Anomalous <sup>1</sup>H NMR chemical shift behavior of substituted benzoic acid esters (2024)

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 1H 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.

Original languageEnglish
Pages (from-to)248-252
Number of pages5
JournalMagnetic Resonance in Chemistry
Volume61
Issue number4
DOIs
StatePublished - Apr 2023

Keywords

  • H
  • NMR
  • benzoic acid esters
  • density functional theory (DFT)

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Gadikota, V., Govindapur, R. R., Reddy, D. S., Roseman, H. J., Williamson, R. T. (2023). Anomalous 1H NMR chemical shift behavior of substituted benzoic acid esters. Magnetic Resonance in Chemistry, 61(4), 248-252. https://doi.org/10.1002/mrc.5326

Gadikota, Vidya ; Govindapur, Rajeshwar Reddy ; Reddy, D. Srinivas et al. / Anomalous 1H NMR chemical shift behavior of substituted benzoic acid esters. In: Magnetic Resonance in Chemistry. 2023 ; Vol. 61, No. 4. pp. 248-252.

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title = "Anomalous 1H NMR chemical shift behavior of substituted benzoic acid esters",

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 1H 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.",

keywords = "H, NMR, benzoic acid esters, density functional theory (DFT)",

author = "Vidya Gadikota and Govindapur, {Rajeshwar Reddy} and Reddy, {D. Srinivas} and Roseman, {Hailey J.} and Williamson, {R. Thomas} and Raab, {Jeffrey G.}",

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Gadikota, V, Govindapur, RR, Reddy, DS, Roseman, HJ, Williamson, RT 2023, 'Anomalous 1H NMR chemical shift behavior of substituted benzoic acid esters', Magnetic Resonance in Chemistry, vol. 61, no. 4, pp. 248-252. https://doi.org/10.1002/mrc.5326

Anomalous 1H NMR chemical shift behavior of substituted benzoic acid esters. / Gadikota, Vidya; Govindapur, Rajeshwar Reddy; Reddy, D. Srinivas et al.
In: Magnetic Resonance in Chemistry, Vol. 61, No. 4, 04.2023, p. 248-252.

Research output: Contribution to journalArticlepeer-review

TY - JOUR

T1 - Anomalous 1H NMR chemical shift behavior of substituted benzoic acid esters

AU - Gadikota, Vidya

AU - Govindapur, Rajeshwar Reddy

AU - Reddy, D. Srinivas

AU - Roseman, Hailey J.

AU - Williamson, R. Thomas

AU - Raab, Jeffrey G.

N1 - Publisher Copyright:© 2022 The Authors. Magnetic Resonance in Chemistry published by John Wiley & Sons Ltd.

PY - 2023/4

Y1 - 2023/4

N2 - 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 1H 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.

AB - 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 1H 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.

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Gadikota V, Govindapur RR, Reddy DS, Roseman HJ, Williamson RT, Raab JG. Anomalous 1H NMR chemical shift behavior of substituted benzoic acid esters. Magnetic Resonance in Chemistry. 2023 Apr;61(4):248-252. doi: 10.1002/mrc.5326

Anomalous <sup>1</sup>H NMR chemical shift behavior of substituted benzoic acid esters (2024)

FAQs

What is the NMR spectra of benzoic acid? ›

The integrated signal proton ratio 1:2:2:1 observed in the very high resolution H-1 NMR spectrum, corresponds with the structural formula of benzoic acid. The high resolution spectra of benzoic acid shows 4 groups of proton resonances and in the 1:2:2:1 ratio expected from the structural formula of benzoic acid.

What is the NMR chemical shift for esters protons? ›

NMR Spectroscopy

In esters, these protons are shifted to 2-2.2 ppm. The protons on the “other” side of the ester, meaning those attached to the carbon adjacent to a carbonyl group, is shifted less far, to 3.7-4.1 ppm.

How many unique hydrogens are in benzoic acid? ›

Number of chemically distinct hydrogens: Number of chemically distinct hydrogens: 6 Hydrogen (label a,b,c) Predicted chemical shift Splitting Pattern (use the n+1 rule) Integral Value Hydrogen (label a,b,c) Predicted chemical shift Splitting Pattern (use the n+1 rule) Integral Value.

What is the chemical shift of h1 NMR? ›

H NMR Chemical Shifts

Chemical shifts in NMR (Nuclear Magnetic Resonance) spectroscopy refer to the phenomenon where the resonant frequency of a nucleus in a magnetic field is influenced by its chemical environment. This effect arises from the shielding or deshielding of the nucleus by the surrounding electron cloud.

What wavelength does benzoic acid absorb? ›

Benzoic acid has an absorption maximum at 230 nm.

What is the spectral data of benzoic acid? ›

The IR spectrum of benzoic acid shows the acidic -OH stretch as a broad peak from 3071 cm −1 to approximately 2940 cm −1 and the C=O. stretch at 1670 cm −1 . ...

Where do esters show up on C NMR? ›

Typical chemical shifts in C-13 NMR spectra
carbon environmentchemical shift (ppm)
C=O (in aldehydes)190 - 200
C=O (in acids and esters)170 - 185
C in aromatic rings125 - 150
C=C (in alkenes)115 - 140
8 more rows
Jan 29, 2023

What does NMR chemical shift tell you? ›

In nuclear magnetic resonance (NMR) spectroscopy, the chemical shift is the resonant frequency of an atomic nucleus relative to a standard in a magnetic field. Often the position and number of chemical shifts are diagnostic of the structure of a molecule.

What is the formula for chemical shift of NMR? ›

The machine measures the observed shift from TMS for you. In practice, the machine prints out the spectrum. shift = δ × spectrometer frequency = 7.27 × 10⁻⁶ × 300 × 10⁶ Hz = 2181 Hz.

What are the unique properties of benzoic acid? ›

Benzoic acid has a crystalline nature. The crystal structure of benzoic acid is monoclinic. The presence of the aromatic ring in benzoic acid gives a faintly pleasant odour. At a temperature of 130^oC, the density of benzoic acid reduces to 1.075 grams per cubic centimetre.

What would be H+ of benzoic acid? ›

[ H + ] = 6 ∗ 10 − 4.

How to identify benzoic acid? ›

Benzoic acid has a colourless appearance in its solid state, which is of a crystalline nature. The crystal structure is monoclinic. The presence of the aromatic ring gives this compound a faintly pleasant odour.

What causes higher chemical shift in NMR? ›

Therefore the chemical shift (delta /ppm) will change depending on the electron density around the proton. Since electronegative groups decrease the electron density, there will be less shielding (ie. deshielding) and the chemical shift will increase.

How to predict chemical shift? ›

When predicting chemical shifts, you need to watch for remote (not geminal) electronegative group/s. If a substituent has a remote electronegative group, an asterisk (*) is add to the chemical shift increment indicating that the chemical shift increment will be increased.

What is the NMR spectrum of C6H5CH3? ›

The 1H NMR spectrum of methylbenzene (C6H5CH3) recorded on a 500 MHz NMR spectrometer consists of signals at chemical shifts of 2.31 ppm and 7.10 ppm.

What is the IR spectrum of benzoic acid functional groups? ›

One of the most prominent peak in the IR spectrum of benzoic acid is due to O-H. This is present at about 3200-3600 cm-1. It can be seen as a broad band present in the spectrum shown. The band of the -OH was overlaped by the various absorptions of aryl C-H of the benzene ring.

What is the NMR shift of benzene? ›

Since benzene has an 1H-NMR chemical shift of about 7.3 ppm for its H-atoms, substituted benzenes will have chemical shifts slightly upfield or downfield of 7.3 ppm.

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