Ignacio Soteras

Continuum solvation models: Dissecting the free energy of solvation

The most usual self-consistent reaction field (SCRF) continuum models for the description of solvation within the quantum mechanical (QM) framework are reviewed, trying to emphasize their common roots as well as the inherent approximations assumed in the calculation of the free energy of solvation. Particular attention is also paid to the specific features involved in the development of current state-of-the-art QM SCRF continuum models. This is used to discuss the need to maintain a close correspondence between each SCRF formalism and the specific details entailing its parametrization, as well as the need to be cautious in analyzing the balance between electrostatic and non-electrostatic contributions to the solvation free energy between different SCRF models. Finally, special emphasis is given to the post-processing of the free energy of solvation to derive parameters providing a compact picture of the ability of a molecule to interact with different solvents, which can be of particular interest in biopharmaceutical studies.

Derivation of Distributed Models of Atomic Polarizability for Molecular Simulations.

The main thrust of this investigation is the development of models of distributed atomic polarizabilities for the treatment of induction effects in molecular mechanics simulations. The models are obtained within the framework of the induced dipole theory by fitting the induction energies computed via a fast but accurate MP2/Sadlej-adjusted perturbational approach in a grid of points surrounding the molecule. Particular care is paid in the examination of the atomic quantities obtained from models of implicitly and explicitly interacting polarizabilities. Appropriateness and accuracy of the distributed models are assessed by comparing the molecular polarizabilities recovered from the models and those obtained experimentally and from MP2/Sadlej calculations. The behavior of the models is further explored by computing the polarization energy for aromatic compounds in the context of cation-π interactions and for selected neutral compounds in a TIP3P aqueous environment. The present results suggest that the computational strategy described here constitutes a very effective tool for the development of distributed models of atomic polarizabilities and can be used in the generation of new polarizable force fields.

Boron-Based Dipolar Multicomponent Reactions: Simple Generation of Substituted Aziridines, Oxazolidines and Pyrrolidines

New multicomponent reactions of aldehydes, isocyanides, trialkylboron reagents and dipolarophiles have been developed as an efficient route to diverse scaffolds, including aziridines, oxazolidines and poly-substituted pyrrolidines. This chemistry, inspired by a report by Hesse in 1965, is simple and involves mild conditions. Computational studies provide a basis to investigate the stereochemical features observed in the formation of oxazolidines and four-component adducts, and permit identification of potential factors that might influence the outcome of the multicomponent reaction. Thus, a rational screening of all the components and reaction parameters is made to examine the manifold mechanistic pathways and establish the practical limits for standard applications. Finally, intramolecular and solid-supported versions of these reactions bring new synthetic possibilities and practical protocols. Overall, the results describe a new family of multicomponent reactions valuable not only for organic reactivity, but also for combinatorial chemistry and drug discovery.

Performance of the IEF-MST solvation continuum model in a blind test prediction of hydration free energies.

The IEF-MST continuum solvation model is used to predict the hydration free energies of a set of 63 multifunctional compounds very recently compiled as a blind test (denoted SAMPL1) for computational solvation methods (Guthrie, J. P. J. Phys. Chem. B 2009, 113, 4501). Computations were performed using the IEF-MST versions parametrized at both HF/6-31G(d) and B3LYP/6-31G(d) levels. For direct comparison with other methods, computations were performed using the frozen geometries provided with the SAMPL1 data set, as well as the gas phase optimized geometries following the implementation of the IEF-MST model. Comparison with experimental data yields a root-mean square deviation for the whole set of compounds of 2.7 and 2.4 kcal/mol at both HF and B3LYP levels. The agreement between IEF-MST and experimental data is then quite remarkable, especially considering the reduced set of training compounds (72 data in water) used in the parametrization of the IEF-MST method.

Structure-Directed Reversion in the π-Facial Stereoselective Alkylation of Chiral Bicyclic Lactams

The reversal of the pi-facial diastereoselectivity observed in the benzyl bromide alkylation of the enolate of phenylglycinol-derived oxazolopiperidone is examined by means of theoretical calculations and experimental assays. When the angular carbon adopts an R configuration, the endo addition is intrinsically favored due to the lower torsional strain induced in the TS, but for the reaction with benzyl bromide, which affords the exo product. This reversal is attributed to the formation of a C-H...pi hydrogen bond between the C-H unit of the C8a angular position and the benzene ring of the alkylating reagent. A similar secondary interaction explains the stereochemical reversion observed in the benzyl alkylation of the enolate of oxazolopyrrolidinone. These findings point out that the delicate balance between factors that dictate the diastereoselectivity in the alkylation of chiral byciclic lactams can be unexpectedly altered by weak secondary interactions. The results presented here provide valuable guidelines to tune the selective preparation of enantiopure bioorganic and pharmaceutical compounds.

Group contributions to the solvation free energy from MST continuum calculations

Group contributions to the free energy of solvation in water and octanol as well as to the octanol/water partition coefficient have been determined from Miertus-Scrocco-Tomasi continuum calculations. Particular attention is paid to the influence exerted by the procedure used to carry out the charge normalization in the MST model, as well as to the formalism of the partitioning scheme. A good agreement is found between the group contributions calculated by using different charge normalization and partitioning schemes in a series of structurally related drug-like molecule. Finally, the transferability of the group contributions determined for common chemical fragments along the series of molecules is discussed.

Solute-Solvent Interactions from QM SCRF Methods

Quantum mechanical (QM) methods have become a very powerful tool to gain detailed insight into chemical structure and reactivity [1–3]. The fascinating evolution of these methods in the last decades has impelled quantum chemistry to approach the limit of “experimental” accuracy in the gas phase. However, the understanding of the structure, energetic and chemical reactivity of molecules in solution is still a challenging task, which demands a close collaborative effort between experimental techniques and theoretical methods [4–12].