A-Cyanohydrination

The hydroxyl group of a cyanohydrin is also a potentially reac... 

Likewise the cyano group of a cyanohydrin can be hydrolyzed to —CO2H... 

An older version of this sequence is called the Kiliani-Fischer synthesis It too proceeds through a cyanohydrin but it uses a less efficient method for converting the cyano group to the required aldehyde... 

As a class of compounds, the two main toxicity concerns for nitriles are acute lethality and osteolathyrsm. A comprehensive review of the toxicity of nitriles, including detailed discussion of biochemical mechanisms of toxicity and stmcture-activity relationships, is available (12). Nitriles vary broadly in their abiUty to cause acute lethaUty and subde differences in stmcture can greatly affect toxic potency. The biochemical basis of their acute toxicity is related to their metaboHsm in the body. Following exposure and absorption, nitriles are metabolized by cytochrome p450 enzymes in the Hver. The metaboHsm involves initial hydrogen abstraction resulting in the formation of a carbon radical, followed by hydroxylation of the carbon radical. MetaboHsm at the carbon atom adjacent (alpha) to the cyano group would yield a cyanohydrin metaboHte, which decomposes readily in the body to produce cyanide. Hydroxylation at other carbon positions in the nitrile does not result in cyanide release. 

Historically these compounds have been made in two-step processes. Eor smaller volumes, reaction of an appropriate ketone or aldehyde with a cyanide salt followed by treatment with an ammonium salt proves satisfactory (Strecker synthesis). Eor larger volumes, treatment of the ketone or aldehyde with HCN to produce a cyanohydrin, followed by treatment with ammonia has been practiced. However, in 1990, DuPont began practicing a new one-step... 

A cyanohydrin is an organic compound that contains both a cyanide and a hydroxy group on an aUphatic section of the molecule. Cyanohydrias are usually a-hydroxy nitriles which are the products of base-cataly2ed addition of hydrogen cyanide to the carbonyl group of aldehydes and ketones. The lUPAC name for cyanohydrias is based on the a-hydroxy nitrile name. Common names of cyanohydrias are derived from the aldehyde or ketoae from which they are formed (Table 1). 

Reaction of cyanohydrins with absolute ethanol in the presence of HCl yields the ethyl esters of a-hydroxy acids (3). A/-substituted amides can be synthesized by heating a cyanohydrin and an amine in water. Thus formaldehyde cyanohydrin and P-hydroxyethylamine lead to A/- (P-hydroxyethyl)hydroxyacetamide (4). 

Addition of hydrogen cyanide to an aldose to form a cyanohydrin is the first step in the Kiliani-Fischer method for increasing the carbon chain of aldoses by one unit. Cyanohydrins react with Grignard reagents (see Grignard reaction) to give a-hydroxy ketones. 

Like the formation of a-cyanohydrins, this reaction is catalyzed by bases or cyanide ion, but unlike the a-cyanohydrin case this reaction is not reversible, and under certain conditions it can proceed with violence. Ethylene cyanohydrin can also be prepared by the reaction of ethylene chlorohydrin and alkaH cyanides (39). 

From a cyanohydrin AC2O, FeCl3, 25-92% yield. Other anhydrides are also effective in this conversion. ... 

Cyanide is a sufficiendy strong nucleophile that it can add directly to aldehydes and ketones, ultimately giving a cyanohydrin. 

The formation of a-amino nitrile 2 is likely to proceed via a cyanohydrin 4 (an a-hydroxy nitrile) as intermediate, which is formed by the addition of hydrogen cyanide to the aldehyde 1 ... 

Antispasmodic activity, interestingly, is maintained even in the face of the deletion of the ethanolamine ester side chain. Reaction of anisaldehyde with potassium cyanide and dibutylamine hydrochloride affords the corresponding a-aminonitrile (72) (a functionality analogous to a cyanohydrin). Treatment with sulfuric acid hydrolyzes the nitrile to the amide to yield ambucet-amide (73). ... 

In a departure from the prototype molecule, the benzylpiperi-done is first converted to the corresponding aminonitrile (a derivative closely akin to a cyanohydrin) by treatment with aniline hydrochloride and potassium cyanide (126). Acid hydrolysis of the nitrile affords the corresponding amide (127). Treatment with formamide followed by reduction affords the spiro oxazinone... 

