Isothiazole, positional reactivities

The positional reactivity order in the 1,2-azole (isothiazole) is 4 > 3 > 5. The 3- versus 5-order is anomalous, the reactivity of the 5-position appearing to be too low, and possible causes for this are described below. 

Acid-catalyzed hydrogen exchange is used as a measure of the comparative reactivity of different aromatic rings (see Table 5). These reactions take place on the neutral molecules or, at high acidities, on the cations. At the preferred positions the neutral isoxazole, isothiazole and pyrazole rings are all considerably more reactive than benzene. Although the 4-position of isothiazole is somewhat less reactive than the 4-position in thiophene, a similar situation does not exist with isoxazole-furan ring systems. 

Substituents on the isothiazole ring are a little more reactive, especially in the 5-position. In cationic rings reactivity is much higher, e.g. for substituents in 1,2-dithiolylium salts. 

For azoles with heteroatoms in the 1,2-positions (7.22), reasoning similar to that above predicts the reactivity order 5 > 3 > 4, and the highest reactivity of the 5-position has been confirmed for isothiazole (66JA4263 69JHC199) and pyrazole (70JOC1146). 

The 2-position in azoles with 1,3-heteroatoms should be more reactive than the 5-position of azoles with 1,2-heteroatoms, but for reactions of the free base this turns out not to be the case because of the adjacent lone pair effect illustrated by the relative reaction rates in Scheme 7.3. Thus the 2-position of thiazole is 7 times less reactive than the 5-position of isothiazole. The same reasoning accounts for the 3-position of isothiazole being less reactive than the 4-position of thiazole. The former should be the more reactive since the electron-withdrawing effect of nitrogen should be greater across the bond of higher order, and the fact that it is not more reactive suggests that the effect of the adjacent lone pair is more severe across the shorter C-3—N bond in isothiazole. For reaction of the azol-... 

Comparison of the reactivity of the 2-position of thiazole with that of the 3-position of isothiazole gives k2 k2 rate ratio of 107, which is 10-to 20-fold greater than that which applies in thiophenes (Chapter 6, Section 2). 

In view of the above, the reactivity of the 5-position of isothiazole in pyrolysis could be expected to be substantially less than in solvolysis, whereas this is not observed. The discrepancy appears to arise because, as already noted above, the reactivity of the 5-position of isothiazole in solvolysis seems too low. This view is also supported by the following argument. The a-position of thiophene is —0.4 a units more reactive than the (3-position. Because of bond fixation, the nitrogen in azoles deactivates more strongly across the 2,3-positions than across the 2,5-positions. Hence it is impossible, unless secondary factors intervene, for the 3-position of isothiazole to be more reactive than the 5-position, so such a factor must be involved in producing the anomalous result in solvolysis. 

Comparison of the reactivity of thiazole, isothiazole, and thiophene (see also Chapter 6, Section 9.A) determined under the same gas-phase conditions permits determination of the effect of the aza substituent at each position in thiazole (assuming that sulfur has the same effect in both thiophene and thiazole) and likewise at the 5-position of isothiazole. This effect (in terms of cr+ values) is shown in Scheme 7.14, together with, for comparison, the values obtained for pyridine under the same conditions (see also Chapter 9). 

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