Benzoin condensation

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The benzoin condensation is a reaction (often called a condensation reaction, for historical reasons) between two aromatic aldehydes, particularly benzaldehyde. The reaction is catalyzed by a nucleophile such as the cyanide anion or an N-heterocyclic carbene. The reaction product is an aromatic acyloin with benzoin as the parent compound.[1] An early version of the reaction was developed in 1832 by Justus von Liebig and Friedrich Woehler during their research on bitter almond oil.[2] The catalytic version of the reaction was developed by Nikolay Zinin in the late 1830s,[3][4] and the reaction mechanism for this organic reaction was proposed in 1903 by A. J. Lapworth.[5]

Reaction mechanism[edit]

In the first step in this reaction, the cyanide anion (as sodium cyanide) reacts with the aldehyde in a nucleophilic addition. Rearrangement of the intermediate results in polarity reversal of the carbonyl group, which then adds to the second carbonyl group in a second nucleophilic addition. Proton transfer and elimination of the cyanide ion affords benzoin as the product. This is a reversible reaction.

Mechanism of the benzoin condensation

The cyanide ion serves three different purposes in the course of this reaction. It acts as a nucleophile, facilitates proton abstraction, and is also the leaving group in the final step. The benzoin condensation is in effect a dimerization and not a condensation because a small molecule like water is not released in this reaction. For this reason the reaction is also called a benzoin addition. In this reaction, the two aldehydes serve different purposes; one aldehyde donates a proton and one aldehyde accepts a proton. 4-Dimethylaminobenzaldehyde is an efficient proton donor while benzaldehyde is both a proton acceptor and donor. In this way it is possible to synthesise mixed benzoins, i.e. products with different groups on each half of the product.

Scope[edit]

The reaction can be extended to aliphatic aldehydes with base catalysis in the presence of thiazolium salts; the reaction mechanism is essentially the same. These compounds are important in the synthesis of heterocyclic compounds. The addition is also possible with enones; for instance methyl vinyl ketone is a reagent in the Stetter reaction.

In biochemistry, the coenzyme thiamine is responsible for biosynthesis of acyloin-like compounds. This coenzyme also contains a thiazolium moiety, which on deprotonation becomes a nucleophilic carbene.

In one study, a custom-designed N-heterocyclic carbene (NHC, the framework is related to thiazolium salts) was found to facilitate an enantioselective intramolecular benzoin condensation (Scheme 2).[6]

Scheme 2. An intramolecular benzoin condensation

This finding was confirmed in another study with a slightly modified NHC using DBU as the base instead of potassium tert-butoxide (Scheme 3).[7]

Scheme 3. A second intramolecular benzoin condensation

References[edit]

  1. ^ Roger Adams and C. S. Marvel (1941), "Benzoin", Org. Synth. ; Coll. Vol. 1: 94 
  2. ^ Wöhler, Liebig; Liebig (1832). "Untersuchungen über das Radikal der Benzoesäure". Annalen der Pharmacie 3 (3): 249–282. doi:10.1002/jlac.18320030302. 
  3. ^ N. Zinin (1839). "Beiträge zur Kenntniss einiger Verbindungen aus der Benzoylreihe". Annalen der Pharmacie 31 (3): 329–332. doi:10.1002/jlac.18390310312. 
  4. ^ N. Zinin (1840). "Ueber einige Zersetzungsprodukte des Bittermandelöls". Annalen der Pharmacie 34 (2): 186–192. doi:10.1002/jlac.18400340205. 
  5. ^ Lapworth, A. (1904). "CXXII.—Reactions involving the addition of hydrogen cyanide to carbon compounds. Part II. Cyanohydrins regarded as complex acids". Journal of the Chemical Society, Transactions 85: 1206–1214. doi:10.1039/CT9048501206.  edit
  6. ^ D. Enders, O. Niemeier and T. Balensiefer (2006). "Asymmetric Intramolecular Crossed-Benzoin Reactions by N-Heterocyclic Carbene Catalysis". Angewandte Chemie International Edition 45 (9): 1463–1467. doi:10.1002/anie.200503885. PMID 16389609. 
  7. ^ H. Takikawa, Y. Hachisu, J. W. Bode and K. Suzuki (2006). "Catalytic Enantioselective Crossed Aldehyde-Ketone Benzoin Cyclization". Angewandte Chemie International Edition 45 (21): 3492–3494. doi:10.1002/anie.200600268. PMID 16637094. 

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