Nucleophilic substitution in nitroarenes: a general corrected mechanism
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Nucleophilic substitution in electron-deficient arenes is one of the fundamental processes in organic chemistry; however, its mechanism as presented in textbooks does not adequately describe the process. According to this generally accepted mechanism, it is limited to substitution of halogens via nucleophilic addition at positions occupied by halogens. The possibility of addition at positions occupied by hydrogen is totally ignored. Research papers have shown that nucleophilic addition at positions occupied by hydrogen is a fast and reversible process, and σH adducts are initially formed as intermediates. These σH adducts can be converted into products of nucleophilic substitution of hydrogen in a few different ways or dissociate so that substitution of halogen can proceed. This general picture is confirmed by many examples presented.
KeywordsArenes Nitro compounds Nucleophilic substitution Aromatic substitution Carbanions
Recently, on the basis of detailed mechanistic studies and calculations, a conclusion was drawn that in some cases, due to the high rate of the departure of X−, the lifetime of the hypothetical intermediate σX is negligible, and hence the reaction proceeds as a concerted process and the σX adducts are in fact transition states [5, 6, 7, 8].
This hypothesis, when confirmed, shall significantly expand the scope and versatility of the nucleophilic aromatic substitution, which should embrace nucleophilic substitution of hydrogen and halogens. Moreover, it should require revision of the commonly accepted mechanism of this reaction. This hypothesis can be confirmed provided that processes for fast conversion of the initially formed σH adducts into products of substitution of hydrogen are designed and executed. Unlike halogen anions that depart spontaneously from the σX adducts (Scheme 4, path a), spontaneous departure of the hydride anion from the σH adducts does not occur; thus it should be removed in a separate operation. Direct removal of hydride anions from organic molecules proceeds under the action of oxidants, and hence one could expect that treatment of the σH adducts with external oxidants should result in the formation of the products of oxidative nucleophilic substitution of hydrogen (ONSH). Alternatively, the hydrogen can be removed from the anionic σH adducts in the form of protons. This seemingly paradoxical process can be realized by means of base-induced β-elimination.
Regardless of how the conversion of the σH adducts occurs in subsequent processes, it is feasible when the equilibrium 4b ensures sufficient concentration and lifetime of the σH adducts. The position of the equilibrium is a function of the electrophilic activity of arenes and the nucleophilicity of the nucleophiles, as well as the reaction conditions—solvents, and particularly temperature. Due to the entropy effects, low temperature favors the addition; thus many processes of SNArH are realized at low temperatures.
Oxidation of the anionic σH adducts
nucleophiles are resistant towards oxidation;
the addition equilibrium is shifted towards adducts, and in an extreme case the addition proceeds irreversibly; and
the rates of oxidation of the σH adducts are higher than the oxidation of nucleophiles.
Taking into account the scope and versatility of oxidative nucleophilic substitution of hydrogen, ONSH is presently a valuable methodology in organic synthesis. A few examples presented above unambiguously confirm the hypothesis shown in Scheme 4b.
Conversion of the σH adducts into substituted nitrosoarenes
Removal of hydrogen from the anionic σH adducts in the form of protons via base-induced β-elimination
When this reaction is carried out at room temperature or lower in the presence of excess t-BuOK, VNS at the ortho position proceeds exclusively (path a). On the other hand, under conditions that favor equilibration and disfavor β-elimination, as for example in the slow addition of a solution of the carbanion to p-fluoronitrobenzene at temperatures above 20 °C, SNAr of fluorine is the main process (path b) [28, 29]. These simple experiments unambiguously confirm that even in the case of p-fluoronitrobenzene, the addition of the carbanion at position ortho occupied by hydrogen is the fast primary and reversible process and that conversion of the σH adducts proceeds via base-induced β-elimination of HCl. Detailed mechanistic studies have provided further pieces of evidence of this picture .
As a rule, both of these reactions, VNS hydroxylation and amination, proceed faster with halonitroarenes than substitution of chlorine.
