Automated transition state theory calculations for high-throughput kinetics

A scarcity of known chemical kinetic parameters leads to the use of many reaction rate estimates, which are not always sufficiently accurate, in the construction of detailed kinetic models. To reduce the reliance on these estimates and improve the accuracy of predictive kinetic models, we have developed a high-throughput, fully automated, reaction rate calculation method, AutoTST. The algorithm integrates automated saddle-point geometry search methods and a canonical transition state theory kinetics calculator. The automatically calculated reaction rates compare favorably to existing estimated rates. Comparison against high level theoretical calculations show the new automated method performs better than rate estimates when the estimate is made by a poor analogy. The method will improve by accounting for internal rotor contributions and by improving methods to determine molecular symmetry.Comment: 29 pages, 8 figure

Exploration of Reaction Pathways and Chemical Transformation Networks

For the investigation of chemical reaction networks, the identification of all relevant intermediates and elementary reactions is mandatory. Many algorithmic approaches exist that perform explorations efficiently and automatedly. These approaches differ in their application range, the level of completeness of the exploration, as well as the amount of heuristics and human intervention required. Here, we describe and compare the different approaches based on these criteria. Future directions leveraging the strengths of chemical heuristics, human interaction, and physical rigor are discussed.Comment: 48 pages, 4 figure

An unexpected Ireland–Claisen rearrangement cascade during the synthesis of the tricyclic core of Curcusone C: Mechanistic elucidation by trial-and-error and automatic artificial force-induced reaction (AFIR) computations

In the course of a total synthesis effort directed toward the natural product curcusone C, the Stoltz group discovered an unexpected thermal rearrangement of a divinylcyclopropane to the product of a formal Cope/1,3-sigmatropic shift sequence. Since the involvement of a thermally forbidden 1,3-shift seemed unlikely, theoretical studies involving two approaches, the “trial-and-error” testing of various conceivable mechanisms (Houk group) and an “automatic” approach using the Maeda–Morokuma AFIR method (Morokuma group) were applied to explore the mechanism. Eventually, both approaches converged on a cascade mechanism shown to have some partial literature precedent: Cope rearrangement/1,5-sigmatropic silyl shift/Claisen rearrangement/retro-Claisen rearrangement/1,5-sigmatropic silyl shift, comprising a quintet of five sequential thermally allowed pericyclic rearrangements

Automated Exploration of Reaction Network and Mechanism via Meta-dynamics Nanoreactor

We developed an automated approach to construct the complex reaction network and explore the reaction mechanism for several reactant molecules. The nanoreactor type molecular dynamics was employed to generate possible chemical reactions, in which the meta-dynamics was taken to overcome reaction barriers and the semi-empirical GFN2-xTB method was used to reduce computational cost. The identification of reaction events from trajectories was conducted by using the hidden Markov model based on the evolution of the molecular connectivity. This provided the starting points for the further transition state searches at the more accurate electronic structure levels to obtain the reaction mechanism. Then the whole reaction network with multiply pathways was obtained. The feasibility and efficiency of this automated construction of the reaction network was examined by two examples. The first reaction under study was the HCHO + NH3 biomolecular reaction. The second example focused on the reaction network for a multi-species system composed of dozens of HCN and H2O compounds. The result indicated that the proposed approach was a valuable and effective tool for the automated exploration of reaction networks

Challenges facing an understanding of the nature of low-energy excited states in photosynthesis

© 2016 Elsevier B.V. While the majority of the photochemical states and pathways related to the biological capture of solar energy are now well understood and provide paradigms for artificial device design, additional low-energy states have been discovered in many systems with obscure origins and significance. However, as low-energy states are naively expected to be critical to function, these observations pose important challenges. A review of known properties of low energy states covering eight photochemical systems, and options for their interpretation, are presented. A concerted experimental and theoretical research strategy is suggested and outlined, this being aimed at providing a fully comprehensive understanding

Determining the dominant degradation mechanisms in Nitrocellulose

Nitrocellulose (NC) is the base component for many modern day propellants and explosives, as well as for everyday items such as printing inks, paint and lacquer coatings. Despite its early beginnings as the first man-made plastic, the decomposition pathways from the bulk material to the products observed from its ambient ageing are still not fully understood. Knowledge of these processes are of critical importance when considering the conservation of NC artefacts, refinement of product formulations, predictions of shelf life and safety improvements. In this study, the dominant degradation pathways of NC were investigated using quantum mechanics (QM) methods to probe the mechanisms leading to the initial cleavage of nitrate groups from the cellulosic backbone. The NC structure was truncated from a polymer chain to monomer, dimer and trimer units. Density functional theory methods (DFT) were used to study the mechanistic detail at individual nitrate sites. Comparison of differently sized units using the quantum theory of atoms in molecules (QTAIM), analysis of the electrostatic potential (ESP) surface and partial charges showed that the most suitable approximation for study of the decomposition reactions was the β-glucopyranose monomer, bi-capped with methoxy groups. The primary thermolytic and hydrolytic denitration routes were explored using transition state (TS) searches and potential energy surface (PES) scans. It was found that the thermolytic behaviour of the NC denitration step matched that of a well studied nitrate ester, pentaerythritol tetranitrate (PETN). The hydrolytic scheme for nitrate cleavage was studied, finding that protonation at the bridging oxygen site was the most likely to lead to denitration. It was not possible to isolate a TS for the hydrolytic reaction, though a number of coordination schemes were tested. Key secondary processes beyond nitrate cleavage were examined to determine the fate of nitrogen in the system and the cause of the transition from a first order reaction rate to autocatalytic decomposition. The energies of reactions in three different decomposition schemes proposed in literature were compared. Ethyl nitrate was used as a test system before extension to the NC monomer. New reaction pathways for decomposition were constructed using the reactions posed in the literature studies. The new schemes revealed that •NO2 was the most likely cause for the experimentally observed autocatalytic rate of degradation

