Henry reaction

Stereochemical course

The figure below illustrates one of the commonly accepted models for stereoselection without any modification to the Henry reaction. In this model, stereoselectivity is governed by the size of the R groups in the model (such as a carbon chain), as well as by a transition state that minimizes dipole by orienting the nitro group and carbonyl oxygen anti each other (on opposite sides of the molecule). The R groups play a role in the transition state of the Henry reaction: the larger the R groups on each of the substrates, the more they will tend to orient themselves away from each other (commonly referred to as steric effects).

Due to the reversibility of the reaction and the tendency for easy epimerization of the nitro-substituted carbon atom (among a number of factors), the Henry reaction will typically produce a mixture of enantiomers or diastereomers. It is for this reason that explanations for stereoselectivity remain scarce without some modification of the reaction. In recent years, research focus has shifted toward modifications of the Henry reaction to overcome this synthetic challenge.

The first example of an enantioselective nitroaldol reaction was reported in 1992 using Shibasaki catalysts. One of the most frequently employed methods for inducing enantio- or diastereoselectivity in the Henry reaction is the use of chiral metal catalysts, in which the nitro group and carbonyl oxygen coordinate to a metal that is bound to a chiral organic molecule. Some metals that have been used include zinc, cobalt, copper, magnesium, and chromium. A depiction of this coordination is illustrated above.

General Features

One of the many features of the Henry reaction that makes it synthetically attractive is that it utilizes only a catalytic amount of base to drive the reaction. Additionally a variety of bases can be used including ionic bases such as alkali metal hydroxides, alkoxides, carbonates, and sources of fluoride anion (e.g. TBAF) or nonionic organic amine bases including TMG, DBU, DBN, and PAP. The base and solvent used do not have a large influence on the overall outcome of the reaction.

Limitations

One of the main drawbacks of the Henry reaction is the potential for side reactions throughout. Aside from the inherent reversibility of the reaction (or "retro–Henry") that can prevent the reaction from proceeding, the β-nitro alcohol also has the potential to undergo dehydration. For sterically hindered substrates, it is also possible for a base-catalyzed self-condensation (Cannizzaro reaction) to occur. A general scheme of the Cannizzaro reaction is depicted below.

Modifications

There have been a series of modifications made to the Henry reaction. Of these some of the most important include employing high-pressure and sometimes solvent free conditions to improve chemo- and regioselectivity and chiral metal catalysts to induce enantio-or diastereoselectivity. The aza-Henry reaction is also used to produce nitroamines and can be a reliable synthetic route for the synthesis of vicinal diamines.

Perhaps one of the most synthetically useful modifications to the Henry reaction is the use of an organocatalyst. The catalytic cycle is shown below.

Benjamin List described that while this is a broad explanation, his brief review illustrates that this is a plausible mechanistic explanation for almost all reactions that involve an organocatalyst. An example of this type of reaction is illustrated in the Examples section of this article.

Other modifications include the conversion of unreactive alkyl nitro compounds to their corresponding dianions which will react faster with carbonyl substrates, reactions can be accelerated using PAP as the base, utilization of the reactivity of aldehydes with α,α-doubly deprotonated nitroalkanes to give nitronate alkoxides that yield syn-nitro alcohols, and generation of nitronate anions in which one oxygen atom on the nitro group is silyl-protected to yield anti-β-nitro alcohols in the presence of a fluoride anion source when reacted with an aldehyde.

Examples

Industrial Application

In 1999, Menzel and coworkers developed a synthetic route to obtaining L-acosamine, the carbohydrate subunit of the anthracycline class of antibiotics:

Industrial Application

An enantioselective aldol addition product can be obtained in asymmetric synthesis by reaction of benzaldehyde with nitromethane and the a catalyst system consisting of zinc triflate as a Lewis acid, diisopropylethylamine (DIPEA), and N-methylephedrine (NME) as and as a chiral ligand. A diastereoselective variation of this reaction is depicted below.

Total Synthesis

In 2005, Barua and coworkers completed the total synthesis of the potent aminopeptidase inhibitor, (–)-bestatin, in an overall yield of 26% overall yield employing Shibasaki's asymmetric Henry reaction as the key step. (illustrated below)

Organocatalysis

In 2006, Hiemstra and coworkers explored the use of quinine derivatives as asymmetric catalysts for the reaction between aromatic aldehydes and nitromethane. Through the use of particular derivatives, they were able to induce direct enantioselection through the use of the proper catalyst.

Biocatalysis

In 2006, Purkarthofer et al. found that (S)-hydroxynitrile lyase from Hevea brasiliensis catalyzes the formation of (S)-β-nitro alcohols. In 2011, Fuhshuku and Asano showed that the (R)-selective hydroxynitrile lyase from Arabidopsis thaliana could catalyze the synthesis of (R)-β-nitro alcohols from nitromethane and aromatic aldehydes.