Cyanide cyanohydrin formation

Nitrile groups m cyanohydrins are hydrolyzed under conditions similar to those of alkyl cyanides Cyanohydrin formation followed by hydrolysis provides a route to the preparation of a hydroxy carboxylic acids... 

The hydrogen of benzaldehyde is not acidic, so it cannot attack a second molecule of the same. However, by addition of cyanide (cyanohydrin formation), the hydrogen atom becomes acidic (the carbanion will be resonance stabilized by the cyano function) and the reaction proceeds. 

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. 

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-. 

Like the Strecker synthesis, the Ugi reaction also involves a nucleophilic addition to an imine as the crucial step in which the stereogenic center of an a-amino acid derivative is formed4. The Ugi reaction, also denoted as a four-component condensation (A), is related to the older Passerini reaction5 (B) in an analogous fashion as the Strecker synthesis is to cyanohydrin formation. In both the Ugi and the Passerini reaction, an isocyanide takes the role of cyanide. 

A different approach involving cyanohydrin formation from the 3-keto sugar was also explored in the D-Fru series (Scheme 17). A mixture of epimeric cyanohydrins was quantitatively formed by reaction with sodium cyanide in methanol, albeit without stereoselectivity. Chromatographic separation of (R)- and (A)-isomers was straightforward and the former epimer was selected to exemplify the two-step transformation into an OZT. Reduction of this nitrile by lithium aluminum hydride led to the corresponding aminoalcohol, which was further condensed with thiophosgene to afford the (3i )-spiro-OZT in ca. 30% overall yield. Despite its shorter pathway, the cyanohydrin route to the OZT was not exploited further, mainly because of the disappointing yields in the last two steps. 

Cyanoanthracene, 50,55 p-Cyanobenzenesulfonamide, reduction with Raney nickel alloy to p-for-mylbenzenesulfonamide, 51,20 p-Cyano-N,N-diethylaniline, 50, S4 Cyanohydrins, formation by use of alkyl-aluminum cyanides, 52, 96... 

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). 

Cyanohydrin formation is a useful synthetic reaction, in that it utilizes a simple reagent, cyanide, to create a new C-C bond. The cyano (nitrile) group may easily be modified to other functions, e.g. carboxylic acids via hydrolysis (see Box 7.9) or amines by reduction. 

Various adaptations of the original procedure have been reported over the years, with variations in catalysts and conditions [7, 8, 52]. However, most of these procedures still encounter a range of shortcomings the need for elevated reaction temperatures, extended reaction times, expensive homogeneous catalysts or an excess of the cyanide source, variable yields and most notably competing cyanohydrin formation that can occur (Scheme 22) [48]. This problem is usually bypassed. 

Not surprisingly, nitriles that liberate cyanide more readily are more toxic. Logically, structural features that are expected to increase a-carbon radical formation and stability are likely to favor hydrogen atom abstraction from the a-carbon. The more quickly hydrogen atom abstraction occurs at the a-carbon, the more quickly cyanohydrin formation occurs and the more quickly cyanide is released and, hence, the more toxic the nitrile is expected to be. 

Usually the products of Cj-elongation are intermediates, rather than the target amino sugars. The elongation can be repeated iteratively [20]. Cyanohydrin formation belongs to the most typical C,-elongation processes. Addition of trimethylsilyl cyanide to a-amino aldehydes of type 1 in the presence of Lewis acid yielded a mixture of diastereoisomers 2 and 3 [21] (Scheme 3). 

URECH CYANOHYDRIN METHOD. Cyanohydrin formation by addition of alkali cyanide to the carbonyl group in the presence of acetic acid (Urech) or by reaction of the carbonyl compound with anhydrous hydrogen cyanide in the presence of basic catalyst (Ultee). 

An important feature of cyanohydrin formation is that it requires a basic catalyst. In the absence of base, the reaction does not proceed, or is at best very slow. In principle, the basic catalyst may activate either the carbonyl group or hydrogen cyanide. With hydroxide ion as the base, one reaction to be expected is a reversible addition of hydroxide to the carbonyl group ... 

Hydrogen cyanide itself has no unshared electron pair on carbon and does not form a carbon-carbon bond to a carbonyl carbon. However, a small amount of a strong base can activate hydrogen cyanide by converting it to cyanide ion, which can function as a carbon nucleophile. A complete sequence for cyanohydrin formation follows ... 

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... 

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