Dynamic chirality in selected diaryl methane containing drugs. An exploratory ab initio conformational study

The complementarity of MO-and-State and VB correlation diagrams is illustrated by the study of very different reactions. Extended basis ab initio SCF+CI calculations are compared with diabatic and adiabatic VB results for the system Na×+HF→ NaF + H. The efficiency of the VB approach, as well for a qualitative understanding of the reaction mechanism as for obtaining accurate data is outlined. The second example deals with the study of oxygen transfer from Fe(IV)-oxo porphyrins to ethylene yielding ethyleneoxide. The radical character of the reaction is emphasized on the ground of qualitative VB considerations. The inherent complementarity of both approaches is discussed throughout.

Hydride abstraction of methylamine with Cu +( 1S) in the gas phase: A density functional theory study

We present a study of anionic states of halocamphor molecules, in which we characterize mechanisms that should produce electron circular dichroism by chiral molecules. We evaluate the electronic cross section for elastic scattering for the 3-bromocamphor, the 3-iodocamphor and the 10-iodocamphor. The results show resonances that give rise to well known spin polarized electron transmission and dissociation asymmetries, which have been observed experimentally but not fully understood. We also presented a developed model for the electron scattering problem accounting for the spin-orbit interaction. We predicted the transmission and dissociation asymmetries for the halocamphor molecules, obtaining clarifying results. We show that the resonance energy, the lifetime, the occupied orbital character, and the potential energy surface topology are fundamental ingredients in the halocamphor chiral sensitivity. This study is an important contribution towards understanding the chiral selectivity in the biomolecules, an interesting problem for the scientific community.

An exploratory study of side-chain–backbone interaction in selected conformations of N-acetyl-l-glutamate-N-methylamide. An ab initio study

Distance geometry and molecular dynamics simulation techniques were compared in their ability to search the conformational potential energy surface of β‐cyclodextrin. Structures generated by the DISGEO program were minimized using three different atomic point charge sets. Some of these structures were used as starting points for molecular dynamics simulation in vacuo at 298K. The distance geometry results showed that the global features of the conformational potential energy surface were generally independent of the point charge set. The distance geometry technique was able to find structures of lower energy than those obtained by direct minimization of the X‐ray or neutron diffraction structures. However, the molecular dynamics simulation technique was consistently able to find structures of lower energy than those generated by distance geometry. Root mean square fit of the trajectory structures to the starting structure showed that the simulation allowed the molecule to explore regions of the potential energy surface in the neighborhood of the starting structure. Both the distance geometry and molecular dynamics simulation techniques showed that β‐cyclodextrin can adopt a wide range of conformations in the gas phase and that these conformations are much less symmetrical than the crystalline structure.

Surface modification by substitution: Changing topology of conformational potential energy surfaces

Stereoelectronic effects and dynamic chirality in ethyl nitrite (Et-ONO) computed at the HF and DFT levels of theory

Predicting the three-dimensional structure of a protein from its amino acid sequence requires a complete understanding of the molecular forces that influences the protein folding process. Each possible conformation has its corresponding potential energy, which characterizes its thermodynamic stability. This is needed to identify the primary intra- and inter-molecular interactions, so that we can reduce the dimensionality of the problem, and create a relatively simple representation of the system. Investigating this problem using quantum chemical methods produces accurate results; however, this also entails large computational resources. In this study, an improved two-rotor potential energy function is proposed to represent the backbone interactions in amino acids through a linear combination of a Fourier series and a mixture of Gaussian functions. This function is applied to approximate the 20 amino acid diamide Ramachandran-type PESs, and results yielded an average RMSE of 2.36 kJ mol−1, which suggest that the mathematical model precisely captures the general topology of the conformational potential energy surface. Furthermore, this paper provides insights on the conformational preferences of amino acid diamides through local minima geometries and energy ranges, using the improved mathematical model. The proposed mathematical model presents a simpler representation that attempts to provide a framework on building polypeptide models from individual amino acid functions, and consequently, a novel method for rapid but accurate evaluation of potential energies for biomolecular simulations.

