Electron withdrawing pyrimidine

The replacement of the thiazole ring with a more electron withdrawing pyrimidine nucleus enhanaces the acidity of the NH proton by stabilizing the anion ultimately. Consequently, sulphadiazine and its metabolite are appreciably ionized at pH of blood thereby rendering them more soluble and less toxic as illustrated below ... 

Much of the reactivity shown by the ring atoms and substituents of pyrimidine is akin to that of the corresponding parts of 1,3-dinitrobenzene and 3-nitropyridine. This arises from the quantitatively similar electron-withdrawing effects of doubly-bound ring nitrogen atoms and of nitro groups in reducing sharply the aromaticity of the cyclic system. 

Muller and co-workers reported the three-component one-pot synthesis of various pyrimidines through the in situ generation of unsaturated carbonyl compounds. The palladium catalyzed coupling of aryl halides bearing electron withdrawing substituents 7 with propargyl alcohols 8 produced unsaturated carbonyl compounds 9 after isomerization, which condensed with amidines 10 to form triaryl pyrimidines 11 . 

Besides quaternary pyrimidinium salts, pyrimidines with a strong electron-withdrawing substituent on one of the carbons of the pyrimidine ring show enhanced reactivity of the heterocyclic ring toward nucleophiles. In light of the results mentioned previously with pyrimidinium salts, it is not too surprising that reflux of an ethanolic solution of 5-nitropyrimidine with benzamidine hydrochloride or pivalamidine hydrochloride in the presence of triethylamine afforded 5-nitro-2-phenylpyrimidine (108, 84%... 

Due to the electron-withdrawing nature of the pyrimidine ring, alkenylpyrimidines can undergo addition reactions at the /3-carbon, and while this is a well-established route to substituted pyrimidine derivatives <1994HC(52)1, 1996CHEC-II(6)93>, it has also been used to prepare quinazolinone derivatives 578 from 2-alkenyM(3//)-quinazo-linones 577 <2000T7245>. 

Nucleophilic aromatic substitutions Pyrimidine is more reactive than pyridine towards nucleophilic aromatic substitution, again due to the presence of the second electron-withdrawing nitrogen in the pyrimidine ring. Leaving groups at C-2, C-4 or C-6 positions of pyrimidine can be displaced by nucleophiles. 

Increasing numbers of nitrogen atoms increase not only the kinetic susceptibility toward attack but also the thermodynamic stability of the adducts. Reversible covalent hydration of C = N bonds has been observed in a number of heterocyclic compounds (76AHC(20)117). Pyrimidines with electron-withdrawing groups and most quinazolines show this phenomenon of covalent hydration . Thus, in aqueous solution the cation of 5-nitropyrimidine exists as (164) and quinazoline cation largely as (165). These cations possess amidinium cation resonance. The neutral pteridine molecule is covalently hydrated in aqueous solution. Solvent isotope effects on the equilibria of mono- (166) and dihydration (167) of neutral pteridine as followed by NMR are near unity (83JOC2280). The cation of 1,4,5,8-tetraazanaphthalene exists as a bis-covalent hydrate (168). 

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