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The valence and core electronic structure of nicotine, nicotinic acid, and nicotinamide have been studied by photoelectron and soft X-ray absorption spectroscopy, supported by theoretical calculations, which take into account conformational isomerism. The core-level photoionization spectra of all molecules have been assigned, and theory indicates that the effects of conformational differences are small, generally less than the natural line widths of the core ionic states. However, in the case of nicotinamide, the theoretical valence ionization potentials of cis and trans conformers differ significantly in the outer valence space, and the experimental spectrum is in agreement with the calculated outer valence cis conformer spectrum. In addition, the C, N, and O K edge near-edge absorption fine structure spectra are reported and interpreted by comparison with reference compounds. We find evidence at the N and O K edges of interaction between the delocalized orbitals of the pyridine ring and the substituents for nicotinic acid and nicotinamide. The strength of the interaction varies because the first is planar, while the second is twisted, reducing the extent of orbital mixing.

Dacomitinib (PF-00299804) was recently approved by the Food and Drug Administration (FDA) as a tyrosine kinase inhibitor (TKI). Unfortunately, side effects and disease resistance eventually result from its use. Off-target effects in some kinase inhibitors have arisen from drug conformational plasticity; however, the conformational states of Dacomitinib in solution are presently unknown. To fill this gap, we have used computational chemistry to explore optimized molecular geometry, properties, and ultraviolet-visible (UV-Vis) absorption spectra of Dacomitinib in dimethyl sulfoxide (DMSO) solution. Potential energy scans led to the discovery of two planar and two twisted conformers of Dacomitinib. The simulated UV-Vis spectral signatures of the planar conformers reproduced the two experimental spectral bands at 275 and 343 nm in solution. It was further discovered that Dacomitinib forms conformers through its three flexible linkers of two C-NH-C bridges, which control the orientations of the 3-chloro-4-fluoroaniline ring (Ring C) and the quinazoline ring (Rings A and B) and the 4-piperidin-1-yl-buten-2-nal side chain, and one CO -C local bridge which controls the methoxy group locally. When in isolation, these flexible linkers form close hexagon and pentagon loops through strong intramolecular hydrogen bonding so that the "planar" conformers Daco-P1 and Daco-P2 are more stable in isolation. Such flexibility of the ligand and its ability to dock and bind with protein also depend on their interaction with the environment, in addition to their energy and spectra in isolation. However, an accurate quantum mechanical study on drug/ligand conformers in isolation provides necessary reference information for the ability to form a complex with proteins.

Intramolecular hydrogen bonding of 2-methoxyphenol (2-MP, guaiacol) is studied using NMR spectroscopy combined with quantum mechanical density functional theory (DFT) calculations. The hydrogen bonding of OH⋯O and HO⋯H is switched on in the conformers of anti–syn (AS, 99.64% dominance) and anti–gauche (AG), respectively, with respect to the anti–anti (AA) conformer (without either such hydrogen bonding interactions). It confirms that the 13C and 1H NMR chemical shift of AS dominates the measured NMR spectra, as the AS conformer reproduces the measurements in CDCl3 solvent (RMSD of 1.86ppm for 13C NMR and of 0.27ppm for 1H NMR). The chemical shift of hydroxyl H(1) at 5.66 pm is identified as the fingerprint of the OH(1)⋯OCH3 hydrogen bonding in AS, as it exhibits a significant deshielding from H(1) of AA (4.24ppm) and H(1) of AG (4.38ppm) without such OH(1)⋯OCH3 hydrogen bonding. The AG conformer (C1 point group symmetry) possesses a less strong hydrogen bonding of HO⋯HCH2O, with the methoxyl group out of the aromatic phenol plane. The substituent effect of AG due to the resonance interaction of methoxyl being out of plane in a concentrated solution shifts the ortho- and para-aromatic carbons, C(3)/C(5), of the AG to ~125.05/125.44ppm from the corresponding carbons in AS at 108.81/121.60ppm. The hydrogen bonding exhibits inwards reduction of IR frequency regions of AS and AG from AA. Finally, energy decomposition analysis (EDA) indicates that there is a steric energy of 45.01kcal mol−1 between the AS and AG when different intramolecular hydrogen bonding is switched on.

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