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Paper No and Title 5, ORGANIC CHEMISTRY-II (Reaction mechanism-1)

Module No and Title Module 34: Reactivity-effect of substrate structure, leaving group and attacking nucleophile in nucleophilic aromatic substitution reactions Module Tag CHE_P5_M34

CHEMISTRY PAPER : 5 , ORGANIC CHEMISTRY-II (Reaction Mechanism- I) MODULE : 34 Reactivity-effect of substrate structure, leaving group and attacking nucleophile in nucleophilic aromatic substitution reactions

TABLE OF CONTENTS

1. Learning Outcomes 2. Introduction 3. Factors Affecting Rate of Aromatic Nucleophilic substitution 3.1 Effect of Substrate Structure 3.2 Effect of Leaving Group 3.3 Effect of Attacking Nucleophile 4. Summary

1. Learning Outcomes

After studying this module, you shall be able to

 Know the differences between aliphatic and aromatic nucleophilic substitution.  Learn about the factors which affect the rates of aromatic nucleophilic substitution reaction.

 Identify suitable substrates, leaving groups and incoming nucleophiles for SRN1

reactions, benzyne reactions and SN1 and SN2 type reactions.  Analyze factors governing suitability of reaction conditions for nucleophilic aromatic substitution reactions

2. Introduction

There are differences between aliphatic and aromatic nucleophilic substitution reactions. The

most important mechanisms for aromatic nucleophilic substitution (SNAr) are

1. SN1 type 2. The addition-elimination mechanism 3. Elimination-addition mechanism or the benzyne mechanism

4. Substitution involving radicals (SRN1) For aromatic nucleophilic reactions the basic mechanisms are SNAr, benzyne

mechanism, SN1 mechanism and SRN1 mechanism. The reactivity considerations are quite unimportant for aromatic nucleophilic reactions since in most cases there is only one potential leaving group in a molecule. Therefore attention is largely focused on the reactivity of one molecule compared with another and not on the comparison of the reactivity of different positions within the same molecule.

3. Factors Affecting Rate of Aromatic Nucleophilic Substitution

The common factors influencing rate of all three of these mechanisms are substrate structure, leaving group and solvent. We shall discuss each of them separately.

3.1 Effect of Substrate Structure

The SNAr mechanisms follow addition-elimination steps, where, first the incoming nucleophile gets attached to the substrate and then elimination of leaving group takes place. In this type of reactions, aryl halides (with suitably placed substituents) react with strong nucleophiles to give substitution products. Interestingly, such reactions proceed via an anionic intermediate called “Meisenheimer complex”. Since, it is difficult for a nucleophile to attack an electron rich ring, when the aromatic ring contains deactivating or electron withdrawing groups, the reactions go faster. If the electron withdrawing groups are present on the ortho or para positions to the leaving group, great accelerations in rate of reactions have been observed. On the contrary, if the substrate has electron donating substituents, then reactions go slower. For common substituents following is the

order of increasing ability to activate aromatic rings for SNAr substitutions

+ + - N2 >NO>NO2>SO2Me>NMe3 >CF3>CN>CHO>COR>COOH>SO3 >Br>Cl>I>COO- >H

As can be seen, the nitrogen containing substituents act as good ligands enhancing rate of reactions manifolds. Of note, the position of substituents also greatly influence the rate of reaction for e.g., if the electron withdrawing nitro group is present at meta position than no delocalization of charge takes place and reactions become difficult.

Table 1: Groups listing in approximate descending order of activating ability in the

SNAr mechanism.

The benzyne mechanism of aromatic nucleophilic substitution involves elimination- addition, whereby, a distinct reaction intermediate benzyne is produced. In such reactions CHEMISTRY PAPER : 5 , ORGANIC CHEMISTRY-II (Reaction Mechanism- I) MODULE : 34 Reactivity-effect of substrate structure, leaving group and attacking nucleophile in nucleophilic aromatic substitution reactions

products with substitution on the carbon directly bonded to the leaving group or to the carbon adjacent to it are formed in equal proportion. The benzyne intermediate has a triple bond in benzene ring which makes it a highly reactive species. When ortho and para substituents are present on the substrate only one benzyne intermediate can formed as shown below:

Fig. 1: Benzyne mechanism of aromatic nucleophilic substitution at ortho and para positions

However, if meta substituents are present then two benzynes may be formed based on which protons are more acidic. More acidic protons will be removed for benzyne formation.

Fig. 2: Benzyne mechanism of aromatic nucleophilic substitution at meta position

The nature of substituent Z is decisive towards benzyne intermediate formation. An electron withdrawing Z group favors removal of the ortho hydrogen, whereas, an electron-releasing Z group favors removal of the para hydrogen. Also, once the aryne

intermediate is formed, there are two possible sites where the nucleophile may attack, again the field effect of substituent Z plays an important role and an intermediate carbanion which gets better stabilized by Z will be favored. For substituents with -I effect, the more stable carbanion is the one in which the negative charge is closer to the substituent.

3.2 Effect of 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, NO2 is a particularly good leaving group. However, this depends greatly on the nature of the ͞ nucleophile, as illustrated by the fact that C6Cl5OCH3 treated with NH2 gives mostly

C6Cl5NH2; that is, one methoxy group is replaced in preference to five chlorines.

Stable anions are good leaving groups which results in lowering the activation energy while reaction rate is increased. An approximate order of leaving-group ability is

+ F > NO2 > OTs > SOPh > Cl, Br, I > N3 > NR3 > OAr, OR, SR, NH2

Amongst the halogens, fluoro is generally a much better leaving group than the other halogens, because of its highest electronegativity, 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 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 SRN1 mechanism. The only important leaving group in the SN1 mechanism + is N2 .

3.3 Effect of Attacking Nucleophile It is not possible to construct an invariant nucleophilicity order since different substrates and different conditions lead to different orders of nucleophilicity, however, an overall approximate order is as given below:

͞ NH2 > Ph3C ͞ > PhNH ͞ (aryne mechanism) > ArS ͞ >RO ͞ > R2NH > ArO ͞ > ͞ OH

> ArNH2 > NH3 > I ͞ > Br ͞ >Cl ͞ > H2O > ROH

In case of aliphatic nucleophilic substitution, nucleophilicity is generally dependent on base strength and nucleophilicity increases as the attacking atom moves down a column in the periodic table, but there are some surprising exceptions (e.g., ͞ OH), a stronger base than ArO͞ , is a poorer nucleophile. In a series of similar nucleophiles (e.g., substituted anilines), nucleophilicity is correlated with base strength. Oddly enough, 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. Studies on the nature of the nucleophile continue. Indeed, the second order rate constants for vicarious nucleophilic substitution reactions of some carbanions were measured to define electrophilicity parameters for electron-deficient heteroarenes.

4. Summary

 The reactivity considerations are quite unimportant for aromatic nucleophilic reactions since in most cases there is only one potential leaving group in a molecule.  If the electron withdrawing groups are present on the ortho or para positions to

the leaving group, great accelerations in rate of reactions in case of SNAr reactions has been observed, however, the reverse is observed for electron donating groups.  For substituents with -I effect, the more stable carbanion is the one in which the negative charge is closer to the substituent in case of benzyne mechanism.  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.

 Fluoro and nitro are good leaving groups in SNAr reactions, but poor leaving groups in case of the benzyne mechanism depending upon the intermediates formed in the rate determining step.  In case of aliphatic nucleophilic substitution, nucleophilicity is generally dependent on base strength and nucleophilicity increases as the attacking atom moves down a column in the periodic table. However, there are many surprising exceptions to these facts also.