NMR Chemical Shift and Methylation of 4-Nitroimidazole: Experiment and Theory*

Frederick Backler; Marc Antoine Sani; Frances Separovic; Vladislav Vasilyev; Feng Wang

doi:10.1071/CH20199

RESEARCH ARTICLE

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NMR Chemical Shift and Methylation of 4-Nitroimidazole: Experiment and Theory*

Frederick Backler ^A , Marc Antoine Sani

^B , Frances Separovic

^B , Vladislav Vasilyev ^C and Feng Wang

^A ^D

+ Author Affiliations

- Author Affiliations

^A Department of Chemistry and Biotechnology and Centre for Translational Atomaterials, Faculty of Science, Engineering and Technology, Swinburne University of Technology, Hawthorn, Vic. 3122, Australia.

^B School of Chemistry, Bio21 Institute, University of Melbourne, Melbourne, Vic. 3010, Australia.

^C National Computational Infrastructure, Australian National University, Canberra, ACT 0200, Australia.

^D Corresponding author. Email: fwang@swin.edu.au

Australian Journal of Chemistry 74(1) 48-55 https://doi.org/10.1071/CH20199
Submitted: 18 June 2020 Accepted: 3 August 2020 Published: 1 October 2020

Abstract

Nitroimidazoles and derivatives are a class of active pharmaceutical ingredients (APIs) first introduced sixty years ago. As anti-infection agents, the structure–activity relationships of nitroimidazole compounds have been particularly difficult to study due to their low reduction potentials and unique electronic structures. In this study, we combine dynamic nuclear polarization (DNP)-enhanced solid-state (100 K), solid-state (298 K), and ¹H-¹³C heteronuclear single quantum coherence (HSQC) solution-state NMR techniques (303 K) with density functional theory (DFT) to study the ¹H, ¹³C, and ¹⁵N chemical shifts of 4-nitroimidazole (4-NI) and 1-methyl-4-nitroimidazole (CH₃-4NI). The 4-NI chemical shifts were observed at 119.4, 136.4, and 144.7 ppm for ¹³C, and at 181.5, 237.4, and 363.0 ppm for ¹⁵N. The measurements revealed that methylation (deprotonation) of the amino nitrogen N₍₁₎ of 4-NI had less effect (Δδ = −4.8 ppm) on the N₍₁₎ chemical shift but was compensated by shielding of the N₍₃₎ (Δδ = 11.6 ppm) in CH₃-4NI. The calculated chemical shifts using DFT for 4-NI and CH₃-4NI agreed well with the experimental values (within 2 %) for the imidazole carbons. However, larger discrepancies (up to 13 %) were observed between the calculated and measured ¹⁵N NMR chemical shifts for the imidazole nitrogen atoms of both molecules, which indicate that effects such as imidazole ring resonant structures and molecular dynamics may also contribute to the nitrogen chemical environment.

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