Molecular electrostatic potential as a general and versatile indicator for electronic substituent effects:...

Area of Science:

• Organic Chemistry
• Computational Chemistry

Background:

• Accurate determination of substituent effects is crucial for understanding organic reaction mechanisms.
• Conventional methods for quantifying substituent effects often lack universal applicability or statistical robustness.

Purpose of the Study:

• To establish molecular electrostatic potential (MESP) as a general and versatile quantitative measure for substituent effects.
• To demonstrate the utility of MESP in predicting substituent effects across diverse chemical reactions.
• To compare the efficacy of MESP with traditional substituent parameter methods.

Main Methods:

• Performed extensive density functional theory (DFT) calculations on over 400 molecules.
• Conducted statistical analyses, including linear regression and residual normality tests.
• Investigated various DFT functionals, basis sets, and solvation models.

Main Results:

• Observed a robust, linear correlation between MESP and established substituent parameters.
• Demonstrated the universal applicability of this linear relationship across different computational conditions.
• Found that MESP provides statistically normal residuals, unlike conventional charge-based methods.
• Showed that MESP can enhance the validity of linear free energy relationships (LFERs).

Conclusions:

• Molecular electrostatic potential (MESP) serves as a physically meaningful and predictive measure of substituent effects.
• MESP offers a versatile and statistically sound alternative to empirical parameters like Hammett and Swain-Lupton constants.
• The MESP shift is a strong predictor of electronic substituent effects in chemical reactions.