Picoline electron densities

Reduction of both the free bases and their quaternary salts proceeds by similar mechanisms. In pyridine and its quaternary salts, a hydride ion, or its equivalent, attacks a position of a low electron density, i.e. the 2- or 4-position. The mechanism of the reduction of quaternary salts of pyridine and its homologs (LukeS and Ferles414) has been elucidated using deuterated formic acid.415 The hydride ion attack in position 2 is followed by addition of a proton to the enamine grouping with the formation of A 3-piperideines (124). If the reduction commences with attack in the 4-position, a saturated base (125) is the final product. In agreement, a-picoline methobromide yields 1,2-dimethyl-... 

On the basis that the transition state for the addition step is as pictured above, it would be expected that the preferential orientation of the entering nucleophile would follow the order of the ground-state 7r-electron densities. Molecular orbital calculations of the w-electron densities at the various nuclear carbon atoms in the ground-state of 3-picoline for several different values of the nitrogen and methyl group... 

As mentioned before, alkyl radicals and acyl radicals have a nucleophilic character therefore, radical alkylation and acylation of aromatics shows the opposite reactivity and selectivity to polar alkylation and acylation with the Friedel-Crafts reaction. Thus, alkyl radicals and acyl radicals do not react with anisole, but may react with pyridine. Eq. 5.1 shows the reaction of an alkyl radical with y-picoline (1). The nucleophilic alkyl radical reacts at the 2-position of y-picoline (1), where electron density is lower than that of the 3-position. So, 2-alkyl-4-methylpyridine (2) is obtained with complete regioselectivity. When pyridine is used instead of y-picoline, a mixture of 2-alkylpyridine and 4-alkylpyridine is obtained. Generally, radical alkylation or radical acylation onto aromatics is not a radical chain reaction, since it is just a substitution reaction of a hydrogen atom of aromatics by an alkyl radical or an acyl radical through the addition-elimination reaction. Therefore, the intermediate adduct radical (a complex) must be rearomatized to form a product and a hydrogen atom (or H+ and e ). Thus, this type of reactions proceeds effectively under oxidative conditions [1-6]. 

Reactivities of n-Bu (sp3 carbon-centered radical) and Ph (sp2 carbon-centered radical) to benzene, y-picoline, protonated y-picoline, protonated benzothiazole are shown in Table 5.1. As can be seen here, the reactivity is greatly increased in both radicals, as the electron-density of aromatics is decreased. Therefore, the reactivity of heteroatomatic bases such as y-picoline and benzothiazole, can be increased by their... 

Fig. 15 Structures of pyridine, picolinate, and three structural isomers of dipicolinate, overlaid with an electron density map of the highest occupied molecular orbital (HOMO) for each hgand. These chromophores were explored to better understand the binding properties of DPA. Electron density maps generated using Titan higher electron density is in black, lower in white.

The electron density map of pyridine (see IOC) clearly shows a high concentration of electron density (more red) on the nitrogen. Note that pyridine has been implicated in male sterility, although some claim this is a myth. Nonetheless, it is reasonable to exercise caution when pyridine is used. Several important pyridine derivatives have substituents on the aromatic ring, including 2,6-lutidine (11) and picolinic acid (12). Many derivatives of pyridine are found in pharmaceutically active compounds. One is nicotinic acid (niacin, 13), which is vitamin Bg and is found in liver, yeast, and meat. A deficiency in this vitamin can lead to pellagra (a wasting disease). Nicotinamide (14, niacinamide) is one of the two principal forms of the B-complex vitamin niacin. Nicotinamide may be useful for individuals with type 1 (insulin-dependent) diabetes. 

The 7r-electron densities in the benzyl anion have already been calculated (see p. 81). The position meta to methylene is inactive and the 7c-electron density is accordingly unity, whereas at the para position the additional electron density q is 1/7. One would therefore expect a heteroatom at the meta position to have little effect on the equilibrium of equation (4.95), while a heteroatom at the para position should favor formation of the conjugate anion. y-Picoline is in fact a much stronger acid than toluene or )5-picoline, the equilibrium of equation (4.97) being pushed toward the right by the gain in TT-electron density at the nitrogen atom. 

The N-nuclear quadrupole resonance frequencies of pyridine and 4-picoline have been discussed in terms of the atomic orbital electron densities of the nitrogen atom. ... 

Kinetic studies of base-catalysed deuterium exchange in the methyl groups of picolines give the sequence 4>2>3, in the oxides 2>4>3 and in the quaternary salts 2 >4, and quaternary salt > oxide > picoline. The reactions resemble nucleophilic substitutions in their p values, and delocalization energies and 7r-electron densities at nuclear carbon atoms carrying the methyl groups are indices of reactivity in the methyl groups . 

Thus, increasing electron density could potentially facilitate CH cleavage as well as destabilize water coordination to lower the overall barrier To accomplish this we examined replacing the neutral N,N bipyrimidine ligand with a potentially more electron-donating, mono-anionic ligand, /c -N,0-picolinate (pic) [18]. 

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