dr Md Ranzu Ahmed, Associate Professor, Dept of Chemistry, BUHS 14

Since oxygen and nitrogen are highly electronegative atoms, the O-H and N-H
bonds that are present in protic solvents result in a hydrogen that is positively
polarized. When protic solvents are used in nucleophilic substitution reactions, the
positively polarized hydrogen of the solvent molecule can interact with the
negatively charged nucleophile. In solution, molecules or ions that are surrounded
by these solvent molecules are said to be solvated. Solvation is the process of
attraction and association of solvent molecules with ions of a solute. The solute, in
this case, is a negatively charged nucleophile.

The following diagram depicts the interaction that can occur between a protic
solvent and a negatively charged nucleophile. The interactions are called hydrogen
bonds. A hydrogen bond results from a from a dipole-dipole force between between
an electronegative atom, such as a halogen, and a hydrogen atom bonded to
nitrogen, oxygen or fluorine. In the case below, we are using an alcohol (ROH) as an
example of a protic solvent, but be aware that this interaction can occur with other
solvents containing a positively polarized hydrogen atom, such as a molecule of
water, or amides of the form RNH2 and R2NH.

Why is this important? Solvation weakens the nucleophile; that is, solvation
decreases nucleophilicity. This is because the solvent forms a "shell" around the
nucleophile, impeding the nucleophile's ability to attack an electrophilic carbon.
Furthermore, because the charge on smaller anions is more concentrated, small
anions are more tightly solvated than large anions.

The picture below illustrates this concept. Notice how the smaller fluoride anion is
represented as being more heavily solvated than the larger iodide anion. This
means that the fluoride anion will be a weaker nucleophile than the iodide anion. In
fact, it is important to note that fluoride will not function as a nucleophile at all in
protic solvents. It is so small that solvation creates a situation whereby fluoride's

Dr Md Ranzu Ahmed, Associate Professor, Dept of Chemistry, BUHS 15

lone pair of electrons are no longer accessible, meaning it is unable to participate in
a nucleophilic substitution reaction.

Previously we learned how nucleophilicity follows basicity when moving across a

row. In our discussion on the effect of protic solvents on nucleophilicity, we learned
that solvation weakens the nucleophile, having the greatest effect on smaller
anions. In effect, when using protic solvents, nucleophilicity does not follow basicity
when moving up and down a column. In fact, it's the exact opposite: when basicity
decreases, nucleophilicity increases and when basicity increases, nucleophilicity
decreases.

Aprotic Solvents

Dr Md Ranzu Ahmed, Associate Professor, Dept of Chemistry, BUHS 16

An aprotic solvent is a solvent that lacks a positively polarized hydrogen. The
next diagram illustrates several polar aprotic solvents that you should become
familiar with.

Aprotic solvents, like protic solvents, are polar but, because they lack a positively
polarized hydrogen, they do not form hydrogen bonds with the anionic nucleophile.
The result, with respect to solvation, is a relatively weak interaction between the
aprotic solvent and the nucleophile.

The consequence of this weakened interaction is two-fold. First, by using an aprotic

solvent we can raise the reactivity of the nucleophile. This can sometimes have
dramatic effects on the rate at which a nucleophilic substitution reaction can occur.
For example, if we consider the reaction between bromoethane and potassium
iodide, the reaction occurs 500 times faster in acetone than in methanol.

A second consequence that results from the weak interaction that occurs between
aprotic solvents and nucleophiles is that, under some conditions, there can be an
inversion of the reactivity order. An inversion would result in nucleophilicity
following basicity up and down a column, as shown in the following diagram. When

Dr Md Ranzu Ahmed, Associate Professor, Dept of Chemistry, BUHS 17

we considered the effects of protic solvents, remember that the iodide anion was the
strongest nucleophile. Now, in considering aprotic solvents under some conditions,
the fluoride anion is the strongest nucelophile.

Increasing Atomic Size Increases Nucleophilicity

Thus far, our discussion on nucleophilicity and solvent choice has been limited to
negatively charged nucleophiles, such as F-, Cl-, Br-, and I-. With respect to these
anions we learned that, when using protic solvents, nucleophilicity does not follow
basicity, and when using aprotic solvents, the same relationship can occur, or there
could be an inversion in the order of reactivity.

What happens as we move up and down a column when considering uncharged

nucleophiles? It turns out that, in the case of uncharged nucleophiles, size dictates
nucleophilicity. This is because larger elements have bigger, more diffuse, and more
polarizable electron clouds. This cloud facilitates the formation of a more effective
orbital overlap in the transition state of bimolecular nucleophilic substitution (SN 2)
reactions, resulting in a transition state that is lower in energy and a nucleophilic
substitution that occurs at a faster rate.

Dr Md Ranzu Ahmed, Associate Professor, Dept of Chemistry, BUHS 18

Sterically Hindered Nucleophiles React More Slowly

In the section Kinetics of Nucleophilic Substitution Reactions, we learned that the

SN2 transition state is very crowded. Recall that there are a total of 5 groups
around the electrophilic center.

For this reason, sterically hindered nucleophiles react more slowly than those
lacking steric bulk.

Dr Md Ranzu Ahmed, Associate Professor, Dept of Chemistry, BUHS 19

Dr Md Ranzu Ahmed, Associate Professor, Dept of Chemistry, BUHS 20