Reaction of the carbonyl group of pi perl done with cyanide and aniline leads to formation of a cyanohydrin-like function known as an oc-aminonitrile (37) hydrolysis under... 

Problem 19.9 Cyclohexanone forms a cyanohydrin in good yield but 2,2,6-trtmethylcyclo-i hexanone does not. Explain. 

Naturally occurring compounds called cyanogenic glycosides, such as lotau-stralin, release hydrogen cyanide, HCN, when treated with aqueous acid. The reaction occurs by hydrolysis of the acetal linkage to form a cyanohydrin, which then expels HCN and gives a carbonyl compound-fa) Show the mechanism of the acetal hydrolysis and the structure of the cyanohydrin that results. 

There are expressions of uncertainty concerning the mechanism of the first step of the Strecker amino acid synthesis13-17. The reaction can proceed via the formation of an imine and subsequent nucleophilic attack of cyanide (path ). Alternatively, it has been speculated that the reaction of the aldehyde with hydrogen cyanide furnishes a cyanohydrin (path ), which then is subjected to a nucleophilic displacement of the hydroxy group by the amino function. 

Stork first demonstrated the utility of protected cyanohydrins as acyl anion equivalents in 1971 [2]. The acetal-protected cyanohydrin 8 was transformed into the corresponding anion with LDA in THF/HMPA, which was then alkylated with a range of alkyl halides, including secondary bromides (Scheme 2). A mild acidic hydrolysis yielded a cyanohydrin, which provided the ketone after treatment with base. The Stork cyanohydrin alkylation and its variants have become important methods in natural product synthesis [3,4]. 

A range of amide bases can be employed. Typically LDA is used, but in certain complex cases, LiNEt2 was found to be more effective. One exceptional case involves the ostensibly simple alkylation of a cyanohydrin acetonide with allyl chloride (Eq. 12). Here, use of LDA gave essentially none of the desired product 39, whereas KHMDS or LHMDS gave excellent yields [5]. 

The upper layer which contains, in addition to acrylonitrile, hydrogen cyanide, acrolein, acetonitrile, and small quantities of other impurities, passes to a second reactor (E) where, at a suitable pH, all the acrolein is converted to its cyanohydrin. (Cyanohydrins are sometimes known as cyanhydrins.) The product from the reactor (E) is fed to a cyanohydrin separation column (F), operating at reduced temperature and pressure, in which acrolein cyanohydrin is separated as the bottom product and returned to the ammox-idation reactor (A) where it is quantitatively converted to acrylonitrile and hydrogen cyanide. 

The psychotropic (stimulant) action of amphetaminil (57) may be intrinsic or due to in vivo hydrolysis of the a-aminonitrile function—akin to a cyanohydrin—to liberate amphetamine itself. It is synthesized by forming the Schiff s base of amphetamine with benzaldehyde to give 56, and then nucleophilic attack on the latter with cyanide anion to... 

As early as 1917, it was known that C2 and C3 in this trimethyl sugar each carried a methoxyl group, since (a) it failed to yield an osazone, and (b) the trimethyl-D-glucoheptonic acid derived from it by a cyanohydrin synthesis gave a lactone only with the concomitant loss of one of the methyl radicals.135 The production of a dimethyl- and not a trimethyl-... 

Addition of cyanide ion to a carbonyl compound leads to a cyanohydrin, a process with many applications including the synthesis of amino adds via an aminonitrile. The dired reaction between an aldehyde, KCN and NH4CI in acetonitrile leads to a mixture... 

When the second crop is contaminated with a polar material (a-cyanohydrin of the product) as evidenced by a lower melting point (m.p. 160-170°) and a thin-layer chromatogram (Kiesel Gel GF, benzene-ethyl acetate, 4 1, Rf =0.2), the residue from the mother liquor must be treated again with alkali before crystallization. 

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). 

The synthesis of " C-labelled o-glucose starts with the pentose o-arabinose and " C-labelled potassium cyanide, which react together to form a cyanohydrin (see Section 7.6.1). Since cyanide can attack the planar carbonyl group from either side, the cyanohydrin product will be a mixture of two diastereoisomers that are epimeric at the new chiral centre. The two epimers are usually formed in unequal amounts because of a chiral influence from the rest of the arabinose structure during attack of the nucleophile. 

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