Pyridines quaternization rates

The reactivity of isoxazole toward quaternization is compared with those of pyridine-2-carbonitrile, pyridine and five other azoles in Table 6 (73AJC1949). Isoxazole is least reactive among the six azoles and times less reactive than pyridine. There is also a good correlation between the rate of quaternization and basicity of the azole. 

Halopyridines undergo self-quaternization on standing while the less reactive 2-halo isomers do not. However, more is involved here than the relative reactivity at the ring-positions. The reaction rate will depend on the relative riucleophilicity of the attack-ing pyridine-nitrogens (4-chloropyridine is more basic) and on the much lower steric hindrance at the 4-position. Related to this self-quatemization are the reactions of pyridine and picolines as nucleophiles with 4-chloro- and 2-chloro-3-nitropyridines. The 4-isomer (289) is. again the more reactive by 10-30-fold (Table VII, p. 276). 

Whereas in all previously mentioned inverse cycloaddition reactions [h]-fused pyrido annelated systems are formed, some reactions are described which lead to [c]-pyridine annelated bicyclic systems. 5-(Butynylthio)pyrimidines (R = Ph, NHCOCH3) give on heating at 180°C in nitrobenzene 5-R-2,3-dihydrothieno[2,3-c]pyridines (89T803). 5-Propynyloxymethylpyrimidines also readily undergo cycloaddition into l,3-dihydrofuro[3,4-c]pyridines (89T5151) (Scheme 39). Considerable rate enhancements were observed with quaternized pyrimidinium salts. Whereas... 

The dielectric constant of the solvent in the microenvironment of the polymer chain has been shown to be different from that in the bulk solvent (19). This change in dielectric constant might enhance the nucleophilicity of the pyridine ring and therefore increase the rate of quaternization. The kinetic results are consistent with the observations of Overberger et al., (20), who showed that increased hydrophobic nature of the substrate led to faster reaction rates in nucleophilic catalysis. In the present case one would expect the butadiene copolymer to be more hydrophobic than the methylvinylether copolymer. An alternative synthesis of supernucleophilic polymers has been achieved using the following reaction sequence. 

Kinetic studies on the quaternization reaction of pentamethylpyridine (154A, Scheme 64) and its deuterated congener suggest that there may be an equilibium between this aromatic pyridine and its valence isomer, pentamethyl-Dewar-pyridine (154B). It is known that such valence isomers are stabilized by steric factors such as encountered in pentamethylpyridine.194195 On determining conductometrically the initial rate of quaternization with methyl iodide for polymethylpyridines in acetone, it was found that all but one followed clean bimolecular kinetics. Pen-... 

The extensive kinetic data available for quaternization of substituted pyridines and derivatives, such as benzologs and diazines, under a uniform set of conditions make possible the calculation of substituent rate factors that are of considerable value in dealing with new substrates. When a heteroaromatic molecule has two or more nucleophilic annular positions that can react, often it is possible to estimate, in some cases very accurately, the ratio of quaternized products using these rate factors. 

All these special cases involve benzologs with an ortho quinonoid structure. But even this pattern is not universal, a deviation being 2-methylindazole (40), which quaternizes 2.2 times more slowly than its parent compound 1-methylpyrazole (37).122 Indeed, except for the molecules just considered and 1,2-benzisothiazole,122 benzo-fusion is rate retarding. Thus, 1,2-benzisoxazole (indoxazene, 39), reacts 3.2 times, and 1-methylindazole (39) 7.1 times, more slowly than their parent compounds.122 Fusing a benzene ring onto an azole where the heteroatoms are situated 1,3 leads to decreases in rate constants by factors of 5.0, 6.3, and 6.8, respectively, when X of 38 is NMe, S, and O.122 These factors are not much smaller than that obtained from a comparison of pyridine and quinoline reactivities.61,78,79... 

The aza substituent constants (vide supra) reflect the fact that electron-withdrawing annular nitrogens decrease the reactivity of any other ring nitrogen in the order ortho meta < para. For this reason, pyrazines should quaternize more readily than pyrimidines and pyridazines, and all three diazines should react faster than triazines. When the diazines are included in a Hammett plot for the methylation of substituted pyridines (p = —2.3), the positive deviations showed that they were all more reactive than indicated by their pK values. Relative rates compared with pyridine were pyridazine, 0.25 pyrimidine, 0.044 and pyrazine, 0.036 (72JA2765). Pyridazine in particular appears to be much more reactive than one would expect. (See Section III, A below). 

Quaternization of two series of 2-alkylthiazoles with methyl iodide shows a completely different behavior (Scheme 10). With the a-series (Me, Et, iPr, t-Bu), the rate decrease is correlated with the Taft Es parameter (67BSF4502) as already observed with pyridines. With the /1-series (Et, nPr, iBu, neopentyl) the rate decrease is very small compared to that suggested by Es parameters (Fig. 2), e.g., the neopentyl group in position-2 of the thiazole appears a little more bulky than the 2-ethyl but far less than the t-butyl, whereas the neopentyl on the Es scale is the largest of the a- and / -series groups. 

Substituent Rate Factors (Logarithmic Values) from /V-Methylation of Pyridine Derivatives by Methyl Iodide in DMSO to be Used for Predicting the Regioselectivity in Polyazines Quaternization... 

The quantitative effects of -substituents in decreasing the rates of these reactions are not additive and also depend considerably on solvent and alkylating agent. They are low in liquid sulfur dioxide as a solvent where solvation effects are small and the high dielectric constant increases the bond breaking in the transition state. For 3- and 4-substituted pyridines a Br nsted correlation exists between the rates of quaternization and the pKa values <1978AFIG(22)71 >. 

N-Aryl substituents usually depress the basic properties of the imidazole or benzimidazole nucleus. The effects of substituents on the aryl group are evident from the data listed in Table 7 which also lists rate constants for quaternization with iodoethane, a reaction which is dependent upon the nucleophilic character of the pyridine-type nitrogen (70CHE194). A phenyl group withdraws electrons from the imidazole ring, but does so rather weakly. The p value of +0.753 for the protonation process is in accord with weak electron transfer from the phenyl substituent to the basic nitrogen. 

Mel followed by hydroxide, 55-98% yield. Quaternization of the pyridine increases the rate of hydrolysis of the ester. 

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