Heterogeneous Intramolecular Electric Field as a Descriptor of Diels–Alder Reactivity

Abstract

External electric fields have proven to be an effective tool in catalysis, on par with pressure and temperature, affecting the thermodynamics and kinetics of a reaction. However, fields in molecules are complicated heterogeneous vector objects, and there is no universal recipe for grasping the exact features of these fields that implicate reactivity. Herein, we demonstrate that topological features of the heterogeneous electric field within the reactant state, as well as of the quantum mechanical electron density-a scalar reporter on the field experienced by the system-can be identified as rigorous descriptors of the reactivity to follow. We scrutinize specifically the Diels-Alder reaction. Its 3-D nature and the lack of a singular directionality of charge movement upon barrier crossing makes the effect of the electric field not obvious. We show that the electric field topology around the dienophile double bond, and the associated changes in the topology of the electron density in this bond are predictors of the reaction barrier. They are also the metrics by which to rationalize and predict how the external field would inhibit or enhance the reaction. The findings pave the way toward designing external fields for catalysis, as well as reading the reactivity without an explicit mechanistic interrogation, for a variety of reactions. File list (2) download file view on ChemRxiv Manuscript.pdf (12.56 MiB) download file view on ChemRxiv SI.pdf (54.98 MiB)

Advances in optimizing enzyme electrostatic preorganization

“…in several variants of an enzyme). In both the KSI and Diels-Alder reactions, we have shown that topologically similar electric fields correspond to similar barriers of the corresponding reaction [19,47]. Furthermore, we showed how fields only at discrete points (which is what is often computed/measured) do not fully capture a relationship to the reaction barrier [47].…”

“…We showed a subset of these features (e.g., the electrostatic potential and electron density at bond and ring critical points) to correlate linearly with the applied electric field, and also correlate with the reaction barrier, thus establishing a rigorous quantum mechanical link between electrostatic preorganization and reactivity. This was shown for Histone Deacetylase 8 (HDAC8) [46], KSI [18], and the Diels-Alder reactions in solution and catalyzed by artificial enzymes [19]. As such, the topology of the electron density contains a signature of the electric field which is applied to the system.…”

“…Recent works by Shaik have emphasized that the electric field parallel with the reaction axis (direction of electron reorganization) controls the forward rate of reaction for single-step reactions [17,44]. For example, for the Diels-Alder reactions, it has been shown that the electric field parallel to the bond-forming axis controls the rate of reaction [19,20,24].…”

“…Electrostatic preorganization indeed has been shown to be present in several enzymes, including the most famously studied enzyme, Ketosteroid Isomerase [5][6][7][8][9]. While the generality of electrostatic preorganization in enzymes (and the role activation entropy plays in enzyme kinetics more generally) has been fiercely debated [10][11][12][13][14][15][16], a properly chosen electric field has been irrefutably shown (theoretically [17][18][19][20][21][22][23] and experimentally [24]) to increase the forward rate of various reactions. Thus, understanding enzymatic catalysis requires including intramolecular fields as one of the likely reactivity regulators.…”

Machine Learning to Predict Diels-Alder Reaction Barriers from the Reactant State Electron Density

“…[54][55][56][57][58] Here, we propose a direct prediction of the reaction barriers through quantum electronic descriptors of the reactant state: the electron density, ( ), and its derived mathematical properties. We are building on the following previous findings: our previous work on the Ketosteroid Isomerase enzyme and its mutants, 59 and the Diels-Alder reaction, 60 with and without external electric field applied, have shown robust linear correlations between topological features of ( ) and Δ ‡ . Furthermore, there exist methods that utilize ( ) to predict changes in chemical parameters such as pKa, 61 as well as reactivity.…”