autodE: Automated Calculation of Reaction Energy Profiles— Application to Organic and Organometallic Reactions

Abstract

Calculating reaction energy profiles to aid in mechanistic elucidation has long been the domain of the expert computational chemist. Here, we introduce autodE (https://github.com/duartegroup/autodE), an open‐source Python package capable of locating transition states (TSs) and minima and delivering a full reaction energy profile from 1D or 2D chemical representations. autodE is broadly applicable to study organic and organometallic reaction classes, including addition, substitution, elimination, migratory insertion, oxidative addition, and reductive elimination; it accounts for conformational sampling of both minima and TSs and is compatible with many electronic structure packages. The general applicability of autodE is demonstrated in complex multi‐step reactions, including cobalt‐ and rhodium‐catalyzed hydroformylation and an Ireland–Claisen rearrangement.

Conformational Sampling for Transition State Searches on a Computational Budget

“…Additionally, constrained conformational sampling can be performed on already converged transition states (TSs) to potentially discover more stable conformations . 8,16 Thus, conformational sampling of the reactant, product, and discovered TSs are all potentially relevant for finding the lowest bar-rier corresponding to the intended reaction. Unless stated otherwise, reactant-side conformational sampling is performed in the benchmarks reported here to keep the computational costs tractable, but in two of the benchmarks the benefits of product-side sampling and TS conformational sampling are also compared.…”

“…In summary, even for this benchmark of reactions on small molecules, applying conformational sampling results in improved success rates, improved intended rates, and the discovery of lower activation energy pathways. 8 and AFIR (red) reported by Lee et al 31 All curves are calculated at the B3LYP-D3BJ/6-311++G(2d,2p) and B3LYP-D3BJ/6-31G(d) levels of theory for the single point calculations and geometry optimizations, respectively. The CPCM(hexane) solvent model was used in autodE, whereas the IEF-PCM(hexane) solvent model was used in this work and AFIR.…”

“…32 Young et al performed a follow-up study using the autoDE method and a heuristic for sampling conformations to localize distinct transition states. 8 Here, conformational sampling was performed on all five reactants to generate reaction conformers that were then ranked using the RF models to down-select up to 8 reaction conformations for each step (N conf = 8). The transition state localization was performed at the B3LYP-D3BJ/6-31G(d) level of theory and further evaluated at the B3LYP-D3BJ/6-311++G(2d,2p) level of theory with the IEF-PCM(hexane) solvent model to be consistent with the earlier AFIR study.…”

“…33 Since these tetrapeptides are the largest systems investigated here, we decided to also use them as a case study of the potential benefits of performing conformational sampling on already localized TSs to search for a lower barrier crossing. In particular, several recent studies have used this approach, 8,16 but no direct comparison has been performed between TS conformational sampling and reactant/product-side conformational sampling. Conformational sampling of TSs is more difficult than that of reactants or products, because a TS is a saddle point and thus conformational sampling can easily lead to an unintended reaction channel.…”

“…For this reason, recent methods development efforts have been focused on automating the convergence of transition state searches, thus eliminating potential biases from user interventions and democratizing the availability of these calculations. 4,5,7,8 Among the challenges to full automation, is that the characteristics of discovered transition states, including the barrier height and identity of intermediates, can be profoundly affected by the conformational details of the reaction configuration. Currently, there is no inexpensive means of automatically in incorporating conformational sampling into transition state characterization workflows, which limits its adoption in high-throughput and reaction discovery applications.…”