Pyridine N-oxides, substituted

Extensive data are available on the N—O stretching frequency at about 1265 cm in substituted pyridine N-oxides. Unfortunately the data from different laboratories are not readily comparable since they were obtained under different conditions, particularly in different solvents in addition, in the realm of the small differences generally encountered in infrared spectra, differences between instruments and... 

Another rather extensive series of similar data, obtained using CS2 solutions and nujol mulls, has been published by Shindo (Fig. 4). His series include considerable data for jS-substituted compounds, for which the question of a choice of substituent constants does not arise. His data also show considerable scatter but seem to suggest strongly that <7+-values are indicated for + M substituents and normal <7-values for —M substituents. The conclusion is confirmed by the short series of similar data reported by Costa and Blasina and by Shupack and Orchin. The data of the latter authors for the NO frequencies in mws-ethylene pyridine N-oxide dichloroplatinum(II) complexes are also moderately well correlated with <7+-values. 

A kinetic study of the electrophilic substitution of pyridine-N-oxides has also been carried out50b,c. Rate-acidity dependencies were unfortunately given in graphical form only and the rate parameters (determined mostly over a 30 °C range) are given in Table 4b. There is considerable confusion in Tables 3 and 5 of the original paper, where the rate coefficients are labelled as referring to the free base. In fact the rate coefficients for the first three substituted compounds in... 

Sharp and Walker (36) have reported good linear plots of Mx - Mh for 3- and 4-substituted pyridines, pyridine-N-oxides and nitrobenzenes against the appropriate substituent constants. Charton (37) has reported correlations of dipole moments for substituted ethylenes and related compounds with eq. (1) using the oj, and Op constants. Best results were generally obtained with Op. 

Subsequently, other authors reacted a series of 3-substituted pyridine N-oxides with 18/NEt3 or with TCS 14/NaCN in DME producing, in high yields, the corresponding 2-cyano (or 6-cyano) pyridines [9-17]. In particular compounds 867e,f,... 

Substituted pyrimidine N-oxides such as 891 are converted analogously into their corresponding 4-substituted 2-cyano pyrimidines 892 and 4-substituted 6-cya-no pyrimidines 893 [18]. Likewise 2,4-substituted pyrimidine N-oxides 894 afford the 2,4-substituted 6-cyano pyrimidines 895 whereas the 2,6-dimethylpyrimidine-N-oxide 896 gives the 2,6-dimethyl-4-cyanopyrimidine 897 [18, 19] (Scheme 7.6). The 4,5-disubstituted pyridine N-oxides 898 are converted into 2-cyano-4,5-disubsti-tuted pyrimidines 899 and 4,5-disubstituted-6-cyano pyrimidines 900 [19] (Scheme 7.6). Whereas with most of the 4,5-substituents in 898 the 6-cyano pyrimidines 900 are formed nearly exclusively, combination of a 4-methoxy substituent with a 5-methoxy, 5-phenyl, 5-methyl, or 5-halo substituent gives rise to the exclusive formation of the 2-cyanopyrimidines 899 [19] (Scheme 7.6). The chemistry of pyrimidine N-oxides has been reviewed [20]. In the pyrazine series, 3-aminopyrazine N-ox-ide 901 affords, with TCS 14, NaCN, and triethylamine in DMF, 3-amino-2-cyano-pyrazine 902 in 80% yield and 5% amidine 903 [21, 22] which is apparently formed by reaction of the amino group in 902 with DMF in the presence of TCS 14 [23] (Scheme 7.7) (cf. also Section 4.2.2). Other 3-substituted pyrazine N-oxides react with 18 under a variety of conditions, e.g. in the presence of ZnBr2 [22]. 

In two publications [36, 37] and a subsequent review [38], a closely related alternative procedure for conversion of pyridine-N-oxides into cyanopyridines was reported in 1983. This used a combination of the mild Lewis acid Me2NCOCl and trimethylsilyl cyanide 18 for the cyanation of pyridine N-oxides such as 860, affording, in CH2CI2, via 932 and 933, 2-cyanopyridine 862 in 94% yield and apparently no 4-cyanopyridine 864 [36-38] (Scheme 7.13). With 3-substituted pyridine N-oxides such as methyl nicotinate N-oxide a mixture of 40% methyl 2-cyanonico-tinate and 60% methyl 6-cyanonicotinate is obtained. 

