Predicting substituent effects on activation energy changes by static catalytic fields
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Catalytic fields illustrate topology of the optimal charge distribution of a molecular environment reducing the activation energy for any process involving barrier crossing, like chemical reaction, bond rotation etc. Until now, this technique has been successfully applied to predict catalytic effects resulting from intermolecular interactions with individual water molecules constituting the first hydration shell, aminoacid mutations in enzymes or Si→Al substitutions in zeolites. In this contribution, hydrogen to fluorine (H→F) substitution effects for two model reactions have been examined indicating qualitative applicability of the catalytic field concept in the case of systems involving intramolecular interactions.
KeywordsSubstrate assisted catalysis Catalytic fields Fluorine substitution Ab initio
Recent experimental studies confirm the catalytic role of external electric fields [1, 2, 3, 4]. This observation is in agreement with previous theoretical studies indicating the electrostatic nature of enzymatic or zeolite catalysis [5, 6, 7, 8, 9, 10, 11]. The catalytic activity measured as the lowering of the activation barrier ∆, is dominated in many macromolecular systems (C), for example enzymes [8, 9, 10] or zeolites , by their electrostatic interactions with corresponding reactants, i.e., transition states E(C.TS) and substrates E(C.S). In the present contribution, we have used catalytic fields  derived as the difference of the MEP of corresponding transition states and substrates in an attempt to estimate catalytic effects resulting from H->F substitutions for two model reactions. This is in line with the study of Prof. Peter Politzer and coworkers , where the relationship of molecular electrostatic potentials (MEP) with experimentally based reactivity indices was postulated earlier.
In addition to external (intermolecular) fields, the catalytic activity can also be modified by intramolecular effects (for example substitutions or deletions of functional groups), which is reminiscent to the well-known phenomenon of substrate assisted catalysis . In this type of catalysis, substrate substituents are introduced to modulate the catalytic activity instead of an external molecular environment.
As a starting point for our calculations, we used geometries of the transition states from the previous study by Bahmanyar and coworkers . Frequency analyses were performed on the optimized geometries to verify the nature of reactant and transition states. Calculations of minimum energy paths (MEP) were done to generate substrate states from the transition states. The MEP calculations were performed using the intrinsic reaction coordinate algorithm (IRC). For all calculations, the B3LYP density functional theory method was used together with the 6-31G(d) basis set. For each substitution site (a hydrogen atom), a calculation of the electrostatic potential was done at a distance of 1.5 A from the site. In what follows, we focus on reaction “6a” from the previous study .
The first model represents a simple single proton transfer reaction in a planar aromatic molecule and the second one involves a much more complex non-planar organocatalytic molecular system.
Results and discussion
In the first model case, we studied tautomeric enol-keto or keto-enol rearrangements within salicydene aniline, a model system representing a larger class of molecular switches . These switches have become a “hot-topic” thanks to their potential application in molecular electronics, data storage and processing devices. In this context, it is vital to understand the role of functional groups introduced to salicydene aniline, as these may modify the energetics of the intramolecular keto-enol tautomerizations and isomerizations.
In the second case, we have considered the minimum energy reaction path for the aldol reaction of cyclohexanone with isobutyraldehyde catalyzed by L-proline . The application of small organic molecules as catalysts in organic synthesis has seen a dramatic increase in recent years, as these catalysts are readily available, low-cost, and do not rely on metal cofactors, whose toxicity is often problematic in the production of pharmaceuticals . Hence, there is a need for better understanding how these organocatalysts operate at the molecular level, which is where computational chemistry can provide some answers. Of particular interest is the knowledge of factors that control the stereoselectivity of asymmetric organocatalytic reactions, for example reactions catalyzed by proline.
In both model cases, H→F substitution effects can be qualitatively predicted based on the values of the catalytic field calculated for distances of 1.5 Å from each substitution site. Some observed deviations from the linear relationship may be due to possible mesomeric effects, especially for the first model involving an aromatic system.
Recent experimental  and theoretical  studies on the effect of fluorine substitutions in O-GlcNAcase substrates provide additional evidence on the substrate assisted catalytic mechanism. The relationship between molecular electrostatic potentials and reaction rates was postulated earlier by Prof. Peter Politzer and coworkers [12, 20].
In conclusion, static catalytic fields can be employed to predict with reasonable accuracy and at a low computational cost substitution effects on activation barriers. The use of catalytic fields is beneficial, since they allow in one computational step rapid evaluation of substituent effects. Usually, such effects are calculated by modeling of the reaction path of each substituted reactant, something that is a tedious and computationally expensive task. In our approach, however, it is sufficient to know only the geometries of the regular, non-substituted reactant and transition state. Once these geometries have been optimized, an “all-at-once” calculation of the electrostatic potential is performed at positions suitable for substitution. For each position, a difference of the electrostatic potential between the reactant and transition state can already provide a reasonable approximation of the corresponding substituent effect.
Since the calculation of catalytic fields is computationally inexpensive and can be for the most part automated, they may find application in areas, such as computer-aided drug design, molecular docking or virtual screening, where there is often a need for the evaluation of substituent effects in hundreds of molecules during a single study.
This work was supported in part by Wrocław Research Centre EIT+ within the project Biotechnologies and advanced medical technologies BIOMED (POIG.01.01.02-02-003/08) co-financed by European Regional Development Fund (Operational Programme Innovative Economy, 1.1.2) and by the Polish Ministry of Science and Higher Education from the funds of ‘Diamond Grant’ programme research project no DI2012 016642. The partial support of the Wrocław University of Technology financed by a statutory activity subsidy for Faculty of Chemistry by Polish Ministry of Science and Higher Education is acknowledged. Calculations were performed at supercomputer centers in Wrocław (WCSS), Poznań (PCSS), and Warsaw (ICM).
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