Basicity of thiazoles

A 2-methylthio substituent decreases the basicity of thiazole pK = 2.52) by 0.6 pK unit (269). The usual bathochromic shift associated with this substituent in other heterocycles is also found for the thiazole ring (41 nm) (56). The ring protons of thiazole are shielded by this substituent the NMR spectrum of 2-methylthiothiazole is (internal TMS, solvent acetone) 3.32 (S-Me) 7.3 (C -H) 6.95 (Cj-H) (56, 270). Typical NMR spectra of 2-thioalkylthiazoles are given in Ref. 266. 

This bathochromic shift is typical of 77 —> tt transitions. The behavior of the water solution when acidified was attributed by Albert (175) absorption by the thiazolium cation, by analogy with pyridine. However, allowance is made for the very weak basicity of thiazole (pK = 2.52) compared with that of pyridine (pK = 5.2), Ellis and Griffiths (176) consider the differences between the spectrum of thiazole in water and in... 

The basicity of thiazole was well documented <1984CHEC(6)235>. A table of pK and free enthalpies of dissociation of some representative thiazoles was presented. 

The basicity of thiazoles is well-documented <84CHEC-I(4)240>, and a number of pK values of some representative thiazoles can be found there as well as in the references cited therein. 

The basicity of a 4-phenyl-substituted thiazole is less than the corresponding methyl-substituted thiazole (16) and the pKa values of quaiemarv salts are in the same order (25). 

As early as 1889 Walker (320), using samples of thiazole, 2,4-dimethylthiazoie, pyridine, and 2,6-dimethylpyridine obtained from Hantzsch s laboratory, measured the electrical conductivity of their chlorhydrates and compared them with those of salts of other weak bases, especially quinoline and 2-methylquinoline. He observed the following order of decreasing proton affinity (basicity) quinaldine>2,6-dimethyl-pyridine>quinoline>pyridine>2,4-dimethylthiazole> thiazole, and concluded that the replacement of a nuclear H-atom by a methyl group enhanced the basicity of the aza-aromatic substrates. 

In all its reactions the lone pair of thiazole is less reactive than that of pyridine. Table 1-61 shows three sets of physicochemical data that illustrate this difference. These are (1) the thermodynamic basicity, which is three orders of magnitude lower for thiazole than for pyridine (2) the enthalpy of reaction with BF3 in nitrobenzene solution, which is 10% lower for thiazole than for pyridine and (3) the specific rate of quaterni-zation by methyl iodide in acetone at 40°C, which is about 50% lower for... 

Although isothiazole (pK = 1.90) is less basic than thiazole, its rale of quaternization by dinitrophenyl acetate in water at 52°C is approximately 2.5 times higher (447). This deviation from the Bronsted relationship (A log k - 0.ApK, with positive) is interpreted as a consequence of the or effect of the adjacent sulfur lone pair in isothiazole that is responsible for its higher nucleophilicity (448, 449). 

The same situation is observed in the series of alkyl-substituted derivatives. Electron-donating alkyl substituents induce an activating effect on the basicity and the nucleophilicity of the nitrogen lone pair that can be counterbalanced by a deactivating and decelerating effect resulting from the steric interaction of ortho substituents. This aspect of the reactivity of thiazole derivatives has been well investigated (198, 215, 446, 452-456) and is discussed in Chapter HI. 

A 2-Alkyl group contributes to the basicity of the thiazole ring. The only significant fall in pK (for 2- -propyl and 2-r-butyl thiazole) is not... 

Usually no difficulties are encountered in the esterification of thiazole acids. Direct esterification with alcohol and add in the presence of an acid catalyst (7, 61, 62), or prior conversion to the add chloride (6, 63, 64) followed by reaction with an alcohol in basic conditions give good yields. 

NMR data for 4-methyloxazole have been compared with those of 4-methylthiazole the data clearly show that the ring protons in each are shielded. In a comprehensive study of a range of oxazoles. Brown and Ghosh also reported NMR data but based a discussion of resonance stabilization on pK and UV spectral data (69JCS(B)270). The weak basicity of oxazole (pX a 0.8) relative to 1-methylimidazole (pK 7.44) and thiazole (pK 2.44) demonstrates that delocalization of the oxygen lone pair, which would have a base-strengthening effect on the nitrogen atom, is not extensive. It must be concluded that not only the experimental measurement but also the very definition of aromaticity in the azole series is as yet poorly quantified. Nevertheless, its importance in the interpretation of reactivity is enormous. 