Summary: initial formation of anionic σH adducts is confirmed
Numerous examples of the conversion of the σH adducts of nucleophiles to nitroarenes and also halonitroarenes into products of nucleophilic substitution of hydrogen via oxidative and eliminative processes that proceed efficiently with a plethora of halonitroarenes provide unambiguous proof that the hypothesis formulated in Scheme 4 is correct. Therefore, it is necessary to accept that nucleophilic substitution of hydrogen proceeds faster than that of halogens, and to reject the commonly accepted mechanism of the SNAr reaction and formulate the following corrected general mechanism. The initial step of the reaction between nucleophiles and electron-deficient arenes is a fast and reversible addition at positions occupied by hydrogen to form σH adducts. When, due to the type of educts and conditions, further rapid conversion of the σH adducts into products of the substitution of hydrogen does not proceed, the σH adducts dissociate, and slower addition at positions occupied by halogens leads to conventional replacement of halogen. On the other hand, when, thanks to the nature of the educts and conditions, σH adducts can be rapidly converted into products of nucleophilic substitution of hydrogen, this process is dominant. Therefore, nucleophilic substitution of hydrogen is the fast primary process, whereas nucleophilic substitution of halogens is the secondary ipso reaction [39, 40]. Of course, the substitution of halogens is a secondary process with respect to rates, not to the importance of these processes. This mechanistic picture of SNAr reactions formulated on the basis of numerous experimental observations and studies is fully confirmed by ab initio calculations. The calculated rates of the addition of some nucleophiles at positions occupied by hydrogen of p-halonitrobenzenes are higher than the rates of addition at positions occupied by halogens [41, 42]. It should be mentioned that in the quantum chemical calculations of nucleophilic aromatic substitution published in numerous reports [4, 9, 10, 11], the possibility of the addition of nucleophiles to halonitrobenzenes at positions occupied by hydrogen is totally ignored. In my opinion, calculations of the reactions between two partners should search for a pathway with the lowest energy barrier, the lowest free energy of the transition state; thus these calculations, in spite of the high theoretical level, have a conceptual deficiency.
Does the addition proceed directly or via single-electron transfer (SET)?
To present a complete picture of nucleophilic aromatic substitution, the question of how the addition proceeds should also be discussed. It is well known that nitroarenes are active single-electron acceptors, and the exposure of nitroarenes to some nucleophiles and/or strong bases generates nitroaromatic anion radicals detected by electron spin resonance (ESR) spectroscopy . On the basis of these and related observations, a concept was formulated that the addition of nucleophiles to nitroarenes often proceeds not directly, but as a two-step process—SET—followed by anion-radical–radical coupling [44, 45, 46, 47]. Such a pathway was confirmed, for instance, for addition of the primary alkyl magnesium bromides to nitroarenes to form σH adducts on the basis of the radical clock criterion .
An interesting effect of conditions on the reaction pathway between carbanions of diphenylacetonitrile and o-chloronitrobenzene was observed .
SET from carbanions of sulfone A to a substituted nitrobenzene should result in the formation of short-lived cyclopropylmethyl radical ·A, which rearranges with the rate constant 109 s−1. As shown in Scheme 21, VNS by this carbanion proceeds without traces of rearrangement; hence intermediacy of the radical ·A is excluded, and the addition proceeds directly and not via SET.
The addition of nucleophiles to p-chloronitrobenzene, a model chloronitroarene, can proceed directly (paths aH and aCl) to produce σH and σCl adducts, or via SET, which initially produces nitroaromatic anion radical and radical Nu· followed by the combination of these paramagnetic species path bH and bCl to produce σH and σCl adducts identical to those produced via direct addition. According to the microscopic reversibility principle, dissociation of these σ adducts to form educts should proceed via identical transition states (identical pathways). Therefore, in the case of both of the σ adducts formed via SET, pathways bH and bCl, the dissociation of C–Nu and C–Cl bonds, should proceed via homolysis to produce nitroaromatic anion radicals and radical Nu· and chlorine atoms followed by SET from nitroaromatic anion radicals to Nu· and Cl·. Such a pathway of dissociation of the σH adducts, while possible, seems unlikely. However, homolysis of C–Cl bonds in anionic σCl adducts and generation of chlorine atoms is highly improbable. On the other hand, in my opinion, different routes for the conversion of the σCl adducts via dissociation of C‒Nu and C‒Cl bonds in terms of the microscopic reversibility principle are difficult to accept. It appears, therefore, that when the SNAr of halogens in halonitroarenes is preceded by reversible addition of the nucleophiles at positions occupied by hydrogen, and such reversibility can be confirmed, SET as the reaction pathway can be excluded.
Consequences and advantages of the use of the general mechanism of substitution
On the basis of the general mechanism discussed above, it was possible to determine the true effects of substituents on the electrophilic activity of nitroarenes. The effect of substituents on rates of nucleophilic substitution of halogens in halonitroarenes has been the subject of numerous studies [1, 2, 3, 4]. However, the results, although practically useful, cannot be considered as a measure of electrophilicity of nitroarenes, for two main reasons: (a) the rates of the substitution were dependent on the nature of the leaving groups, and (b) the substitution is a secondary process preceded by fast and reversible addition at positions occupied by hydrogen and formation of the σH adducts. The true effects of substituents on the electrophilic activity of nitroarenes were determined by measuring of the rates of nucleophilic addition at positions occupied by hydrogen [50, 51].
I certainly hope that the general mechanism presented in this paper will find a way to classrooms and textbooks and will be helpful in solving many synthetic problems. I also hope that the examples and reasoning presented in the paper will promote wider application of these processes in practical organic synthesis and will inspire the design of new reactions.
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