Pyridines, substituted basicity

In their acidity, basicity, and the directive influence exerted on electrophilic substitution reactions in benzenoid nuclei, acylamino groups show properties which are intermediate between those of free amino and hydroxyl groups, and, therefore, it is at first surprising to find that the tautomeric behavior of acylaminopyridines closely resembles that of the aminopyridines instead of being intermediate between that of the amino- and hydroxy-pyridines. The basicities of the acylaminopyridines are, indeed, closer to those of the methoxy-pyridines than to those of the aminopyridines, the position of the tautomeric equilibrium being determined by the fact that the acyl-iminopyridones are strong bases like the iminopyridones and unlike the pyridones themselves. Thus, relative to the conversion of an... 

The more basic and less hindered pyridines undergo nucleophilic attack at an ethylene coordinated to platinum(II). Pyridine substitution reactions at platinum also occur, and in the presence of excess ethylene, alkene replacement is observed.72 ... 

Pyridine shows all the characteristics of aromatic compounds. It has a resonance energy of 113 kJ/mol (27 kcal/mol) and it usually undergoes substitution rather than addition. Because it has an available pair of nonbonding electrons, pyridine is basic (Figure 16-11). In an acidic solution, pyridine protonates to give the pyridinium ion. The pyridinium ion is still aromatic because the additional proton has no effect on the electrons of the aromatic sextet It simply bonds to pyridine s nonbonding pair of electrons. 

Reactives of Side-Chains of Monocyclic Thiophens. - The rate constants for the esterification of some 3-, 4-, and 5-substituted thiophen-2-carboxylic acids and of some 2- and 4-substituted thiophen-3-carboxylic acids with diazodiphenylmethane in methanol solution have been measured, and linear correlations gave information about the transmission of substituent effects. The rates of alkaline hydrolysis of ethyl thiophen-2-carboxylate in ethanol-water and DMSO-water media have been measured and compared with those of other heterocyclic esters. The kinetics of iodination of 2-acetylthiophen in methanol-water, using different carboxylate buffers, have been studied.Basicity constants have been measured for j3-(2-thienyl)-acrylamides and compared with those of the corresponding benzene and furan derivatives. The acidity constants of ( )-a-phenyl-j3-(2-thienyl)-acrylic acids and analogous furan-, selenophen-, and pyridine-substituted compounds have been measured, and have been rationalized by an equation involving separate contributions of polar, conjugative, and steric effects of the heterocycles. ... 

Benzenesulphonyl chloride reacts with primary and secondary, but not with tertiary, amines to yield substituted sulphonamides (for full discussion, see Section IV,100,3). The substituted sulphonamide formed from a primary amine dissolves in the alkaline medium, whilst that produced from a secondary amine is insoluble in alkali tertiary amines do not react. Upon acidifying the solution produced with a primary amine, the substituted sulphonamide is precipitated. The reactions form the basis of the Hinsberg procedure for the separation of amines see Section IV,100,(viii) for details. Feebly basic amines, such as o-nitroaniline, react slowly in the presence of allcali in such cases it is best to carry out the reaction in pyridine solution see Section IV,100,3. ... 

Acylation of pyridazinones and related compounds in the presence of weakly basic catalysts such as pyridine or sodium acetate produces IV-acylated products, while O-acylated products are obtained under strongly basic conditions. However, the reaction between 6-chloropyridazin-3(2//)-one with chlorocarbonates and that of maleic hydrazide with unsaturated acid chlorides or chloromethylsulfonyl chloride gives preferentially N-substituted products. 

The cleavage of fused pyrazines represents an important method of synthesis of substituted pyrazines, particularly pyrazinecarboxylic acids. Pyrazine-2,3-dicarboxylic acid is usually prepared by the permanganate oxidation of either quinoxalines or phenazines. The pyrazine ring resembles the pyridine ring in its stability rather than the other diazines, pyridazine and pyrimidine. Fused systems such as pteridines may easily be converted under either acidic or basic conditions into pyrazine derivatives (Scheme 75). 

There is another important factor in the low reactivity of pyridine derivatives toward electrophilic substitution. The —N=CH— unit is basic because the electron pair on nitrogen is not part of the aromatic n system. The nitrogen is protonated or complexed with a Lewis acid under many of the conditions typical of electrophilic substitution reactions. The formal positive charge present at nitrogen in such species further reduces the reactivity toward electrophiles. 

The only reaction series involving a reaction at a heteroatom which has been extensively studied is the basicity of substituted pyridines. The Hammett equation was first applied to this reaction simultaneously by Brown and co-workers and by Jaffe and Doak. A sampling... 

It is interesting to speculate why the basicities of the substituted pyridines are well correlated by normal a-values, rather than by a+-values. Writing the resonance structures for the conjugate acid (5<->6)... 

Closely related to the basicity of pyridine is its hydrogen-bonding ability two indices of this property have been measured for a very short series of substituted pyridines and are very well correlated by CT-values. ... 

The first reaction series to be considered are the basicities of the various quinolines. Baciocchi and Illuminati have demonstrated that the pK values of quinolines substituted in the B-ring follow the Hammett equation well if ApK, i.e., the difference between the pK values of substituted and unsubstituted compounds, is plotted against a, the quinoline points fall on the same line as the pyridine points, as shown in Fig. 5, so that the p-values for the two series are identical. 

These constants, K toK/, may be estimated by use of the Hammett equation. Estimation of 1 and K 4 involves application of the methods outlined in Section II, A, i.e., application of substituent constants for and N+H to the Hammett equation for the acid-base equilibria of benzoic acids. Estimation of A2 and involves application of the method used in Section III,A, i.e., the p-value for the basicity of substituted pyridines, with cr-values for COOH and COO . Provided the necessary a- and p-values are known, this procedure permits the calculation of four independent, or virtually independent, estimates of Krp. A check on the method is available from the relationships shown in Eq. (16) which is readily obtained by multiplication of Eq. (12) and (14) and of Eq. (13) and (15). 

The methods outlined, of course, are readily applicable to a wide variety of substituted heterocycles like the carboxyl, hydroxy and mercapto derivatives of pyridines, pyridine 1-oxides, pyrroles, etc. The application to amines and to diaza compounds such as pyrimidine, where the two centers are basic, is obvious except that now 23 takes the role of the neutral compound, 21 and 22 the roles of the tautomeric first conjugate bases, and 20 the role of the second conjugate base. Extensions to molecules with more than two acidic or basic centers, such as aminonicotinic acid, pyrimidinecarboxylic acids, etc., are obvious although they tend to become algebraically cumbersome, involving (for three centers) three measurable Kg s, four Ay s, and fifteen ideal dissociation constants (A ), a total of twenty-two constants of which seven are independent. 

In spite of the potential complexity of the general problem, even when restricted to the reagent family of amines, the nucleophilicities of such series as meta- and pom-substituted pyridines and anilines appear to correlate very closely with the expected substituent effects and with the basicities. This has been verified in the following cases (i) The reaction of pyridines (R = H, m- andp-CHs) with 2-chloro-3-nitro-, 2-chloro-5-nitro-, and 4-chloro-3-nitro-pyridines. ... 

To establish a mechanism for the formation of 33, the reaction has been monitored by H-NMR spectroscopy (91CB2013).Tlie basicity of the azine is a rate-determining effect as well as a steric hindrance. Pyridine is more reactive than pyrimidine. 2-Substituted pyridines do not give the corresponding salts. 

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