Thiazoles basicity

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... 

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

The nitro group increases the acidity of the hydrogen born by the exocyclic nitrogen, and alkylation of 2-nitraminothiazole with diazomethane is possible (87), The formed 2-(A"-methylnitramino)-thiazole also may be obtained from the reaction of 2-nitraminothiazole with dimethylsulfate in basic medium (194). 

Oxidation, already described in neutral and acidic media, may also be performed in basic medium. An alkaline solution of H2O2 reacts with 4-thiazoline 2-thione to yield thiazole-2-sulfonic acid (201-203), whereas alkaline oxidation performed with (NH )2S20g yields the disulfides (148). 

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. 

Another objective is to discuss briefly recent and major trends in the field of methine dyes color. Indeed, because of its relatively simple structure, the thiazole ring has been chosen in the past for studying color-structure relations. Using Brooker s basicity concepts (5), numerous valuable attempts in different countries succeeded in establishing semiempirical rules for explaining the effects of structural changes on color. 

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). 

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... 

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. 

With the exception of the nuclear amination of 4-methylthiazole by sodium amide (341, 346) the main reactions of nucleophiles with thiazole and its simple alkyl or aryl derivatives involve the abstraction of a ring or substituent proton by a strongly basic nucleophile followed by the addition of an electrophile to the intermediate. Nucleophilic substitution of halogens is discussed in Chapter V. 

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. 

Another bright blue dye from diazotized 2-amiao-6-methoxybenzothiazole [1747-60-0] by azo coupling, eg, with 2(/V-ethy1ani1ino)ethano1 is Basacryl Blue X-3GL [12270-13-2] (133) (Cl Basic Blue 41 Cl 1110S). After couphng, the water-iusoluble dye is methylated at the thiazole nitrogen. 

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. 

Prior to the 1947 report by Cook and Heilbron on their novel synthesis, 5-aminothiazoles were mostly unknown in the literature. Previous syntheses included the Curtius degradation of ethyl thiazole-5-carboxylates which did not have general applicability there was also difficultly in obtaining the necessary starting materials. During a study on penicillin, Cook and Heilbron found that the reaction between methyl dithiophenylacetate and ethyl aminocyanoacetate gave what was initially believed to be ethyl phenylthionacetamidocyanoacetate 4. However further studies proved the compound to be 5-amino-4-carbethoxy-2-benzyl-thiazole 5, which was basic. 

Acidic and basic hydrolysis of ethyl 4-oxo-4//-pyrido[l, 2-u]pyrimidin-3-carboxylates gave 3-carboxylic acid derivatives (OlMIPl). Stirring rerr-butyl ( )-3-(2-hydroxy-8-[2-(4-isopropyl-l, 3-thiazol-2-yl)-l-ethenyl]-4-oxo-4//-pyrido[l,2-u]pyrimidin-3-yl)-2-propenoate in CF3CO2H at room temperature yielded ( )-3-substituted 2-propenoic acid. 

Other common five-membered heterocyclic amines include imidazole and thiazole. Imidazole, a constituent of the amino acid histidine, has two nitrogens, only one of which is basic. Thiazole, the five-membered ring system on which the structure of thiamin (vitamin Bt) is based, also contains a basic nitrogen that is alkylated in thiamin to form a quaternary ammonium ion. 

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