Thiazoles substituent constants

The extension " of this work to several substituted l-(5-thiazolyl)ethanol derivatives has provided information on the transmission of substituent effects in this heterocyclic system. For the series l-(2-X-5-thiazolyl)ethyl and l-(5-X-2-thiazolyl)ethyl chlorides, reaction rates are well correlated by Brown s substituent constants o- for the substituents X. The results suggest that in situations where direct conjugation, in a classical valence-bond sense, is permissible, substituent constants from benzene appear applicable to substituted thiazoles. 

In contrast, neither electrophilic substituent constants nor constants provide a suitable basis for correlating the relative rates of solvolysis of l-(2-substituted 4-thiazolyl)ethyl chlorides, recalling similar poor correlations in several other heterocyclic systems. An alternative working model, based on a comparison of appropriately substituted pyridines and thiazoles, provides an adequate treatment of the substituent effects in these instances. ... 

The amino group activates the thiazole ring toward electrophilic centers. This point is illustrated by the rate constants of the reaction between 2-dialkylaminothiazoles (32) and methyl iodide in nitromethane at 25 C (Scheme 23) (158). The steric effects of substituents on nitrogen are... 

Ultraviolet photoelectron spectroscopy allows the determination of ionization potentials. For thiazole the first experimental measurement using this technique was preformed by Salmona et al. (189) who later studied various alkyl and functional derivatives in the 2-position (190,191). Substitution of an hydrogen atom by an alkyl group destabilizes the first ionization potential, the perturbation being constant for tso-propyl and heavier substituents. Introduction in the 2-position of an amino group strongly destabilizes the first band and only slightly the second. 

In the second, which belongs to a systematic study of the transmission of substituent effects in heterocyclic systems, Noyce and Forsyth (384-386) showed that for thiazole, as for other simple heterocyclic systems, the rate of solvolysis of substituted hetero-arylethyl chlorides in 80% ethanol could be correlated with a constants of the substituent X only when there is mutual conjugation between X and the reaction center. In the case of thiazole this situation corresponds to l-(2-X-5-thiazolyl)ethyl chlorides (262) and l-(5-X-2-thiazolyl)ethyl chlorides (263). 

The quatemization reaction of the thiazole nitrogen has been used to evaluate the steric effect of substituents in heterocyclic compounds since thiazole and its alkyl derivatives are good models for such study. In fact, substituents in the 2- and 4-positions of the ring only interact through their steric effects (inductive and resonance effects were constant in the studied series). The thiazole ring is planar, and the geometries of the ground and transition states are identical. Finally, the 2- and 4-positions have been shown to be different (259. 260). 

Thiazoles readily undergo AT-alkylation by alkyl halides or tosylates (Menshutkin reaction). The sensitivity of this SN2 quaternization reaction to the molecular environment of the nitrogen atom has been used to evaluate, in a quantitative way, steric and electronic effects of ring substituents. The electronic effect of alkyl substituents (unperturbed by any steric effect) may be evaluated from the rate constants for the reaction of 5-alkylthiazoles with methyl iodide (in nitrobenzene at 30 °C) Table 19 shows that introducing a methyl group at the 5-position corresponds to an acceleration of the rate by a factor of 2 but that each addition of a methyl ramification to the 5-alkyl group enhances the rate only by a factor of 1.1. The data in Table 19 fit well with a Hammett-Taft equation (3) ... 

On the basis of these results it has been suggested that electronic factors— Hammett s sigma (a) constant, dipole moment (/z) and Swain and Lupton s polarity (F)—are crucial for the antithrombotic activity of these compounds. Interestingly, in all the active compounds presented in Fig. 24 the arrangement of substituents around the thiazole skeleton is different from one another. This has further widened the scope of this skeleton in the exploration of potential platelet aggregation inhibitors and thromboxane A2 receptor antagonist. 

TT-Electron densities, correlation with proton chemical shift, of alkylthiazoles, 344 of phenylthiazoles, 345 Electronic charges, of thiazole, 31 of aminothiazoles, 44 of chlorothiazoles, 44 of methylthiazoles, 40 Electronic effects, of 5-substituents on quaternization, 390 Electronic paramagnetic resonance, 84 coupling constants for nitrothiazoles, 84 coupling constants for 2-thiazolyl radical, 84... 

When the azomethine group is part of an electron-deficient ring, such as pyridine, pyrimidine or thiazole, the compounds exist as tetrazoles in the solid state, and at equilibrium with the azido form in solution . The equilibrium constants depend on the solvent, the nature of the substituents and the temperature . 2-Azido-4,6-dimethylpyrimidine (288a) thus exists in equilibrium with tetrazolo-pyrimidine (288b). Its chemical behaviour is, however, in accord with the azide structure 288a, including dipolar addition reactions and nitrene reactions . 

Conformational analysis of 1,3-thiazolidines and other thiazole derivatives has been carried out by NMR methods (see Section 3.06.3.6.1). Thus, the analysis of the coupling constants of the H NMR spectra <74JA1465> permitted to postulate envelopes with either C-4 or C-5 as the flap atom and with the 2-substituent anti to the flap as the predominant conformations (Equation (2)). 

The natural abundance C chemical shifts for thiazole (and its 2-, 4-, 2,4-, and 4,5-methyl derivatives) have been measured at 25.15 MHz against 50% enriched 82. The results confirm the accuracy of the C-H coupling constants, and show that the methyl groups exert an appreciable substituent effect on the carbon atoms to which they are attached. 2-Thiazoline (and its 2-methyl, 5-methyl, and 5-methyl-2-ethyl homologues) have also been studied from this point of view. ... 

Pyrazole-, Thiazole>, and Imidazole>fused Thiophens.—Starting from (410) and carrying out nucleophilic substitution with thioglycolate followed by ring-closure, as described for (384) and (408), the thieno[2,3-d]pyrazole system (411) was synthesized. Their ionization constants have been determined and the transmission of the influence of the substituents R has been studied and found to be more feeble than in naphthalene d benzo[b]thiophen. From the cyano-derivative (412), thiophen-fused derivatives such as (413) and (414) have been synthesized. Electrophilic... 

A detailed study of n.m.r. spectra has provided extensive data on chemical shifts and coupling constants in respect of a series of monophenyl-thiazoles, and their derivatives bearing alkyl and functional substituents in their hetero-rings. The chemical shifts were correlated with the net from electron density and energy diagrams, and the overall results were compared with those previously obtained in respect of thiazole and its methyl derivatives. 

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