Nitriles groups

Carboxyl and nitrile groups are usually introduced in synthesis with commercial carboxylic acid derivatives, nitriles, or cyanide anion. Carbanions can be carboxylated with carbon dioxide (H.F. Ebel, 1970) or dialkyl carbonate (J. Schmidlin, 1957). 

A classical way to achieve regioselectivity in an (a -i- d -reaction is to start with a-carbanions of carboxylic acid derivatives and electrophilic ketones. Most successful are condensations with 1,3-dicarbonyl carbanions, e.g. with malonic acid derivatives, since they can be produced at low pH, where ketones do not enolize. Succinic acid derivatives can also be de-protonated and added to ketones (Stobbe condensation). In the first example given below a Dieckmann condensation on a nitrile follows a Stobbe condensation, and selectivity is dictated by the tricyclic educt neither the nitrile group nor the ketone is enolizable (W.S. Johnson, 1945, 1947). 

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... 

In the Strecker synthesis an aldehyde is converted to an a ammo acid with one more carbon atom by a two stage procedure m which an a ammo nitrile is an mterme diate The a ammo nitrile is formed by reaction of the aldehyde with ammonia or an ammonium salt and a source of cyanide ion Hydrolysis of the nitrile group to a car boxylic acid function completes the synthesis... 

The exceUent chemical resistance of acryhc fibers may stem from its unique lateraUy bonded stmcture. Dipole bonds, formed between nitrile groups... 

This tendency is related to the polarization properties of the monomer substituents (42). Monomers that are dissimilar in polarity tend to form alternating monomer sequences in the polymer chain. An example is the monomer pair acrylonitrile—styrene. Styrene, with its pendent phenyl group, has a relatively electronegative double bond whereas acrylonitrile, with its electron-withdrawing nitrile group, tends to be electropositive. 

Physical properties for naphthalene mono-, di-, tri-, and tetracarboxyhc acids are summari2ed in Table 9. Most of the naphthalene di- or polycarboxyLic acids have been made by simple routes such as the oxidation of the appropriate dior polymethylnaphthalenes, or by complex routes, eg, the Sandmeyer reaction of the selected antinonaphthalenesulfonic acid, to give a cyanonaphthalenesulfonic acid followed by fusion of the latter with an alkah cyanide, with simultaneous or subsequent hydrolysis of the nitrile groups. 

With solvents having a nitrile group like acetonitrile, the selectivity of y-butyrolactone is increased, resulting in a yield of 60%. 

The tertiary amine is formed in a similar manner from the imine and a secondary amine. This side reaction can be minimized by carrying out the hydrogenation in the presence of ammonia, which tends to shift the equiHbrium back towards the imine. When a compound with two or more nitrile groups is hydrogenated, the formation of both cycHc and acycHc secondary and tertiary amines is possible, depending on whether the side reaction is intramolecular or intermolecular. For example, for the hydrogenation of adiponitfile ... 

Reactions. Reactions of cyanamide are either additions to the nitrile group or substitutions at the amino group. Both are involved in the dimerization to dicyandiamide. 

Additions. The addition reactions of ammonia and amines to the cyanamide nitrile group have been thoroughly studied (15). For optimum conditions, the reaction should be carried out ia an aqueous medium at about 140°C. Gradual addition of the cyanamide to the amine salt minimises dimerization. 

Reactions. The reactions of dicyandiamide resemble those of cyanamide. However, cycUzations take place easily and the nitrile group is less reactive. Under pressure and ia the presence of ammonia, dicyandiamide cyclizes to melamine. Considerable toimages of melamine have been made ia this manner however, melamine is produced chiefly by the urea process (43). 

The nitrile groups of these three heterocycHc thiacyanocarbons behave normally and are convertible to amide, imide, or carboxyUc acid groups. 

Cyanohydrins can react either at the nitrile group or at the hydroxyl group. 

Nitrile Group. Hydrolysis of the nitrile group proceeds through the amide to the corresponding carboxyUc acid. Because cyanohydrins are unstable at high pH, this hydrolysis must be cataly2ed by acids. In cases where amide hydrolysis is slower than nitrile hydrolysis, the amide may be isolated. 

Elastomers, syntpietic-nitrile rubber). It is the nitrile group, —C=N, that confers oil resistance to this polymer, and the nitrile content can vary from 10 to 40%, leading to increasing solvent resistance. 

Cyclization reactions effected by intramolecular attack of the heteroatom on a nitrile group provide a useful source of 2-amino heterocycles. Some illustrative examples are depicted in Scheme 16. 

The synthetic application of reactions based upon the intramolecular addition of a carbanion or its enamine equivalent to a carbonyl or nitrile group has been explored extensively. One class of such reactions, namely the Dieckman, has already been discussed in Section 3.03.2.2, since ring closure can often occur so as to form either the C(2)—C(3) or C(3)—C(4) bond of the heterocyclic ring. Some illustrative examples of the application of this type of ring closure are presented in Scheme 46. 

Photolysis of 2,3-diphenyl-A -azirine (442) generates benzonitrile ylide (443). Irradiation in the presence of ethyl cyanoformate resulted in a mixture of the oxazoline (444) and the imidazole (445) by 1,3-dlpolar cycloaddition to the carbonyl and nitrile group, respectively (72HCA919). 

Deuterium labeling of C-18 has also been accomplished by an alternate procedure adapted from the Nagata steroid synthesis. During the course of the total synthesis of pregnanolone, thevC-18 function is introduced in the form of a nitrile group. Reduction of this function in intermediate (247) with lithium aluminum deuteride leads to a deuterated imine (248), which upon Wolff-Kishner reduction and acid-catalyzed hydrolysis... 

Better yields are attributed to intimate association of the basic nitrile group at the surface of the mtrosomum salt causing nitrosative decomposition of the azide to occur in close proximity to the weakly nucleophilic complex fluoride anion Fluorination yields can be further enhanced to 59-81% by lengthening the azido nitrile chain, but the reaction is accompanied by pronounced secondary fluoronitnle formation arising from rearrangement [100, 101] (Table 8)... 

Replacement of hydrogen with bromine alpha to a carbonyl or a nitrile group lakes place under mild conditions and in good yield [41, 42] (equations 23 and 24)... 

Spectroscopic investigation of enamines conjugated with ketone, ester and nitrile groups established the prevalence of enamine rather than imine-enol tautomers in examples of secondary amines (206-212). Similar studies have been made with enamines of acylpyridines and acetophenones (213,214). 

Aniline 77 was converted into its diazonium salt with nitrous acid and this was followed by reduction with stannous chloride to afford the corresponding arylhydrazine 78. Condensation of 78 with 3-cyanopropanal dimethylacetal 79 gave the arylhydrazone 80. Treatment of 80 with PPE resulted in cyclization to indole 81. The nitrile group was then reduced to the primary amine by catalytic hydrogenation. Reaction of the amine with excess formalin and sodium borohydride resulted in Imitrex (82). 

This reaction is believed to proceed via an amidine (34) and it has been shown that the reactivity of the nitrile group toward nucleophiles is a more important factor than amine basicity in controlling cyclization. 

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