Anomalous 1H NMR chemical shift behavior of substituted benzoic acid esters. (13th December 2022)

• Record Type: Journal Article
• Authors: Gadikota, Vidya; Govindapur, Rajeshwar Reddy; Reddy, D. Srinivas; Roseman, Hailey J.; Williamson, R. Thomas; Raab, Jeffrey G.
• Is Part Of: Magnetic resonance in chemistry. Volume 61:Number 4(2023)
• Page Start: 248
• Page End: 252
• Publication Date: 2022-12-13
• Subjects: 1H -- benzoic acid esters -- density functional theory (DFT) -- NMR; Nuclear magnetic resonance spectroscopy -- Periodicals; Chemistry, Organic -- Periodicals; Magnetic resonance -- Periodicals; 538.36
• DOI: 10.1002/mrc.5326
• Languages: English
• ISSNs: 0749-1581

Abstract

Abstract: Benzoic acid esters represent key building blocks for many drug discovery and development programs and have been advanced as potent PDE4 inhibitors for inhaled administration for treatment of respiratory diseases. This class of compounds has also been employed in myriad industrial processes and as common food preservatives. Recent work directed toward the synthesis of intermediates for a proprietary medicinal chemistry program led us to observe that the 1 H NMR chemical shifts of substituents ortho to the benzoic acid ester moiety defied conventional iterative chemical shift prediction protocols. To explore these unexpected results, we initiated a detailed computational study employing density functional theory (DFT) calculations to better understand the unexpectedly large variance in expected versus experimental NMR chemical shifts. Abstract : A report of various substituted benzoic acids and benzoic methyl esters whose ortho alkyl proton chemical shifts are not accurately estimated by conventional iterative chemical shift prediction protocols. A detailed comparison between the iteratively predicted, DFT‐calculated, and observed chemical shifts for a survey of this class of compounds is described.