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Abstract
We propose a fully automated composite scheme for the calculation of molecular entropies efficiently, accurately and numerically stable by a combination of DFT, semiempirical quantum chemical (SQM) and force-field (FF) levels. A modified rigid-rotor-harmonic-oscillator (msRRHO) approximation and the Gibbs-Shannon formula for extensive conformer ensembles (CEs) are applied and
efficiently account for effects of anharmonicity. CEs of systematically increasing quality are generated by a modified metadynamics search algorithm and extrapolated to completeness. Variations of the ro-vibrational entropy over the CE are accounted for by a Boltzmann population average for the first time consistently. The proposed procedure was extensively tested with two standard DFT methods (B97-3c and B3LYP) and at GFN-SQM/FF levels for the conformation term in comparison with experimental gas phase entropies and heat capacities. Excellent performance is observed with mean deviations <1 cal/mol K (about < 1-2%) for the total molecular entropy. Even for extremely flexible linear alkanes (C14H30-C16H34),
unprecedentedly small errors of about 3 cal/mol K are obtained. For 25 typical drug molecules, the conformational entropy depends weakly to strongly on the underlying theory level revealing the complex potential energy surfaces as main source of error. The approach is systematically expandable and moreover can be applied straightforward together with continuum solvation models.
efficiently account for effects of anharmonicity. CEs of systematically increasing quality are generated by a modified metadynamics search algorithm and extrapolated to completeness. Variations of the ro-vibrational entropy over the CE are accounted for by a Boltzmann population average for the first time consistently. The proposed procedure was extensively tested with two standard DFT methods (B97-3c and B3LYP) and at GFN-SQM/FF levels for the conformation term in comparison with experimental gas phase entropies and heat capacities. Excellent performance is observed with mean deviations <1 cal/mol K (about < 1-2%) for the total molecular entropy. Even for extremely flexible linear alkanes (C14H30-C16H34),
unprecedentedly small errors of about 3 cal/mol K are obtained. For 25 typical drug molecules, the conformational entropy depends weakly to strongly on the underlying theory level revealing the complex potential energy surfaces as main source of error. The approach is systematically expandable and moreover can be applied straightforward together with continuum solvation models.
