Synthesis And Theoretical Study Of 3, 4-Dihydropyrimidin-2(1H)-ones

In 1893, Biginelli reported the the synthesis of 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) by one-pot condensation of benzaldehyde, urea and ethyl acetoacetate under strongly acidic conditions. Since 1990s, Biginelli reactions are ranked as one of the most powerful tools for the facile synthesis of complex heterocyclic scaffolds due to their wide range of therapeutical and pharmacological properties. So the synthesis and molecular properties of DHPMs have attracted considerable attentions.This dissertation includes experiment and theoretical studies. In the experimental part, Biginelli reaction was extensively investigated in the presence of antimony trichloride (SbCl3) as a Lewis acid. In the theoretical calculation part, the molecular properties of DHPMs and the mechanisms of Biginelli reaction were studied by quantum chemistry methods. Furthermore, mechanism and dynamics for the reaction of urea with formaldehyde were studied using the canonical variational transtition state theory with the small-curvature tunneling correction method. Major valuable results are listed as follows:1. An efficient synthesis of DHPMs using SbCl3 as the catalyst under solvent-free conditions is described. The optimum conditions are: the molar ratio of aldehyde,β-dicarbonyl compound and urea is 1:1:1.5, the amount of catalyst is 10 mol% of aldehydes and the best reaction temperature is 70℃. The advantages of this condensation reaction include the simple work-up procedure, high product yields, short reaction time and free solvent. Therefore, this is an important alternative to the synthesis of DHPMs.2. The structures of four DHPMs were fully optimized by B3LYP, HF and MP2 methods at 6-31G(d) or 6-311G level. The charge distribution, frontier molecular orbital, bond formations and natural bond orbital (NBO) were also analysed. The pyridine ring in DHPMs adopts boat conformation. In DHPMs, nitrogen atoms, oxygen atoms and carbon atoms which connected with hydrogen atoms carry negative electronics. The positive charges are mainly carried by the carbon atoms which linked to nitrogen atom or oxygen atom. The energy difference between frontier molecular orbitals is lower. DHPMs may have good biological activities because of hard stability. In DHPMs, the lone pair electrons of the two nitrogen atoms in the pyridine ring both have strong interactions with neighboring bonds.3. The mechanisms of Biginelli reaction were investigated at B3LYP/6-31G(d), B3LYP/6-31+G(d,p) and B3LYP/6-311+G(3df,2p)//B3LYP/6-31+G(d,p) levels. The equilibrium constants of the reactions were also computed. Mechanism of the classical Biginelli reaction is described as follows: The first step of the reaction is the acid-catalyzed formation of a N-acyliminium ion intermediate from aldehyde and urea. Interception of the iminium ion by ethyl acetoacetate through its enol tautomer, produces an open-chain ureide which subsequently cyclizes to dihydropyrimidine. The calculated equilibrium constant is 70.80 . The mechanism of synthesis of 3,4-dihydropyrimidin-2(1H)-thiones is similar with the classical Biginelli reaction's. The calculated equilibrium constant is 947.73 .4. As expansion to the first step of the classical Biginelli reaction, the reaction mechanism of urea with formaldehyde was investigated by MP2 method. Reaction rate of urea and formaldehyde between 200~3000K has been studied using the canonical variational transtition state theory with the small-curvature tunneling correction method. The reaction of urea with formaldehyde is a simple addition reaction. The elementary processes of this reaction are the breaking of nitrogen-hydrogen bond and the formation of oxygen-hydrogen bond. The forward potential barrier at MP2/6-31+G(d) level is 32.83 kcal/mol. The reasult shows that the calculated CVT/SCT rate constants exhibit typical non-Arrhenius behavior. The relativity of rate-temperature can be described as follows: k (T ) = (3.32×10 ?43 )T 8.32exp( ? 9027.8/ T) cm3·molecule-1·s-1.