The Interplay between Chemistry and Mechanics in the Transduction of a Mechanical Signal into a Biochemical Function

There are many processes in biology in which mechanical forces are generated. Force-bearing networks can transduce locally developed mechanical signals very extensively over different parts of the cell or tissues. In this article we conduct an overview of this kind of mechanical transduction, focusing in particular on the multiple layers of complexity displayed by the mechanisms that control and trigger the conversion of a mechanical signal into a biochemical function. Single molecule methodologies, through their capability to introduce the force in studies of biological processes in which mechanical stresses are developed, are unveiling subtle intertwining mechanisms between chemistry and mechanics and in particular are revealing how chemistry can control mechanics. The possibility that chemistry interplays with mechanics should be always considered in biochemical studies.Comment: 50 pages, 18 figure

Exploring the Complex Folding Free Energy Landscapes of a Series of β-rich Proteins

Protein aggregation is deleterious to human health and detrimental to therapeutic shelf-life. The physical processes that induce aggregation are the same processes that drive productive folding reactions. As such, protein aggregation is a non-productive form of protein folding. To gain insight into the steps that serve as a partition between the folding and aggregation reactions, the folding mechanisms of several β-rich proteins with links to human disease or medicine were examined. In the ALS-linked protein, SOD1, a subpopulation of the unfolded ensemble is found to be a common source of both nonnative structure and frustrated folding. These behaviors are only observed upon the reduction of the intrinsic disulfide bond, indicating that this covalent interaction wards against aggregation. The nonnative structure presents an attractive target for the development of new therapeutic agents. In VH domains from therapeutic mAbs, the intramolecular disulfide bond protects against aggregation. However, it can also introduce complexity to the folding mechanism. This complexity is linked to the formation of a strained orientation of the disulfide bond. This strained orientation of the disulfide in certain VH domains is energetically unfavorable enough to disrupt the formation of the disulfide in the full length mAbs. The novel relationship observed between disulfide orientation, folding complexity, and incomplete oxidation warrants further examination in other Ig domains. Overall, these results demonstrate that mapping the folding free energy landscape for proteins with roles in human disease or therapeutics can provide valuable insights for developing and improving treatment options

Development of Reaction Discovery Tools in Photochemistry and Condensed Phases

Photochemistry obeys different rules than ground-state chemistry and by doing so opens avenues for synthesis and materials properties. However, the different rules of photochemistry make understanding the fine details of photochemical reactions difficult. Computational chemistry can provide the details for understanding photochemical reactions, but the field of computational photochemistry is still new, and many techniques developed for ground-state reactions are not directly applicable to photochemical reactions. As a result, many photochemical mechanisms are not understood, and this hinders the rational design and synthesis of new photochemistry. To address this need, this thesis develops techniques to search for and study photochemical reactions. Chapter 2 and 3 develop methods to calculate photochemical reactions in gas- and condensed-phases via minimum energy reaction paths. First, Chapter 2 develops a method to search the molecular 3N-6 space for photochemical reactions. This space, although vast, is not chaotic and can be efficiently searched using a concept familiar to chemists: breaking and adding bonds and driving angles and torsions. Furthermore, this procedure can be automated to predict new chemistry not previously identified by experiments. Chapter 3 furthers this research by leveraging the concept of molecules to enable the computational study of reactions in large multi-molecular systems like crystals. Specifically, the use of a new coordinate system involving translational and rotational coordinates allows decoupling of the coordinate systems of the individual molecules, which is necessary for the efficient algebra. Importantly, these methods are general, they can be used to study single molecules and crystals, and much in between. These methods are demonstrated on complex chemical problems including the isomerization pathways of ethylene and stilbene (Chapter 2), the photocycloaddition of butadiene (Chapter 2), the rotation of a crystalline gyroscope (Chapter 3), the bicycle pedal rotation of cis,cis-diphenylbutadiene (Chapter 4), and the mechanism of a reversible photoacid (Chapter 5). These problems have value in understanding the processes of vision, optomechanics, and high-energy materials, and through their xx study much needed insight is gained that can be useful for designing new syntheses and materials. Furthermore, the new computational methods open the possibility for many future investigations. The results of Chapter 2 find a novel roaming-atom and hula-twist isomerization pathway and use automated reaction discovery tools to identify a missing butadiene photoproduct and why the [4+2] cycloaddition is forbidden. The results of Chapter 3 and 4 build on Chapter 2 by including the influence of a steric environment. Chapter 3 demonstrates by application to a molecular gyroscope that extreme long-range correlated motion can be captured with GSM, and Chapter 4 details how the one-bond flip and hula-twist mechanisms are suppressed by the crystal cavity, the nature of the seam space in steric environments, and the features of the bicycle pedal mechanism. For example, the bicycle pedals rotate through the passageway in the adjacent monomers. However, the models do not capture the quantitative activation barriers and more work is needed. Finally, Chapter 5 provides the ultrafast details of how the photoacid isomerizes and ring-closes with experimental and computational evidence. Unfortunately, quantitative calculation of pKa cannot be provided with the computations employed herein. In summary, this thesis provides an advancement in the knowledge of photochemical mechanisms that can be used for the development of new syntheses and offers new tools with capacity to study complex photochemical problems.PHDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/163005/1/craldaz_1.pd