Ketones cyanohydrin formation

Cyanohydrin formation is reversible and the position of equilibrium depends on the steric and electronic factors governing nucleophilic addition to carbonyl groups described m the preceding section Aldehydes and unhindered ketones give good yields of cyanohydrins... 

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). 

Cyanohydrin formation (Section 17.7) Hydrogen cyanide adds to the carbonyl group of aldehydes and ketones. 

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-. 

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 endo-spiro-OZT could be prepared through a reaction sequence similar to that applied for the exo-epimer, with spiro-aziridine intermediates replacing the key spiro-epoxides (Scheme 18). Cyanohydrin formation from ketones was tried under kinetic or thermodynamic conditions, and only reaction with the d-gluco derived keto sugar offered efficient stereoselectivity, while no selectivity was observed for reaction with the keto sugar obtained from protected D-fructose. The (R) -cyanohydrin was prepared in excellent yield under kinetic conditions (KCN, NaHC03, 0 °C, 10 min) a modified thermodynamic procedure was applied to produce the (S)-epimer in 85% yield (Scheme 18). 

S)-Selective Cyanohydrin Formation from Aromatic Ketones 259... 

The reaction is reversible, and cyanohydrin formation is more favoinable with aldehydes than with ketones, as with other addition reactions. The reverse reaction is easily effected by treating a cyanohydrin with aqueous base, since cyanide is a reasonable leaving group (see Section 6.1.4). 

Cyanohydrins are readily prepared from 3-ketones by exchange with acetone cyanohydrin.54 Selective cyanohydrin formation at C-3 is achieved in the presence of a 20-ketone unsubstituted at the 17- and 21-positions in dilute solution. Thus 5or-pregnane-3,20-dione (60) gives the 3-monocyanohydrin (61) in ethanol, but in neat acetone cyanohydrin the dicyanohydrin (62) is obtained.73... 

However, such addition is not likely to facilitate formation of cyanohydrin because it represents a competitive saturation of the carbonyl double bond. Indeed, if the equilibrium constant for this addition were large, an excess of hydroxide ion could inhibit cyanohydrin formation by tying up the ketone as the adduct 1. 

Several carbonyl additions have characteristics similar to those of cyanohydrin formation. A typical example is the addition of sodium hydrogen sulfite, which proceeds readily with good conversion in aqueous solution with most aldehydes, methyl ketones, and unhindered cyclic ketones to form a carbon-sulfur bond. No catalyst is required because sulfite is an efficient nucleophilic agent. The addition step evidently involves the sulfite ion—not hydrogen sulfite ion ... 

Cyanohydrin formation is reversible, and the equilibrium constant may or may not favor the cyanohydrin. These equilibrium constants follow the general reactivity trend of ketones and aldehydes ... 

Formaldehyde reacts quickly and quantitatively with HCN. Most other aldehydes have equilibrium constants that favor cyanohydrin formation. Reactions of HCN with ketones have equilibrium constants that may favor either the ketones or the cyanohydrins, depending on the structure. Ketones that are hindered by large alkyl groups react slowly with HCN and give poor yields of cyanohydrins. 

The failure with bulky ketones is largely due to steric effects. Cyanohydrin formation involves rehybridizing the sp2 carbonyl carbon to sp3, narrowing the angle between the alkyl groups from about 120° to about 109.5°, increasing their steric interference. 

Cyanohydrin formation is reversible just dissolving a cyanohydrin in water can give back the aldehyde or ketone you started with, and aqueous base usually decomposes cyanohydrins completely. 

Cyanohydrin formation is therefore an equilibrium between starting materials and products, and we can only get good yields if the equilibrium favours the products. The equilibrium is more favourable for aldehyde cyanohydrins than for ketone cyanohydrins, and the reason is die size of the groups attached... 

This reaction, like the cyanohydrin formation we discussed at the beginning of the chapter, is an equilibrium, and is quite general for aldehydes and ketones. But, as with the cyanohydrins, the position of the equilibrium depends on the structure of the carbonyl compound. Generally, the same steric factors (pp. 138-139) mean that simple aldehydes are hydrated to some extent while simple ketones are not. However special factors can shift the equilibrium towards the hydrated form even for ketones, particularly if the carbonyl compound is reactive or unstable. 

Cyanohydrin formation is an equilibrium process. Because formation of the product of addition of HCN to 2,2,6-trimethylcyclohexanone is sterically hindered by the three methyl groups, the equilibrium lies toward the side of the unreacted ketone. 

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