Chemistry of Nitriles

Lithium aluminum hydride reduction is equally effective with both acyclic and cyclic amides, or lactams. The reduction of a lactam is a good method for preparing a cyclic amine. 

Problem 21.22 How would you convert JV-ethylbenzamide to each of the following products  

Problem 21.23 How would you use the reaction of an amide with LiAlH4 as the key step in going from bromocyclohexane to W V-dimethylaminomethybcyclohexane Write all the steps in the reaction sequence. 

Nitriles are analogous to carboxylic acids in that both have a carbon atom with three bonds to an electronegative atom, and both contain a w bond. Thus, the reactions of nitriles and carboxylic acid derivatives are similar. 

CHAPTER 21 Carboxylic Add Derivatives and Nucleophilic Acyl Substitutions 

Problem 20.11. How might you prepare 2-phenylethanol from benzyl bromide More than one step 

Problem 20.12 How might you carry out the following transformation More than one step is 

The simplest method of nitrile preparation is the S j2 reaction of CN with a primary or secondary alkyl halide, as discussed in Section 20.5. Another method for preparing nitriles is by dehydration of a primary amide, RCONH2- Thionyl chloride is often used for the reaction, although other dehydrating agents such as POCI3 also work. 

The dehydration occurs by initial reaction of SOCI2 on the nuclcopliilic amide oxygen atom, followed by deprotonation and a subsequent E2-likc elimination reaction. 

Both methods of nitrile synthesis—Sn2 displacement by CN on an alkyl halide and amide dehydration—are useful, but the synthesis from amides is more general because it is not limited by steric hindrance. 

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The chemistry of nitrile oxides is well documented. Several important monographs either specially devoted to nitrile oxides or including corresponding comprehensive chapters should be mentioned (1—5). Several reviews appeared (6—8), which concern preparation, reactivity, and synthetic applications of nitrile oxides. Some books and reviews devoted to individual aspects of nitrile oxide chemistry will be cited elsewhere. 

The chemistry of nitrile oxides, in particular their application in organic synthesis, has been continuously developed over the past two decades and represents the main theme of this chapter. The parent compound, fulminic acid (formonitrile oxide), has been known for two centuries, and many derivatives of this dipole have been prepared since that time. Several simple and convenient methods for the preparation of nitrile oxides have evolved over the years. Dehydrochlorination of hydroximoyl chlorides was first introduced by Werner and Buss in 1894 (1). A convenient synthesis of isoxazoles was reported by Quilico et al. (2 ), and then the discovery of nitrile oxide cycloadditions to alkenes was subsequently noted by the same group (5). 

For reviews of the chemistry of nitrile oxides, see Torsscll Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis-. VCH New York, 1988, pp. 55-74 Grundmann Fortschr. Chem. Forsch. 1966, 7, 62-127,... 

The effect of substituents on benzenoid reactivity has been one of the most extensively investigated branches of chemistry. The scattered data on pyridine substitution are now assembled in a review by R. A. Abramovitch and J. G. Saha which is as valuable for showing what remains to be done as for what has been achieved. R. E. Lyle and P. S. Anderson survey reactions of nitrogen heterocycles with complex hydrides, and the heterocyclic chemistry of nitriles and nitrilium salts is covered by F. Johnson and R. Madronero. 

Summary of the Chemistry of Acid Chlorides 1019 21-11 Summary of the Chemistry of Anhydrides 1020 21-12 Summary of the Chemistry of Esters 1023 21-13 Summary of the Chemistry of Amides 1027 21-14 Summary of the Chemistry of Nitriles 1030 21-15 Thioesters 1031... 

The chemistry of nitrile oxides has been well reviewed (see, for example, Grundmann et a/.59-61), and only those features which are pertinent to the synthesis of isoxazoles are summarized here. The electronic structure may be represented as a hybrid of the canonical forms 19-23. The formula 20 is commonly used, but formula 19 embodies their 1,3-dipolar character, and formula 23 their nitrosocarbenoid nature. 

How do these results correspond to the chemistry of nitrile ylides, and the variations observed upon substitution Because of preparative limitations, most nitrile ylides which have been studied have a 1-aryl substituent and frequently a 3-alkyl... 

We end Chapter 22 with the chemistry of nitriles (RC=N). Nitriles have a carbon atom in the same oxidation state as in the acyl compounds that are the principal focus of Chapter 22. Moreover, the chemical reactions of nitriles illustrate some of the concepts first discussed earlier in Chapter 22 and in Chapters 20 and 21. 

The chemistry of nitriles is similar in many respects to the chemistry i carbonyl compounds. Like carbonyl groups, a nitrile group is strongly polarized, making the carbon atom electrophilic. Nitriles are therefore attacked by nucleophiles to yield sp -hybridized imine anions in a reaction analogous to the formation of an sp -hybridized alkoxide ion by nucleophilic addition to a carbonyl group. 

Also included in this chapter is a discussion of the chemistry of nitriles, compounds of the type RC=N. Nitriles may be hydrolyzed to carboxylic acids or to amides and, so, are indirectly related to the other functional groups presented here. 

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