Nucleophilic Addition of HCN Cyanohydrin Formation

When dissolved in water, trichloroacetaldehyde exists primarily as its hydrate, called chloral hydrate. Show the structure of chloral hydrate. 

The oxygen in water is primarily (99.8%) but water enriched with the heavy isotope is also available. When an aldehyde or ketone is dissolved in 0-enriched water, the isotopic label becomes incorporated into the carbonyl group. Explain. 

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 Lapworth 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 . 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 acids such as H2O, HBr, HCl, and H2SO4 don t normally yield carbonyl addition products because the equilibrium constants are unfavorable. With HCN, however, the equilibrium favors the cyanohydrin adduct. 

Cyanohydrin formation is useful because of the further chemistry that can be carried out on the product. For example, a nitrile (R-C=N) can be reduced with 

Arthur Lapworth (1872-1941) was born in Galashiels, Scotland, and received a D.Sc. at the City and Guilds Institute, London. He was professor of chemistry at the University of Manchester from 1909 until his retirement in 1937. 

Problem 19.9 [ Cyclohexanone forms a cyanohydrin in good yield but 2,2,6-trimcthylcy clo- 

Aldehydes and unhindered ketones react with HCN to yield cyanohydrins, RCH(OH)CsN. For example, benzaldehyde gives the cyanohydrin commonly called mandelonitrile in 88% yield on treatment with HCN  

Addition of CN to a ketone or aldehyde occurs by a typical nucleophilic addition pathway, yielding a tetrahedral intermediate that is protonated by HCN to give cyanohydrin product plus regenerated CN . 

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Nuclet ilk Addition of HCN Cyanohydrin Formation 19.6 Nucleophilic Addition of Orignaid Reagents and... 

Chain extension by way of cyanohydrin formation (Section 25.20) The Kiliani-Fischer synthesis proceeds by nucleophilic addition of HCN to an aldose, followed by conversion of the cyano group to an aldehyde. A mixture of stereoisomers results the two aldoses are epimeric at C-2. Section 25.20 describes the modern version of the Kiliani-Fischer synthesis. The example at the right illustrates the classical version. 

Entry 2 is cyanohydrin formation by nucleophilic addition of HCN to the carbonyl group. It is the basis of a synthetic method for extending the carbon chain of an aldose. In the example shown in Table 23.2 the two diastereomeric cyanohydrins derived fromL-arabinose were separated, and their—C=N groups converted to—CH=0 to yield L-maimose and L-glucose, as shown below for one of the diastereomers. In this conversion, the nitrile group is hrst reduced to an imine (—C=NH), which is then hydrolyzed to the aldehyde. The sequence extends the chain of L-arabinose, a pentose, to that of L-glucose, a hexose. 

Other examples of the ElcB pathway are benzyne formation from C6HsF (cf. p. 174), reversal of simple nucleophilic addition to 0=0, e.g. base-induced elimination of HCN from cyanohydrins (20 cf. p. 212),... 

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 Strecker synthesis occurs by initial reaction of the aldehyde with ammonia to give an imine intermediate (Section 19.9), which then adds HCN in a nucleophilic addition step similar to what occurs in cyanohydrin formation (Section 19.7). The o-amino nitrile that results undergoes hydrolysis in the usual way (Section 21.8). 

Cyanohydrins form fastest under conditions where cyanide anions are present to act as the nucleophile. Use of potassium cyanide, or any base that can generate cyanide anions from HCN, increases the reaction rate as compared to the use of HCN alone. The addition of hydrogen cyanide itself to a carbonyl group is slow because the weak acidity of HCN (pA 9) provides only a small concentration of the nucleophilic cyanide anion. The following is a mechanism for formation of a cyanohydrin. 

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