Restricted Rotation about the C-N Bond in Thienopyridine Derivatives: NMR and DFT Study

Abstract: N-acyl tetrahydrothienopyridine derivatives serve as important structural motifs in bioorganic chemistry. Restricted rotation of C-N bond in such molecules gives rise to two distinct chemical environments. Thienopyridine derivatives 4a-4i were synthesized and characterised by 1H and 13C NMR spectroscopy. The NMR spectra reveal a doubling of signals, which suggests the presence of two rotamers in the solution. Variable temperature (VT) 1H-NMR studies supported this hypothesis. The NOESY analysis confirmed that Zrotamer is present in major form as compared to E-rotamer. The results were further corroborated through density functional theoretic calculations. background: N-acyl tetrahydrothienopyridine derivatives are widespread and important structural motif in bioorganic chemistry. Restricted rotation of C-N bond in such molecules gives rise to two distinct chemical environments objective: We observed doubling of signals in 1H NMR spectra of N-acyl tetrahydrothienopyridines derivatives. Herein, attempts were taken to investigate the cause and isomeric equilibrium ratio due to the rotation barrier of the amide bond using the different NMR experiments and DFT studies. We also studied the effect of substituents on molecular geometry and the equilibrium between E/Z diastereomers of thienopyridine derivatives 4a-4g. method: The NMR spectra of these derivatives revealed doubling of signals, which suggested presence of two rotamers in solution. Variable-temperature (VT) 1H-NMR studies supported this hypothesis. NOESY analysis confirmed that Z-rotamer is present in major form as compare to E-rotamer. To support these studies, we used DFT calculations to understand the pattern of the 1H NMR chemical shifts, the energies of Z/E rotamers and their intramolecular magnetic effects. result: We have synthesized different N-acyl tetrahydrothienopyridine derivatives 3, 4a-4g (Fig. 3). The 1H NMR spectra of all these compounds showed doubling of signals due to the restricted rotation about C-N bond. The ratio of isomers was found to be different for each compound. To investigate the effect of substituents on the isomer ratio, we compared our results with parent compounds; N-acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (4h) and N-acyl-piperidine (4i)