Pyridine relative aromaticity

The reactivity of pyridine relative to that of benzene has been measured using the competitive technique developed by Ingold and his schoool for corresponding studies of electrophilic aromatic substitution. The validity of the method applied to free-radical reactions has been discussed. Three sources of the phenyl radical have been used the results obtained are set out in Table II. 

It is difficult to treat the effect of a heteroatom on the localization energies of aromatic systems, but Brown has derived molecular orbital parameters from which he has shown that the rates of attack of the phenyl radical at the three positions of pyridine relatively to benzene agree within 10% with the experimental results. He and his co-workers have shown that the formation of 1-bromoisoquinoline on free-radical bromination of isoquinoline is in agreement with predictions from localization energies for physically reasonable values of the Coulomb parameters, but the observed orientation of the phcnylation of quinoline cannot be correlated with localization ener-... 

Magnetic susceptibility anisotropy has been used for the estimation of relative aromaticity of some azines in comparison with benzene (77JCS(P2)897). If the extent of ir-electron delocalization for benzene is taken as 1.0, the corresponding values for azines are pyridine 0.7, pyridazine 0.7, pyrimidine 0.5, and 1,3,5-triazine 0.3. 

How does this concept of aromaticity apply to typical heterocycles such as pyridine 5.1 and pyrrole 2.1 Pyridine can formally be derived from benzene by replacement of a CH unit by an sp2 hybridised nitrogen atom. Consequently, pyridine has a lone pair of electrons instead of a hydrogen atom. However the six 7t electrons are essentially unchanged, and the pyridine is a relatively aromatic heterocycle. 

Since there are no extensive studies on the relative aromaticity of the heterocycles covered in this chapter, the relative order of aromaticity of these systems has been gleaned from disparate studies. A priori, the combined effects of the 7i-electron-deficient five-membered heterocycles annelated to a pyridine nucleus provides a series of bicyclic heterocycles with low reactivity towards electrophiles. In the presence of suitable leaving groups, they are prone to undergo nucleophilic substitution. Since these heterocycles are readily obtained from either appropriately substituted pyridines or five-membered heterocycles, methods for direct functionalization of the parent heterocycles are not frequently studied. Based on the diversity of reactions these heterocycles undergo, it can be inferred that the pyridofuroxans are the least aromatic. 

Magnetic susceptibility anisotropy has been used to estimate relative aromaticities of some azines <1977JOC897>. If the extent of -electron delocalization for benzene is taken as 1.0, the corresponding values for azines are pyridine 0.7, pyridazine 0.7, pyrimidine 0.5, and 1,3,5-triazine 0.3. Another quantitative magnetic index is the exaltation of the total magnetic susceptibility (A). All aromatic systems reveal large A values, whereas for nonaromatic compounds A is close to zero and it is assumed that aromaticity increases with A. For six-membered monocycles the following values of A have been reported (in units of cm3 mol-1 x —106) benzene (17.9), pyridine (18.3), pyridazine (8.7), pyrimidine (18.2), pyrazine (12.7), l-ethyl-2-pyridone (13.0), and 1,3,5-triazine (19.0). 

Table 42 gives an overview of annular tautomerism data for azoles in the gas phase and in solution or crystals. In the gas phase the stability of alternative tautomers largely depends on their relative aromaticities. In Section 2 A.4.2.2 it was noted that 1,2-relationships between pyrrole- and pyridine-type nitrogen atoms favor aromaticity (Figure 21) and this is consistent with the relative stabilities of triazole and tetrazole tautomers in the gas phase (Table 42) <2010T2695>. In solution (and crystals) other factors such as solvent polarity, hydrogen bonding, and temperature become important and the relative stabilities can be reversed. Polar solvents tend to stabilize the tautomer with the largest dipole moment and this probably accounts for the observation of both 2H-1,2,3-triazole (p = 0.12D) and H-1,2,3-triazole (p = 4.55D) in...

Kruszewski and Krygowski36 have calculated the value of DEsp (Section II,A,3a) to be 0.350 (benzene = 0.333) and the Ai value (Section II,B) to be 1.0 Julg65 reports a value for A of 0.97 (benzene = 1). At the same time they showed that the KK values (Section II,E) for both benzene and pyridine are 3.53. The decreased reactivity of pyridine (relative to benzene) towards electrophiles is reflected in the value of +23 for Balaban and Simon s aromaticity constant169 (Section II,F, 1). Finally, Berezin162 has calculated the coefficient of influence (Section II,F, 3) of pyridine to be 1.987 (benzene 2.130) but the interpretation here seems somewhat difficult. 

