Reactivity - Lesson 3 - Aromatic Substitution: Nucleophilic and Organometallic - Introduction - March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (2013)

March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (2013)

Part II. Introduction

Chapter 13. Aromatic Substitution: Nucleophilic and Organometallic

13.B. Reactivity

13.B.i. The Effect of Substrate Structure

In the discussion of electrophilic aromatic substitution (Chapter 11), equal attention was paid to the effect of substrate structure on reactivity (activation or deactivation) and on orientation. The question of orientation was important because in a typical substitution there are four or five hydrogen atoms that could serve as leaving groups. This type of question is much less important for aromatic nucleophilic substitution, 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.

SNAr Mechanism. These substitutions are accelerated by electron-withdrawing groups, especially in positions ortho and para to the leaving group72 and hindered by electron-attracting groups. This is, of course, opposite to the effects of these groups on electrophilic substitutions, and the reasons are similar to those discussed in Section 11.A.i. When attached to a benzene ring, the rate of reaction depends on the substituent.73 Activating groups include 2-nitro,74,75 N2+, NO, or C=N units with stong nucleophiles and when a nitro group is attached to SO2Me, NMe3 CF3 CN, CHO, COR CO2H, SO3, halogen, H, Me, or OMe activate.73 Table 13.1 contains a list of groups arranged approximately in order of activating or deactivating ability.73–7676 Nitrogen atoms are also strongly activating (especially to the α and γ positions) and are even more so when quaternized.77 Both 2- and 4-chloropyridine, for example, are often used as substrates. Heteroaromatic amine N-oxides are readily attacked by nucleophiles in the 2 and 4 positions, but the oxygen is generally lost in these reactions.78 The most highly activating group (N2+) is seldom deliberately used to activate a reaction, but it sometimes happens that in the diazotization of a compound (e.g., p-nitroaniline or p-chloroaniline), the group para to the diazonium group is replaced by OH from the solvent or by X from ArN2+ X√ untouched. By far, the most common activating group is the nitro group and the most common substrates are 2,4-dinitrophenyl halides and 2,4,6-trinitrophenyl halides (also called picryl halides).79 Polyfluorobenzenes80 (see 11) also undergo aromatic nucleophilic substitution quite well.81 Benzene rings that lack activating substituents are generally not useful substrates for the SNAr mechanism, because the two extra electrons in 1 are in an antibonding orbital (Sec. 2.A). Activating groups, by withdrawing electron density, are able to stabilize the intermediates and the transition states leading to them. Reactions taking place by the SNAr mechanism are also accelerated when the aromatic ring is coordinated with a transition metal.82

Just as electrophilic aromatic substitutions were found more or less to follow the Hammett relationship (with σ+ instead of σ; see Sec. 9.C) so do nucleophilic substitutions, with σ instead of σ for electron-withdrawing groups.83

Benzyne Mechanism. Two factors affect the position of the incoming group, the first being the direction in which the aryne forms.84 When there are groups ortho or para to the leaving group, there is no choice:

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but when a meta group is present, the aryne can form in two different ways:

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In such cases, the more acidic hydrogen is removed. Since acidity is related to the field effect of Z, it can be stated that an electron-attracting Z favors removal of the ortho hydrogen while an electron-donating Z favors removal of the para hydrogen. The second factor is that the aryne, once formed, can be attacked at two positions. The favored position for nucleophilic attack is the one that leads to the more stable carbanion intermediate. This in turn also depends on the field effect of Z. For -I groups, the more stable carbanion is the one in which the negative charge is closer to the substituent. These principles are illustrated by the reaction of the three dichlorobenzenes (13-15) with alkali metal amides to give the predicted products shown. In each case, the predicted product was the one chiefly formed.85 The observation that m-aminoanisole is obtained, mentioned in Section 13.A.iii, is also in accord with these predictions.

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Table 13.1 Groups Listed in Approximate Descending Order of Activating Ability in the SNAr Mechanism73

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13.B.ii. The Effect of the Leaving Group86

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, SO2R87, 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.88 An approximate order of leaving-group ability is89 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 C6Cl5OCH3 treated with NH2 gives mostly C6Cl5NH2; that is, one methoxy group is replaced in preference to five chlorines.90 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.91 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.60 The only important leaving group in the SN1 mechanism is N2+.

13.B.iii. The Effect of the Attacking Nucleophile92

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 img img img.93 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 (e.g., img), a stronger base than ArO, is a poorer nucleophile.94In a series of similar nucleophiles (e.g., 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 (13-30) and Rosenmund–von Braun (13-8) 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.95