Quaternization azoles

Some weak electrophilic reagents, which are usually inert toward azoles, also react with quaternized azoles. Diazonium salts yield phenylhydrazones (Scheme 48) in a reaction analogous to the Japp-Klingemann transformation of /S-keto esters into phenylhydrazones in the dithiolylium series illustrated the product has bicyclic character. Cyanine dye preparations fall under this heading (see also Section 4.02.1.6.5). Monomethine cyanines are formed by reaction with an iodo quaternary salt, e.g. Scheme 49. Tri- and penta-methinecar-bocyanines (384 n = 1 and 2, respectively) are obtained by the reaction of two molecules of a quaternary salt with one molecule of ethyl orthoformate (384 n = 1) or/S-ethoxyacrolein acetal (384 n =2), respectively. 

N- Methyl chemical shifts in quaternized azoles and their benzo analogs appear to be determined by resonance interaction from the heteroatom, with the order of donating ability of the heteroatom being NMe>0>S Se (74JHClon). 

The N-methyl chemical shifts in quaternized azoles, isoazoles, diazoles, and their benzologs (60-66) were reported by Davis and co-workers.31 The shifts appear to be determined by resonance from the heteroatom, decreasing in the order of the donating ability of the heteroatom NMe > O > S Se. In the 1,2 orientation, the electronegativity effects were also important, as evidenced by a general downfield shift the order of donation is NMe > S Se > O. 

A study has been made of the chemical shifts of the methyl group in a comprehensive series of quaternized azoles and their benzologs, N-methyl-indoxazenium perchlorate being one of the compounds reported.36... 

For both azole and benzazole rings the introduction of further heteroatoms into the ring affects the ease of quaternization. In series with the same number and orientation of heteroatoms, rate constants increase in the order X = 0requires stronger reagents and conditions methyl fluorosulfonate is sometimes used (78AHC(22)71). The 1-or 2-substituted 1,2,3-triazoles are difficult to alkylate, but methyl fluorosulfonate succeeds (7IACS2087). 

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. 

For both azole and benzazole rings, introduction of a heteroatom or group X into a ring affects the ease of quaternization.44,122,123 Rate constants increase in the order X = O < S < NMe (Table III) the magnitude of the effect of a particular heteroatom is dependent on the structure of the substrate. The difference in reactivity between oxa and thia azoles generally is less than that between thia and aza nucleophiles (Table III). However, 39 provides an exception to this pattern a larger separation is found between the first, rather than the second, pair of heteroatoms considered. 

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... 

Fio. 1. Bronsted plot for azoles reacting with methylating agents in quaternization reactions. Pyridine is the reference substrate. 1, 1-methylimidazole 2, 1-methylbenzimidazole 3, thiazole 4, 1-methylpyrazole 5, 2-methylindazole 6, benzo-thiazole 7, oxazole 8, 1-methylindazole 9, benzoxazole 10, 2,1-benzisothiazole 11, isothiazole 12, 2,1-benzisoxazole 13, isoxazole and 14, 1,2-benzisoxazole. 

Clearly, there is a distinct difference between the kinetic results for the benzologs of azines and azoles. The former definitely show a sizable steric effect in N-methylation reactions when the site of quaternization is a peri position, while any effect for the latter is insignificant. Perhaps this simply reflects the smaller internal bond angles for five- over six-membered rings. 

Information is not yet available to indicate whether Eq. (15) will apply to poly azoles where there are two or more sites of protonation and of quaternization. It also is not known whether substituted azoles will fit the correlation line. Clearly, a start has been made additional studies need to be undertaken. 

We will see in the next section that quaternization of azines and azoles has been used to test the applicability and validity of steric parameters, to show their conformational dependence, and to propose new steric parameters suitable for ortho positions. 

Azoles having heteroatoms in the 1,3-orientation are more reactive than those in which the arrangement is 1,2. However, the magnitude of the factor varies, thus oxazole is 68 times more reactive than isoxazole, whereas benzox-azole quaternizes 26 times faster than does 1,2-benzisoxazole. 

Methylation of benzoselenazoles with dimethyl sulfate has been reported to give the 3-methylbenzoselenazolium salts. The rate of methylation of a number of azoles, including benzoselenazoles, has been followed by nuclear magnetic resonance (NMR), and it is reported that rates were controlled by the inductive effect of the other heteroatom. There is a good Bronsted correlation between rates of quaternization and the pK of the azoles. 

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