Calculations Of Rotational Barriers Research Articles

Synthesis, characterization and SAR studies of bis(imino)pyridines as antioxidants, acetylcholinesterase inhibitors and antimicrobial agents

In this study we synthesized a series of sixteen bis(imino)pyridines (BIPs) starting from 2,6-diaminopyridine and various aromatic aldehydes, and evaluated their antioxidant, antibacterial, antifungal and acetylcholinesterase (AChE) inhibitory activity. The chemical structures were elucidated by FTIR, elemental analysis, ESR and HRMS. 1H and 13C NMR spectra couldn’t be acquired due to the formation of stable, carbon-centered radical cations in a solution, as confirmed by ESR spectroscopy and DFT calculations. The in vitro antioxidant potency was evaluated using four assays: free radical scavenging activity (DPPH and ABTS), reducing power and total antioxidant capacity assay. BIPs demonstrated excellent antioxidant properties, and two derivatives proved to be more potent than reference antioxidants (ascorbic acid and Trolox) in all assays. DFT calculations on ωB97XD/6-311++g(d,p) level of theory provided valuable insights into the radical scavenging mechanism of BIPs. For hydroxyl-substituted BIPs, hydrogen atom transfer (HAT) is a predominant mechanism, while the single electron transfer coupled with proton transfer (SET-PT) governs the antioxidant activity of other derivatives. Intramolecular hydrogen bonding (IHB) plays an important role in the mechanism of antioxidant activity as revealed by noncovalent interaction analysis and rotational barrier calculations. The spin density of radical cations is localized on carbon atoms of a pyridine ring, which corroborates with g-factors and multiplicity obtained from ESR analysis. The most potent BIP exhibited moderate inhibitory activity toward AChE (IC50 = 20 ± 4 μM), while molecular docking suggested binding at the peripheral anionic site of AChE with the MMFF94 binding enthalpy of −43.4 kcal/mol. Moderate in vitro antimicrobial activity of BIPs have been determined against several pathogenic bacterial strains: Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus and clinical isolate of methicillin resistant S. aureus (MRSA). The antifungal activity of BIPs toward Candida albicans was also confirmed. The similarity ensemble approach combined with molecular docking suggested leucyl aminopeptidase as the probable antimicrobial target for the three most potent BIP derivatives.

Calculation of Rotational Barriers of 4-Acyloxy-4’-N-N-Butylcarbamyloxy-Biphenyls by Molecular Calculation and Linear Free Energy Relationships

Rotational barriers of ten 4-acyloxy-4'-N-n-butylcarbamyloxy-biphenyls were calculated by density functional theory. Linear free energy relationships between rotational barriers and reduced mass existed in these compounds...

Reversible Control of Crystalline Rotors by Squeezing Their Hydrogen Bond Cloud Across a Halogen Bond-Mediated Phase Transition

We report on a crystalline rotor that undergoes a reversible phase transition at 145 K. Variable-temperature X-ray and 1H spin–lattice relaxation experiments, and calculations of rotational barriers, provide a description (i) of the way in which the rotators’ dynamics changes back and forth at the onset of the phase transition and (ii) of the mechanism responsible for the abrupt switching of the crystalline rotors from a very low-energy 4-fold degenerate equilibrium state, in which the rotation is ultrafast (9.6 GHz at 145 K), to a single higher-energy state associated with a slower motion (2.3 GHz at 145 K). Our results provide evidence that the reversible change observed in the rotational barriers at the transition is due to a cooperative modulation of the C–Hrotator···Istator hydrogen bond cloud across a C–Istator···Istator–C halogen bond-mediated phase transition. In addition, we report evidence for second-harmonic generation from this material, thereby confirming with a second example the benefit of ...

Solid state ¹H spin-lattice relaxation and isolated-molecule and cluster electronic structure calculations in organic molecular solids: the relationship between structure and methyl group and t-butyl group rotation.

We report ab initio density functional theory electronic structure calculations of rotational barriers for t-butyl groups and their constituent methyl groups both in the isolated molecules and in central molecules in clusters built from the X-ray structure in four t-butyl aromatic compounds. The X-ray structures have been reported previously. We also report and interpret the temperature dependence of the solid state (1)H nuclear magnetic resonance spin-lattice relaxation rate at 8.50, 22.5, and 53.0 MHz in one of the four compounds. Such experiments for the other three have been reported previously. We compare the computed barriers for methyl group and t-butyl group rotation in a central target molecule in the cluster with the activation energies determined from fitting the (1)H NMR spin-lattice relaxation data. We formulate a dynamical model for the superposition of t-butyl group rotation and the rotation of the t-butyl group's constituent methyl groups. The four compounds are 2,7-di-t-butylpyrene, 1,4-di-t-butylbenzene, 2,6-di-t-butylnaphthalene, and 3-t-butylchrysene. We comment on the unusual ground state orientation of the t-butyl groups in the crystal of the pyrene and we comment on the unusually high rotational barrier of these t-butyl groups.

