Reactions of Nitriles

Of course a nitrile is not a carbonyl. But nitrile and carbonyl chemistries are similar, and an examination of nitrile reactions naturally belongs in this section. Like carhonyl compounds, nitriles are both electrophiles and nucleophiles. As in carhonyl compounds, a polar resonance form contributes to the structure of nitriles (Fig. 18.44). Consequently, the triple bond is polarized and the carhon acts as a Lewis add. One might antidpate that nudeophiles would add to nitriles, and that idea is correct. These similarities mean that many of the reactions of carhonyl groups are also possible for nitriles, and the mechanisms are generally dosely related. Students sometimes have trouble with the nitrile reactions, however, so it is important not to dismiss them with only a cursory look. For some reason, the analogy between the carbon—oxygen double bond and the carbon—nitrogen triple bond is not always easy to keep in mind. 

FIGURE 18.44 Nitriles are electrophiles, and nucleophiles add to them to give imine anions. There is a close analogy to carbonyl chemistry here. 

The nitrogen atom of the nitrile bears a pair of nonbonding electrons and is therefore the center of nucleophilicity and Bronsted basidty. The nitrogen is r -hybridized, however, and is a relatively weak base. 

PROBLEM 18.18 Explain why an r -hybridized nitrogen should be a weaker base than an ry -hybridized nitrogen. What about r/ -hybridized nitrogens  

Both acid- and base-induced hydrolysis of a nitrile gives the amide, but rather severe conditions are required for the reactions, and further hydrolysis of the intermediate amides gives the carboxylic acids (p. 902). In acid, the first step is protonation of the nitrile nitrogen to give a strong Lewis acid (A, Fig. 18.45), which is attacked by water. A series of proton shifts then gives an amide that is hydrolyzed to the carboxylic acid. 

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Intramolecular reactions of nitrile imines as a fruitful source of heterocycles 98H(47)541. 

The greatest attention is at present paid to the second variant which forms the 1—5 and 3—4 bonds, i.e., the addition reaction of nitrile... 

The first, and so far only, metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction of nitrile oxides with alkenes was reported by Ukaji et al. [76, 77]. Upon treatment of allyl alcohol 45 with diethylzinc and (l ,J )-diisopropyltartrate, followed by the addition of diethylzinc and substituted hydroximoyl chlorides 46, the isoxazolidines 47 are formed with impressive enantioselectivities of up to 96% ee (Scheme 6.33) [76]. 

Nitriles are analogous to carboxylic acids in that both have a carbon atom with three bonds to an electronegative atom, and both contain a tt bond. Thus, some reactions of nitriles and carboxylic acids are similar. Both kinds of... 

Among the most useful reactions of nitriles are hydrolysis to yield first an amide and then a carboxylic acid plus ammonia, reduction to yield an amine, and Grignard reaction to yield a ketone (Figure 20.3). 

Reaction of Nitriles with Organometallic Reagents Grignard reagents add to a nitrile to give an intermediate imine anion that is hydrolyzed by addition of water to yield a ketone. 

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. 

Reactions of nitriles (Section 20.71 (a) Hydrolysis to yield carboxylic acids... 

Bcnzotriazepincs 10 are produced in the reaction of nitrile imines 9 with 2-phenyl-benzazctc.379... 

Using classical reactions of nitriles of low molecular weight7 a number of conversions can be effected in the PAN polymer chain ontaining new derivatives. 

Addition and substitution reactions of nitrile-stabilized carbanions S. Arseniyadis, K. S. Kyler and D. S. Watt, Organic Reactions 31,1 (1984). Note. Includes ArC (OTMS)CN, and HetAr (OTMS)CN. 

Both cis- and trans-chrysanthemic nitriles and amides were resolved into highly enantiopure amides and acids by Rhodococcus sp. whole cells [85]. The overall enantioselectivity of reactions of nitriles originated from the combined effects of a higher (lJ )-selective amidase and a (IJ )-selective nitrile hydratase (Figure 6.29). Chrysanthemic acids are related to constituents of pyrethrum flowers and insecticides. 

Table 10. Molecular mechanics calculations on the INOC reactions of nitrile oxides 98 (energies in kcal/mol)...

Reactions of nitriles may be promoted by the presence of divalent Co. The conversion of sterically unhindered nitriles RCN (R = Me, Et, n-Pr, w-Bu) into the corresponding amidines RC(NH2) = NH occurs in the presence of Co(N03)2.6H20 and the ketoxime Me2C=NOH. The metal free amidinium ions were crystallized as their nitrate salts.358... 

