Cyanohydrin, formation,

Optically active cyanohydrins are synthetic precursors of a-hydroxy carboxylic acids, a-amino carboxylic acids, /1-hydroxy amines, and several other classes of organic compound of biological importance [146]. Several efficient catalysts have been developed by using titanium as the central metal. 

In the addition reaction of cyanotrimethylsilane [147] to aliphatic aldehydes, another synthetic application of a BINOL-Ti catalyst was reported by Reetz [88]. In this instance, however, BINOL-TiCh was prepared by treatment of the lithium salt of BINOL with TiCU in ether (vide supra). The BINOL-TiCh thus obtained was used as a catalyst for the cyanosilylation reaction to give the cyanohydrins in up to 82 % ee (Sch. 62). 

Narasaka has reported that TADDOL-Ti dichloride catalyzes the asymmetric addition of trimethylsilylcyanide to aromatic and aliphatic aldehydes (Sch. 63) [148]. The reactions proceed only in the presence of MS 4A. In reactions with aliphatic aldehydes a chiral cyanotitanium species obtained by mixing of the TADDOL-Ti dichloride and trimethylsilylcyanide before addition of the aldehydes acts as a better chiral cyanating agent and affords higher enantiomeric excesses. Chiral titanium complexes obtained from an alcohol ligand and salicylaldehyde-type Schiff bases and a salen ligand have been reported to catalyze the asymmetric addition of hydrogen cyanide or 

Strecker-type addition of cyanide to imines has been reported to be catalyzed by chiral Ti Schiff base-tripeptide complexes (Sch. 65) [161]. The reaction is efficient ( 93 % conversion) and proceeds with excellent enantioselectivity (85-97 % ee) in the presence of 1.5 equiv. 2-propanol. Hoveyda and Snapper pointed out that catalyst turnover is significantly facilitated by the presence of 2-propanol. Optically pure products are usually isolated in 80 % yields. 

The formation of aldehyde cyanohydrin esters has been achieved under phase transfer catalytic conditions in which the two liquid phases are aqueous sodium or potassium cyanide and a methylene chloride solution of an aromatic aldehyde and an acid chloride. Both quaternary ammonium salts and 18-crown-6 are effective catalysts in this reaction. The formation of aldehyde cyanohydrin esters according to equation 7.7 probably occurs by a mechanism similar to that proposed for the formation of benzoyl cyanide dimers (see Eq. 7.5) [3, 22]. Accordingly, cyanide anion adds to the aldehyde carbonyl group to yield an alkoxide anion which in turn is acylated by the acid chloride. 

Attempts to substitute alkyl chloroformates for acid chlorides in this reaction gave cyanoformates rather than the anticipated alkyl cyanohydrin carbonates (Eq. 7.8) [22]. It seems likely that this fact reflects a reactivity difference among the carbonyl groups in the order chloroformates aromatic aldehydes aromatic acyl chlorides. 

Allylic ethers of aldehyde cyanohydrins have also been prepared under phase transfer conditions [23]. The organic phase, consisting of aldehyde cyanohydrin, an allylic halide (preferably the bromide) and dichloromethane is brought into contact with aqueous sodium hydroxide and tricaprylmethylammonium chloride. Anion exchange in the aqueous phase leads to the tricaprylmethylammonium/hydroxide ion pair, which reacts with the cyanohydrin to form the corresponding alkoxide. Reaction of the alkoxide with the allylic halide leads to the allylic ether of the cyanohydrin (Eq. 7.9). The formation of small amounts of allylic nitriles is apparently due to the side 

TABLE 14.1 Equilibrium Constants for Cyanohydrin Formation in Aqueous Solution 

FIGURE 14.14 Reaction of a ketone with trimethylsilyl cyanide (The 18-crown-6 sequesters potassium, breaking up KCN ion pairs, so that the cyanide acts as a better nucleophile). 

Despite, or perhaps because of, the high toxicity of cyanide, cyanohydrins are widely distributed in nature. The cyanohydrin of benzaldehyde, PhCH(OH)CN, is used as a defense mechanism by the millipede Apheloria corrugata. When the millipede is attacked, it excretes the cyanohydrin, which is then enzymatically converted to benzaldehyde and HCN, the latter being toxic to the attacker. 

Study the reaction sequence in the following and answer the questions given  

Explain the equilibrium constants shown in the following for cyanohydrin formation  

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

The reactivity of aldehydes and ketones toward cyanide may be influenced by the steric and/or electronic properties of the carbonyl substituents, X. Examine spacefilling models of formaldehyde (X=H), acetone (X=Me), and benzophenone (X=Ph). Which compound offers the least steric hindrance to nucleophilic attack The most  

Compare electrostatic potential maps for formaldehyde, acetone, and benzophenone. Which compound contains the most electron-poor carbonyl carbon Rationalize what you observe. 

Another useful way to think about carbon electrophilicity is to compare the properties of the carbonyls lowest-unoccupied molecular orbital (LUMO). This is the orbital into which the nucleophile s pair of electrons will go. Examine each compound s LUMO. Which is most localized on the carbonyl group Most delocalized Next, examine the LUMOs while displaying the compounds as space-filling models. This allows you to judge the extent to which the LUMO is actually accessible to an approaching nucleophile. Which LUMO is most available Least available  

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. 

