Positional Reactivity Order

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). 

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). 

Substituent effects in the more reactive oxazole system appear to be smaller (Table 7.3) which is to be expected by the reactivity-selectivity principle. The A rel value (0.95) [69JCS(B)270] for 2-deuteriation of 1-meth-yl-1,2,4-triazole (7.33) was also determined. Thus, assuming that the activation by the 5-nitrogen upon the 2-position is the same as in thiadiazole, 

Many substituent effects have been determined in imidazole. Rate coefficients were measured for deuteriation at 50°C of imidazolium ion and 

Finally, for 5-exchange of I-aryltetrazoles, electron-supplying substituents in the aryl ring decreased, and electron-withdrawing substituents in the aryl ring increased the reaction rate, as expected. The p factor at 30°C is 1.4 for reaction of the 4-ethyltetrazolium ion via the ylide mechanism (in 9 M CF,C02D) and 1.3 for reaction of the free base (in piperidine-MeOD-DMF) (69TL3377). 

---

Partial rate factors calculated for indazole bromination indicate that the benzo derivative is less reactive than pyrazole a positional reactivity order of 5 > 3 > 7 (in the ratio 10.7 6.9 I) was obtained [78JCS(P2)865]. 

Under mild conditions nitration and acetylation of hexahelicene give the 5-nitro-and 5-acetyl substitution product as the main product in about 50% yield. In both cases another monosubstitution product is formed, which was identified tentatively by NMR as the corresponding 8-substituted hexahelicene. From the relative rates of detritiation (krel) or the partial rate factors (f) given in Table 27, it seems more probable, however, that the 7-isomers are formed as the side product, as the positional reactivity order of detritiation is C(5) >C(7) >C(8) >C(1) >C-(4) >C(6) >C(2) > C-(3). The preferred reactivity at C(5), found in electrophilic substitutions, is predicted by all the simple Hiickel parameters, whereas the next two positions are correctly predicted by Nr and Lr. Judging from Nr-, Fr- and Lr-values the C-(l) position does not experience much steric hindrance in the H-exchange. Relative to some other positions (C(4), C(6)) its reactivity is higher than expected. The Mulliken overlap population predicts, however, the highest reactivity for C(l) and leaves room for the supposition that this position is considerably masked. 

Oxazoles resemble 1-substituted imidazoles in their positional reactivity order for electrophilic substitution, 5 > 4 > 2 [59LA(626)83, 59LA(626)92 74AHC(17)99 84MI29]. The compounds can be regarded as hybrids of... 

The above positional reactivity orders are predicted for pyrazole and imidazole by CNDO/2 calculations [78JCS(P2)865]. 

The positional reactivity order becomes 2 >> 5 > 4 in the electrophilic bromodechlorination of 2,4,5-trichlorothiazole (76JHC1297). This finding indicates that the 5- and 4-positions are mutually strongly deactivated by the -/ effect of the adjacent chlorine, which is enhanced by the short C-4—C-5 bond length. 

Mercuriation of diphenyloxazoles occurs only in the heterocyclic rings. The order of reactivity, namely 2,4-diphenyl- > 2,5-diphenyl- > 4,5-di-phenyloxazole, suggests a positional reactivity order of 5 > 4 >> 2 (66CHE14), though this conclusion is not rigorous because of the differential activating effects of the phenyl rings. 

From the ease of mercuriation of mono,- di-, and trimethylthiazoles, the positional reactivity order is indicated to be 5 > 4 > 2 (60CA24661c). Surprisingly, 2-acetamido-4-methylthiazole is said not to mercuriate (59JIC434), though the 5-position should be strongly activated it may be sterically hindered. Steric hindrance must be partly responsible for the reactivity order for substituted thiazoles 2-Ph- > 4-Me-2-Ph- > 2-Me-thiazole in this work the 4,5-dimethyl compound was unreactive [72CA(76)72617]. 

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. 

The positional reactivity order in thiazole is again the expected one. However, the magnitudes of the different from those in Scheme 7.12. The most probable cause for this is that the azoles are very susceptible to demands for resonance stabilization of the transition state for a particular reaction. This is not unexpected, because the reactivity of the azoles is the product of two opposing electronic effects from the heteroatoms, which are each large. A small alteration in the demand for resonance in a particular reaction may dramatically upset this balance. 

The positional reactivity order in thiazole has been calculated to be 5... 

Scheme 7.15. Predicted positional reactivity order for azoles (1 = most reactive).

Fusion of a benzene ring onto a five-membered heterocycle produces a change in the positional reactivity order associated with the latter. In the single-ring, five-membered heterocycles, 2-substitution is favored over 3-substitution. This can be explained in valence-bond terminology as due to there being three canonicals for the transition state for the former, and only two for the latter (see Chapter 6, Section 10.A). 

For benzo[b]furan and indole no such precise data are available, but it is possible to adduce some information from the various reactions described below. The positional reactivity orders for these molecules and also for benzo[b]thiophene, which have been calculated by various methods, are given in Table 8.1. In principle the ab initio calculations should be the more reliable, but neither the tt nor the (a + it) order is correct for benzo[6]thiophene, suggesting that these are incorrect for the other molecules also. The calculations using the STO-3G basis set certainly wrongly predict the site of most rapid protonation. Notably, only the Hiickel calculations give the correct order for benzo[b]thiophene and indeed they are usually the most reliable indicators for electrophilic aromatic substitution. 

Lastly, the 2- versus 3-positional reactivity order for benzo[6]thio-phene appears to be affected by steric hindrance from the sulfur d orbitals [82JCS(P2)1489], and this is discussed in detail in Section 2.A.C. For indoles it has been proposed that 2-substitution may take place by initial attachment of the electrophile to the 3-position, followed by migration (69T227). 

Calculated Positional Reactivity Orders for Benzo(7>]furan, Benzo(7>]thiophene, and Indolf. 

Attempts to predict the positional reactivity orders in these compounds by MO calculations have had only limited success. The problem is that the molecules can be considered as substituted biphenyls (8.122), in which case positions b and d would be the most reactive (as they are in fluorene). Alternatively, they can be considered as derivatives of diphenyl ether, etc., as in 8.123, in which case positions a and c, which are,... 

Calculated Positional Reactivity Order for Dibenzofuran, Dibenzothiophene, and Carbazole... 

Dibenzoselenophene is nitrated (nitric acid/acetic acid) 48% in the expected 2-position, but also 25% in the 4-position (55JA1061), implying that the positional reactivity order may be different from that in the oxygen and sulfur analogues. 

Calculations predict the most reactive sites in thieno[2,3-b]quinoline (8.132) to be the expected 2- or 3-positions [77ZN(B)1331], but there is little agreement on the positional reactivity order in 6-methylindolo-[2,3-6]quinoxaline (8.133) (84CHE687). tt Densities predict the order 7 > 9 > 1 (Huckel) or 7 > 9 > 3,4 (CNDO/2), localization energies (Huckel) predict 4 > 7 > 1, superdelocalizabilities predict 4 > 1 > 7, and frontier electron densities predict 1 > 4 > 3 (Huckel) or 4 > 1 > 2 (CNDO/2). The observed nitration and bromination at the 9-position serve to underline the inadequacy of all these theoretical methods. Localization energies predict that pyrrolo[l,2-[Pg.251]

The positional reactivity order in each molecule is sulfur a >P> positions in the benzene ring. 

---