ORGANIC CHEMISTRY-II MSCCH-507

2.0 OBJECTIVES

Objective of this unit, Aromatic Nucleophilic Substitution reaction is to make students

aware about the SNAr, S N1, benzyne and SNR1 mechanism. This chapter will also provide
knowledge of reactivity effect of substrate structure, leaving group and attacking nucleophile.
Besides important name reactions of synthetic utility alongwith the von Richter, Sommelet-
Hauser and Smiles rearrangements.

2.1 INTRODUCTION

A Nucleophilic Aromatic Substitution reaction is a reaction in which one of the substituent's

in an aromatic ring is replaced by a nucleophile (Ipso Substitution).

X Nu

Nu

X
R R
X= halogen etc.
Nu= nucleophile

Unlike aliphatic compounds having a nucleophilic group as a leaving group, aromatic

compound having the same group bonded directly to the aromatic rings, which do not
undergo nucleophilic substitution under ordinary conditions. This unusual reactivity of
aromatic compounds arises due to the presence of a lone pair of electrons/π-bond on the
leaving group/key atom. As a result result of delocalization of this lone pair of e - / π-bond
through conjugation with the π e - of the ring, there is partial double bond character between
the carbon of the ring and the key atom. Thus, the key atom/leaving group become soundly
bonded to the aromatic ring and cannot be replaced by easily.

L L L L

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Another reason for the low reactivity is the aromatic rings behave like a nucleophile due to
the presence of electron cloud above and below the plane of aromatic rings. This shields
the ring carbon from the attack of a nucleophile.

Aromatic nucleophilic substitution may take place in extreme conditions like high pressure
or high temperature or both, catalyst etc. Aromatic nucleophilic substitution reactions
undergoes with less difficulties by proper substitution of aromatic rings with –R or –I group
at ortho or para or both the positions and aromatic nucleus having electronegative
heteroatom (O, N, S etc.) because –R or –I group are the activating groups for aromatic
nucleophilic substitution. These groups decrease electron density on the aromatic ring and
activate it for nucleophilic substitution. There are four principal mechanisms for aromatic
nucleophilic substitution. Each of the four is similar to one of the aliphatic nucleophilic
substitution mechanisms.

1. The SNAr Mechanism

2. The SN1 Mechanism
3. The Benzyne Mechanism
4. The SRN1 Mechanism

2.2 THE SNAr MECHANISM

The IUPAC designation is AN+DN (the same as for the tetrahedral mechanism). This
mechanism is generally found where activating groups are present on the ring. Nucleophilic
aromatic substitution (SNAr) mechanism consists of following two main steps:

Step 1: Attack of the nucleophilic species at the ipso carbon (the carbon bearing the
leaving group) of the aromatic ring. It is a rate determining step (not always).

Y Y
Y
X
slow X X
Y ipso X
addition

Meisenheimer complex

Step 2: Elimination of the leaving group and regeneration of the aromatic ring.

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Y Y
fast X
X elimination

It resembles the arenium ion mechanism of aromatic electrophilic substitution. In both the
cases (aromatic nucleophilic substitution & aromatic electrophilic substitution), the
attacking species form a bond with the substrate, giving an intermediate and then the
leaving group depart, i.e., both involve an addition elimination process.

2.2.1 Evidence for Nucleophilic aromatic substitution (SNAr) mechanism:

1. Probably the most convincing evidence for nucleophilic aromatic substitution

mechanism was the isolation of Meisenheimer or Meisenheimer–Jackson salts
intermediate, prepapred by the reaction between 2,4,6-trinitrophenetole and
methoxide ion. The structures have been proved by NMR and by X-ray
crystallography.

