Dissected Nucleus-Independent Chemical Shift Analysis of π-Aromaticity and Antiaromaticity.

This article describes the extension of the Merck Molecular Force Field (MMFF94) to a much broader range of organic systems. It also describes a preliminary parameterization of MMFF94 for the hydronium and hydroxide ions and for various halide, alkalai, and alkalai earth ions as well as for such “protein” metals as Zn2+, Ca2+, Cu2+, Cu+, Fe2+, and Fe3+. The extension employed computational data on charge distributions, molecular geometries, and conformational energies for a series of oxysulfur (particularly sulfonamide) and oxyphosphorous compounds and for a diverse set of small molecules and ions not covered in the core parameterization. It also employed experimental data for approximately 2800 good-quality structures extracted from the Cambridge Structural Database (CSD). Some of the additional computational data were used to extend the explicit parameterization of electrostatic interactions and to more widely define a useful additive approximation for the “bond polarity” parameters (bond charge increments) used in MMFF94. Both the experimental and computational data served to define reference bond lengths and angles that the extended force field uses in conjunction with force constants obtained from carefully calibrated empirical rules. The extended torsion parameters consist partly of explicit parameters derived to reproduce MP2/6-31G* conformational energies and partly of “default parameters” provided by empirical rules patterned after those used in DREIDING and UFF but calibrated, where possible, against computationally derived MMFF94 torsion parameters. Comparisons to experimental data show that MMFF94 reproduces crystallographic bond lengths and bond angles with relatively modest root mean square (rms) deviations of approx. 0.02 A and 2°, respectively. © John Wiley & Sons, Inc.

Merck molecular force field. V. Extension of MMFF94 using experimental data, additional computational data, and empirical rules

Ferroptosis is a form of regulated necrosis associated with the iron-dependent accumulation of lipid hydroperoxides that may play a key role in the pathogenesis of degenerative diseases in which lipid peroxidation has been implicated. High-throughput screening efforts have identified ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1) as potent inhibitors of ferroptosis − an activity that has been ascribed to their ability to slow the accumulation of lipid hydroperoxides. Herein we demonstrate that this activity likely derives from their reactivity as radical-trapping antioxidants (RTAs) rather than their potency as inhibitors of lipoxygenases. Although inhibited autoxidations of styrene revealed that Fer-1 and Lip-1 react roughly 10-fold more slowly with peroxyl radicals than reactions of α-tocopherol (α-TOH), they were significantly more reactive than α-TOH in phosphatidylcholine lipid bilayers − consistent with the greater potency of Fer-1 and Lip-1 relative to α-TOH as inhibitors of ferroptosis. None of ...

On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death.

There is a growing interest in organic compounds containing the difluoromethyl group, as it is considered a lipophilic hydrogen bond donor that may act as a bioisostere of hydroxyl, thiol, or amine groups. A series of difluoromethyl anisoles and thioanisoles was prepared and their druglike properties, hydrogen bonding, and lipophilicity were studied. The hydrogen bond acidity parameters A (0.085–0.126) were determined using Abraham’s solute 1H NMR analysis. It was found that the difluoromethyl group acts as a hydrogen bond donor on a scale similar to that of thiophenol, aniline, and amine groups but not as that of hydroxyl. Although difluoromethyl is considered a lipophilicity enhancing group, the range of the experimental Δlog P(water–octanol) values (log P(XCF2H) – log P(XCH3)) spanned from −0.1 to +0.4. For both parameters, a linear correlation was found between the measured values and Hammett σ constants. These results may aid in the rational design of drugs containing the difluoromethyl moiety.

Difluoromethyl Bioisostere: Examining the “Lipophilic Hydrogen Bond Donor” Concept

An integrated molecular graphics and computational chemistry framework is described which has been designed primarily to handle small molecules of up to 300 atoms. The system provides a means of integrating software from any source into a single framework. It is split into two functional subsystems. The first subsystem, called COSMIC. runs on low-cost, serial-linked colour graphics terminals and allows the user to prepare and examine structural data and to submit them for extensive computational chemistry. Links also allow access to databases, other modelling systems and user-written modules. Much of the output from COSMIC cannot be examined with low level graphics. A second subsystem, called ASTRAL, has been developed for the high-resolution Evans & Sutherland PS300 colour graphics terminal and is designed to manipulate complex display structures. The COSMIC minimisers, geometry investigators, molecular orbital displays, electrostatic isopotential generators and various interfaces and utilities are described.

