Benzoin condensations

The benzoin condensation is the coupling of two aldehyde molecules to give an a-hydroxyketone (acyloin) product. In its most classical form, the homocoupling of benzaldehyde gives the parent benzoin (R = R = Ph). Contemporary modifications of the benzoin condensation include the use of acylsilanes as well as imine derivatives in place of one aldehyde partner.  

Metal cyanides and heterocyclic carbenes are commonly employed catalysts for the benzoin condensation. Symmetrical acyloins can be prepared by dimerization of a wide range of aromatic and aliphatic aldehydes. Chiral heterocyclic carbene catalysts have also been developed that provide symmetrical acyloin products with high levels of enantiomeric purity. 

The cross-benzoin reaction between two different aldehydes typically produces a statistical mixture of products, although in some cases a single thermodynamic product predominates. A number of approaches have been developed to circumvent the limitations of the cross-benzoin reaction. In one approach, a thiamine diphosphate-dependent enzyme is used to promote a selective cross-benzoin reaction, often with high levels of asymmetric induction. In other approaches, one aldehyde coupling partner is replaced with a selective acyl donor. Cyanohydrin derivatives have proven to be ideal preformed acyl donors, and their use constitutes a stepwise benzoin condensation that is stoichiometric in cyanide. The discovery that acylsilanes can serve as cyanohydrin precursors has led to the development of a highly selective cyanide-catalyzed cross-benzoin condensation. By employing a chiral metallophosphite catalyst instead of potassium cyanide, good to excellent levels of asymmetric induction are possible. 

Modified benzoin condensations in which the acyl acceptor is not an aldehyde constitute a variation of the classical cross-benzoin condensation. Aldehydes and ketones can be coupled in an intramolecular annulation reaction to give tertiary a-hydroxyketones. The selective cross-coupling of 

The widely accepted Lapworth mechanism for the cyanide-catalyzed condensation and Breslow mechanism for the heterocyclic carbene- 

It is found that benzoin condensation of aldehydes are strongly catalysed by a PTC (quaternary ammonium cyanide in a two phase system). In a similar way, acyloin condensations are easily effected by stirring aliphatic or aromatic aldehydes with a quaternary catalyst (PTC), N-laurylthiazolium bromide in aqueous phosphate buffer at room temperature. The aromatic aldehydes reacted in a short time (about 5 min). However, aliphatic aldehydes require longer time (5-10 hr) for completion. Mixtures of aliphatic and aryl aromatic aldehydes give mixed a-hydroxy ketones.  

On the basis of extensive work, Breslow found that the benzoin condensation in aqueous media using inorganic salts (e.g., LiCl) is about 200 times faster than in ethanol (without any salt). The addition of y-cyclodextrin also accelerates the reaction, whereas the addition of p-cyclodextrin inhibits the condensation. 

Cyanide-catalyzed condensation of aryl aldehyde to benzoin. Now cyanide is mostly replaced by a thiazolium salt. Cf. Stetter reaction. 

Lapworth, A. J. J. Chem. Soc. 1903, 83, 995. Arthur Lapworth (1872—1941) was bom in Scotland. He was one of the great figures in the development of the modem view of the mechanism of organic reactions. Lapworth investigated the Benzoin condensation at the Chemical Department, The Goldsmiths Institute, New Cross, UK. 

Name Reactions, 4Hi ed., DOI 10.1007/978-3-642-01053-8 18, Springer-Verlag Berlin Heidelberg 2009 

Benzoin condensation. M Name Reactions for Homologations-Part 1 Li, J. J., Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2009, pp381-392. (Review). 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 22, Springer International Publishing Switzerland 2014 

Cyanide-catalyzed condensation of aryl aldehyde to benzoin 

A variant is represented by the benzilic ester rearrangement, where an alkoxide is used as nucleophile. The alkoxide should not be sensitive towards oxidation. The reaction product is the corresponding benzilic acid ester 5  

Substrates can be 1,2-diketones with aryl groups as well as some aliphatic substituents, cyclic and heterocyclic diketones. However the benzilic acid rearrangement is of limited preparative importance. 

Aromatic aldehydes 1 can undergo a condensation reaction to form a-hydroxy ketones 2 (also called benzoins) upon treatment with cyanide anions.This reaction, which is called benzoin condensation, works by that particular procedure with certain aromatic aldehydes and with glyoxals (RCOCHO). 

A cyanide anion as a nucleophile adds to an aldehyde molecule 1, leading to the anionic species 3. The acidity of the aldehydic proton is increased by the adjacent cyano group therefore the tautomeric carbanion species 4 can be formed and then add to another aldehyde molecule. In subsequent steps the product molecule becomes stabilized through loss of the cyanide ion, thus yielding the benzoin 2  

One aldehyde molecule has transferred its aldehyde hydrogen during course of the reaction onto another aldehyde molecule, which is why the reactants are called donor and acceptor (see below). 

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Benzoin condensation. Aromatic aldehydes when treated with an alkali cyanide, usually in aqueous solution, undergo condensation to the -hydroxyketone or benzoin. The best known example is the conversion of benzaldehyde to benzoin ... 

