Pyridines methyl affinity

Goldschmidt and Beer.372 The 2-alkylated product is the main one formed. This orientation is not unexpected since, compared with the phenyl radical, an alkyl radical should have some nucleophilic character. The j8-/y- ratio is also lower than in the phenylation, as expected for a more nucleophilic radical.371 Pyridine has a methyl affinity of 3 compared with benzene.373 This, however, does not represent the relative amount of picolines and toluene formed with acetyl peroxide.371... 

In order to obtain well-defined AB diblock copolymers by anionic polymerization and sequential monomer addition, some crucial conditions must be fulfilled (1) the carbanion formed by the second monomer must be more, or at least equally, stable than the one derived from the first monomer, and (2) the initiation of polymerization of the second monomer by the anion of the first monomer must be higher than the rate of propagation of monomer B. To fulfill these requirements, the monomers used must be added sequentially in the order of increasing electron affinity (e.g., a-methyl styrene (aMeSt) < St butadiene (Bd)< vinyl pyridine < methyl methacrylate (MMA)) and the nucleophilicity of the intermediate macromolecular carbanion A formed should at least match (though... 

As early as 1889 Walker (320), using samples of thiazole, 2,4-dimethylthiazoie, pyridine, and 2,6-dimethylpyridine obtained from Hantzsch s laboratory, measured the electrical conductivity of their chlorhydrates and compared them with those of salts of other weak bases, especially quinoline and 2-methylquinoline. He observed the following order of decreasing proton affinity (basicity) quinaldine>2,6-dimethyl-pyridine>quinoline>pyridine>2,4-dimethylthiazole> thiazole, and concluded that the replacement of a nuclear H-atom by a methyl group enhanced the basicity of the aza-aromatic substrates. 

Ethyl substitution at the imidazole 5-position (469) was found to increase potency over the unsubstituted analogue (468), while methyl substitution (470) had a slightly deleterious effect on binding (Table 6.41). Chloro (491), bromo (492), cyano (493) and fluoromethyl (494) substitution at this position were all well tolerated (Table 6.43). Introduction of a chloro-substituted pyridine (475) in place of the more usual / -chlorophenyl group (470) resulted in a slight loss of affinity for the CBi receptor, as did replacement of the p-chloro group of (470) with bromo (471), fluoro (472) and in particular, met-hoxy (473). Trifluoromethyl substitution (474) however, was well tolerated. 

Application of pulsed ion gas-phase cyclotron resonance (ICR) spectroscopy to proton affinities of the derivatives 2-methoxypyridine and N- methylpyridin-2-one confirm previous deductions on the enthalpy of 2-hydroxypyridine-pyridin-2-one tautomerism (76JA6048), provided that the difference between the influences of O-methylation on 2-hydroxypyridine and A-me thy lat ion in pyridin-2-one are taken into account. These measurements have been further clarified and extended to other gas phase basicity measurements (79JA1361). A similar estimation of the gas phase basicities of 2- and 4-pyridinethiols and 2- and 4-pyridinethiones confirms that the thiol form is predominant in the gas phase (77TL1777), in line with previous studies involving mass spectrometric deuterium isotope studies (75BSB465). Photoelectron spectroscopy has also been employed in such studies (see Section 2.04.3.6 and Figure 21 for details) <77JCS(P2)1652>. 

A steric parameter based on the proton affinity Ah and methyl cation affinity Ach3, calculated by computational chemistry methods, for reaction at the nitrogen atom series of compounds in which the nitrogen atom was unhindered, e.g. pyridines in which the 2- and 6-positions are unsubstituted [Jenkins et al, 1994 Jenkins et al., 1995 Baxter et al, 1996]. Using these affinity values, a reference regression model was found which correlates the methyl cation affinity Achs to the proton affinity Ah for unhindered compounds ... 

Fig. 26. Correlation of relative proton affinities of pyridines (APA) with their solution nucleophilicities (N) toward methyl fluorosulfonate in 2-nitropropane at 25°C (squares) and ethyl iodide in nitrobenzene at 60°C (circles) (8IJOC635).

Abe et al. reported that the imidazol [l,2-a]pyridine moiety of the basic framework of a class of the non-peptide bradykinin B2 receptor antagonists (11, Figure 15.14) could be successfully replaced by several heterocyclic bioisosteres. Among those, the l-methyl-2-methoxy-l//-benzimidazole, 2-methylquinoxaline and 2-methylquinoline derivatives showed potent B2 binding affinities against both human and guinea pig B2 receptors (Figure 15.14). 

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