Theoretical Study Of Intramolecular Nucleophilic Substitution On Nitrogen And Tautomerism Of 2-Aminothiazole

Intramolecular nucleophilic substitution (S_Ni) is a new way to synthesize heterocyclic compounds. Through the SNi reaction on nitrogen, pyrrole derivatives, the five-membered heterocyclic compounds containing nitrogen, can be obtained. Using the –^CHR-(CH₂)₃-NFCH₃ (R = H, CH₃, CH₂CF₃, CHO, COCH₃) as the computational model, the two possible intramolecular reactions, nucleophilic substitution on nitrogen and elimination reaction, are studied at the theoretical level of MP2(full)/6-31+G(d,p). The results indicate that the elimination mechanism will be preferred, leading to linear products R-CH₂-(CH₂)₃N=CH₂ when the –CHR is more basic (R = H, CH₃, CH₂CF₃). In contrast, electro-withdrawing groups –CHO and –COCH₃ on the attacking site will be favorable for the intramolecular nucleophilic displacement at nitrogen and form five-membered heterocyclic compounds. These theoretical predictions agree with the available experiments. In order to investigate whether the SNi reaction on nitrogen is easier than that on carbon, we take the C instead of the N in –CHR-(CH₂)₃-NFCH₃. As a result, –CHR-(CH₂)₃-CHFCH₃ has been the subject in the third chapter with three different substituent groups, R = H, CH₃, COCH₃ chose. At the same MP2(full)/6-31+G(d,p) level, the two possible intramolecular reactions, nucleophilic substitution at carbon and elimination reaction, are also studied. The computational results demonstrate that the elimination mechanism will still be facile when the –CHR is more basic (R = H, CH3). Conversely, electro-withdrawing groups –COCH3 on the attacking site will be preferred for the intramolecular nucleophilic displacement on carbon. But in general, the SNi reaction on nitrogen will be easier than that on carbon both in dynamics and thermodynamics. These theoretical results consist with the available experimental conclusion that the SN2 reaction on nitrogen is easier than that on carbon. The amino-imino tautomeric equilibrium A B of 2-aminothiazole is one of the most fundamental tautomerisms of aminothiazole derivatives. By adopting density functional theory (B3LYP) combined with 6-31+G(d,p) and 6-311+G(3df,2p) basis sets, the relative stabilities of the isomers and the three possible proton transfer pathways,(â…°)intramolecular direct proton transfer, A→B; (â…±)water-assisted transfer, A·nH2O →B·nH2O (n=1,2,3); ( â…²) intermolecular transfer through dimerization, A2→B2, are studied in gas phase, protic polar solvent (water) and apolar solvent (CCl4). The computational results reveal that A form is the most populated tautomer, and dimerization provides the most favorable path to the tautomerization, which keep the same in water and CCl4. In addition, the more polar the solvent is, the easier the equilibrium can be shifted towards B form, and meanwhile the stability of B form is promoted. The B3LYP/6-31+G(d,p) NICSs (nucleus-independent chemical shifts) are about -10 ppm and -8 ppm of form A and B, respectively, showing form A is more aromatic than B. The TDDFT calculations of electronic absorption spectra suggest that the λmax of dimer-A is 255 nm which agrees well with the experimental value. The A forms have relatively stronger oscillator strengths f than B forms. With the increasing polarity of solvents, the f values of B forms are also bigger; meanwhile, the differences between the two kinds of tautomers become smaller. Clearly, the calculated results for this tautomerism are in reasonable line with the known experiments.