CHEMISTRY

PAPER No. : 5; Organic Chemistry-II MODULE No. : 32, Aromatic Nucleophilic substitution

Subject Chemistry

Paper No and Title 5; Organic Chemistry-II

Module No and Title Aromatic Nucleophilic substitution

Module Tag CHE_P5_M32

CHEMISTRY

PAPER No. : 5; Organic Chemistry-II MODULE No. : 32, Aromatic Nucleophilic substitution

TABLE OF CONTENTS 1. Learning Outcomes 2. Introduction 3. Mechanism of aromatic nucleophilic substitution 3.1 Addition/Elimination mechanisms 3.2 Elimination/Addition mechanisms 4. SN1 mechanism for Nucleophilic aromatic substitution 5. Summary

CHEMISTRY

PAPER No. : 5; Organic Chemistry-II MODULE No. : 32, Aromatic Nucleophilic substitution

1. Learning Outcomes

After studying this module, you shall be able to

• Know what are Aromatic Nucleophilic Substitution reactions • Learn mechanism of Aromatic Nucleophilic Substitution • Identify benzyne mechanism • Evaluate product formation as a result of Aromatic Nucleophilic Substitution • Analyze mechanistic differences between addition/elimination and elimination/addition

mechanisms

2. Introduction

Aromatic Nucleophilic Substitution

Nucleophilic substitutions on aromatic rings are relatively less common reactions that involve bond formation between aromatic carbon atom and nucleophile along with bond breaking to the leaving group. The reasons for less reactivity of aromatic rings to undergo nucleophilic substitution is the presence of aromatic ring π-electrons, which make the aromatic system an electron rich, that are more likely to be attacked by electrophile, rather than nucleophile. Secondly, the aromatic ring loses its stabilization due to the resonance by attack of nucleophile, which it subsequently gains by removal of leaving group. Therefore, overall under special substrate structure, nucleophile properties and reaction conditions, aromatic substitution reactions are facilitated, as we shall learn in the following sections.

3. Mechanism of Aromatic Nucleophilic Substitution

In general aromatic nucleophilic substitution reactions require:

i) A good nucleophile such as one carrying oxygen, nitrogen, or cyanide group

ii) A good leaving group such as halides

iii) Electron withdrawing substituents on the benzene ring such as carbonyl, nitro, or cyanide groups located ortho or para to the leaving group

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PAPER No. : 5; Organic Chemistry-II MODULE No. : 32, Aromatic Nucleophilic substitution

The mechanism of aromatic nucleophilic substitution can be divided into two major sets. One, which follows second order kinetics, and one, which follows first order kinetics. First, we shall look at reactions that follows second order kinetics, thus the rate of reaction is determined by concentration of both the reactant and nucleophile. Mechanistically, second order nucleophilic aromatic substitution can be defined by following two types:

a) Addition/elimination mechanism

b) Elimination/addition mechanism

3.1 Addition/elimination mechanism

Alkyl halides are common substrates reported to undergo aromatic nucleophilic substitution reactions (SNAr). Following is the general schematic for addition/elimination reaction:

As can be seen, it is a two step reaction, where, in the first step, the incoming nucleophile attacks at the same position where the leaving group is attached (such attack is called ipso attack). In the second step, the leaving group gets detached leading to regeneration of aromatic ring. As mentioned before for such mechanisms, suitable electron withdrawing groups on the substrate favors the reaction as they stabilize the intermediate carbanion. Evidence for this mechanism were known as early as in 1902, when a stable intermediate for the following reaction between 2,4,6-trinitrophenetole and methoxide ion was isolated. Intermediates of this type are stable salts, called Meisenheimer or Meisenheimer-Jackson salts.

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PAPER No. : 5; Organic Chemistry-II MODULE No. : 32, Aromatic Nucleophilic substitution

Meisenheimer-Jackson salt

Till date, a great number of such complex intermediates have been isolated and characterized by NMR and X-ray techniques.

Nucleophilic aromatic substitution occurs with a variety of strong nucleophiles, including –OH,–OR, –NH2, –SR, NH3 and RNH2. For these reactions the reactivity of nucleophiles is significantly enhanced if the reaction is carried out in polar, aprotic solvents. In polar solvents, the incoming nucleophile anion becomes soluble though it may not get stabilized by hydrogen bonds.

Further, the position of substituent that best facilitate the reaction is -ortho or -para substitution, this is because only then the negative charge acquired by the ring may get accommodated by the substituent as shown below. In contrast if the substituent is present on the meta position, no stabilization is achieved. This becomes clearer from the following resonating structures.

Increasing the number of electron-withdrawing groups also increase the reactivity of the aryl halides drastically towards nucleophilic substitutions as shown below:

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PAPER No. : 5; Organic Chemistry-II MODULE No. : 32, Aromatic Nucleophilic substitution

According to the Hammond postulate, electron-withdrawing groups stabilize the intermediate carbanion by lowering the energy of the transition state. Interestingly, increasing the electronegativity of the halogen atom in substrates increases the reactivity of the aryl halide. This trend is opposite to reactivity for aliphatic nucleophilic substitution, but the reason behind this is that a more electronegative halogen stabilizes the intermediate carbanion better by an inductive effect. Thus, aryl fluorides (ArF) are much more reactive than other aryl halides, which contain less electronegative halogens.