Benzoin condenses with hydroxylamine hydrochloride in the presence of alkah to give a-benzoinoxime ( cupron ) as the main product ... 

Apart from the thoroughly studied aqueous Diels-Alder reaction, a limited number of other transformations have been reported to benefit considerably from the use of water. These include the aldol condensation , the benzoin condensation , the Baylis-Hillman reaction (tertiary-amine catalysed coupling of aldehydes with acrylic acid derivatives) and pericyclic reactions like the 1,3-dipolar cycloaddition and the Qaisen rearrangement (see below). These reactions have one thing in common a negative volume of activation. This observation has tempted many authors to propose hydrophobic effects as primary cause of ftie observed rate enhancements. 

The product is called benzoin and the reaction is known therefore as the benzoin condensation. No base is needed other than cyanide ion. 

One may find many publications in the literature on the theoretical aspects of thiazolium quaternary salts, because of the biological importance of thiamine and their use as catalysts for benzoin condensation. 

Thiazolecarboxaldehydes in the presence of a strong base (103) give equal amounts of the corresponding alcohol and carboxylic acid (Canniz-aro reaction). In the presence of potassium cyanide thiazolecarboxalde-hyde undergoes the benzoin condensation (104, 105),... 

LAPWORTH (BENZOIN) Condensation Condensation of two molecules of aryl aldehydes fo an alpha-hydroxy ketone catalysed by CN (via cyanohydnns). 

Although the catalysis of the dimerization of aldehydes to acyloins by thiazolium ion has been known for some tlrae, the development of procedures using anhydrous solvents which give satisfactory yields of acyloins on a preparative scale was first realized in the submitters laboratories. The mechanism proposed by Breslow - for the thiazolium ion-catalyzed reactions is similar to the Lapworth mechanism for the benzoin condensation with a thiazolium ylide replacing the cyanide ion. Similar mechanisms are involved... 

Upon heating of a carboxylic ester 1 with sodium in an inert solvent, a condensation reaction can take place to yield a a-hydroxy ketone 2 after hydrolytic workup. " This reaction is called Acyloin condensation, named after the products thus obtained. It works well with alkanoic acid esters. For the synthesis of the corresponding products with aryl substituents (R = aryl), the Benzoin condensation of aromatic aldehydes is usually applied. 

The cyanide ion plays an important role in this reaction, for it has three functions in addition to being a good nucleophile, its electron-withdrawing effect allows for the formation of the carbanion species by proton transfer, and it is a good leaving group. These features make the cyanide ion a specific catalyst for the benzoin condensation. 

In a cross-coupling benzoin condensation of two different aldehydes, usually a mixture of products is obtained, with the ratio being determined by the relative stabilities of the four possible coupling products under thermodynamic control. If, however, an acyl silane, e.g. 5, is used as the donor component, the a-silyloxy-ketone 6 is obtained as a single product " ... 

Highly selective cross-coupling benzoin condensations have been achieved via the use of enzymatic methods. ... 

There have been very few examples of PTV derivatives substituted at the vinylene position. One example poly(2,5-thienylene-1,2-dimethoxy-ethenylene) 102 has been documented by Geise and co-workers and its synthesis is outlined in Scheme 1-32 [133]. Thiophene-2,5-dicarboxaldehyde 99 is polymerized using a benzoin condensation the polyacyloin precursor 100 was treated with base to obtain polydianion 101. Subsequent treatment with dimethyl sulfate affords 102, which is soluble in solvents such as chloroform, methanol, and DMF. The molar mass of the polymer obtained is rather low (M = 1010) and its band gap ( ,.=2.13 eV) is substantially blue-shifted relative to PTV itself. Despite the low effective conjugation, the material is reasonably conductive when doped with l2 (cr=0.4 S cm 1). 

Acyloins (a-hydroxy ketones) are formed enzymatically by a mechanism similar to the classical benzoin condensation. The enzymes that can catalyze reactions of this type arc thiamine dependent. In this sense, the cofactor thiamine pyrophosphate may be regarded as a natural- equivalent of the cyanide catalyst needed for the umpolung step in benzoin condensations. Thus, a suitable carbonyl compound (a -synthon) reacts with thiamine pyrophosphate to form an enzyme-substrate complex that subsequently cleaves to the corresponding a-carbanion (d1-synthon). The latter adds to a carbonyl group resulting in an a-hydroxy ketone after elimination of thiamine pyrophosphate. Stereoselectivity of the addition step (i.e., addition to the Stand Re-face of the carbonyl group, respectively) is achieved by adjustment of a preferred active center conformation. A detailed discussion of the mechanisms involved in thiamine-dependent enzymes, as well as a comparison of the structural similarities, is found in references 1 -4. 

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 nse of NHCs to catalyse the benzoin condensation of aldehydes was first reported by Ugai in 1943 [38], with the now generally accepted mechanism for this transformation first proposed by Breslow in 1958 [39],... 

Scheme 12.20 Triazolium pre-catalysts for the asymmetric benzoin condensation...

Benzoin Condensation. The benzoin condensation is a related reaction consisting of treating an aromatic aldehyde with potassium cyanide or sodium cyanide usually in an aqueous ethanolic solution. Breslow studied the effects of inorganic salts on the rate... 

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