Thiazoles protonation, basicity

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. 

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. 

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. 

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)]. 

The weakly basic portion of thiamin or of its coenzyme forms is protonated at low pH, largely on N-l of the pyrimidine ring. 86 88 The pKa value is 4.9. In basic solution, thiamin reacts in two steps with an opening of the thiazole ring (Eq. 14-15) to give the anion of a thiol form which may be crystallized as the sodium salt.79 84 This reaction, like the competing reaction described in Eq. 7-19, and which leads to a yellow... 

In the first step, pyruvate dehydrogenase catalyzes the decarboxylation of pyruvate. A nucleophile is formed when a basic residue of the enzyme extracts a proton from the thiazole ring of thiamine pyrophosphate (TPP). The intermediate, hydroxyethyl-TPP (HETPP), forms after the nucleophilic thiazole ring attacks the carbonyl group of pyruvate with the resulting loss of COz (Figure 9.8). 

Thiazole is more basic than oxazole but less so than pyridine. The p of thiazole is 2.52. Protonation occurs on the N-atom. Unlike oxazoles, thiazoles form crystalline and stable salts, e.g. picrates. 

The specific exchange at C-2 in the azoles in neutral solution, via an ylide, has already been discussed (section 21.1.2.1). In strongly basic solution, deprotonation takes place by direct abstraction of proton from the neutral heterocycle at the positions adjacent to the oxygen and the sulfur in oxazole and thiazole and, less easily, at C-5 in 7f-methylimidazole. ... 

With a pATa of 2.5, pyrazole is significantly less basic than imidazole, whose p/fa is 7.1. In fact, having an adjacent heteroatom near the N atom always has the effect of lowering the basicity of the N because of their inductive effect. Therefore, the N atoms on isothiazole (p/Ca, -3.0) and isoxazoles (pATa, -0.5) are less basic than those of thiazole (pA a, 2.5) and oxazole (pAfa, 0.8), respectively. Nonetheless, pyrazole is basic enough to be protonated with most strong inorganic acids. ... 

The 1,3-azoles are quatemised easily at the imine nitrogen with alkyl halides the relative rates are 1-methylimidazole thiazole oxazole, 900 15 1." In the case of imidazoles which have an A -hydrogen, the immediate product is a pro-tonated N-alkylimidazole this can lose its proton to unreacted imidazole and react a second time, meaning that reactions with alkyl halides give a mixture of imidazolium, 1-alkylimidazolium and 1,3-dialkylimidazolium salts. Furthermore, an unsymmetrically-substituted imidazole can give two isomeric 1-alkyl derivatives. The use of a limited amount of the alkylating agent, or reaction in basic solution, when it is the imidazolyl anion (section 21.4.1) which is alkylated, can minimise these complications. 

The pyrimidine heterocycle is chemically more inert than the thiazole heterocycle. At pH <4, the N-1 of the pyrimidine ring is protonated, while the N-3 is protonated only under extreme conditions such as in concentrated sulfuric acid. The 4 -amino group has no basic character and is not protonated even in strong acids. However, it plays an important role in positioning the cofactor ThDP in the active site of the apoenzymes. 

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