EtO OMe
OEt
O2N NO2
O2N NO2
etc.
OMe

N
NO2 O O
Meisenheimer-Jackson salts intermediate

2. Studies of the effect of the leaving group on the nucleophilic aromatic substitution
reaction. If the nucleophilic aromatic substitution mechanism were similar to either
the SN1 or SN2 mechanisms, the Ar–X bond would be broken in the rate-
determining step. In the nucleophilic aromatic substitution mechanism, this bond is
not broken until after the rate-determining step (i.e. if step 1 is rate determining).
There is some evidence that electron transfer may be operative during this process.
We would predict from this that if the S NAr mechanism is operating, a change in
leaving group should not have much effect on the reaction rate. In the reaction of
dinitro compound with piperidine, when X was Cl, Br, I, SOPh, SO 2Ph, or p-
nitrophenoxy, the rates differed only by a factor of 5.

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NO2 N
O2N X
N
NO2
NO2
H

This behavior would not be expected in a reaction in which the Ar–X bond is
broken in the rate-determining step. We do not expect the rates to be identical,
because the nature of X affects the rate at which Y attacks. An increase in the
electronegativity of X causes a decrease in the electron density at the site of attack,
resulting in a faster attack by a nucleophile. The very fact that fluoro is the best
leaving group among the halogens in most aromatic nucleophilic substitutions is
good evidence that the mechanism is different from the S N1and the SN2
mechanisms, where fluoro is by far the poorest leaving group of the halogens.

Some examples of nucleophilic aromatic substitution (SNAr) reaction:

a. With substrate having no activating group.

Cl

300oC CuCN/ o
C
Aq. NaOH Aq. NH3/ oC 200
200 atm 200
Cu2O Pyridine

OH NH2 CN

b. With substrates having activating group (s)

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Cl
1 .

NO2

o
NH3/EtOH o 150 C 200 C
NaOH

NH2 OH

NO2 NO2

2.
OMe OH

NaOH
Temp.

NO2
NO2

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NH2

NO2
NH3
o
170 C

3 . NO2
Cl OH

NO2 NO2
aq Na2CO3

NO2
NO2
NHNH2

NO2
NH2NH2
o
130 C

NO2

2.3 THE SN1 MECHANISM

A unimolecular SN1 mechanism (IUPAC: DN+AN) is very rare; it has only been observed
for aryl triflates in which both ortho positions contain bulky groups (tert-butyl or SiR 3). A
unimolecular SN1 mechanism are mainly given by aromatic diazonium salts.

ArN N Nu Ar Nu N2
Mechanism:

Step 1:

N N
N2

Step2:

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Y
Y

Aryl cation is highly unstable but nitrogen is highly stable. Hence nitrogen is very good
leaving group, this makes the generation of aryl cation extremely easy.

2.3.1 Evidence for a unimolecular SN1 mechanism

1. The reaction rate is first order in diazonium salt and independent of the concentration of
nucleophile.

2. When high concentrations of halide salts are added, the product is an aryl halide but the
rate is independent of the concentration of the added salts.

3. The effects of ring substituents on the rate are consistent with a unimolecular rate-
determining cleavage e.g., electron releasing m substituents (OH, OMe, Me, etc.) increase
the rate and electron withdrawing m substituents (COOH, NO 2, Cl, etc.) decrease the rate
of reaction.

4. When reactions were run with substrate deuterated in the ortho position, isotope effects of
1.22 were obtained. It is difficult to account for such high secondary isotope effects in any
other way except that an incipient phenyl cation is stabilized by hyperconjugation, which is
reduced when hydrogen is replaced by deuterium.

H
H

Some examples of unimolecular SN1 reactions of aromatic diazonium cation are given
below:

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N N

H2O X N3 CH3OH N2
N2 N2 N2

X N3 OCH3
OH

H
H

2.4 THE BENZYNE (ARYNES) MECHANISM

Some aromatic nucleophilic substitutions are clearly different in character from those that
occur by the SNAr mechanism or the SN1 mechanism. Unactivated aryl halides having at
lest one hydrogen in ortho position undergo nucleophile substitution with a very strong
base like potassium amide or sodium amide in liquid ammonia. The reaction also occurs
with bases such as PhLi and BuLi. This reaction proceeds through benzyne (aryne)
intermediate and the mechanism is called benzyne (aryne) mechanism.
Some important facts involve in the benzyne (arynes) mechanism are:
i. Substitutions occur on aryl halides that have no activating groups.
ii. Bases are required that are stronger than those normally used.
iii. The incoming group does not always take the position vacated by the leaving
group (Cine substitution).
Example of aromatic nucleophilic substation via benzyne:

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CPh3
Ph3C

Cl
KNH2

chlorobenzene benzyne NH3

NH2

2.4.1 Benzyme (Aryne) Mechanism: This mechanism involves elimination followed by

addition. Hence, it is called elimination-addition mechanism of aromatic nucleophilic
substitution.
Step 1: a suitable base removes the ortho hydrogen, with subsequent (or
concomitant) loss of the chlorine (leaving group) to generate symmetrical
intermediate is called benzyne.

Cl
NH2
NH3 Cl

Step 2: benzyne is attacked by the

NH3
NH3 NH2
NH3

Evidence in support of the benzyne (aryne) mechanism:

i. 1-14C-chlorobenzene reacts with potassium or sodium amide in liquid ammonia
gives almost equal amounts of 1-14C-aniline and 2-14c-aniline, due to the
formation of symmetrical intermediate benzyne.
14 NH2
NH3

14 Cl 14
KNH2/NH3

14
H
NH3
NH2

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ii. Aryl halides having no hydrogen, ortho to the halogen do not react under the
same conditions.

Br
H3C CH3
KNH2
No Reaction
NH3

CH3

iii. Benzynes are usually detected by spectroscopy or by their participation in

dimerisation and trapping through cycloaddition.

dimerisation
2

cycloaddition

cycloaddition

2.5 THE SRN1 MECHANISM

When 5-iodo-1,2,4-trimethylbenzene treated with KNH 2 in NH3, gives A and B in the ratio
0.63:1. The presence of an unactivated substrate and a strong base, the cine substitution
occur along with normal substitution product indicate that the reaction proceeds through
the benzyne mechanism. However the 6-iodo isomer of 5-iodo-1,2,4-trimethylbenzene
should have given A and B in the same ratio (because the same aryne intermediate would
be formed in both cases), but in this case the ratio of A–B was 5.9:1 (the chloro and bromo
analogs did give the same ratio, 1.46:1, showing that the benzyne mechanism may be taking
place there).

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CH3 CH3
CH3
CH3 H2N CH3
CH3
NH2

I H2N
CH3 CH3
CH3
5 Iodo A B
1,2,4 trimethylbenzene

To explain the result of iodo analogue of 5-iodo-1,2,4-trimethylbenzene, it has been proposed

that besides the benzyne mechanism, this free-radical mechanism is also operating here:

electron
ArI ArI Ar I
donor

ArI
Ar NH ArNH ArNH ArI
2 2 2

This is called the SRN1 mechanism (The IUPAC designation is T+D N+AN). The above
reaction involves a chain mechanism. An electron donor is required to initiate the reaction
and solvated electrons from KNH2 in NH3.

2.5.1 Evidence for the SRN1 mechanism:

1. The addition of potassium metal (a good producer of solvated electrons in

ammonia) completely suppressed the cine substitution.
2. Addition of radical scavengers (which would suppress a freeradical mechanism)
led to A:B ratios much closer to 1.46:1.
3. Some 1,2,4-trimethylbenzene was found among the products. This could be
easily formed by abstraction of H by Ar from the solvent NH3.
4. Besides initiation by solvated electrons, SRN1 reactions have been initiated
photochemically, electrochemically, and even thermally.
The SRN1 reactions have a fairly wide scope. The efficiency of the reaction has been traced to
the energy level of the radical anion of the substitution product. There is no requirement for

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activating groups or strong bases, but in DMSO haloarenes are less reactive as the stability
of the anion increases. The reaction has also been done in liquid ammonia, promoted by
ultrasound and ferrous ion has been used as a catalyst. Alkyl, alkoxy, aryl, and COO-
groups do not interfere, although Me2N, O-, and NO2 groups do not interfere.