The SNAr reactions follow a second order kinetics according to the following equation:

Rate = k[aryl halide] [nucleophile]

Following data illustrates the significant differences observed between reactivity of alkyl halides.

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PAPER No. : 5; Organic Chemistry-II MODULE No. : 32, Aromatic Nucleophilic substitution

As can be seen, the reactivity of substituted aryl fluoride is almost 780 times more as compared to aryl iodide. Following diagram presents the reaction co-ordinates for a general aromatic Nucleophilic substitution reaction (SNAr).

As can be seen it involves two transition states for two consecutive steps.

The Chichibabin reaction exemplified below is an example of second order addition/elimination aromatic nucleophilic substitution reactions.

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PAPER No. : 5; Organic Chemistry-II MODULE No. : 32, Aromatic Nucleophilic substitution

In the reaction pyridine is attacked by a strong nucleophile NH2- which displaces hydride

ion. On treatment with water the desired 2-amino pyridine is obtained.

Another name reaction involving nucleophilic aromatic substitution is Von Richter rearrangement. It involves reaction of substituted aromatic nitro compounds with potassium cyanide to give rise to carboxylation of ortho position relative to the leaving nitro group.

These are extremely useful reactions to bring about introduction of carboxylic acid functionality in the ring.

3.2 Elimination/addition Mechanism

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PAPER No. : 5; Organic Chemistry-II MODULE No. : 32, Aromatic Nucleophilic substitution

Without a substituent it is hard for aryl halides to undergo nucleophilic substitution and only under drastic conditions they react with nucleophiles. For example, chlorobenzene can be converted into phenol by heating it with NaOH above 300 °C and at 170 atmosphere pressures.

Yet in another reaction p-chlorotoluene with strong base NaNH2 lead to the formation of para- and meta-substitution products. This result was surprising and explained by the fact that nucleophilic attacks on reaction intermediate at either C3 or C4 position. Such reactions indicate that nucleophilic aromatic substitution by an elimination-addition mechanism lead to products with substitution on the carbon directly bonded to the leaving group or to the carbon adjacent to it.

These elimination/addition reactions proceed via benzyne intermediates. The benzyne intermediate has a triple bond in benzene ring. The triple bond in benzyne is unusual as each carbon of the six-member ring is sp2 hybridized, and as a result, the σ bond and two π bonds of the triple bond are formed with the overlapping orbitals. Although, benzyne is

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PAPER No. : 5; Organic Chemistry-II MODULE No. : 32, Aromatic Nucleophilic substitution

best described as to having a strained triple bond, a biradical representation is also useful and describes properties of the system.

Benzyne intermediates are highly reactive and readily undergo Nucleophilic substitution reactions. Due to their high reactivity benzyne intermediates are synthetically useful to prepare various useful products. There are alternate ways to prepare benzyne and thus formed benzynes are used as diene component for the Diels Alder reaction.

Benzyne undergo Diels Alder reaction with anthracene to give a symmetrical cage structure as shown below

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PAPER No. : 5; Organic Chemistry-II MODULE No. : 32, Aromatic Nucleophilic substitution

4. SN1 Mechanism for Nucleophilic Aromatic Substitution

The SN1 mechanism represent first order nucleophilic substitution reactions, where, the rate of reaction depends only upon the nature of substrate and there is no effect of concentration of incoming nucleophile. Such substrates are rare to find unless highly substituted benzene rings are present or with diazonium salts. When primary aromatic amines are treated with nitrous acid (HONO) under cold conditions, they gave diazonium salts. These diazonium salts are good substrates for reactions proceeding via SN1 mechanisms. This is because in diazonium salts the leaving group is di-nitrogen, which is an excellent leaving group, and on leaving it affords a positive charge on benzene ring, making it available for attack by incoming nucleophiles.

Follwing are the few reactions of benzonium cation formed by diazonium salts.

As can be seen, these are very useful reactions affording the introduction of a variety of functional groups on the benzene ring under relatively mild conditions.

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PAPER No. : 5; Organic Chemistry-II MODULE No. : 32, Aromatic Nucleophilic substitution

5. Summary

• Aromatic nucleophilic substitution reactions involve attack of nucleophile on substituted aromatic rings and thus are relatively rare.

• Based on the order of reaction, aromatic nucleophilic substitutions are classified as unimolecular or bimolecular reactions.

• Bimolecular SNAr reactions operate via two mechanisms; addition/elimination or elimination/addition.

• Meisenheimer complexes are 1:1 reaction adducts intermediates in bimolecular nucleophilic aromatic substitution that are stable and isolated as early as in 1902.

• Aromatic nucleophilic substitutions are favored by electron withdrawing substituents on benzene ring and good leaving groups.

• Benzynes are highly reactive and synthetically useful intermediates with a strained triple bond in the benzene ring. They also possess some bi-radical character.

• Benzyne mechanism gives rise to regio-selectivity in product formation. • For unimolecular aromatic nucleophilic substitution diazonium salts are good

substrates as di-nitrogen is a good leaving group. • A number of useful name reactions such as Chichibabin reaction and Von Ritcher

rearrangement involve aromatic nucleophilic substitution mechanism.