Acid ionic liquids will catalyze the addition of the sp C-H bond of methyl pyridines to aromatic aldehydes (Scheme 51) (14TL5462).The best yields where found with a co-solvent of water and dioxane and using [Hmim] [H2PO4] as the acid. Sterics appeared to be irrelevant to the reaction as ortho-, meta-, and para-substituted aryl aldehydes combined with methyl pyridines in relatively the same yields. The reaction was also robust if the pyridine was swapped for quinolines. However, when the methyl group was moved to C-4 on the pyridine, no reaction was observed. Finally, the acidic ionic liquid could be recycled with very little loss in yield. 

The higher reactivity of 2-halogenothiazoles with respect to halogenopyridines can be related to the different aromaticity of the two systems, less for thiazole than for pyridine, for example, the relatively stronger fixation of the tt bond in the thiazole than in the case of pyridine. As the data reported in Table V-1 (footnote a) indicates, the free thiophenol is more reactive than the thiolate anion toward the 2-halogenothiazoles. This fact should be considered when one prepares the thiazolyl sulfides. 

Tobacco Alkaloids. The relatively small number of alkaloids derived from nicotinic acid (27) (the tobacco alkaloids) are obtained from plants of significant commercial value and have been extensively studied. They are distinguished from the bases derived from ornithine (23) and, in particular, lysine (24), since the six-membered aromatic substituted pyridine nucleus common to these bases apparendy is not derived from (24). 

Both pyrimidine and purine aie planai. You will see how important this flat shape is when we consider the structure of nucleic acids. In tenns of their chemistry, pyrimidine and purine resemble pyridine. They are weak bases and relatively unreactive toward electrophilic aromatic substitution. 

Pyridine is a polar, stable, relatively unreactive liquid (bp 115°C) with a characteristic strong penetrating odor that is unpleasant to most people. It is miscible with both water and organic solvents. Pyridine was first isolated, like pyrrole, from bone pyrolysates. Its name is derived from the Greek for fire (pyr) and the suffix idine used to designate aromatic bases. Pyridine is used as a solvent, in addition to many other uses including products such as pharmaceuticals, vitamins, food flavorings, paints, dyes, rubber products, adhesives, insecticides, and herbicides. Pyridine can also be formed from the breakdown of many natural materials in the environment. 

It is notable that pyridine is activated relative to benzene and quinoline is activated relative to naphthalene, but that the reactivities of anthracene, acridine, and phenazine decrease in that order. A small activation of pyridine and quinoline is reasonable on the basis of quantum-mechanical predictions of atom localization encrgies, " whereas the unexpected decrease in reactivity from anthracene to phenazine can be best interpreted on the basis of a model for the transition state of methylation suggested by Szwarc and Binks." The coulombic repulsion between the ir-electrons of the aromatic nucleus and the p-electron of the radical should be smaller if the radical approaches the aromatic system along the nodal plane rather than perpendicular to it. This approach to a nitrogen center would be very unfavorable, however, since the lone pair of electrons of the nitrogen lies in the nodal plane and since the methyl radical is... 

It would be expected that the stabilization of the adsorbed species by an extended conjugated system should increase with the number of aromatic rings in the adsorbed azahydrocarbon. However, data suitable for comparison are available only for phenanthridine, benzo-[/]quinoline, and benzo[h] quinoline. The large difference in the yields of biaryl obtained from the last two bases could be caused by steric interaction of the 7,8-benz-ring with the catalyst, which would lower the concentration of the adsorbed species relative to that with benzo[/]quinoline. The failure of phenanthridine to yield any biaryl is also noteworthy since some 5,6-dihydrophenanthridine was formed. This suggests that adsorption on the catalyst via the nitrogen atom is possible, but that steric inhibition to the combination of the activated species is involved. The same effect could be responsible for the exclusive formation of 5,5 -disubstituted 2,2 -dipyridines from 3-substi-tuted pyridines, as well as for the low yields of 3,3, 5,5 -tetramethyl-2,2 -bipyridines obtained from 3,5-lutidine and of 3,3 -dimethyl-2,2 -... 

A wide variety of other heterocyclic ring systems can conceivably serve as the conjugated backbone in nonlinear organic molecules. We will give examples from preliminary work on two of these, the thiazole and pyrimidine heterocycle derivatives 65-72 in Table VIII. These two heterocycles were chosen because the appropriate haloderivatives are commercially available as starting materials for nucleophilic aromatic substitution. The pyrimidine derivatives are of particular interest since their absorption edges ( 400 nm) are shifted hypsochromically an additional 30 nm relative even to the pyridines. 

The UV-VIS cutoffs of some model compounds clearly demonstrate a variety of structural effects discussed earlier. Although these spectra were obtained in solution (4xlO 4M in EtOH) the trends in transparency of these simple molecules are generally applicable to the crystalline state as well. Two of the more clear-cut comparisons involve the D-A substituted parent pyridine 73-74 and benzene 75-76 molecules (Figure 1). First, the cutoffs of the pyrrolidine substituted aromatics 74 and 76 have a bathochromic shift relative to their dimethylamino substituted analogs 73 and 74 due to the better donor... 

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