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Vicarious Nucleophilic Substitution (VNS)

Vicarious Nucleophilic Substitution allows the nucleophilic replacement of hydrogen in nitroaromatics and heteroaromatics by using carbanions that bear leaving groups at the nucleophilic center.

Mechanism of the Vicarious Nucleophilic Substitution

It was well known that polynitroarenes form stable adducts with various nucleophiles (Meisenheimer complexes) and that bond formation to carbon atoms bearing hydrogen is faster than to those bearing other substituents, including halogens. However, no general nucleophilic replacement of hydrogen was known until the end of the 1970s, when Mieczysław Makosza began elaborating the direct nucleophilic replacement of hydrogen in electrophilic arenes.

He hypothesized that σ-adducts formed from carbanions that contain leaving groups at the carbanionic center proceed to lose the leaving group. This was first proven by treatment of nitrobenzene with chloromethyl phenyl sulfone.

As the chloride in this case acts vicariously as a leaving group, the reaction was named "vicarious nucleophilic substitution of hydrogen" (VNS).

In typical vicarious nucleophilic substitutions, nitroarenes react with carbanions that are usually generated from active methylenes by reaction with a base that is also consumed in a later elimination step. Thus, the reaction runs best with more than two equivalents of a strong base. The proper choice of solvent and base assures a fast deprotonation of the active methylenes and a fast β-elimination from the σ-adducts. The nitrobenzylic carbanions that form are highly colored (blue, red, etc.), which offers some diagnostic value. Acidic work-up leads to the products.

For VNS of substituted nitroarenes: 4-substituted nitroarenes give only one product (VNS ortho to nitro group), whereas 2- and 3-substituted nitroarenes normally lead to mixtures of isomeric products (VNS ortho and para to nitro group). In halonitroarenes, VNS is normally faster than aromatic nucleophilic substitution of halogen, except for 2- or 4-F-substituted nitroarenes where fluoride is a superior leaving group.

Nucleophilic substitution is disfavored by direct conjugation of anions, such as in the case of nitrophenolates. As the nitrobenzylic carbanions themselves do not add nucleophiles, the reaction is very selective for monosubstitution. However, a second or third nitro group substituent compensates the negative charge, although here the rates of introduction of the substituents are very different.

VNS reactions have been reported between chloromethyl sulfone and heterocycles such as 2- and 3-nitrothiophenes, 2-nitrofurans, 2-, 3- and 4-nitropyridines and many others.

For nitropyrroles, replacement of the acidic N-H by an alkyl group is necessary because the nitropyrrole anion itself does not undergo VNS.

For carbanions stabilized with sulfonyl groups or phosphorus-containing substituents, chloride is a convenient leaving group. For α-cyanoalkylation, though, (thio-)phenoxy nitriles (leaving group: PhO or PhS) often assure better yields, because the chloronitriles are frequently unstable in basic media or undergo fast self-condensation. For α-carboalkoxyalkylation, carbanions of esters that contain PhS are of general use, although ethyl α-chloropropionate and α-chlorobutyrate also afford VNS products, often in good yields. The following are some examples of suitable nucleophiles:

As both the addition and elimination step are sensitive to steric effects, tertiary carbanions (R: Me, Ph,...) react preferably at the para position.

A general overview of VNS, including detailed mechanistic discussions and examples dealing with the synthesis of heterocycles in which VNS is used for ring closure, can be found in a review written by Makosza and Winiarski (Acc. Chem. Res. 1987, 20, 282. DOI). For recent applications of VNS, including protocols for amination and hydroxylation, please also refer to the recent literature section in this site.

Recent Literature

para-Formylation of nitroarenes via vicarious nucleophilic substitution of hydrogen with tris(benzotriazol-1-yl)methane
A. R. Katritzky, L. Xie, Tetrahedron Lett., 1996, 37, 347-350.

1,1,1-Trimethylhydrazinium Iodide: A Novel, Highly Reactive Reagent for Aromatic Amination via Vicarious Nucleophilic Substitution of Hydrogen
P. F. Pagoria, A. R. Mitchell, R. D. Schmidt, J. Org. Chem., 1996, 61, 2934-2935.

Hydroxylation of Nitroarenes with Alkyl Hydroperoxide Anions via Vicarious Nucleophilic Substitution of Hydrogen
M. Makosza, K. Sienkiewicz, J. Org. Chem., 1998, 63, 4199-4208.