Cyanide addition to carbonyl

In 1850, A. Strecker accidently accomplished the first synthesis of the amino acid alanine by mixing of acetaldehyde, ammonia, and HCN and subsequent hydrolysis of the formed adduct [1]. Whereby this three-component-reaction is in general known as the Strecker reaction, the addition of a cyanide source to a preformed imine species is often referred to as the modified Strecker reaction, The so-formed a-amino nitriles, or from cyanide addition to carbonyl compounds the so-obtained cyanohydrins, are versatile building blocks that can be converted, for example, into a-hydroxy carbon acids, amino acids, amino alcohols and diamines. 

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

The same structural factors come into play in determining the position of equilibria in reversible additions to carbonyl compoimds. The best studied of such equilibrium processes is probably addition of cyanide to give cyanohydrins. 

These reactions mainly involve conjugate additions to carbonyl compounds by nucleophiles such as the cyanide ion, CN, and primary or secondary amines, RNH2 or R2NH. Figure 11-31 shows the conjugate addition by the cyanide ion, and Figure 11-32 shows the conjugate addition by a secondary amine. 

In an aqueous system, the only possible way to suppress the unwanted chemical HCN addition to carbonyl compounds is to work at low pH to reduce the concentration of the cyanide ion-the reactive species-and at low temperature to increase the selectivity. However, in an acidic medium, most HNLs lose activity very fast [15, 16], and it is therefore necessary to find reaction conditions to avoid these problems. 

When, in 1832, Wohler and Liebig first discovered the cyanide-catalyzed coupling of benzaldehyde that became known as the benzoin condensation , they laid the foundations for a wide field of growing organic chemistry [1]. In 1903, Lapworth proposed a mechanistical model with an intermediate carbanion formed in a hydrogen cyanide addition to the benzaldehyde substrate and subsequent deprotonation [2]. In the intermediate active aldehyde , the former carbonyl carbon atom exhibits an inverted, nucleophilic reactivity, which exemplifies the Umpo-lung concept of Seebach [3]. In 1943, Ukai et al. reported that thiazolium salts also surprisingly catalyze the benzoin condensation [4], an observation which attracted even more attention when Mizuhara et al. found, in 1954, that the thiazolium unit of the coenzyme thiamine (vitamin Bi) (1, Fig. 9.1) is essential for its activity in enzyme biocatalysis [5]. Subsequently, the biochemistry of thiamine-dependent enzymes has been extensively studied, and this has resulted in widespread applications of the enzymes as synthetic tools [6]. 

The reaction has two steps nucleophilic addition of cyanide, followed by protonation of the anion. In fact, this is a general feature of all nucleophilic additions to carbonyl groups. 

C/C-connections pericyclic reactions, ene reactions, allylation of carbonyls, Grignard-type additions to carbonyl, aldol-type additions of silyl enol ethers to carbonyl, epoxide opening with cyanide, etc. 

Cyanohydrin NC — RR COII, the product of hydrogen cyanide addition to the carbonyl group. 

In this section, we will focus primarily on nucleophilic additions to carbonyl groups. The carbonyl substrate may be an aldehyde or ketone, as well as various carboxylic acid derivatives such acid halides and esters. Among the variety of nucleophiles that can participate in these reactions are hydride, hydroxide, alkoxide, and a variety of carbon-based nucleophiles. For carbonyl substrates, attack by a nucleophile typically results in an opening up of the C-O ar-bond, leading to a tetrahedral intermediate, as shown below for the addition of cyanide to a ketone in the presence of water. 

Cyanide addition to the lactamic carbonyl group has been described in a reaction in which the cyanide ion acts as a catalyst (Fig. 14).The intermediate acyl cyanide can be attacked by an added nucleophile (allylic, propargylic, benzylic alcohols, aniline, benzylmercaptan). Comparative experiments were carried out using more classical procedures, such as under catalysis by potassium cyanide with stirring at room temperature, and with sodium alkoxides at -78 C. This last method provides the highest yields, up to 95% in most of the cases tested, but the sonochemical method proceeds under less basic conditions. Both methods preserve the integrity of the asymmetric center. 

Hydrogen cyanide adds to an olefinic double bond most readily when an adjacent activating group is present in the molecule, eg, carbonyl or cyano groups. In these cases, a Michael addition proceeds readily under basic catalysis, as with acrylonitrile (qv) to yield succinonitnle [110-61-2], C4H4N2, iu high yield (13). Formation of acrylonitrile by addition across the acetylenic bond can be accompHshed under catalytic conditions (see Acetylene-DERIVED chemicals). 

Finally, examine transition states for cyanide addition cyanide+formaldehyde, cyanide+acetone, cyanide+ benzophenone) What relationship, if any, is there between the length of the forming CC bond and the various carbonyl properties determined above Try to rationalize what you find, and see if there are other structural variations that can be correlated with carbonyl reactivity. 

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. 

Acyloins (a-hydroxy ketones) are formed enzymatically by a mechanism similar to the classical benzoin condensation. The enzymes that can catalyze reactions of this type arc thiamine dependent. In this sense, the cofactor thiamine pyrophosphate may be regarded as a natural- equivalent of the cyanide catalyst needed for the umpolung step in benzoin condensations. Thus, a suitable carbonyl compound (a -synthon) reacts with thiamine pyrophosphate to form an enzyme-substrate complex that subsequently cleaves to the corresponding a-carbanion (d1-synthon). The latter adds to a carbonyl group resulting in an a-hydroxy ketone after elimination of thiamine pyrophosphate. Stereoselectivity of the addition step (i.e., addition to the Stand Re-face of the carbonyl group, respectively) is achieved by adjustment of a preferred active center conformation. A detailed discussion of the mechanisms involved in thiamine-dependent enzymes, as well as a comparison of the structural similarities, is found in references 1 -4. 

---