Development of a ¹³C NMR Chemical Shift Prediction Procedure Using B3LYP/cc-pVDZ and Empirically Derived Systematic Error Correction Terms: A Computational Small Molecule Structure Elucidation Method

Abstract

An accurate and efficient procedure was developed for performing C NMR chemical shift calculations employing density functional theory with the gauge invariant atomic orbitals (DFT-GIAO). Benchmarking analysis was carried out, incorporating several density functionals and basis sets commonly used for prediction ofC NMR chemical shifts, from which the B3LYP/cc-pVDZ level of theory was found to provide accurate results at low computational cost. Statistical analyses from a large data set of C NMR chemical shifts in DMSO are presented with TMS as the calculated reference and with empirical scaling parameters obtained from a linear regression analysis. Systematic errors were observed locally for key functional groups and carbon types, and correction factors were determined. The application of this process and associated correction factors enabled assignment of the correct structures of therapeutically relevant compounds in cases where experimental data yielded inconclusive or ambiguous results. Overall, the use of B3LYP/cc-pVDZ with linear scaling and correction terms affords a powerful and efficient tool for structure elucidation.

Calculations of 13C NMR chemical shifts and F–C coupling constants of ciprofloxacin

“…Taking into account the solvent effect with PCM model contributed slightly to better results. In a study of the shift prediction procedure on a large data set of 13 C chemical shifts of pharmaceutically relevant structures in DMSO using the B3LYP/aug‐cc‐pVDZ method, Xin et al . reported it as a robust and accurate method for chemical shift prediction of small molecules with low computational cost.…”

Vollautomatisierte quantenchemische Berechnung von Spin‐Spin‐ gekoppelten magnetischen Kernspinresonanzspektren

“…B. auf Basis der Dichtefunktionaltheorie (DFT), ist die Ab-initio-Berechnung der NMR-Parameter, also der magnetischen Abschirmungskonstanten (oder der chemischen Verschiebung d)u nd der indirekten Spin-Spin-Kopplungskonstanten (J, SSCCs), zur Routine geworden [3] (kürzlich vorgestellte Ansätze,d ie DFT-Rechnungen und empirische Korrekturen verbinden, sind in Lit. [4] zu finden). Fürd iese Eigenschaften zweiter Ordnung kçnnen mit üblichen Hybridfunktionalen angemessene Genauigkeiten von etwa 0.1-0.3 ppm (für d)u nd 0.5 Hz (für J)f üro rganische Moleküle erreicht werden.…”

Synthesis and structural elucidation of a phthalide analog using NMR analysis and DFT calculations

“…In the last decades, advances in computational chemistry have provided new tools for chemists to overcome these problems. [9] The evolution of quantum chemical methods and the increase in computational power in recent years have made computational chemistry able to help in the analyses of complex organic structures. Density functional theory (DFT) methods have become the most used for predicting NMR chemical shifts of organic molecules.…”