Simple position and orientation preconditioning scheme for minimum energy path calculations

Abstract

Minimum‐energy path (MEP) calculations, such as those typified by the nudged elastic band method, require input of reactant and product molecular configurations at initialization. In the case of reactions involving more than one molecule, generating initial reactant and product configurations requires careful consideration of the relative position and orientations of the reactive molecules in order to ensure that the resulting MEP calculation proceeds without converging on an alternative reaction‐path, and without requiring excessive numbers of optimization iterations; as such, this initial system set‐up is most commonly performed “by hand,” with an expert user arranging reactive molecules in space to ensure that the following MEP calculation runs smoothly. In this Article, we introduce a simple preconditioning scheme which replaces this labor‐intensive, human‐knowledge‐based step with an automated deterministic computational scheme. In our approach, initial reactant and product configurations are generated such that steric hindrance between reactive molecules is minimized in the reactant and product configurations, while also simultaneously requiring minimal structural differences between the reactants and products. The method is demonstrated using a benchmark test‐set of >3400 organic molecular reactions, where comparison of the reactant/product configurations generated using our approach compare very well to initial configurations which were generated on an ad hoc basis.

Computational Insight into the Rope-Skipping Isomerization of Diarylether Cyclophanes

“…Synthetic efforts utilizing an Ullmann coupling or S N Ar as a key step show promise and with additional optimization would lead to experimental measurement of these conformational barriers. A complete mapping of the conformational ensemble would be useful but is likely only worth pursuing with assistance from automated transition state search techniques [23,[31][32][33][34]. In understanding the relationship between intramolecular tether length and DAEC racemization, this information may provide guidance toward future synthesis of diarylether ligands or pharmaceuticals with atropisomeric properties created or tuned by the attachment of an intramolecular tether.…”

Graph-Driven Reaction Discovery: Progress, Challenges, and Future Opportunities

“…For example, the method used in the YARP code is based on using bond-order matrices, where the element G ij identifies the bond-order (e.g., G ij = 1 for single-bonds, G ij = 2 for double-bonds); such an approach readily enables one to keep track of atomic valences. In our work, ,,− we use the simpler adjacency matrix , defined as Here, r ij is the distance between atoms i and j in a given molecular structure, and r ij cut defines a cutoff distance. As such, G ij defined in eq simply identifies whether or not two atoms i , j are bonded or not, as judged by a standard geometric definition.…”

“…Overview of reaction class definitions, as employed in our recent work. ,,− The left-hand panel shows the initial and final bonding graphs for three representative two- or three-atom reactions, namely, (1) dissociation, (2) association, and (3) diatomic dissociation. Here, the bonding matrices show the connectivity for atoms ( i , j ) or ( i , j , k ) before and after a given reaction is applied to a reactant set; by selecting a reaction class and related atomic indices, one can automatically induce reactions on a system’s bonding graph to generate new products.…”

“…In many standard applications, these approaches can work well; however, in the setting of CRN generation, where one could potentially be generating hundreds or thousands of unique elementary chemical reactions, TS-finding can present challenges to high-throughput automation. For example, TS-finding algorithms can be quite sensitive to the initial configuration; as such, preconditioning schemes can be useful, aiming to preferentially orientate molecules in space before TS-finding begins . Furthermore, give numerical noise in typical self-consistent-field-type calculations, accurately converging TS geometries to unambiguously identify single negative eigenvalues is often challenging too.…”

“…Our own work in this field ,,− and the focus of this article is exclusively on methods which fall into the second CRN generation category (Figure ), being based on concepts of molecular graphs. As described below, graphs such as adjacency matrices offer a compact description of the chemical bonding in a collection of molecules; put simply, such graphs identify which atoms are bonded and which are not.…”