Nitroaldol reaction
| Henry reaction | |
|---|---|
| Named after | Louis Henry |
| Reaction type | Coupling reaction |
| Identifiers | |
| Organic Chemistry Portal | henry-reaction |
| RSC ontology ID | RXNO:0000086 |
The Henry Reaction (also referred to as the nitro-aldol reaction) is a classic carbon–carbon bond formation reaction in organic chemistry. Discovered in 1895 by the Belgian chemist Louis Henry (1834-1913), it is the combination of a nitroalkane and an aldehyde or ketone in the presence of a base to form β-Nitro alcohols. This type of reaction is commonly referred to as a "nitro-aldol" reaction (nitroalkane, aldehyde, and alcohol) It is nearly analogous to the aldol reaction that had been discovered 23 years prior that couples two carbonyl compounds to form β-hydroxy carbonyl compounds known as "aldols" (aldehyde and alcohol). The Henry reaction is a useful technique in the area of organic chemistry due to the synthetic utility of its corresponding products, as they can be easily converted to other useful synthetic intermediates. These conversions include subsequent dehydration to yield nitroalkenes, oxidation of the secondary alcohol to yield α-nitro ketones, or reduction of the nitro group to yield β-amino alcohols.
Many of these uses have been exemplified in the syntheses of various pharmaceuticals including the β-blocker (S)-propranolol, the HIV protease inhibitor Amprenavir (Vertex 478), and construction of the carbohydrate subunit of the anthracycline class of antibiotics, L-Acosamine. The synthetic scheme of the L-Acosamine synthesis can be found in the Examples section of this article.
The Henry reaction begins with the deprotonation of the nitroalkane on the α-carbon position forming a resonance stabilized anion. The pKa of most nitroalkanes is approximately 17. This is followed by alkylation of the nitroalkane with the carbonyl containing substrate to form a diastereomeric β-nitro alkoxide. The protonation of the alkoxide by the previously protonated base will yield the respective β-nitro alcohol as product. (Scheme below)
It is important to note that all steps of the Henry reaction are reversible. This is due to the lack of a committed step in the reaction to form product. It is for this reason that research has been geared towards modifications to drive the reaction to completion. More information about this can be found in the modification section of this article.
One of the commonly accepted models for stereoselection without any modification to the Henry reaction is shown below where stereoselectivity is governed by the size of the R groups in the model (ex. carbon chain) as well as a transition state that minimizes dipole by orienting the nitro group and carbonyl oxygen anti (on opposite sides) each other. The R groups play a role in the transition state of the Henry reaction in that the larger the R groups are on each of the substrates, the more they will want to orient themselves away from each other (commonly referred to as steric effects)
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