Ketones with cyanide ion

Problem 19.5 Treatment of an aldehyde or ketone with cyanide ion (- C=N), followed by protonation of the tetrahedral alkoxide ion intermediate, gives a c)>anohyi1rin. Show the structure of the cyanohydrin obtained from cyclohexanone. 

Reaction of an aldehyde or a ketone with cyanide ion under acidic conditions forms a cyanohydrin (Section 17.6). The mechanism is shown on page 802. 

Section 20 18 Nitnles are prepared by nucleophilic substitution (8 2) of alkyl halides with cyanide ion by converting aldehydes or ketones to cyanohydrins (Table 20 6) or by dehydration of amides... 

Nitriles are similar in some respects to carboxylic acids and are prepared either by SN2 reaction of an alkyl halide with cyanide ion or by dehydration of an amide. Nitriles undergo nucleophilic addition to the polar C=N bond in the same way that carbonyl compounds do. The most important reactions of nitriles are their hydrolysis to carboxylic acids, reduction to primary amines, and reaction with organometallic reagents to yield ketones. 

Several alternative procedures have been developed in which other reagents replace carbon monoxide as the migration terminus.11 The most generally applicable of these methods involves the use of cyanide ion and trifluoroacetic anhydride (TFAA). In this reaction the borane initially forms an adduct with cyanide ion. The migration is induced by N-acylation of the cyano group by TFAA. Oxidation and hydrolysis then give a ketone. 

Although nitriles lack an acyl group, they are considered acid derivatives because they hydrolyze to carboxylic acids. Nitriles are frequently made from carboxylic acids (with the same number of carbons) by conversion to primary amides followed by dehydration. They are also made from primary alkyl halides and tosylates (adding one carbon) by nucleophilic substitution with cyanide ion. Aryl cyanides can be made by the Sandmeyer reaction of an aryldiazonium salt with cuprous cyanide. a-Hydroxynitriles (cyanohydrins) are made by the reaction of ketones and aldehydes with HCN. 

In the reaction of 2-hydroxyalkyl halides with cyanide ions the intermediate formation of oxiranes can give rise to rearrangement products. Epoxides may also be encountered if CN ions are reacted with a-halo ketones (Scheme On heating with quaternary ammonium halides in acetonitrile or DMSO at 80-130 C these cyanooxiranes (3) are converted into 2-cyano ketones (4). Phenacyl bromide, in contrast, gives rise to 3-oxo-3-phenylpropionitrile (5) on treatment with cyanide ions. Not much is known about the reaction of the corresponding a-halo sulfides with cyanide ethylthioacetonitrile was obtained from the chloro sulfide by treatment with Hg(CN)2. ... 

Upon treating certain (but not all) aromatic aldehydes or glyoxals (a-keto aldehydes) with cyanide ion (CN ), benzoins (a-hydroxy-ketones or acyloins) are produced in a reaction called the benzoin condensation. The reverse process is called the retro-benzoin condensation, and it is frequently used for the preparation of ketones. The condensation involves the addition of one molecule of aldehyde to the C=0 group of another. One of the aldehydes serves as the donor and the other serves as the acceptor. Some aldehydes can only be donors (e.g. p-dimethylaminobenzaldehyde) or acceptors, so they are not able to self-condense, while other aldehydes (benzaldehyde) can perform both functions and are capable of self-condensation. Certain thiazolium salts can also catalyze the reaction in the presence of a mild base. This version of the benzoin condensation is more synthetically useful than the original procedure because it works with enolizable and non-enolizable aldehydes and asymmetric catalysts may be used. Aliphatic aldehydes can also be used and mixtures of aliphatic and aromatic aldehydes give mixed benzoins. Recently, it was also shown that thiazolium-ion based organic ionic liquids (Oils) promote the benzoin condensation in the presence of small amounts of triethylamine. The stereoselective synthesis of benzoins has been achieved using chiral thiazolium salts as catalysts. 

Reaction with Cyanide Ion Reaction with Ilalide Ions Reaction with Amines Acetoxylation Reaction with Aromatics Reaction with Olefins Reaction with Ketones... 

The synthesis of secondary nitriles by the reaction of secondary alkyl halides with cyanide ion is a process which normally gives poor results. Two methods have been introduced to circumvent this difficulty, in each case a ketone is the starting material. The first method consists of converting a ketone to its tosyl hydrazone which adds HCN to give (48) in excellent yield. The decomposition of this product was attempted with basic reagents but the yield was poor (20-30%) however, good results were obtained by adding (48) to a bath of decalin maintained at 180°. Decomposition was complete in two hours and for the two examples quoted (cyclohexanone and heptan-4-one) yields of 60% were obtained [122],... 

Some imine-forming reactions are shown in Figure 14.30—all of these were part of longer synthetic sequences. Imines undergo many of the same types of addition reactions as aldehydes and ketones. A particularly useful example of this is their reaction with cyanide ion, the Strecker reaction (Figure 14.31). When a carbonyl compound is treated with ammonia and sodium or KCN, the ammonia adds to the carbonyl to give an unstable imine. This is attacked by cyanide to give the a-aminocyanide. Since the cyanide can be hydrolyzed to a carboxylic acid, this constitutes a simple amino acid synthesis. 

The formation of ethyl isopropylidene cyanoacetate is an example of the Knoevenagel reaction (see Discussion before Section IV,123). With higher ketones a mixture of ammonium acetate and acetic acid is an effective catalyst the water formed is removed by azeotropic distillation with benzene. The essential step in the reaction with aqueous potassium cyanide is the addition of the cyanide ion to the p-end of the ap-double bond ... 

Cya.nideExcha.nge, Acetone cyanohydrin and methyl isobutyl ketone cyanohydrin [4131 -68-4] dissolved in an organic solvent, such as diethyl ether or methyl isobutyl ketone, undergo cyanide exchange with aqueous cyanide ion to yield a significant cyanide carbon isotope separation. The two-phase system yields cyanohydrin enriched in carbon-13 and aqueous cyanide depleted in carbon-13. Fquilibrium is obtained in seconds. 

The reduction of carbonyl compounds by reaction with hydride reagents (H -) and the Grignard addition by reaction with organomagnesium halides (R - +MgBr) are examples of nucleophilic carbonyl addition reactions. What analogous product do you think might result from reaction of cyanide ion with a ketone ... 

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-. 

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