Base-strengthening effect

A comparison of the relative basicities of pyrrole, furan and thiophene may be made by comparing the pK values of their 2,5-di-t-butyl derivatives, which were found to be -1.01, —10.01 and —10.16, respectively. In each case protonation was shown by NMR to occur at position 2. The base-strengthening effect of alkyl substitution is clearly apparent by comparison of pyrrole and its alkyl derivatives, e.g. A-methylpyrrole has a pKa. for a-protonation of -2.9 and 2,3,4,5-tetramethylpyrrole has a pK of 4-3.7. In general, protonation of a-alkylpyrroles occurs at the a -position whereas /3-alkylpyrroles are protonated at the adjacent a-position. As expected, electron-withdrawing groups are base-weakening thus A-phenylpyrrole is reported to have a p/sTa of -5.8. The IR spectrum of the hydrochloride of 2-formylpyrrole indicates that protonation occurs mainly at the carbonyl oxygen atom and only to a limited extent at C-5. 

NMR data for 4-methyloxazole have been compared with those of 4-methylthiazole the data clearly show that the ring protons in each are shielded. In a comprehensive study of a range of oxazoles. Brown and Ghosh also reported NMR data but based a discussion of resonance stabilization on pK and UV spectral data (69JCS(B)270). The weak basicity of oxazole (pX a 0.8) relative to 1-methylimidazole (pK 7.44) and thiazole (pK 2.44) demonstrates that delocalization of the oxygen lone pair, which would have a base-strengthening effect on the nitrogen atom, is not extensive. It must be concluded that not only the experimental measurement but also the very definition of aromaticity in the azole series is as yet poorly quantified. Nevertheless, its importance in the interpretation of reactivity is enormous. 

Here again the base-strengthening effect of methyl groups is clearly marked, as may be seen by comparing 2-methyl-butene-2 and 2,3-dimethylbutene-2 in Table 16. 

Values of pKa for some selected derivatives are also listed to give some idea of how the position and nature of a substituent affects basicity. In quinoline 2- and 4-methyl groups have the greatest base-strengthening effect. Attachment of nitro groups at any position in either system has a strong base-weakening effect. 

A) is in keeping with the greater base strengthening effect of primary amino groups over that of secondary amino groups (see Sections V,B and D). 

The effect of structure on basicities of enamines may be seen from examples in Table 16. a-Alkyl substituents have a pronounced base-strengthening effect on enamines, both in the gas phase (see 145 and 147) and in solution285 (see 160 and 161). /7-Alkyl substituents are decreasing the basicity in solution (see 160 and 161 or 163 and 164), but not in the gas phase (see 143 and 145). 

TABLE 13. Comparison of the base-strengthening effects of nitrogen and oxygen atoms attached to multiple bonds (H20, 25 °C)a b... 

Methyl-l,2,3-triazole shows a comparable basicity, but 2-methyl-l,2,3-triazole is a much weaker base. That the A-alkyl groups show no base-strengthening effect can be explained in terms of the formation of imidazolium-type cations (68) (1-methyl) and (69), whilst 2-methyl-2//-1,2,3-triazole must achieve a pyrazolium-type cation (70). 

The pXa value of oxazole itself has been determined240 by the chemical shifts of H-2 in acidic media and is 0.8 0.2 at 33°C. The feebly basic strength of oxazole relative to thiazole (pKa 2.53),297 pyridine (5.23),297 or 1-methylimidazole (7.33 )W8 is attributed primarily to the powerful inductive effect of the electronegative oxygen atom. This effect, evident in isoxazole (pX —2.03),240 299 is clearly more important than any base-strengthening effect from delocalization of the oxygen lone pair in oxazole. 

The acidity constant of the unsubstituted heterocycle is 3.94 in 50% aqueous ethanol, indicating the relatively weak basic nature of the ring system. Nevertheless pyrrolo[l,2-a]quinoxalines are appreciably stronger bases than quinoxalines. Substitution of the ring system by methyl groups results in a base-strengthening effect dependent on the site of substitution. The 4-methyl compound has a pK<, of 4.58 in 50% alcohol, which is consistent with protonation at the 5-position, as the increase in pKa (0.64) is characteristic of the effect of methyl substitution in six-membered rings a to the site of protonation. The much smaller increase in pKa between the 4-methyl compound (4.58) and 2,4-dimethyl compound (4.89) is also consistent with protonation at the 5-position. 

---