Cyanide Ions as the Nucleophile

In contrast to the deactivation observed in the metal-catalyzed process, the photochemical reaction tolerates the use of an excess of KCN, a relatively inexpensive cyanating agent, to generally improve the yield. 

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An Sn2 displacement constitutes the key operation in which the ester group at C-3 of catharanthine is introduced [62], Thus, a contrapolarizing change of the 11-position from d to a allows the desired reaction to be performed, using cyanide ion as the nucleophile. 

The first such process was realized over one and a half centuries ago with the discovery of the Strecker reaction [10] which has a cyanide ion as the nucleophile, leading to the formation of a-amino nitriles 10 (Scheme 7.2). These highly versatile synthetic intermediates can be hydrolyzed to a-amino acids or can be converted to other molecules [11, 12]. 

The same disconnection 41 can be used for carboxylic acids with CO2 as the electrophile for a Grignard reagent 40. Dry ice (solid CO2) is particularly convenient for these reactions. Switching polarity by FGI to the nitrile 42, the same disconnection now uses cyanide ion as the nucleophile but the same alkyl halide 39 that was used to make the Grignard reagent. Mechanistic considerations should decide between these alternatives. 

At first glance the conversion of bromobenzene to benzenenitrile looks simple—just carry out a nucleophilic substimtion using cyanide ion as the nucleophile. Then we remember that bromobenzene does not undergo either an S l or an 5 2 reaction (Section 6.14A). The conversion can be accomplished, however, though it involves several steps. Oudine possible steps. 

If we use cyanide ion as the nucleophile (entry 14 in Table 6.1), the alkyl halide must have the halogen (Cl, Br, or I) attached to a propyl group. The... 

Figure 3-22 shows a nucleophilic aliphatic substitution with cyanide ion as a nucleophile, i his reaction is assumed to proceed according to the S f2 mechanism with an inversion in the stereochemistry at the carbon atom of the reaction center. We have to assign a stereochemical mechanistic factor to this reaction, and, clearly, it is desirable to assign a mechanistic factor of (-i-1) to a reaction with retention of configuration and (-1) to a reaction with inversion of configuration. Thus, we want to calculate the parity of the product, of 3 reaction from the parity of the... 

Cyanide ion ( C = N ) The negatively charged carbon atom of cyanide ion IS usually the site of its nucleophilic character Use of cyanide ion as a nucleophile permits the extension of a carbon chain by carbon-carbon bond formation The product is an alkyl cyanide or nitrile... 

The most frequently used method for the preparation of isoquinoline Reissert compounds is treatment of an isoquinoline with acyl chloride and potassium cyanide in water or in a dichloromethane-water solvent system. Though this method could be successfully applied in a great number of syntheses, it has also some disadvantages. First, the starting isoquinoline and the Reissert compound formed in the reaction are usually insoluble in water. Second, in the case of reactive acyl halides the hydrolysis of this reaction partner may became dominant. Third, the hydroxide ion present could compete with the cyanide ion as a nucleophile to produce a pseudobase instead of Reissert compound. To decrease the pseudobase formation phase-transfer catalysts have been used successfully in the case of the dichloromethane-water solvent system, resulting in considerably increased yields of the Reissert compound. To avoid the hydrolysis of reactive acid halides in some cases nonaqueous media have been applied, e.g., acetonitrile, acetone, dioxane, benzene, while utilizing hydrogen cyanide or trimethylsilyl cyanide as reactants instead of potassium cyanide. 

The use of acetylides as nucleophiles is a particularly important example of nucleophilic substitution because it results in a new carbon-carbon bond. Thus, larger organic molecules can be assembled from smaller ones using this method. The same is true for cyanide ion as a nucleophile (part b). 

The use of cyanide ion as a nucleophile in an SN2 reaction (see Section 10.8), followed by hydrolysis of the product nitrile, provides a useful preparation of carboxylic acids that contain one more carbon than the starting compound ... 

A cyanide anion as a nucleophile adds to an aldehyde molecule 1, leading to the anionic species 3. The acidity of the aldehydic proton is increased by the adjacent cyano group therefore the tautomeric carbanion species 4 can be formed and then add to another aldehyde molecule. In subsequent steps the product molecule becomes stabilized through loss of the cyanide ion, thus yielding the benzoin 2 ... 

Rate constants for the substitution reactions of square-planar dithio-phosphates and dithiocarbonate complexes of Ni(II), Pd(II), and Pt(II), with ethylenediamine and cyanide ion as nucleophiles, have been measured in methanol. The results were compared with those obtained in previous investigations, and interpreted in terms of the stabilities of 5-coordinate species that are formed prior to substitution (377). 