Alkyl and silyl nitronates are, in principle, /V-alkoxy and /V-silyloxynitrones, and they can react with alkenes in 1,3-dipolar cycloadditions to form /V-alkoxy- or /V-silyloxyisoxaz.olidine (see Scheme 8.25). The alkoxy and silyloxy groups can be eliminated from the adduct on heating or by acid treatment to form 2-isoxazolines. It should be noticed that isoxazolines are also obtained by the reaction of nitrile oxides with alkenes thus, nitronates can be considered as synthetic equivalents of nitrile oxides. Since the pioneering work by Torssell et al. on the development of silyl nitronates, this type of reaction has become a useful synthetic tool. Recent development for generation of cyclic nitronates by hetero Diels-Alder reactions of nitroalkenes is discussed in Section 8.3. 

An alternative strategy for generating 4,5-dihydropyrazoles is to perform 1,3-dipo-lar cydoaddition reactions of nitrile imines and alkenes. Langa and coworkers have... 

Table 21 Reaction of nitriles with acylhydrazides to give 3,5-disubstituted 1,2,4-triazole derivatives (Equation 38)...

A new three-component approach to the highly substituted 2,5-dihydro-l,2,4-oxadiazoles 359 has been reported from the reaction of nitriles 354 under mild conditions with iV-alkylhydroxylamines 355 in the presence of electron-deficient alkynes 356 (Scheme 60) <20050L1391>. This synthesis is proposed to proceed via the initial formation of the alkyl or arylamidoximes 357, which then undergo a sequential double Michael addition to the electron deficient alkyne. The intermediate alkyl or arylamidoximes 357 can be isolated and then reacted with the alkyne to produce the product. The initial Michael adduct 358 is stable in cases where R2 is H. 

The reaction of nitrile oxides with nitrilium salts, which are more reactive than the corresponding nitriles, as discussed in CHEC-II(1996) <1996CHEC-II(4)179>, is the main route through to oxadiazolium salts. Further advances in this area have not been reported. 

Type G syntheses are typified by the 1,3-dipolar cycloaddition reactions of nitrile sulfides with nitriles. Nitrile sulfides are reactive 1,3-dipoles and they are prepared as intermediates by the thermolysis of 5-substituted-l,3,4-oxathiazol-2-ones 102. The use of nitriles as dipolarophiles has resulted in a general method for the synthesis of 3,5-disubstituted-l,2,4-thiadiazoles 103 (Scheme 11). The thermolysis is performed at 190°C with an excess of the nitrile. The yields are moderate, but are satisfactory when aromatic nitrile sulfides interact with electrophilic nitriles. A common side reaction results from the decomposition of the nitrile sulfide to give a nitrile and sulfur. This nitrile then reacts with the nitrile sulfide to yield symmetrical 1,2,4-thiadiazoles <2004HOU277>. Excellent yields have been obtained when tosyl cyanide has been used as the acceptor molecule <1993JHC357>. 

A novel high-yielding synthetic route to 3,5-disubstituted-l,2,4-thiadiazoles 104 has been reported which involves the reaction of nitriles with the arsenic complex S AsFg in liquid SO2 (Equation 29) <1999CC1801>. 

An alternative route to C-linked derivatives involves the 1,3-dipolar cycloaddition reaction of nitrile sulfides with nitriles which yields 3,5-disubstituted-l,2,4-thiadiazoles of unequivocal structure (see Section 5.08.9.8). 

The scope of this reaction (Scheme 16) has been extended to other 5-substituted tetrazoles, readily prepared by the reaction of nitriles with aluminium azide <2002J(P1)1543>. Using triphenylphosphine under mild conditions, the resulting dithiazolimines 169 are rapidly converted into cyanothiadiazoles 170 in high yield (Equation 61 and Table 10). 

Thiomorpholides have been obtained by the reaction of nitriles or ketones and elemental sulfur with morpholine under microwave irradiation (Scheme 5).21,22... 

Primary selenoamides are prepared by reaction of nitriles with appropriate selenating reagent, such as phosphorus (V) selenide (P2Se5), hydrogen selenide (H2Se), Al2Se3, NaSeH, trw(trimethylsilyl)monoselenophosphate or potassium selenobenzoate (Scheme 81).248 252... 

A new, simple, high yielding synthetic route to 3,5-disubstituted 1,2,4-thiadiazoles 75 was described by Passmore and co-workers which involved the reaction of nitriles with S (AsF6)2 in liquid S02 <99CC1801>. 

Some routes of chemical transformations of nitrile oxides connected with the problem of their stability were briefly discussed in Section 1.2. Here only two types of such reactions, proceeding in the absence of other reagents, viz., dimerization to furoxans and isomerization to isocyanates, will be considered. All other reactions of nitrile oxides demand a second reagent (in some cases the component is present in the same molecule, and the reaction takes place intramolecularly) namely, deoxygenation, addition of nucleophiles, and 1,3-dipolar cycloaddition reactions. Also, some other reactions are presented, which differ from those mentioned above. 

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