Protomeric equilibrium

Charge diagrams suggest that the 2-amino-5-halothiazoles are less sensitive to nucleophilic attack on 5-position than their thiazole counterpart. Recent kinetic data on this reactivity however, show, that this expectation is not fulfilled (67) the ratio fc.. bron.c.-2-am.noih.azoie/ -biomoth.azoie O (reaction with sodium methoxide) emphasizes the very unusual amino activation to nucleophilic substitution. The reason of this activation could lie in the protomeric equilibrium, the reactive species being either under protomeric form 2 or 3 (General Introduction to Protomeric Thiazoles). The reactivity of halothiazoles should, however, be reinvestigated under the point of view of the mechanism (1690). 

As expected. 2-aminothiazole is more basic (piVj, = 5.28) than thiazole (pXj = 2.52) (681. Ultraviolet absorption properties as a function of pH 

General trends in substituents effects on a protomeric equilibrium may be obtained by HMO approximations, as illustrated m Figs. 3 and 4 of the 

TABLE VI-L REPRESENTATIVE pK VALUES OF 2-AMINOTHIAZOLES AND 2-IMlNO-4-THIAZOLINES 

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For this class of thiazoles most of the chemical and physicochemical studies are centered around the protomeric equilibrium and its consequences. The position of this equilibrium may be determined by spectroscopic and titrimetric methods, as seen in each section. A simple HMO (Hiickel Molecular Orbitals) treatment of 2-substituted compounds however, may, exemplify general trends. This treatment considers only protomeric forms 1 and 2 evidence for the presence of form 3 has never been found. The formation energy reported in Table 1 is the energy difference in f3 units. 

Fig. 1. Trends in effects of 4- and 5-substituenls (expressed as an a variation of R) on the proiomeric equilibrium calculated using the HMO method. When curves do not cross no inversion of protomeric equilibrium is expected to be induced by electronic substituent effects, 4-R-(----) 5-R-(-----). F,E formation energy (see Table 1).

Physicochemical studies on aminothiazoles are mainly centered on two problems the position of imino-amino protomeric equilibrium and IsRR substitution effects on the thiazole nucleus. 

Angyal and Angyal measured the pK of 2-aminothiazoles and 2-imino-4-thiazolines to obtain the protomeric equilibrium constants (Scheme l4) (74). The higher pK values of the imino derivative (9.65) compared with that of 2-aminothiazole (5.68) prove that the amino form is highly predominant, Xp = 2x 10" (72), The limitations of such a method of Kp determination are discussed by Elguero. Marzin and Katntzky in a review of protomeric equilibria in heterocycles (75). 

A protomeric equilibrium favors the acetamido rather than the acetimido form (105, 121). The parent molecular ion has been reported to be absent in the mass spectrum of 2-acylaminothiazoles (130). 

Both 2-hydroxythiazoie and 2-mercaptothiazoIe have been studied to determine the position of the protomeric equilibrium 43 7 43a 43b (Scheme 17). Most studies indicate that form 43a is largely predominant in neutral solution for X = 0 and X=S (52-56, 887, 891). The basic principle is to compare a physical property of the investigated product with that of a model representative of each protomeric form. The similarity of physicochemical properties between the product and one of the model compounds is taken as evidence for the position of the protomeric equilibrium. The limits of such an approach have been discussed in detail elsewhere (57). 

Steric effects of the substituents in positions 4 and 5 cannot shift the protomeric equilibrium sufficiently to permit spectroscopic observation of the thiol form (43b) ultraviolet spectra of 4-terr-butyl-5-methyl-A-4-thia2oline-2-thione (49a) in neutral solvents do not reveal any trace of the thiol protomer (49bi (Scheme 21) (70). 

Physical properties of A-4-thiazoline-2-one and derivatives have received less attention than those of A-4-thiazoline-2-thiones. For the protomeric equilibrium, data obtained by infrared spectroscopy favors fbrm 51a in chloroform (55, 96, 887) and in the solid state (36. 97. 98) (Scheme 23). The same structural preference is suggested by the ultraviolet spectroscopy studies of Sheinker (98), despite the fact that previous studie.s in methanol (36) suggested the presence of both 51a and... 

The third compound of this protomeric equilibrium corresponds to the mesoionic 4-hydroxy thiazo e. Its existence has been suggested recently from reactivity experiments (416). When R in 174 is also a protomeriza-ble group, other stable protomeric species have been observed (Scheme 91) (417. 418). They are out of the scope of this review. 

The reactivity of A-2-thiazoline-5-one is closely related to the protomeric equilibrium shown in Scheme 108. 

The general structure of these compounds is described in Scheme 75. Type 1 compounds Can show a protomeric equilibrium and thus can be classed eventually with the 2-aminoselei>azolines when this latter structure predominates. 

Thiazolin-5-one, 2-alkoxy-4-arylazo-rearrangements, 5, 777 2-Thiazolin-5-one, 4-methyl-2-phenyl-protomeric equilibrium, 6, 249 4-Thiazolin-2-one, 4-aryl-reactions, 6, 286 4-Thiazolin-2-one, 3,4-dimethyl-protonation, 6, 286 4-Thiazolin-2-one, 4-methyl-reactions, 6, 286 Thiazolinones electrophilic attack, 5, 99 Thiazolin-2-ones IR spectroscopy, 6, 241 nucleophilic displacement, 5, 100 2-Thiazolin-4-ones reactions, 6, 287 2-substituted synthesis, 6, 306 synthesis, 5, 129 6, 309, 310 tautomerism, 6, 248 2-Thiazolin-5-ones IR spectroscopy, 6, 242 reactions, 6, 288 synthesis, 5, 138 tautomerism, 6, 249 4-Thiazolin-2-ones synthesis, 6, 314 4-Thiazolin-3-ylacetic acid esters... 

Fig. 4. Trends in effects of NR substituents (expressed as an a variation of R on the protomeric equilibrium. See Fig. 1 for explanation.

NMR data of, 105 by oxidation, 102, 105 paper electrophoretic, 107 pKa of, 107 polarography of, 108 protomeric equilibrium with, 107 X-Ray data, 107 Bacteria leaf blight, 136 Bactericide, 134, 136, 137, 138, 139, 140, 438,439,441,442 Bacteriostatic properties, 139, 152 Bacterium citri, control of, 441 Barrier to rotation, around Nsp -Csp bond, in N-alkyl, A-4-thiazoline-2-thione, 387... 

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