Many other examples of synthetic equivalent groups have been developed. For example, in Chapter 6 we discussed the use of diene and dienophiles with masked functionality in the Diels-Alder reaction. It should be recognized that there is no absolute difference between what is termed a reagent and a synthetic equivalent group. For example, we think of potassium cyanide as a reagent, but the cyanide ion is a nucleophilic equivalent of a carboxy group. This reactivity is evident in the classical preparation of carboxylic acids from alkyl halides via nitrile intermediates. 

Diphenylpyrido[l,2-3][l,2,4]triazinium fluoroborate 97 promptly reacted with nucleophiles (such as hydroxide, alkoxide, or cyanide ion) at the 2-position to give the stable pseudobases 100 (Equation 9) <2003ARK155>. 

Nucleophiles such as hydroxide or cyanide ion, in the presence of an oxidant, cause deboronation of ions (99) and (100) to give ion (96) and benzeneboronic acid. If no other oxidant is present the ions (99) and (100) themselves serve as oxidizing species to give a disproportionation. The use of mild reaction conditions stops the oxidation of (100) at the stage of (99). Nucleophiles like pyridine and hydride ion (from sodium borohydride) add to the borinate ring, pyridine to the boron atom and hydride to carbon atoms (79CB607). 

The cyanide ion is the only known catalyst for this condensation, because the cyanide ion has unique properties. For example, cyanide ions are relatively strong nucleophiles, as well as good leaving groups. Likewise, when a cyanide ion bonds to the carbonyl group of the aldehyde, the intermediate formed is stabilized by resonance between the molecule and the cyanide ion. The following mechanism illustrates these points. 

Intermolecular addition of carbon nucleophiles to the ri2-pyrrolium complexes has shown limited success because of the decreased reactivity of the iminium moiety coupled with the acidity (pKa 18-20) of the ammine ligands on the osmium, the latter of which prohibits the use of robust nucleophiles. Addition of cyanide ion to the l-methyl-2//-pyr-rolium complex 32 occurs to give the 2-cyano-substituted 3-pyrroline complex 75 as one diastereomer (Figure 15). In contrast, the 1-methyl-3//-pyrrolium species 28, which possesses an acidic C-3-proton in an anti orientation, results in a significant (-30%) amount of deprotonation in addition to the 2-pyrroline complex 78 under the same reaction conditions. Uncharacteristically, 78 is isolated as a 3 2 ratio of isomers, presumably via epimerization at C-2.17 Other potential nucleophiles such as the conjugate base of malononitrile, potassium acetoacetate, and the silyl ketene acetal 2-methoxy-l-methyl-2-(trimethylsiloxy)-l-propene either do not react or result in deprotonation under ambient conditions. 

These are O-, S- and iVnucleophiles. Halide ions are not able to react as nucleophiles with carbonyl compounds, but a pseudohahdethat is, the cyanide ion, is. The addition of the cyanide ion to aldehydes and ketones displays considerable analogies with the addition reactions of ()-, S- and N nucleophiles and this is why Section 9.1 addresses these cyanide additions. 

This reaction is presented in a style with which you will become familiar. The organic starting material is written first and then the reagent over the reaction arrow and the solvent under it. We must decide what happens. NaCN is an ionic solid so the true reagent must be cyanide ion. As it is an anion, it must be the nucleophile and the carbonyl group must be the electrophile. Let us try a mechanism. 

Displacement of the bromide by cyanide ion, using the copper (I) salt as the nucleophile, gives a mixture of nitriles in which the more stable primary nitrile predominates even more. These can be separated by a clever device. Hydrolysis in concentrated HCl is successful with the predominant primary nitrile but the more hindered secondary nitrile does not hydrolyse. Separation of compounds having two different functional groups is easy in this case the acid can be extracted into aqueous base, leaving the neutral nitrile in the organic layer. 

Selenocyanates produce selenols or diselenides upon either reduction (e g. with sodium borohydride) or hydrolysis (see Scheme 1). They undergo displacement of the cyanide ion by various nucleophiles and add to alkenes in a maimer similar to selenenyl halides (see equation 14), except that catalysis with Lewis acids is required in the case of unactivated alkenes. The selenocyanates are also popular reagents for the preparation of selenides from alcohols, and (8) from carboxylic acids, as indicated in Scheme 3. 

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