The data do not support a reaction as simple as this, however, the rate law implicates a second PyO at this stage. Similar experiments were extended with the use of a series of ring-substituted pyridine N-oxides, RC5H4NO, as the substrates. Correlation of the values of kcat against ctr gave a particularly large and negative Hammett reaction constant, = —3.84. This is so because PyO enters in three steps of the scheme, each of which is improved by electron donation. 

This structure validates a point made earlier, that ligand access occurs in the indicated position. At the point where this plausible but unproven assertion was first made, the reference was to reactions in which pyridine N-oxides were acting as oxygen donors. It remains pertinent for ligand substitution as well, but also for oxygen transfer reactions where sulfoxides are the oxygen donor atoms. 

Pyridine N-oxides are frequently used in place of pyridines to facilitate electrophilic substitution. In such reactions there is a balance between electron withdrawal, caused by the inductive effect of the oxygen atom, and electron release through resonance from the same atom in the opposite direction. Here, the resonance effect is more important, and electrophiles react at C-2(6) and C-4 (the antithesis of the effect of resonance in pyridine itself). 

The preferred position for electrophilic substitution in the pyridine ring is the 3 position. Because of the sluggishness of the reactions of pyridine, these are often carried out at elevated temperatures, where a free radical mechanism may be operative. If these reactions are eliminated from consideration, substitution at the 3 position is found to be general for electrophilic reactions of coordinated pyridine, except for the nitration of pyridine-N-oxide (30, 51). The mercuration of pyridine with mercuric acetate proceeds via the coordination complex and gives the anticipated product with substitution in the 3 position (72). The bromina-tion of pyridine-N-oxide in fuming sulfuric acid goes via a complex with sulfur trioxide and gives 3-bromopyridine-N-oxide as the chief product (80). In this case the coordination presumably deactivates the pyridine nucleus in the 2 and... 

The same reaction course was observed using different cyclic analogs of 113. The -substituted pyridine N-oxides 125, a special class of nitrones,... 

Increments of selected substituents in positions 2, 3 and 4 of the pyridine ring are listed in Table 4.83 (b). The 13C shifts of C-2,6 (149.7 ppm), C-3,5 (124.2 ppm) and C-4 (136.2 ppm) have been used as references. As can be seen in Table 4.67, N-oxidation causes a significant shielding (— 10 ppm) of the carbons a and y to nitrogen, while those in the / position are slightly shielded. This analogy to the behavior of pyridine-N-oxide towards electrophilic substitution can be rationalized by remembering the known canno-nical formulae of this molecule in contrast to pyridine itself. 

Recently37, the importance of CT complexes in the chemistry of heteroaromatic N-oxides has been investigated in nucleophilic aromatic substitutions. Electron acceptors (tetracyanoethylene and p-benzoquinones) enhance the electrophilic ability of pyridine-N-oxide (and of quinoline-N-oxide) derivatives by forming donor-acceptor complexes which facilitate the reactions of nucleophiles on heteroaromatic substrates. 

A DFT study of the reactivity of pyridine and the diazabenzenes towards electrophilic substitution, assuming frontier orbital control of the reactions, predicts their low reactivity as the HOMOs of these substrates are not n-orbitals.5 For pyridine-N-oxide, however, the HOMO is an aromatic orbital. DFT studies giving Fukui indices predict6 the preferred sites of electrophilic attack on pyrrole, furan, and thiophene and calculation of the local softness of the reactive sites rationalizes relative reactivities. 

Manchanda, V.K. Subramanian, M.S. Infrared and P.M.R. investigations of some complexes of uranyl beta diketonates with methyl substituted pyridine N-oxides, Aust. J. Chem. 27 (1974) 1573-1577. 

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