Generation and analysis of the conformational potential energy surfaces of N-acetyl- N-methyl- l-alanine- N′-methylamide. An exploratory ab initio study

Ab initio simulations have been performed to study the structure, energetics and stability of several plausible stacking sequences in graphite. These calculations suggest that in addition to the standard structures, graphite can also exist in AA-simple hexagonal, AB-orthorhombic and ABC-hexagonal type stacking. The free energy difference between these structures is very small (∼1 meV/atom), and hence all the structures can coexist from purely energetic considerations. Calculated x-ray diffraction patterns are similar to those of the standard structures for 2θ ⩽ 70°. Shear elastic constant C44 is negative in AA-simple hexagonal, AB-orthorhombic and ABC-hexagonal structures, suggesting that these structures are mechanically unstable. Phonon dispersions show that the frequencies of some modes along the Γ–A direction in the Brillouin zone are imaginary in all of the new structures, implying that these structures are dynamically unstable. Incorporation of zero point vibrational energy via the quasi-harmonic approximation does not result in the restoration of dynamical stability. Potential energy surfaces for the unstable normal modes are seen to have the topography of a potential hill for all the new structures, confirming that all of the new structures are inherently unstable. The fact that the potential energy surface is not in the form of a double well implies that the structures are linearly as well as globally unstable.

By analyzing the dynamics of model potential energy surfaces we systematically investigate the processes involved in passing from a high energy state to the global minimum and how the probability of reaching the global minimum depends upon the topography and topology of the potential energy surface (PES). Relaxation to the global minimum is easiest for PES’s consisting of a single funnel (a set of convergent pathways which lead to the global minimum) with low barriers and a significant potential energy gradient towards the global minimum. The presence of additional funnels on the surface can severely reduce the rate of relaxation to the global minimum. Such secondary funnels act most efficiently as kinetic traps when they terminate at a low energy minimum, have a steep potential energy gradient and are wide (i.e., have a large configurational entropy) compared to the primary funnel. Indeed, it is even possible to construct PES’s for which the system relaxes to the minimum at the bottom of a secondary funnel rather than the global minimum and then remains in this metastable state over a long time scale. Our results for these model PES’s are discussed in the context of theoretical and experimental knowledge of the dynamics of proteins, clusters, and glasses.

In this work we have theoretically studied the splittings experimentally observed in 5-methyl tropolone in the first excited singlet state, S1. Tropolone shows a vibrational level splitting due to delocalization of the wave function over the symmetric potential energy double well in the proton-transfer coordinate. This splitting dramatically decreases when asymmetry is introduced. However, a noticeable splitting is observed in 5-methyltropolone internal rotational levels indicating a coupling between methyl internal rotational and proton-transfer degrees of freedom. We have developed a reduced-dimensionality model for the potential energy surface (PES), which maintains the main characteristics of the molecule and that can be fitted to electronic structure calculations. For this PES we have calculated stationary wave functions using a full quantum method. We have performed test calculations using different energy barrier heights in order to observe the splitting behavior for this kind of molecules. In order to fit our PES to the real system surface we have also performed an extensive set of ab initio calculations in the S1 state using different methods. Finally we present a discussion about such electronic calculations, showing the present difficulties to obtain excited state potential energy surfaces with great accuracy beyond the Franck–Condon vertical excitation region.

The conformational analysis of the HIV-1 reverse transcriptase inhibitor, (+)-(s)-4,5,6,7-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)imidazol[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione or 9-Cl TIBO, has been investigated using high level of calculations, ab initio, and DFT theory. The potential energy surface as the function of two important rotatable dihedral angles of the 9-Cl TIBO side chain was generated by the Hartree−Fock method at the 3-21G basis set. Eight pronounced local minima were found to exist within an energy difference of less than 10 kJ/mol. The energy barriers between the different local minima are lower than 15 kJ/mol. A second derivative (frequency) analysis showed that all conformers are stable at this level of theory. These structures were used as starting points for full geometry optimizations at the HF/6-31G** and B3LYP/6-31G** levels of theory to obtain the absolute geometries and structural information. The comparisons of calculated conformers with the bound conformer in th...

