Retaining local chemical effects: An error cancellation strategy for calculating standard gas-phase enthalpy of formation

Conventional error cancellation approaches separate molecules into smaller fragments and sum the errors of all fragments to counteract the overall computational error of the parent molecules. However, these approaches may be ineffective for systems with strong localized chemical effects, as fragmenting specific substructures into simpler chemical bonds can introduce additional errors instead of mitigating them. To address this issue, we propose the Substructure-Preserved Connection-Based Hierarchy (SCBH), a method that automatically identifies and freezes substructures with significant local chemical effects prior to molecular fragmentation. The SCBH is validated by the gas-phase enthalpy of formation calculation of CHNO molecules. Therein, based on the atomization scheme, the reference and test values are derived at the levels of Gaussian-4 (G4) and M062X/6-31+G(2df, p), respectively. Compared to commonly used approaches, SCBH reduces the average computational error by half and requires only 15% of the computational cost of G4 to achieve comparable accuracy. Since different types of local effect structures have differentiated influences on gas-phase enthalpy of formation, substituents with strong electronic effects should be retained preferentially. SCBH can be readily extended to diverse classes of organic compounds. Its workflow and source code allow flexible customization of molecular moieties, including azide, carboxyl, trinitromethyl, phenyl, and others. This strategy facilitates accurate, rapid, and automated computations and corrections, making it well-suited for high-throughput molecular screening and dataset construction for gas-phase enthalpy of formation. • A strategy called SCBH is proposed to improve the calculation accuracy of gas-phase enthalpy of formation. • SCBH achieves a MAE of ∼1 kcal/mol at moderate DFT levels, an accuracy that comparable to the high-cost method G4. • SCBH demonstrates superior performance over conventional CBH strategies for molecules with localized chemical effects. • The method requires only 15% cost of G4, enabling high-throughput computation of thermochemical properties. • An open-source workflow is developed to support flexible application to diverse organic compounds.