Cyanohydrins benzoin condensation

The addition of HCN to aldehydes or ketones produces cyanohydrins. This is an equilibrium reaction. For aldehydes and aliphatic ketones the equilibrium lies to the right therefore the reaction is quite feasible, except with sterically hindered ketones such as diisopropyl ketone. However, ketones ArCOR give poor yields, and the reaction cannot be carried out with ArCOAr since the equilibrium lies too far to the left. With aromatic aldehydes the benzoin condensation (16-54) competes. With oc,p-unsaturated aldehydes and ketones, 1,4 addition competes (15-33). Ketones of low reactivity, such as ArCOR, can be converted to cyanohydrins by treatment with diethylaluminum cyanide (Et2AlCN see OS VI, 307) or, indirectly, with cyanotrimethylsilane (MesSiCN) in the presence of a Lewis acid or base, followed by hydrolysis of the resulting O-trimethylsilyl cyanohydrin (52). The use of chiral additives in this latter reaction leads to cyanohydrins with good asymmetric... 

Frequently, it is the bisulfite addition product that is treated with CN. This method is especially useful for aromatic aldehydes, since it avoids competition from the benzoin condensation. If desired, it is possible to hydrolyze the cyanohydrin in situ to the corresponding a-hydroxy acid. This reaction is important in the Kiliani-Fischer method of extending the carbon chain of a sugar. 

The mechanism of the cyanide- and thioazolium ion-catalyzed conjugate addition reactions is considered to be analogous to the Lapworth mechanism for the cyanide-catalyzed benzoin condensation. Thus the cyano-stabilized carbanion resulting from deprotonation of the cyanohydrin of the aldehyde is presumed to be the actual Michael donor. After conjugate addition to the activated olefin, cyanide is eliminated to form the product and regenerate the catalyst. 

The so-called acyloin or benzoin condensation is a further interesting aldehyde reaction. In the aromatic series it takes place as a result of the action of potassium cyanide, and it is very probable that the potassium compound of the cyanohydrin is formed as an intermediate pro-... 

Benzoin condensation.1 The benzoates of cyanohydrins of aromatic aldehydes undergo benzoin condensation with an aromatic aldehyde in 50% NaOH/C6H6 in the presence of a phase-transfer catalyst, benzyltriethylammonium chloride. Theoretically two symmetrical and two unsymmetrical benzoins are possible, but in practice only one unsymmetrical benzoin is formed, that in which the carbonyl group is adjacent to the benzene ring substituted by the more electron-donating group. 

This reaction, similar in nature to the benzoin condensation, led to analogs of ascorbic acid. It was observed that the reaction proceeded especially well when a methyl alcoholic solution containing an acetylated sugar cyanohydrin and ethyl glyoxylate was treated with alkali. 

The bifunctional nature and the presence of a stereocenter make a-hydroxyketones (acyloins) amenable to further synthetic transformations. There are two classical chemical syntheses for these a-hydroxyketones the acyloin condensation and the benzoin condensation. In the acyloin condensation a new carbon-carbon bond is formed by a reduction, for instance with sodium. In the benzoin condensation the new carbon-carbon bond is formed with the help of an umpolung, induced by the formation of a cyanohydrin. A number of enzymes catalyze this type of reaction, and as might be expected, the reaction conditions are considerably milder [2-4, 26, 27]. In addition the enzymes such as benzaldehyde lyase (BAL) catalyze the formation of a new carbon-carbon bond enantioselectively. Transketolases (TK)... 

Aromatic aldehydes generally do not produce cyanohydrins on reaction with hydrogen cyanide, but undergo the benzoin condensation (Scheme 6.12). The initial product from nucleophilic attack by cyanide ion is depro-tonated to form a resonance-stabilized carbanion, which attacks a second molecule of the aldehyde. Elimination of HCN leads to an a-hydroxy ketone, benzoin (2-hydroxy-1,2-diphenylethanone). The benzoin condensation is catalysed specifically by cyanide ion, which assists in both the formation and stabilization of the carbanion. The reaction is limited to aromatic aldehydes, since the aryl ring also stabilizes the anion. 

The eyanohydrins of aromatic aldehydes participate in the benzoin condensation- The carbon-bound hydrogen (formerly the aldehydic hydrogen) of the cyanohydrin is made weakly acidic by the adjacent nitrile. The related carbanion may condense with a second molecule of the aldehyde. The resultant cyanohydrin is that of a ketone which is less stable and collapses to give benzoin (Scheme 3.51). 

In the benzoin condensation, one molecule of aldehyde serves as an electrophile. If a carbanion is generated from protected cyanohydrins, a-aminonitriles or dithioacetals, it can react with electrophiles such as alkyl halides, strongly activated aryl halides or alkyl tosylates to form ketones. Amongst other electrophiles which are attacked by the above carbanions are heterocyclic A -oxides, carbonyl compounds, a,p-unsaturated carbonyl compounds, a,3-unsaturated nitriles, acyl halides, Mannich bases, epoxides and chlorotiimethyl derivatives of silicon, germanium and tin. 

The mechanism of the benzoin condensation, as depicted in Scheme 1, suggested that anions derived from a protected aldehyde cyanohydrin should function as nucleophilic acylating reagents. The use of protected cyanohydrins as carbanion equivalents has been studied by Stork and by Hunig and has found wide applicability in chemical synthesis. Such species may serve as either acyl anion equivalents or homoenolate anions. ... 

The benzoin condensation was the key carbon-carbon bond forming step during the synthesis of anti-inflammatory 4,5-diarylimidazoles by T.E. Barta and co-workers. " The benzaldehyde was first converted to the cyanohydrin using TMSCN. Deprotonation was followed by the addition of 4-(MeS)-benzaldehyde to afford the benzoin. 

Aromatic aldehydes generally do not produce cyanohydrins on reaction with hydrogen cyanide, but undergo the benzoin condensation (Scheme... 

LAPWORTH (BENZOIN) Condensation Condensation ot two molecules of aryl aldehydes to an alpha-hydroxy Ketone catalysed by CN (via cyanohydrins). 

A number of methods for the generation of acyl anion equivalents from aldehydes have been developed. Related to the benzoin condensation, aldehyde cyanohydrins, protected as their ether derivatives, are readily transformed into anions by treatment with lithium diisopropylamide (LDA). Reaction with an alkyl halide gives the protected cyanohydrin of a ketone from which the ketone is liberated easily. Reaction with an aldehyde or ketone leads to the formation of an a-hydroxy ketone (1.109). ... 

Benzoin condensation can be considered to occur through a formal Knoevenagel type addition (Scheme 47). The key step of the reaction is the loss of the aldehydic proton, which gives rise to the cyanohydrin anion. In this case the acidity of the proton is increased by the electron-withdrawing power of the cyano group. 

PROBLEM 19.91 Show why hydroxide or ethoxide is ineffective in promoting the benzoin condensation. Those anions do add to the carbonyl group of benzaldehyde to form compounds much like a cyanohydrin. 

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