Hydroxynitrile lyase enzymes catalyze the asymmetric addition of hydrogen cyanide onto a carbonyl group of an aldehyde or a ketone thus forming a chiral cyanohydrin [1520-1524], a reaction which was used for the first time as long ago as 1908 [1525]. Cyanohydrins are rarely used as products per se, but they represent versatile starting materials for the synthesis of several types of compounds [1526]  

Chiral cyanohydrins serve as the alcohol moieties of several commercial pyre-throid insecticides (see below) [1527]. Hydrolysis or alcoholysis of the nitrile group affords chiral a-hydroxyacids or -esters and Grignard reactions provide acyloins [1528], which in turn can be reduced to give vicinal diols [1529], Alternatively, the cyanohydrins can be subjected to reductive amination to afford chiral ethanol-amines [1530]. a-Aminonitriles as well as aziridines are obtained via the corresponding a-sulfonyloxy nitriles [1531]. 

On the other hand, (5)-hydroxynitrile lyases [1541-1544] were found in Sorghum bicolor [1545] (millet), Hevea brasiliensis [1546, 1547] (mbber tree). 

The (5)-hydroxynitrile lyase from Hevea brasiliensis has been made available in sufficient quantities by cloning and overexpressirai to allow industrial-scale applications [1563]. It should be noted that also a,p-unsaturated aliphatic aldehydes were transformed into the corresponding cyanohydrins in a clean reaction. No formation of saturated p-cyano aldehydes through Michael-type addition of hydrogen cyanide across the C=C double bond occurred. The latter is a common side reaction using traditional methodology. 

Of particular interest is the industrial-scale synthesis of the (5)-conligured cyanohydrin from wi-phenoxybenzaldehyde (Table 2.8), which is an important intermediate for synthetic pyrethroids. 

The product of addition of hydrogen cyanide to an aldehyde or a ketone contains both a hydroxyl group and a cyano group bonded to the same carbon. Compounds of this type are called cyanohydrins. 

Mechanism 17.3 describing cyanohydrin formation is analogous to the mechanism of base-catalyzed hydration. The nucleophile (cyanide ion) bonds to the carbonyl carbon in 

Steric and electronic effects influence the rate of nucleophilic addition to a proton-ated carbonyl group in much the same way as they do for the case of a neutral one, and protonated aldehydes react faster than protonated ketones. 

With this as background, let us now examine how the principles of nucleophilic addition apply to the characteristic reactions of aldehydes and ketones. We U begin with the addition of hydrogen cyanide. 

The addition of hydrogen cyanide is catalyzed by cyanide ion, but HCN is too weak an acid to provide enough C=N= for the reaction to proceed at a reasonable rate. Cyanohydrins are therefore normally prepared by adding an acid to a solution containing the carbonyl compound and sodium or potassium cyanide. This procedure ensures that free cyanide ion is always present in amounts sufficient to increase the rate of the reaction. 

Cyanohydrin formation is reversible, and the position of equilibrium depends on the steric and electronic factors governing nucleophilic addition to carbonyl groups described in the preceding section. Aldehydes and unhindered ketones give good yields of cyanohydrins. 

Step 1 The negatively charged carbon of cyanide ion is nucleophilic and bonds to the carbonyl carbon of the aldehyde or ketone. Hydrogen cyanide itself is not very nucleophilic and does not ionize to form cyanide ion to a significant extent. Thus, a source of cyanide ion such as NaCN or KCN is used. 

Step 2 The alkoxide ion formed in the first step abstracts a proton from hydrogen cyanide. This step yields the cyanohydrin product and regenerates cyanide ion. 

In substitutive lUPAC nomenclature, cyanohydrins are named as hydroxy derivatives of nitriles. Because nitrile nomenclature will not be discussed until Section 19.1, we will refer to cyanohydrins as derivatives of the parent aldehyde or ketone as shown in the examples. This conforms to the practice of most chemists. 

Great care must be taken when working with hydrogen cyanide due to its high toxicity and voiatiiity. Reactions invoiving HCN must be conducted in an efficient fume hood. 

Cyanohydrins are useful intermediates in organic synthesis because they can be converted to several other functional groups. 

The mechanism for this hydrolysis is discussed in Section 17.8H. The preparation of a-hydroxy acids from cyanohydrins is part of the Kiliani-Fischer synthesis of simple sugars (Section 22.9A)  

Provide the missing reagents and intermediate in the following synthesis. 

STRATEGY AND ANSWER Step (1) requires oxidation of a primary alcohol to an aldehyde use PCC (Section 12.4). To reach the final product from the aldehyde we need to add a carbon atom to the chain and introduce a primary amine. This combination suggests use of a nitrile, which we know can be reduced to a primary amine. Thus, adding HCN to the aldehyde in step (2) forms the cyanohydrin (3), shown below. This step also affords the alcohol group present in the final product. In step (4) we reduce the nitrile to a primary amine using LiAIH4. 

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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 reaction is used for the chain extension of aldoses in the synthesis of new or unusual sugars In this case the starting material l arabinose is an abundant natural product and possesses the correct configurations at its three chirality centers for elaboration to the relatively rare l enantiomers of glucose and mannose After cyanohydrin formation the cyano groups are converted to aldehyde functions by hydrogenation m aqueous solution Under these conditions —C=N is reduced to —CH=NH and hydrolyzes rapidly to —CH=0 Use of a poisoned palladium on barium sulfate catalyst prevents further reduction to the alditols... 

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