In 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). 

The Strecker synthesis occurs by initial reaction of the aldehyde weth ammonia to give an imirte intermediate (Section Ld.9), which then adds HCX ir> a nucleof ilrc aridition step similar to what occurs in cyanohydrin formation (Section 16.7). The o amino nitrile that results undergnes hydml-ysts in the usual way (Section 21.SX... 

There are two reasons to use reagents in cyanohydrin formation that act both as the HCN source and the derivatizing agent for the newly formed cyanohydrin ... 

The cyclohexene (58 X = H), after bromination, has been hydroxylated via adsorption on silica gel and contact with ozone at 195 K. Debromination of the resulting dibromo-alcohol with zinc in acetic acid gives a 30 % overall yield of the alcohol (58 X = OH). The stereoselectivity in cyanohydrin formation has been... 

The reaction is used for the chain extension of aldoses in the synthesis of new or unusual sugars In this case the starting material l arabinose is an abundant natural product and possesses the correct configurations at its three chirality centers for elaboration to the relatively rare l enantiomers of glucose and mannose After cyanohydrin formation the cyano groups are converted to aldehyde functions by hydrogenation m aqueous solution Under these conditions —C=N is reduced to —CH=NH and hydrolyzes rapidly to —CH=0 Use of a poisoned palladium on barium sulfate catalyst prevents further reduction to the alditols... 

As a class of compounds, the two main toxicity concerns for nitriles are acute lethality and osteolathyrsm. A comprehensive review of the toxicity of nitriles, including detailed discussion of biochemical mechanisms of toxicity and stmcture-activity relationships, is available (12). Nitriles vary broadly in their abiUty to cause acute lethaUty and subde differences in stmcture can greatly affect toxic potency. The biochemical basis of their acute toxicity is related to their metaboHsm in the body. Following exposure and absorption, nitriles are metabolized by cytochrome p450 enzymes in the Hver. The metaboHsm involves initial hydrogen abstraction resulting in the formation of a carbon radical, followed by hydroxylation of the carbon radical. MetaboHsm at the carbon atom adjacent (alpha) to the cyano group would yield a cyanohydrin metaboHte, which decomposes readily in the body to produce cyanide. Hydroxylation at other carbon positions in the nitrile does not result in cyanide release. 

Production of cyanohydrins is accompHshed through the base-cataly2ed combination of hydrogen cyanide and the carbonyl compound in a solvent, usually the cyanohydrin itself (17). The reaction is carried out at high dilution of the feeds, at 10—15°C, and pH 6.5—7.5. The product is continuously removed from the reaction 2one, cooled to push the equilibrium toward cyanohydrin formation, and then stabili2ed with mineral acid. Purification is usually effected by distillation. 

The cyanohydrin of methyl perfluoroheptyl ketone was synthesized by a two-step process addition of sodium bisulfite and subsequent treatment with sodium cyanide. When the ketone was reacted with sodium cyanide, cyclic addition products were obtained, instead of the product of cyanohydrin formation. This result was attributed to the solubility characteristic of a long perfluoroalkyl group, which makes the compound less soluble in water and polar organic solvents [54] (equation 40) (Table 14). 

Nitrile groups in cyanohydrins are hydrolyzed under conditions similar- to those of alkyl cyanides. Cyanohydrin formation followed by hydrolysis provides a route to the preparation of a-hydroxy carboxylic acids. 

Aldehydes and unhindered ketones undergo a nucleophilic addition reaction with HCN to yield cyanohydrins, RCH(OH)C=N. Studies carried out in the early 1900s by Arthur Eapworth showed that cyanohydrin formation is reversible and base-catalyzed. Reaction occurs slowly when pure HCN is used but rapidly when a small amount of base is added to generate the nucleophilic cyanide ion, CN. Alternatively, a small amount of KCN can be added to HCN to catalyze the reaction. Addition of CN- takes place by a typical nucleophilic addition pathway, yielding a tetrahedral intermediate that is protonated by HCN to give cyanohydrin product plus regenerated CN-. 

Cyanohydrin formation is somewhat unusual because it is one of the few examples of the addition of a protic acid (H—Y) to a carbonyl group. As noted in the previous section, protic adds such as H20, HBr, HC1, and H2S04 don t normally yield carbonyl addition products because the equilibrium constants ate unfavorable. With HCN, however, the equilibrium favors the cyanohydrin adduct. 

Like the Strecker synthesis, the Ugi reaction also involves a nucleophilic addition to an imine as the crucial step in which the stereogenic center of an a-amino acid derivative is formed4. The Ugi reaction, also denoted as a four-component condensation (A), is related to the older Passerini reaction5 (B) in an analogous fashion as the Strecker synthesis is to cyanohydrin formation. In both the Ugi and the Passerini reaction, an isocyanide takes the role of cyanide. 

Griengl reported the first example of hydroxynitrile lyase-catalyzed cyanohydrin formation in a mixed solvent system of [bmim][BF4] and buffer (pH 3.7) (1 1) (Fig. 19). In the reaction, a mixed solvent system was essential, but excellent results were obtained. 

Figure 19 Enantioselective cyanohydrin formation using hydroxynitrile lyase in...

PaHNL catalyzed cyanohydrin formation in H20/Et0H and in organic solvents, respectively... 

Those carbonyl compounds for which the equilibrium with HCN does not lie over in favour of cyanohydrin formation may often be converted satisfactorily into a derivative of the cyanohydrin through reaction with Me3SiCN ... 

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