Carbonyl compounds 1,4-addition reactions with cyanohydrins

Addition of cyanide ion to a carbonyl compound leads to a cyanohydrin, a process with many applications including the synthesis of amino adds via an aminonitrile. The dired reaction between an aldehyde, KCN and NH4CI in acetonitrile leads to a mixture... 

Two common procedures in carbohydrate chemistry result in adding or removing one carbon atom from the skeleton of an aldose. The Wohl degradation shortens an aldose chain by one carbon, whereas the Kiliani-Fischer synthesis lengthens it by one. Both reactions involve cyanohydrins as intermediates. Recall from Section 21.9 that cyanohydrins are formed from aldehydes by addition of the elements of HCN. Cyanohydrins can also be re converted to carbonyl compounds by treatment with base. 

The 1,2-addition of a cyanide ion to a carbonyl compound to form a cyanohydrin is a fundamental carbon-carbon bond-forming reaction in organic chemistry, and has frequently been at the forefront of advances in chemical transformations. In 2000, Belokon and North developed a catalytic system based on a vanadium-salen complex (Scheme 9.1). The synthesis of vanadium(iv) complex 1 was accomplished by refluxing a mixture of the corresponding Schiff base with vanadium(iv) sulfate and pyridine in ethanol under an argon atmosphere. A very low catalyst loading of 0.1 mol% was employed to convert aromatic and aliphatic aldehydes to cyanohydrin silyl ethers 3 with enantioselectivities of 68-95% after 24 h. Further investigations... 

Attack by eCN is slow (rate-limiting), while proton transfer from HCN or a protic solvent, e.g. HzO, is rapid. The effect of the structure of the carbonyl compound on the position of equilibrium in cyanohydrin formation has already been referred to (p. 206) it is a preparative proposition with aldehydes, and with simple aliphatic and cyclic ketones, but is poor for ArCOR, and does not take place at all with ArCOAr. With ArCHO the benzoin reaction (p. 231) may compete with cyanohydrin formation with C=C—C=0, 1,4-addition may compete (cf. p. 200). 

URECH CYANOHYDRIN METHOD. Cyanohydrin formation by addition of alkali cyanide to the carbonyl group in the presence of acetic acid (Urech) or by reaction of the carbonyl compound with anhydrous hydrogen cyanide in the presence of basic catalyst (Ultee). 

The second step regenerates the cyanide ion. Each step of the reaction is reversible but, with aldehydes and most nonhindered ketones, formation of the cyanohydrin is reasonably favorable. In practical syntheses of cyanohydrins, it is convenient to add a strong acid to a mixture of sodium cyanide and the carbonyl compound, so that hydrogen cyanide is generated in situ. The amount of acid added should be insufficient to consume all the cyanide ion, therefore sufficiently alkaline conditions are maintained for rapid addition. 

The nucleophilic reaction of the cyanide ion on the carbonyl group is facilitated by protonat-ing the latter to a carboxonium ion. The addition of acid promotes the formation of cyanohydrins, but mainly for a thermodynamic reason. Under acidic conditions cyanohydrins equilibrate with the carbonyl compound and HCN. Under basic conditions they are in equilibrium with the same carbonyl compound and NaCN or KCN. The first reaction has a smaller equilibrium constant than the second, that is, the cyanohydrin is favored. So when cyanohydrins are formed under acidic or neutral (see Figure 9.8) instead of basic conditions, the reversal of the reaction is suppressed. 

The addition of hydrogen cyanide to carbonyl compounds gives a-hydroxy cyanides (cyanohydrin synthesis). The reaction is reversible, and the extent of the cyanohydrin formation depends upon the structure of the Carbonyl compound. The equilibrium highly favors the formation of aliphatic and alicyclic cyanohydrins however, aryl alkyl ketones react to a lesser extent, and diaryl ketones, not at all. The reaction may be accomplished by mixing the carbonyl compound with liquid hydrogen cyanide in the presence of a basic catalyst. The equilibrium... 

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