Understanding chemical reactivity using the activation strain model

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How Lewis acids catalyze ring-openings of cyclohexene oxide

We have quantum chemically studied the Lewis acid-catalyzed epoxide ring-opening reaction of cyclohexene epoxide by MeZH (Z = O, S, and NH) using relativistic dispersion-corrected density functional theory. We found that the reaction barrier of the Lewis acid-catalyzed epoxide ring-opening reactions decreases upon ascending in group 1 along the series Cs+ > Rb+ > K+ > Na+ > Li+ > H+. Our activation strain and Kohn-Sham molecular orbital analyses reveal that the enhanced reactivity of the Lewis acid-catalyzed ring-opening reaction is caused by the reduced steric (Pauli) repulsion between the filled orbitals of the epoxide and the nucleophile, as the Lewis acid polarizes the filled orbitals of the epoxide more efficiently away from the incoming nucleophile. Furthermore, we established that the regioselectivity of these ring-opening reactions is, aside from the "classical" strain control, also dictated by a hitherto unknown mechanism, namely, the steric (Pauli) repulsion between the nucleophile and the substrate, which could be traced back to the asymmetric orbital density on the epoxide. In all, this work again demonstrates that the concept of Pauli-lowering catalysis is a general phenomenon.Bio-organic Synthesi

How the Lewis Base F– Catalyzes the 1,3-Dipolar Cycloaddition between Carbon Dioxide and Nitrilimines

Bio-organic Synthesi

How solvation influences the S(N)2 versus E2 competition

We have quantum chemically investigated how solvation influences the competition between the S(N)2 and E2 pathways of the model F- + C2H5Cl reaction. The system is solvated in a stepwise manner by going from the gas phase, then via microsolvation of one to three explicit solvent molecules, then last to bulk solvation using relativistic density functional theory at (COSMO)-ZORA-OLYP/QZ4P. We explain how and why the mechanistic pathway of the system shifts from E2 in the gas phase to S(N)2 upon strong solvation of the Lewis base (i.e., nucleophile/protophile). The E2 pathway is preferred under weak solvation of the system by dichloromethane, whereas a switch in reactivity from E2 to S(N)2 is observed under strong solvation by water. Our activation strain and Kohn-Sham molecular orbital analyses reveal that solvation of the Lewis base has a significant impact on the strength of the Lewis base. We show how strong solvation furnishes a weaker Lewis base that is unable to overcome the high characteristic distortivity associated with the E2 pathway, and thus the S(N)2 pathway becomes viable.Bio-organic Synthesi

An Algorithm to Explore Molecular Potential Energy Surfaces

The work is aimed at modifying an algorithm called the Activation-Relaxation Technique (ART). The algorithm was initially envisioned by the original authors to be applied to the study of materials. This work, however, aims to take the original vision forward by applying it to the exploration of potential energy surfaces (PESs) of chemical and enzymatic reactions. To make ART more efficient in terms of the force evaluations needed and, consequently, to reduce the computational time and cost, it has been modified to include additional algorithms that significantly speed up the exploration of the PES. Each such algorithm is designed such that it allows for a strategic displacement of the atoms and subsequent sharing of atomic displacement vector information. Such a strategic displacement of atoms, for example, involves exploiting an a priori knowledge of the reactants in order to avoid atomic displacement moves that would not contribute to the tracing of their PES. A molecule like N-methylacetamide, for instance, which is a good model system for proteins, only undergoes a conformational change (a gradual dihedral rotation) which acts as the sole reaction coordinate for its PES and thus algorithms are included in ART that disallow for any other atomic displacement moves except for a gradual rotation of the dihedral. The sharing of atomic displacement vector information can prove helpful, for example, in enzymatic reactions where the enzyme mutants (which are similar in structure to the wild-type) can be made to follow the displacement vector information of the wild-type in order to avoid going astray along the PES and to have a good starting point from the beginning. The goal, ultimately, is to apply ART to the study of complex chemical reactions and enzymatic reactions involving large-scale rearrangements of the protein environment. As validation steps in the development of this algorithm, we illustrate the modified ART method on selected small molecules -- ethane, propane, methyl acetate, N-methylacetamide, etc. -- highlighting pitfalls and successes

PyFrag 2019—Automating the exploration and analysis of reaction mechanisms

We present a substantial update to the PyFrag 2008 program, which was originally designed to perform a fragment-based activation strain analysis along a provided potential energy surface. The original PyFrag 2008 workflow facilitated the characterization of reaction mechanisms in terms of the intrinsic properties, such as strain and interaction, of the reactants. The new PyFrag 2019 program has automated and reduced the time-consuming and laborious task of setting up, running, analyzing, and visualizing computational data from reaction mechanism studies to a single job. PyFrag 2019 resolves three main challenges associated with the automated computational exploration of reaction mechanisms: it (1) computes the reaction path by carrying out multiple parallel calculations using initial coordinates provided by the user; (2) monitors the entire workflow process; and (3) tabulates and visualizes the final data in a clear way. The activation strain and canonical energy decomposition results that are generated relate the characteristics of the reaction profile in terms of intrinsic properties (strain, interaction, orbital overlaps, orbital energies, populations) of the reactant species