Formation of Cyanohydrins

Hydrogen cyanide adds to an aldehyde or ketone to give a compound called a cyanohydrin. In the product, the nucleophihc cyano group is bonded to the carbonyl carbon and the proton is bonded to the carbonyl oxygen. As we noted above, because ketones are more stable than aldehydes, the addition reactions of ketones are less favorable (have smaller equihbrium constants) than addition reactions of aldehydes. Thus, the equilibrium constant for the addition of HCN is much more favorable for aldehydes than for ketones. 

Many addition reactions of aldehydes and ketones are reversible. Under acidic conditions, the reaction for ethanal has a favorable equihbrium constant however, the equilibrium constant for cyanohydrin of propanone is quite unfavorable. Cyanohydrins are stable under acidic conditions. 

Under basic conditions, a cyanohydrin readily undergoes elimination to give an aldehyde. Thus, we cannot make a cyanohydrin under basic conditions. Note that the 1,2 elimination reaction of the cyanohydrin is analogous to the P-ehmination reactions of haloalkanes to give alkenes that we discussed in Chapters 9 and 10. 

Cyanohydrin Formation 1. Carbonyl addition reactions of aldehydes have larger equihbrium constants than addition reac- 

Compound K 2. tions of ketones. Carbonyl addition reactions have smaher equihbrium constants when groups bonded to the car- 

Hydrogen cyanide (H—C=N) is a toxic, water-soluble liquid that boils at 26°C. Because it is mildly acidic, HCN is sometimes called hydrcx yanic acid. 

The conjugate base of hydrogen cyanide is the cyanide ion ( C=Ns). Cyanide ion is a strong base and a strong nucleophile. It attacks ketones and aldehydes to give addition products called t anohydrins. The mechanism is a base-catalyzed nucleophilic addition attack by cyanide ion on the carbonyl group, followed by protonation of the intermediate. 

Cyanohydrin formation is a perfect example of base-catalyzed addition to a carbonyl group. The strong nucleophile adds in the first step to give an alkoxide. Protonation gives the cyanohydrin. 

Cyanohydrins may be formed using liquid HCN with a catalytic amount of sodium cyanide or potassium cyanide. HCN is highly toxic and volatile, however, and therefore dangerous to handle. Many procedures use a full equivalent of sodium or potassium cyanide (rather than HCN), dissolved in some other proton-donating solvent. 

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  

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

The optical purities were determined solely from the optical rotations of the (/ -cyanohydrins thus obtained. Only for (/ )-a-hydroxybcnzeneacetonitrile, available from benzaldehyde, was an optical purity determined by comparison with the natural product. Variation of the reaction conditions (pH, temperature, concentration) in water/ethanol led to no appreciable improvementsl4. The use of organic solvents that are not miscible with water, but in which the enzyme-catalyzed reaction can still take place, resulted in suppression of the spontaneous addition to a significant extent, whereas the enzyme-catalyzed formation of cyanohydrins was only slightly slower (Figure l)13. 

Hernandez, L., Luna, H., Solfsa, A. and Vazquez, A. (2006) Application of crude preparations of leaves from food plants for the formation of cyanohydrins with high enantiomeric excesses. Tetrahedron Asymmetry, 17, 2813-2816. 

A short synthesis of D-gulono-1,4-lactone (2) from the inexpensive and readily available D-xylose (34) was first reported by Fischer and Stahel,18 and subsequently by others,12,25-31 and is shown in Scheme 6. The addition of hydrogen cyanide to D-xylose (34) resulted in the formation of cyanohydrins 35 and 36 which, on hydrolysis, afforded a mixture of D-gulonic acid (4) and D-idonic acid (37). D-Gulono-1,4-lactone may be obtained in 30-33% yield by recrystallization of the reaction products. In a similar way, L-xylose (l-34) has been converted32,33 in high yield into a mixture of L-gulonic and L-idonic acids. 

Reactions of cyanide with the salts or esters of some amino acids (e.g., pyruvate, a-ketoglutarate, oxaloacetate) lead to formation of cyanohydrin intermediates and their incorporation into intermediary metabolism. 

Griengl, H., Hickel, A., Johnson, D.V., Kratky, C., Schntidt, M. and Schwab, H. (1997) Enzymatic cleavage and formation of cyanohydrins a reaction of biological and synthetic relevance. Chem. Commun., 1997,1933-1940. 

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. 

Cyanohydrin formation, shown below, may involve rate-determining attack of either H+ or CN. From the p value for the formation of cyanohydrins from substituted benzaldehydes (Table 2.3), which step do you think is rate-determining ... 

Benzaldehyde cyanohydrin formation shown below may involve rate-determining attack by either H+ or CN-. A p value of +2.3 was found for the rate of formation of cyanohydrins from a series of substituted benzaldehydes. Which step is rate determining Based on the fact that cyanohydrin formation does not occur in basic solution, write a complete mechanism for the process. 

The constant of equilibrium 22 may be calculated by several methods. A competitive method was used211 to evalute the equilibrium constant in the formation of cyanohydrin anions of substituted benzaldehydes in DMSO (equilibrium 24). 

Figure 7.8 a) Enzymatic (oxynitrilase-catalyzed) formation of cyanohydrins from aldehydes, b) Chemical hydrolysis of cyanohydrins to hydroxy acids. 

Cyanide Formation of cyanohydrins Titration Toxic reagents, overestimation [85]... 

Activation of Me3SiCN by coordination of the Si to lithium BINOL-ate as catalyst has been shown to result in the enantioselective formation of cyanohydrins 73 from aromatic and heteroaromatic aldehydes with 82-98% ee (Scheme 7.15) [71]. (For experimental details see Chapter 14.5.4). Several other groups have used dual activation with a chiral Lewis acid and a non-chiral Lewis base [72]. Asymmetric cyanosilylation of PhCOMe and its congeners has also been reported to occur in the presence of sodium phenyl glycinate as catalyst, with up to 94% ee [73],... 

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. 

Fig. 9.9. Formation of cyanohydrin or a-aminonitrile from a carbonyl compound, ammonium chloride and sodium cyanide a matter of reaction time. The formation of the cyanohydrin proceeds fast and reversibly, that of a-aminonitrile slowly and irreversibly.

Lapworth A (1903) Qualitative study on the formation of cyanohydrin in water. J Chem Soc 83 995... 

Cyanohydrins are versatile building blocks that are used in both the pharmaceutical and agrochemical industries [2-9]. Consequently their enantioselective synthesis has attracted considerable attention (Scheme 5.1). Their preparation by the addition of HCN to an aldehyde or a ketone is 100% atom efficient. It is, however, an equilibrium reaction. The racemic addition of HCN is base-catalyzed, thus the enantioselective, enzymatic cyanide addition should be performed under mildly acidic conditions to suppress the undesired background reaction. While the formation of cyanohydrins from aldehydes proceeds readily, the equilibrium for ketones lies on the side of the starting materials. The latter reaction can therefore only be performed successfully by either bio- or chemo-cat-... 

Scheme 5.6 HNL-catalyzed formation of cyanohydrins from ketones and their application in synthesis.

Enzyme-catalyzed reactions in this area include reaction with glycine catalyzed by L-threonine aldolase to afford 164 <2000SL1046> and the use of almond oxynitrilase to catalyze the formation of cyanohydrin 165 by reaction of 161 with acetone cyanohydrin <2001T2213>. 

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