Carbonyl compounds, addition reactions cyanohydrin formation

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. 

There are many examples of acid catalyzed carbonyl addition reactions, such as formation of hydrates (R2C(OH)2), hemiacetals, hemiketals, cyanohydrins, bisulfite compounds, azomethines, oximes, hydrazones, etc. These important reactions are discussed in Vol. 11. 

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... 

Carbonyl compounds react via the tetrahedral mechanism. In this case, on the addition of the nucleophile, the negative charge is borne by the oxygen atom, which is an inherently more stable intermediate than the carbanion version. The tetrahedral intermediate may be isolated when a suitable substrate is used. An example is the formation of the cyanohydrin on the addition of a cyanide ion, which we studied in the chapter on addition reactions to a carbon/ oxygen system. 

The addition of hydrogen cyanide to carbonyl compounds such as aldehydes or ketones leads to 2-hydroxynitriles (cyanohydrins). This reaction as depicted in Fig. 1 is remarkable in several ways it represents one of the easiest routes to carbon-carbon bond formation, and in many cases it creates a new stereocenter. 

Most of the elementary reactions in the classic MCRs are equilibrium processes. Therefore, thermodynamic factors can significantly impact the reaction pathways in addition to the reaction kinetics. A classic example is the Strecker synthesis of a-amino nitrile 9 from aldehydes, amines, and cyanide (Scheme 15.5). The key step in this reaction is the nucleophilic addition of cyanide to the in situ formed iminium. However, condensation of a carbonyl compound with an amine leading to iminium is an equilibrium process, especially under aqueous conditions. Therefore, the desired addition reaction is in competition with direct addition of cyanide to the aldehyde, leading to cyanohydrin 10. However, since the formation of both 9 and 10 were reversible, only the more stable adduct 9 was produced at the expense of cyanohydrin 10 under thermodynamically controlled conditions. 

Enzymes of the hydroxynitrilase dass catalyze the addition of HCN to aldehydes, produdng cyanohydrins. Recendy, the reaction has been extended to a few ketones with modified hydroxynitrilase enzymes. In many cases, these are formed with good optical purities and such reactions are the simplest type of enzyme catalyzed carbon-carbon bond formation. By pairing hydroxynitrile lyases with nitrilases or nitrile hydratases, one-pot, multistep conversions become possible, and this also shifts the equilibrium to favor the addition products. Such concerns are particularly important when applying these catalysts to ketones where the equilibrium generally favors the starting carbonyl compound (Figure 1.17). 

An important role for Znl2 has been found in the catalysis of RsSiCN addition to ketones and aldehydes to afford silyl protected cyanohydrins. This is a very general reaction that is effective even with very hindered carbonyl compounds (eq 7). Diastere-oselective cyanohydrin formation has been reported when these reaction conditions are applied to asymmetric carbonyl substrates (eq... 

Ethyl acetoacetate (CH3COCH2COOC2H5) gives the reactions of a carbonyl (C=0) group, such as formation of cyanohydrin with HCN, bisulfate addition compound with sodium bisulfate, and phenyl hydrazone derivative with phenyl hydrazine. In addition to these, it behaves as an unsaturated alcohol (enol) as it evolves hydrogen on treatment with sodium, shows reddish-violet coloration with ferric chloride, and decolorizes bromine water and adds diazomethane. These chemical properties of ethyl acetoacetate suggest that it exists in two forms a saturated ketone 11 (keto-form) and an unsaturated alcohol 12 (enol-form) that is an example of prototropy (Scheme 3.46). 

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