Accurate rotational barrier calculations with diffusion quantum Monte Carlo

Accurate quantum Monte Carlo, MP2, coupled cluster, and DFT calculations of rotational barriers of several small molecules are presented. With the diffusion quantum Monte Carlo method (DMC) excellent agreement with experimental barriers is obtained except for the gauche–gauche barriers of n-butane and ethylmethylether. It is argued that these two experimental values might be erroneous. Additionally, barriers calculated with the more efficient variational quantum Monte Carlo method (VMC) are presented. The VMC barriers are less accurate than the DMC results, but it is demonstrated that accurate barriers can be obtained with sophisticated Jastrow correlation functions.

Crystalline Arrays of Pairs of Molecular Rotors: Correlated Motion, Rotational Barriers, and Space-Inversion Symmetry Breaking Due to Conformational Mutations

The rod-like molecule bis((4-(4-pyridyl)ethynyl)bicyclo[2.2.2]oct-1-yl)buta-1,3-diyne, 1, contains two 1,4-bis(ethynyl)bicyclo[2.2.2]octane (BCO) chiral rotators linked by a diyne fragment and self-assembles in a one-dimensional, monoclinic C2/c centrosymmetric structure where two equilibrium positions with large occupancy imbalance (88% versus 12%) are identified on a single rotor site. Combining variable-temperature (70-300 K) proton spin-lattice relaxation, (1)H T1(-1), at two different (1)H Larmor frequencies (55 and 210 MHz) and DFT calculations of rotational barriers, we were able to assign two types of Brownian rotators with different activation energies, 1.85 and 6.1 kcal mol(-1), to the two (1)H spin-lattice relaxation processes on the single rotor site. On the basis of DFT calculations, the low-energy process has been assigned to adjacent rotors in a well-correlated synchronous motion, whereas the high-energy process is the manifestation of an abrupt change in their kinematics once two blades of adjacent rotors are seen to rub together. Although crystals of 1 should be second harmonic inactive, a large second-order optical response is recorded when the electric field oscillates in a direction parallel to the unique rotor axle director. We conclude that conformational mutations by torsional interconversion of the three blades of the BCO units break space-inversion symmetry in sequences of mutamers in dynamic equilibrium in the crystal in domains at a mesoscopic scale comparable with the wavelength of light used. A control experiment was performed with a crystalline film of a similar tetrayne molecule, 1,4-bis(3-((trimethylsilyl)ethynyl)bicyclo[1.1.1]pent-1-yl)buta-1,3-diyne, whose bicyclopentane units can rotate but are achiral and produce no second-order optical response.

Theoretical studies of phenol disubstituted porphyrins

Calculations on neutral and oxidized phenol disubstituted porphyrins were performed. Two electron oxidation may be accompanied by loss of one or more protons at either the central NH positions or the outer OH positions. These latter oxidized and deprotonated structures may be stabilized by quinonelike forms. Our calculations support the idea that quinonelike structures are important, based both upon energetic and rotational barrier calculations.

Steric trigger as a mechanism for CB1 cannabinoid receptor activation.

To determine the moiety that behaves as the steric trigger to activate the CB(1) cannabinoid receptor, conformational properties of the nonclassical cannabinoid CP55244, one of the most potent CB(1) receptor agonists, were characterized by conformational analysis, rotational barrier calculations, and molecular dynamics (MD) simulations. It was shown from the present MD simulations that the torsion angles phi1 and phi4 of the C3 side chain showed the most dramatic change when compared with the ground-state receptor-bound conformation, indicating that rotation around these torsion angles is responsible for releasing the ligand strain energy. Multiple stages would be involved in the ligand conformational change. As a molecular mechanism for the ligand-induced CB(1) receptor conformational change, we propose that the C3 side chain serves as the steric trigger, while the ACD-ring moiety of CP55244 serves as the plug. Steric clash with helices within the binding pocket would induce microconformational adaptation within the protein. This mechanism would suggest that rotational flexibility in a ligand may be as important a determinant of agonist activity as the pharmacophoric elements that can be identified.

Some New exo,exo-Bis(isodicyclopentadienyl)titanium and -zirconium Dichloride Derivatives: Synthesis, Characterization, and Evaluation as Propene Polymerization Catalysts

Exo,exo derivatives of the efficient catalyst precursors (diisodicyclopentadienyl)titanium and -zirconium dichloride substituted at the central position have been synthesized. These compounds have been characterized by solution NMR measurements, which also permitted the calculation of rotational barriers. The solid-state structures of exo,exo-bis(3-diphenylphosphinoisodicyclopentadienyl)titanium and -zirconium dichloride were determined by X-ray crystallography. Unfortunately, after activation by methylalumoxane, these complexes are shown to serve as poor catalysts for the polymerization of propene.

