An approach has been developed for calculating the vibrational spectra of linear methine-bridged tetrapyrroles constituting the chromophoric sites of various photoreceptor proteins. Using Pulay's scaling procedure (Pulay, P.; Fogarasi, G.; Pongor, G.; Boggs, J. E.; Vargha, A. J. Am. Chem. Soc. 1983, 105, 7037), scaling factors were determined for a set of 10 training molecules which mimic structural elements of the tetrapyrrole target molecules. Geometries and force fields were calculated at three theoretical levels, i.e., by the Hartree−Fock (HF), second-order Møller−Plesset perturbation (MP2), and B3LYP density functional theory methods using 6-31G* basis sets. A global optimization yielded sets of 14, 11, and 10 scaling factors for HF, MP2, and B3LYP, respectively. B3LYP provided the best results both with regard to the geometries and the vibrational frequencies. The root-mean-square deviation for the calculated frequencies was 11 cm-1 for B3LYP as compared to 13 and 17 cm-1 for HF and MP2, respectively. On the basis of the Morse model for an anharmonic oscillator, an expression was derived for correcting scaling factors for the anharmonicity changes in (deuterio) isotopomers. The effects of hydrogen bonding interactions via N−H···OC bonds on the structures and vibrational spectra were studied in the case of maleimide. For the N−H stretching, deformation, and out-of-plane wagging vibrations, modifications of the scaling factors are required in order to reproduce the vibrational spectra of the hydrogen bonded dimer. The IR and Raman intensities calculated by the B3LYP method were found to agree well with experimental spectra. For the Raman intensities, a fourth-order differentiation formula was derived for the numerically accurate calculation of polarizability derivatives with respect to Cartesian displacements, by using the finite field method.

The resonance Raman (RR) spectra of monomeric 3,3‘,4,4‘,5,5‘-hexamethylpyrromethene (HMPM) were measured upon excitation in resonance with the strong 436 nm absorption band. The experimental spectra were analyzed by comparison with calculated RR spectra that were obtained on the basis of scaled quantum chemical force fields in combination with the transform theory. The ground-state structure and force field of HMPM were calculated by density functional theory (DFT) using the B3LYP exchange functional and the 6-31G* basis set. The monomeric HMPM adopts a planar structure in contrast to HMPM dimers in which the intermolecular hydrogen-bonding interactions induce a slight torsion of the methine bridges as revealed by both the experimental and the calculated structures. The force fields were scaled by using a global set of scaling factors determined previously (Magdó, I.; Németh, K.; Mark, F.; Hildebrandt, P.; Schaffner, K. J. Phys. Chem. A 1999, 103, 289). To account for the effect of the intramolecular hydrogen bond between the pyrrolic N−H group and the pyrroleninic nitrogen in the monomeric HMPM, only the scaling factor for the N−H in-plane bending force constant required a slight adjustment. Electronic transitions were calculated by means of CNDO/S, Hartree−Fock single configuration interaction (HF-CIS), and time-dependent DFT, which all predict one strong and one or two adjacent weak transitions for the lowest electronic excitations. This pattern is in line with band fitting analyses of the 436 nm absorption band. The best agreement in excitation energies was obtained by time-dependent DFT calculations. Excited-state displacements as required for evaluating RR intensities were determined for the lowest excited singlet state S1 using the equilibrium geometries optimized for the ground and excited states by means of the HF and HF-CIS methods, respectively. For the second lowest excited state (S2), only an approximate equilibrium geometry could be used for determining the excited-state displacements as the S2 state became quasi-isoenergetic with the S1 state during the geometry optimization. Employing the transform theory, RR spectra were calculated for resonance enhancement via the S1 and S2 states. The experimental RR spectrum of HMPM excited at 413 nm agrees well with the calculated S1-RR spectrum, allowing a plausible and consistent vibrational assignment for most of the observed bands of HMPM and its isotopomer deuterated at the pyrrolic nitrogen. The root-mean-square deviations between the experimental and calculated frequencies are 7 and 5 cm-1 for nondeuterated and deuterated HMPM, respectively. Experimental RR intensities and their dependence on the excitation wavelength are reproduced in a semiquantitative manner. The only significant exceptions refer to the CC stretching and CH rocking modes of the methine bridge, ν21 and ν49. On one hand, these discrepancies may reflect intrinsic deficiencies of the HF/HF-CIS method in calculating excited-state displacements. On the other hand, the unique deviation o...

(4-Benzylpiperidine-1-yl)-(6-hydroxy-1H-indole-2-yl)-methanone (6a) derived from (E)-1-(4-benzylpiperidin-1-yl)-3-(4-hydroxy-phenyl)-propenone (5) was identified as a potent NR2B subunit-selective antagonist of the NMDA receptor. To establish the structure-activity relationship (SAR) and to attempt the improvement of the ADME properties of the lead, a series of compounds were prepared and tested. Several derivatives showed low nanomolar activity both in the binding and in the functional assay. In a formalin-induced hyperalgesia model in mice, 6a and (4-benzylpiperidine-1-yl)-[5(6)-hydroxy-1H-benzimidazol-2-yl]-methanone (60a) were as active as besonprodil (2) after oral administration. A CoMSIA model was developed based on binding data of a series of indole- and benzimidazole-2-carboxamides.

This paper reports the application of a scaled ab initio calculated harmonic force field to predict the frequencies, infrared intensities, Raman intensities, and depolarization ratios of benzofuran, benzothiophene, indole, benzothiazole, and benzoxazole. The theoretical calculations were made using the Hartree–Fock HF/3-21G* and HF/6-31G* basis sets and density-functional theory (DFT)B3-LYP/6-31G* levels. The equilibrium calculated force constants are scaled according to the method of Pulay and compared with the experimentally determined frequencies, intensities, and depolarization ratios to assess the accuracy and fit of the theoretical calculation. Methods for quantitative comparison of intensities were developed. The double numerical differentiation algorithm of Komornicki and McIver was analyzed and used to calculate the Raman intensities for the (DFT)B3-LYP/6-31G* model. The (DFT)B3-LYP/6-31G* model is approaching the harmonic limit in the planar and nonplanar refinement of these bicyclics with wave number fits of 5 and 4 cm−1, respectively. It reduces the need for scale factors and increases their transfer accuracy, largely because the scale factors values cluster near unity. The Komornicki and McIver algorithm is still a viable method for calculating Raman intensity information for methods that do not have analytic routines programmed. The main shortcoming to this method may lie in the tighter self-consistent field (SCF) convergence criterion possibly needed to calculate Raman intensities for the totally symmetric modes of large molecules. The (DFT)B3-LYP/6-31G* model was superior for calculating the planar intensities, but equal to the HF methods for predicting the nonplanar intensities.