Isothiazoles protonation, basicity

The relative basicity and acidity of isothiazole and its methyl derivatives have been compared by IR spectroscopy (77MI41702). The isothiazoles, dissolved in inert solvents (e.g. CCI4, CS2) containing traces of butanol (a proton donor), interact with the butanol OH... 

The aromatic sextet is completed by delocalisation of the lone pair from the second heteroatom, 4.4a-e. Consequently, as in pyridine, the nitrogen atoms of the 1,2-azoles have a lone pair available for protonation. However the 1,2-azoles are significantly less basic than the 1,3-azoles because of the electron-withdrawing effect of the adjacent heteroatom. Isoxazole and isothiazole are essentially non-basic heterocycles (pAas <0), and even pyrazole (pAa=2.5) is a much weaker base than the corresponding 1,3-azole imidazole (pAa=7). 

The fate of isocyanosulfide (70) depends on the nature of the substituent originally at C-4 of the isothiazole ring. If R is aryl, as in 55, the extended conjugation of the sulfide and the aryl group is expected to lower the basicity of the sulfide resulting in reprotonation at the isocyano carbon to yield 71. Protonation at this site renders the carbon more susceptible to nucleophilic attack by the negative sulfur. As a result, these substituted isocyanides spontaneously cyclize to 4-arylthiazoles 73 (R=Ar). 

With a pATa of 2.5, pyrazole is significantly less basic than imidazole, whose p/fa is 7.1. In fact, having an adjacent heteroatom near the N atom always has the effect of lowering the basicity of the N because of their inductive effect. Therefore, the N atoms on isothiazole (p/Ca, -3.0) and isoxazoles (pATa, -0.5) are less basic than those of thiazole (pA a, 2.5) and oxazole (pAfa, 0.8), respectively. Nonetheless, pyrazole is basic enough to be protonated with most strong inorganic acids. ... 

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