2.6 EFFECTS OF REACTIVITY & STRUCTURE, LEAVING

GROUP AND ATTACKING NUCLEOPHILE

2.6.1 The Effect of Substrate Structure:

Generally, ArSN2 reactions are accelerated by electron withdrawing groups, especially in
the ortho and para positions to the leaving group and retarded by electron donating groups.
Heteroatoms of the ring are also strongly activating e.g., nitrogen which is more activating
when quaternized. The decreasing order of activating power of some groups in Ar SN2
reaction is given below:
NH3>NO2>CF3>CN>SO3H>CHO>CO>COOH>COOR>CONH2>F>Cl>Br>I
2.6.2 The Effect of the Leaving Group:
The common leaving groups in aliphatic nucleophilic substitution (halide, sulfate,
sulfonate, NR3+, etc.) are also common leaving groups in aromatic nucleophilic
substitutions, but the groups NO2, OR, OAr, SO2R and SR, which are not generally lost in
aliphatic systems, are leaving groups when attached to aromatic rings. Surprisingly, NO 2 is
a particularly good leaving group. An approximate order of leaving-group ability is F >
NO2 > OTs > SOPh > Cl, Br, I > N3 > NR3+> OAr, OR, SR, NH2. However, this depends
greatly on the nature of the nucleophile, as illustrated by the fact that C 6Cl5OCH3 treated
with NH2- gives mostly C6Cl5NH2; that is, one methoxy group is replaced in preference to
five chlorines. As usual, OH can be a leaving group if it is converted to an inorganic ester.
Among the halogens, fluoro is generally a much better leaving group than the other
halogens, which have reactivities fairly close together. The order is usually Cl > Br > I, but
not always. The leaving-group order is quite different from that for the SN1 or SN2
mechanisms. The most likely explanation is that the first step of the SNAr mechanism is
usually rate determining, and this step is promoted by groups with strong –I effects. This
would explain why fluoro and nitro are such good leaving groups when this mechanism is
operating. Fluoro is the poorest leaving group of the halogens when the second step of the
SNAr mechanism is rate determining or when the

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benzyne mechanism is operating. The four halogens, as well as SPh, NMe3-, and
OPO(OEt)2, have been shown to be leaving groups in the S RN1 mechanism. The only
important leaving group in the SN1 mechanism is N +.
2

2.6.3 The effect of the attacking nucleophile:

It is not possible to construct an invariant nucleophilicity order because different substrates

and different conditions lead to different orders of nucleophilicity, but an overall approximate
order is -NH2 > Ph3C- > PhNH- (aryne mechanism) > ArS- > RO- > R2NH > ArO->-OH >
ArNH2 > NH3 > I- > Br- > Cl- > H2O > ROH. As with aliphatic nucleophilic substitution,
nucleophilicity is generally dependent on base strength and nucleophilicity increases as the
attacking atom moves down a column of the periodic table, but there are some surprising
exceptions, for example, -OH, a stronger base than ArO-, is a poorer nucleophile. In a series
of similar nucleophiles, such as substituted anilines, nucleophilicity is correlated with base
strength. Oddly, the cyanide ion is not a nucleophile for aromatic systems, except for
sulfonic acid salts and in the von Richter and Rosenmund-von Braun reactions, which are
special cases.

2.7 VON RICHTER REARRANGEMENT

The Von-Richter reaction, also named Von-Richter rearrangement & it is named after
Victor von Richter, who discovered this reaction in year 1871. In this reaction, aromatic
nitro compounds with potassium cyanide giving carboxylation ortho to the position of the
former nitro group. As with other aromatic nucleophilic substitutions, the reaction gives
best results when an electron-withdrawing group (Z) is present in ortho and/or para
positions. For example-conversion of bromonitrobenzene into bromobenzoic acid in the
presence of cyanide ion.

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