Strategic approaches to drug design. I. An integrated software framework for molecular modelling.

It is shown that the difference in the 1H NMR chemical shift of a protic hydrogen in DMSO and CDCl3 solvents is directly related to the overall, or summation, hydrogen bond acidity for a wide range of solutes. This provides a new and direct method of measuring the hydrogen bond acidity. For 54 compounds, the observed shifts for 72 protic hydrogens could be correlated to the Abraham solute hydrogen bond acidity parameter, A, with a correlation coefficient squared, R2, of 0.938 and a standard deviation, SD, of 0.054 units in A. A training equation that used half the data could predict A values for the remaining data with an average error of 0.001 and a standard deviation, SD, of 0.053 units, thus demonstrating the predictive power of the method. Unlike any previous method for the determination of solute hydrogen bond acidities, the NMR method allows the determination of A values for individual protic hydrogens in multifunctional solutes.

NMR Method for the Determination of Solute Hydrogen Bond Acidity

Alternative methods of estimating atomic charges in haloalkanes are presented, derived from quantum mechanical and classical treatments. A scheme based on a breakdown of the transmission of charge by polar atoms into one-bond, two-bond, and three-bond additive contributions is given, in which the one-bond effect is proportional to the difference in the electronegativities of the bonded atoms, and the two- and three-bond effects functions of the atomic electronegativity and polarizability. Suitable developments of the basic scheme, including an iterative self-consistent process, give calculated dipole moments for a variety of haloalkanes in good agreement with the observed values. The atomic charges obtained by this scheme are compared with other estimates of these charges. They are similar to those derived from a simple LCAO–MO scheme but differ from those obtained by population analysis of more refined quantum mechanical calculations.

Approaches to charge calculations in molecular mechanics

The proton resonance spectra of a variety of condensed aromatic compounds including benzene, naphthalene, anthracene, phenanthrene, pyrene, acenaphthylene and triphenylene were obtained in dilute CDCl3 solution. Comparison of the proton chemical shifts obtained with previous literature data for CCl4 solution shows small but significant differences. A previous model (CHARGE6) for calculating the proton chemical shifts of aliphatic compounds was extended to aromatic compounds. This was achieved by including an automatic identification of both five- and six-membered aromatic rings based on atomic connectivities plus a dipole calculation of the aromatic ring current. The ring current intensity in the molecules was calculated by two alternative methods. a) The ring current intensity in the individual benzenoid rings was a function of the number of adjoining rings and b) the molecular ring current was proportional to the molecular area divided by the molecular perimeter. This, plus the inclusion of deshielding steric effects for the crowded protons in these molecules, gave a good account of the observed chemical shifts. The model was also applied successfully to the non-alternant hydrocarbons of fulvene and acenaphthylene and to the aliphatic protons near to and above the benzene ring in tricyclophane and [10]cyclophane.The Huckel calculation of the π electron densities in CHARGE6 was used to calculate the π electron densities in substituted benzenes. The π-inductive effect was used to simulate the effect of CX3 groups (X = H, Me, F) on the benzene ring. These together with the long range effects of the substituent groups identified previously allowed a precise calculation of the SCS of a variety of substituents on all the benzene ring protons.The model gives the first accurate calculation of the proton chemical shifts of condensed aromatic compounds and of the proton SCS in the benzene ring. For the data set of 55 proton chemical shifts spanning 3 ppm the rms error of the observed vs. calculated shifts was ca. 0.1 ppm. The model also allows the interpretation of the shifts in terms of the separate interactions calculated in the programme, i.e.
π electron densities and steric, anisotropic and electric field effects. Previous correlations of the proton SCS with π electron densities and substituent parameters are shown to be over simplified. The relative proportions of these different interactions are very different for each substituent and for each ring proton.
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Proton chemical shifts in NMR. Part 14. Proton chemical shifts, ring currents and π electron effects in condensed aromatic hydrocarbons and substituted benzenes

Lee Griffiths

Papers

NMR Method for the Determination of Solute Hydrogen Bond Acidity

Approaches to charge calculations in molecular mechanics

Proton chemical shifts in NMR. Part 14. Proton chemical shifts, ring currents and π electron effects in condensed aromatic hydrocarbons and substituted benzenes

Conformational equilibria in halocyclohexanones, an NMR and solvation study

Direct lanthanide-induced-shift NMR determination of conformer populations in substituted cyclohexanones