The basicities of the parent azole systems in water are shown in Table 1. When both heteroatoms are nitrogen, the mesomeric effect predominates when the heteroatoms are in the 1,3-positions, whereas the inductive effect predominates when they are in the 1,2-positions. The predominance of the mesomeric effect is illustrated by the pK value of imidazole (82 Z = NH), which is 7.0, whereas that of pyrazole (83 Z = NH) is 2.5 cf. pyridine, 5.2). An fV-methyl group is base-strengthening in imidazole, but base-weakening in pyrazole, probably because of steric hindrance to hydration. When the second heteroatom is oxygen or sulfur the inductive, base-weakening effect increases the pK of thiazole (82 Z = S) is 3.5 and that of isoxazole (83 Z = 0) is 1.3. 

Thiamin, structure of, 530, 1045 thiazolium ring in, 530 Thiamin diphosphate, p/Ca of, 1151 reaction with pyruvate, 1151-1153 structure of. 1151 ylide from. 1151 Thiazole, basicity of. 948 thio-, thioester name ending, 787 Thioacetal, synthesis of, 743 Thioanisole, electrostatic potential map of. 777... 

Thiazole. 4-methyl, basicity of, 75 pK value of, 62 4-phenyl, basicity of. 75 quaternization of, 31... 

Furthermore, the strongly metallic character of selenium weakens the C-Se bond and thus favors reactions involving opening of the ring. The basicity of the three heterocycles is approximately in the same order, the nitrogen atom of selenazole and thiazole possessing much the same properties as the heteroatom of pyridine. Of the two carbon atoms ortho to nitrogen, that is, the 2-carbon and the 4-carbon, only the one in the 2-position is fairly active as a result of its interaction with selenium or sulfur. The 4- and 5-positions of thiazole and selenazole are more susceptible to electrophilic substitution than the 3- and 5-positions of pyridine. This is particularly true of the 5-position of selenazole. Thus it can be said that the 2- and 5-positions of the selenazoles and thiazoles... 

Care must be taken in the choice of organic solvent. Chloroform should never be used under the basic conditions due to the risk of the formation of isocyanides (see Chapter 7) and the use of carbon disulphide can lead to formation of dithiocarba-mates, e.g. dimethyl A -(ethoxycarbonylmethyl)iminodithiocarbonate is formed (35-39%), as the major product in high purity, in the liquiddiquid two-phase methyl-ation of ethyl glycinate in carbon disulphide [15]. The product is useful as an intermediate in the synthesis of thiazoles [15] and dihydrooxazoles [16]. 

Oxazole (pATa 0.8) and thiazole (pATa 2.5) are weak bases. The basicity of the nitrogen is reduced by the presence of the other heteroatom. Oxygen and sulfur provide a stronger electron-withdrawing inductive... 

Little work has been reported. From studies of proton/deuterium exchange rates, 2-methylpyrrolo[2,l-6]thiazole (478) was estimated to have a pKa of 6.4,394 a value comparable with that of 2-methylindolizine (pKa = 5.9).394 In the same way, the basicity of 3,4-dimethylimidazo-[l,5-a]benzimidazole (468b) (pA = 6.01) resembles that of imidazo-[l,2-a]pyridines (pA = 5.05-5.96).398 It would seem, therefore, that the basicity of azapentalenes parallels that of related indolizine derivatives [Eq. (40)]. 

Despite the weak basicity of isoxazoles, complexes of the parent methyl and phenyl derivatives with numerous metal ions such as copper, zinc, cobalt, etc. have been described (79AHC(25)147). Many transition metal cations form complexes with imidazoles the coordination number is four to six (70AHC(12)103). The chemistry of pyrazole complexes has been especially well studied and coordination compounds are known with thiazoles and 1,2,4-triazoles. Tetrazole anions also form good ligands for heavy metals (77AHC(2l)323). 

The oxidation of thiazoles by peroxy acids leads to the corresponding A-oxides. Peracetic, MCPBA, permaleic, and trifluoroperacetic acid have been employed for this reaction. Chemical yields range from 4% to 50%, the more basic thiazoles producing higher yields. Thus, thiazole, 2,4-dimethyl- and 4,5-dimethylthiazoles, and 2-phenylthiazole can be oxidized in moderate to good yields. However, neither 4-chloro-2-phenylthiazole nor 5-chloro-2-phenylthiazole could be oxidized. 3-Oxides were also obtained by oxidation of 1,2,3-thiadiazoles and 5-phenylthiatriazole (121—>122) (75T1783). 

The structural formulas of several cyclic compounds containing both nitrogen and sulfur are shown in Figure 17.4. Basic to the structures of these compounds is the simple ring structure of thiazole. It is a colorless liquid (bp, 117°C). One of its major uses has been for the manufacture of sulfathiazole, one of the oldest of the sulfonamide class of antibacterial drugs. The use of sulfathiazole is now confined to the practice of veterinary medicine because of its serious side effects. 

What is the basic structure of thiazole For which major pharmaceutical can it serve as a raw material Why is this pharmaceutical no longer widely used Give the names, structures, and properties or uses of some compounds related to thiazole. 

---