Conformational complexity of morphine and morphinum in the gas phase and in water. A DFT and MP2 study

The structural and conformational properties of morphine and protonated morphine (morphinum) in the gas phase and in water solution have been explored with quantum calculations. Fully optimized calculations using the cc-pVTZ basis set, with various methods (MP2, B3LYP, and PBE0) for the species in the gas phase and with B3LYP with simulation of the solvent effect as a continuum with the SMD method were conducted. The study focuses on the determination of the relative energies of the 12 possible conformers that arise from the orientation of the two OH groups and the equatorial vs. axial position of the methyl group on the nitrogen and the energy barriers that separate these minima. The calculations indicate a preference for conformers having the methyl group equatorial, but corresponding axial conformers are not significantly higher in energy. Only 8 of the 12 possible conformers of gaseous morphine were found to be minima on the potential energy hypersurface. All 12 conformers of morphinum are minima according to MP2 computations. B3LYP/SMD (water) calculations predict the coexistence of 12 conformers for both morphine and morphinum with energy ranges of 17 kJ mol−1 for morphine, and as low as 13 kJ mol−1 for morphinum. In morphinum, energy differences of less than 8 kJ mol−1 are computed for 8 conformers, including axial forms. The inversion at nitrogen is calculated to be energetically accessible at room temperature since the activation barrier is less than 30 kJ mol−1 in the gas phase and only around 40 kJ mol−1 with simulated water solvation. The many conformers within a small energy span, the fact that a thermodynamic equilibrium exists between morphine and morphinum in water, and the rapid nitrogen inversion show that morphine and morphinum have a large conformational diversity in water, and thus in the physiological media, which could be a clue to the interaction of this drug with receptors

Conformational complexity of morphine and morphinum in the gas phase and in water. A DFT and MP2 study

The structural and conformational properties of morphine and protonated morphine (morphinum) in the gas phase and in water solution have been explored with quantum calculations. Fully optimized calculations using the cc-pVTZ basis set, with various methods (MP2, B3LYP, and PBE0) for the species in the gas phase and with B3LYP with simulation of the solvent effect as a continuum with the SMD method were conducted. The study focuses on the determination of the relative energies of the 12 possible conformers that arise from the orientation of the two OH groups and the equatorial vs. axial position of the methyl group on the nitrogen and the energy barriers that separate these minima. The calculations indicate a preference for conformers having the methyl group equatorial, but corresponding axial conformers are not significantly higher in energy. Only 8 of the 12 possible conformers of gaseous morphine were found to be minima on the potential energy hypersurface. All 12 conformers of morphinum are minima according to MP2 computations. B3LYP/SMD (water) calculations predict the coexistence of 12 conformers for both morphine and morphinum with energy ranges of 17 kJ mol−1 for morphine, and as low as 13 kJ mol−1 for morphinum. In morphinum, energy differences of less than 8 kJ mol−1 are computed for 8 conformers, including axial forms. The inversion at nitrogen is calculated to be energetically accessible at room temperature since the activation barrier is less than 30 kJ mol−1 in the gas phase and only around 40 kJ mol−1 with simulated water solvation. The many conformers within a small energy span, the fact that a thermodynamic equilibrium exists between morphine and morphinum in water, and the rapid nitrogen inversion show that morphine and morphinum have a large conformational diversity in water, and thus in the physiological media, which could be a clue to the interaction of this drug with receptors

The Stereochemistry of Overcrowded Homemerous Bistrucyclic Aromatic Enes With Alkylidene Bridges

The objective of the research was to study the e ff ects of alkylidene bridges on the conformations and the conformational behaviour of overcrowded homomerous bistricyclic aromatic ethenes ( 1 ). The isopropylidene- bridged bistricyclic ethene 2 and 3 were synthesized by a reductive “dimerization” of 7 , using TiCl 4 –Zn–pyridine–THF. The methylene-bridged bistricyclic ethenes 4 – 6 were synthesized by LiAlH 4 –AlCl 3 –Et 2 O reductions of the corresponding bianthrones. The structures of 2 – 6 were established by 1 H- and 13 C-NMR spectroscopy and in the cases of 2 and 3 , also by X-ray analysis. Compounds 2 and 3 adopted C i - anti -folded conformations with 53.0 and 28.8 folding dihedrals between pairs of benzene rings of tricyclic moieties. The central C 9 C 9 bond in 2 was essentially planar. A short C 9 C 10 distance of 2.81 Å in 2 indicated an intramolecular overcrowding e ff ect in the highly folded bistricyclic ethene. Semiempirical PM3 and AM1 calculations of the anti -folded, syn -folded, twisted and orthogonally twisted conformations of 2 and 4 indicated that anti -folded 2 and 4 were the most stable conformations with folding dihedrals of 48.7 and 45.0 , respectively at AM1. A DNMR spectroscopic study of E , Z -isomerizations and conformational inversions gave ∆ G c ‡ ( E Z ) = 99.6 kJ mol 1 (CDBr 3 ) and ∆ G c # (inversion) = 97.9 kJ mol 1 (hexachlorobutadiene) in 5 and ∆ G c ‡ (inversion) > 108 kJ mol 1 (benzophenone) in 3 . These high energy barriers were interpreted in terms of less overcrowded fjord regions in the anti -folded ground-state conformations

The Stereochemistry of Overcrowded Homemerous Bistrucyclic Aromatic Enes With Alkylidene Bridges

The objective of the research was to study the e ff ects of alkylidene bridges on the conformations and the conformational behaviour of overcrowded homomerous bistricyclic aromatic ethenes ( 1 ). The isopropylidene- bridged bistricyclic ethene 2 and 3 were synthesized by a reductive “dimerization” of 7 , using TiCl 4 –Zn–pyridine–THF. The methylene-bridged bistricyclic ethenes 4 – 6 were synthesized by LiAlH 4 –AlCl 3 –Et 2 O reductions of the corresponding bianthrones. The structures of 2 – 6 were established by 1 H- and 13 C-NMR spectroscopy and in the cases of 2 and 3 , also by X-ray analysis. Compounds 2 and 3 adopted C i - anti -folded conformations with 53.0 and 28.8 folding dihedrals between pairs of benzene rings of tricyclic moieties. The central C 9 C 9 bond in 2 was essentially planar. A short C 9 C 10 distance of 2.81 Å in 2 indicated an intramolecular overcrowding e ff ect in the highly folded bistricyclic ethene. Semiempirical PM3 and AM1 calculations of the anti -folded, syn -folded, twisted and orthogonally twisted conformations of 2 and 4 indicated that anti -folded 2 and 4 were the most stable conformations with folding dihedrals of 48.7 and 45.0 , respectively at AM1. A DNMR spectroscopic study of E , Z -isomerizations and conformational inversions gave ∆ G c ‡ ( E Z ) = 99.6 kJ mol 1 (CDBr 3 ) and ∆ G c # (inversion) = 97.9 kJ mol 1 (hexachlorobutadiene) in 5 and ∆ G c ‡ (inversion) > 108 kJ mol 1 (benzophenone) in 3 . These high energy barriers were interpreted in terms of less overcrowded fjord regions in the anti -folded ground-state conformations