Ab initio calculation of the thermochemical properties of polysulphanes (H 2S n)

Thermochemical properties of gaseous polysulphanes (H 2S n ) were calculated using the G2 and CBS-Q ab initio theoretical methods. The temperature dependence of the heat capacities and entropies for the polysulphanes are computed between 300 and 1000 K. The difference between the available experimental heat capacity of disulphane (298 K) and the calculated one is found to be quite small (0.7 cal/mol K). The latter is indicative of hindered internal rotation in polysulphanes. Ab initio calculations of rotational barriers in polysulphanes show that the relatively high barriers of internal rotations can be due to the interplay of attractive stabilization, π-character of the S–S bonds (due to hyperconjugation effects) and the participation of the sulphur 3d orbitals in bonding.

Comparison of pi-Bond Strengths in M-E (M = B, Al, Ga; E = O, N, S) Compounds. Ab Initio Calculation of Rotational Barriers.

Results of ab initio calculations of the electronic structure of compounds of the type R(2)MER'(x) and R(2)MEMR'(2) with R = H, Me, M = Al, Ga, and E = O, N, S are reported at the Hartree-Fock level with split-valence, polarization basis sets for all atoms except hydrogen where a split-valence basis set is used. Full optimizations for the equilibrium geometry and partial optimization at constrained rotational transition states have been performed to evaluate the barriers to rotation as a measure of the pi interactions in these compounds. We conclude that, although important for determining the final conformational equilibrium geometries, pi interactions are weak in these compounds as the rotational barriers are smaller than that for ethylene by 1 or 2 orders of magnitude.

Conformational energetics of sugar thioureas and synthesis of glycosyl thioureido sugars

The rate and outcome of the reaction of 6-deoxy-6-isothiocyanatoaldopyranoside derivatives with ammonia depend strongly on the nature of the hydroxyl protecting groups and solvent. In pyridine as solvent, the expected thioureas are obtained as the sole reaction products. A marked preference for the E configuration at the sugarNHC(S) bond is observed for silylated as compared to acetylated derivatives. Rotational barrier calculations, temperature-induced NH shifts, and other NMR data indicate a strict relationship between the E rotamer population and the existence of an intramolecular NH…O-5 hydrogen bond that fits a pseudo γ-turn. Competition between inter- and intra-molecular hydrogen bonding rather than steric factors probably explain these results. Acetal and trimethylsilyl ether derivatives have been further used in the preparation of fully unprotected derivatives. The procedure has been extended to the first synthesis of (1→6)-linked glycosyl phosphosugar analogues incorporating thiourea bridges as phosphate surrogates.

Calculation of rotational barriers in amorphous polymers

AbstractThe Monte Carlo method was used for generation of amorphous polyethylene configurations on a diamond lattice. Chain building was performed on the tetrahedral lattice of edges 36, 62 and 43 Å with periodic boundary conditions imposed.32 chains were generated, each with a length of 100 CH2‐groups (resulting density = 0.81 g·cm−3). Small spherical volumes with a radius of 10 Å were chosen at random from the total volume for the calculation of rotational barriers. The rotating bond was chosen to be close to the center of this sphere. We employed the method of molecular mechanics in order to calculate the rotational barriers. The calculation was made for 578 rotating bonds and the obtained distribution of rotational barriers is approximated by the corresponding Γ‐distribution.

A study by Raman spectroscopy and the semiempirical AM1 method on several 1,2-dihydroxybenzene solutions

The Raman spectra of 1,2-dihydroxybenzene (catechol) dissolved in six different compounds have been obtained and, on the basis of frequencies and depolarization ratios, the relevant structure of the solute has been inferred in every case. In addition, rotational barrier calculations using the AMI semiempirical method have been performed on several catechol—solvent systems. The theoretical results were in accord with experimental data and were related to structural properties of the solvents.

Normal coordinate and rotational barrier calculations on 1,2-dihydroxybenzene

The infrared and Raman spectra of solid catechol were obtained and a new assignment of the observed frequencies is proposed on the basis of depolarization ratios measured from aqueous solution, force field and normal coordinate calculations, factor group analysis and previously reported data. In addition, a conformational study involving rotational barrier calculations was performed by using the AM1 semi-empirical method in order to establish the minimum energy geometry. The MNDO force field at this point was scaled and a good description of the vibrational specta was obtained.

On the feasibility of bond pair calculations of rotational barriers: a preliminary investigation

The feasibility of the previously proposed bond pair approximation is examined for rotational barriers upon expansion of the penetration energy to order S2. Ab initio non-orthogonal bond orbital calculations on five single rotor XHmYHn molecules show that many-body purely electrostatic effects are unimportant but three-body non-additivity due to overlap is non-negligible for quantitative predictions.

CNDO/2 calculations of rotational barriers in N.N-dimethylamino-azines: Lineshape study of the barrier in 3-dimethylamino-1,2,4-triazine

3-Dimethylamino-1,2,4-triazine has been prepared and the hindered rotation around the exocyclic C-N bond has been studied by a complete lineshape method. CNDO/2 calculations on dimethylamino derivatives of pyridine, pyrimidine, 1,2,4-triazine and 1,3,5-triazine have been performed, and it is found that the calculations satisfactorily reproduce the experimental data. The barrier heights are also discussed in terms of total and π-charge densities obtained from CNDO/2 calculations.