Chirality and activity relationships are paramount to pharmaceutical design and synthesis. Generally, point chirality (enantiomeric R and S configurations) is emphasized most in molecules and drugs; however, axis chirality (present when structures adopt conformations with asymmetrical distributions of electron density) must also be considered as a stereogenic unit of interest. Together, stereogenic units and optical isomerism describe the chiral disposition of electron density about nuclei. In this essence, different components of chirality are always present in molecular systems. In assessing the different chiral parameters of pharmaceuticals, the cardiovascular drug carvedilol serves as an ideal example because both enantiomers produce different physiological effects. In the current study, R- and S-4-(2-hydroxypropoxy)carbazol (carvedilol fragment A), along with prochiral and chiral analogues, are studied to investigate the chiral components of carvedilol. Further, the effects of substituent variation about a stereocenter are investigated and discussed using conformational energy as a surrogate of structure (based on the fact that energy is a function of molecular spatial orientation) to determine the energetic equivalency of prochiral and chiral structures. Multidimensional conformational analysis (MDCA) was performed on selected structures using restricted Hartree−Fock (RHF) and density functional theory (DFT with the Becke 3LYP hybrid exchange-correlation functional) molecular orbital computations to elucidate the structural and energetic basis of chirality. The analogues had the following prochiral and chiral structures: R−CH2−OH, [R] and [S] R−CHMe−OH, and R−CMe2−OH, with substituent R being either MeCH2- or ArCH2-, where Ar is the carbazole moiety. Potential energy curves (PECs) of torsional angles χ1, χ2, χ3, and χ10 for R- and S-4-(2-hydroxypropoxy)carbazol verified that all torsional angles are indeed enantiomeric. Correspondingly, the potential energy hypersurfaces (PEHSs) of R- and S-4-(2-hydroxypropoxy)carbazol were also enantiomeric, as illustrated with optimizations of conformational minima; converged minima occurred in equivalent point chiral and axis chiral pairs. Similarly to R- and S-4-(2-hydroxypropoxy)carbazol, achiral and chiral analogues analyzed by MDCA displayed axis chirality while chiral structures displayed both axis and point chirality. As such, the presence of point and axis chirality in molecular systems allows predictions to be made concerning the orientations of viable conformations of a respective PEHS. Further, the data indicate that chirality induced by an asymmetric distribution of electron density (axis chirality) is always present whenever a structure adopts asymmetric conformations. Like enantiomers of point chirality, axis chiral conformers also occur in pairs. Potential energy surfaces (PESs) were generated about the prochiral and chiral centers for all structures at the RHF/3-21G level of theory and used to test the equivalency of conformational energy between sufficiently constructed achiral and chiral structures. It is hypothesized that, with regard to conformational energy, the addition of two chiral enantiomers minus the addition of two achiral structures will give a zero result (assuming the only structural differences occur at the stereocenters). The combination of prochiral and chiral potential energy surfaces, according to an equation describing two consecutive and concerted methyl substitutions, gave a practically flat, virtually zero surface, indicating that sufficiently constructed achiral structures are energetically equivalent to chiral enantiomers. Thus, solely on the basis of molecular structure, chiral properties such as energy, number of converged conformers in a PEHS, conformations of corresponding point chiral and axis chiral pairs, and intramolecular interactions can be predicted from achiral structures. It remains to be seen how this can be utilized in drug research and development.

P⋯N type pnicogen bonding in phosphorus trichloride–pyridine adduct: A matrix isolation infrared, DFT and ab initio study