During cyanohydrin formation it is important to have free cyanide ions available to react with the ketone or aldehyde. This can be achieved by using a salt (e.g. KCN or NaCN) form of cyanide under acidic conditions or by using HCN with some base added to produce the needed CN− nucleophile.
Hydrogen cyanide (HC≡N) adds reversibly to aldehydes and many ketones forming hydroxyalkanenitrile adducts commonly known and as cyanohydrins. Cyanohydrins have the structural formula of R2C(OH)CN. The “R” on the formula represents an alkyl group, aryl group, or hydrogen.
Figure 19.6.119.6.1: General Reaction of Cyanohydrin Formation
An important feature of cyanohydrin formation is that it requires a basic catalyst. Since hydrogen cyanide itself is a weak acid (pKa = 9.25), the best results occur when a small amount of a strong base activates hydrogen cyanide by converting it to cyanide ion (–C≡N), which can function as a carbon nucleophile. In the absence of base, the reaction does not proceed, or is at best very slow. Cyanohydrin formation is weakly exothermic, and is favored for aldehydes, and unhindered cyclic and methyl ketones.
Example
Hydrogen cyanide (HCN) is hazardous to handle because it is highly toxic. Therefore, in many syntheses of cyanohydrins, HCN is created in situ by adding 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.
Mechanism of Cyanohydrin Formation
In the first step of the mechanism, the cyanide ion acts as a nucleophile and forms a C-C bond with the electrophilic carbonyl carbon. The two electrons in the carbonyl pi bond are pushed on to the electronegative oxygen forming a tetrahedral alkoxide ion intermediate. In the second step, the alkoxide ion is protonated by HCN which regenerates the cyanide ion.
Step 1: Nucleophilic attack
Step 2: Protonation
Chemistry of Cyanohydrins
Cyanohydrin functional groups often prove useful because of the further chemistry that can be carried out due to the presence of a hydroxyl and a nitrile functionality. In particular, dehydration can convert the hydroxyl group into an alkene. The nitrile can be converted into a carboxylic acid function group through reaction with a hot acidic aqueous solution. The nitrile can be reduced by the addition of LiAlH4 to form a primary amine.
