Equilibria/equilibrium cyanohydrin formation

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. 

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). 

Since the carbonyl group has gone in R2C(OH)CN, we would expect very little effect from any of these substitutents. There can t be any conjugation, and inductive effects on the distant 0 atom will be small. What effect would an inductively withdrawing substituent have on the equilibrium for cyanohydrin formation ... 

For aldehydes and most aliphatic ketones, the position of equilibrium favors cyanohydrin formation. For many aryl ketones (ketones in which the carbonyl carbon is bonded to a benzene ring and stericaUy hindered aliphatic ketones, however, the position of equilibrium favors starting materials cyanohydrin formation is not a useful reaction for these types of compounds. The following synthesis of ibuprofen, for example, failed because the cyanohydrin was formed only in low yield. 

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... 

Table 3. Equilibrium Constants for Formation of Cyanohydrins from Hydrogen Cyanide Plus Carbonyl Compounds ...

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. 

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 ... 

It will destabilise the carbonyl compound a lot, and have very little effect on the product it will therefore push the equilibrium over to the cyanohydrin side. Consider cyanohydrin formation from ... 

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. 

Exercise 16-10 One possible way of carrying out the cyanohydrin reaction would be to dispense with hydrogen cyanide and just use the carbonyl compound and sodium cyanide. Would the equilibrium constant for cyanohydrin formation be more... 

Exercise 16-12 Explain what factors would operate to make the equilibrium constant for cyanohydrin formation 1000 times greater for cyclohexanone than for cyclo-pentanone. Why What would you expect for cyclobutanone relative to cyclopenta-none Why ... 

In the special case of a low, continuous flow of ammonia, this process allows the formation of substantial amounts of AA by displacement of the cyanohydrin-aminonitrile equilibrium. The cyanohydrin form can be consid-... 

Explain why p-me tho xyacetophenone has a smaller equilibrium constant for cyanohydrin formation than does acetophenone. 

The methoxy group donates electrons to the carbonyl carbon by resonance, making it less electrophilic and less reactive. Therefore, the equilibrium constant for cyanohydrin formation is larger for acetophenone than for p-methoxyacetophenone. 

Explain which compound has the larger equilibrium constant for cyanohydrin formation O O... 

Arrange these compounds in order of increasing equilibrium constant for cyanohydrin formation and explain your reasoning ... 

Explain the difference in the equilibrium constants for cyanohydrin formation for these compounds ... 

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. 

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. 

A completely different enzyme-catalyzed synthesis of cyanohydrins is the lipase-catalyzed dynamic kinetic resolution (see also Chapter 6). The normally undesired, racemic base-catalyzed cyanohydrin formation is used to establish a dynamic equilibrium. This is combined with an irreversible enantioselective kinetic resolution via acylation. For the acylation, lipases are the catalysts of choice. The overall combination of a dynamic carbon-carbon bond forming equilibrium and a kinetic resolution in one pot gives the desired cyanohydrins protected as esters with 100% yield [19-22]. 

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. 

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... 

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