# Structure–Reactivity Relationships in N-Methylpyridinium Aldoxime Isomers: Comparative Experimental and Computational Studies

## TL;DR

This study compares how the position of an oxime group in pyridinium compounds affects their chemical properties and reactivity using experiments and computational methods.

## Contribution

The work provides a first-of-its-kind structure–reactivity map of three pyridinium oxime isomers using an integrated experimental and computational approach.

## Key findings

- The position of the oxime group significantly influences ionization behavior, electronic structure, and nucleophilicity.
- DFT analysis revealed electronic properties not accessible through experiments alone.
- Substitution kinetics and coordination modes were determined for the isomers in aqueous solution.

## Abstract

The relative position of the oxime group within pharmaceutically relevant pyridinium oximes is a pivotal factor that governs their intrinsic physicochemical properties and their biological reactivity. However, studies providing in-depth, molecular-level insight into these structure–reactivity relationships are still limited. In this work, we present an integrated experimental and computational study of N-methylpyridinium-2-aldoxime chloride (PAM2-Cl), N-methylpyridinium-3-aldoxime iodide (PAM3-I), and N-methylpyridinium-4-aldoxime iodide (PAM4-I), aimed at elucidating discrete differences in their ionization behavior, electronic structure, σ-donor properties, and nucleophilicity. The crystal structure of PAM3-I was determined by X-ray diffraction. Comparative structural and spectroscopic (UV–Vis, NMR, IR) analyses elucidated the structural and electronic effects arising from the position of the oxime group. Kinetic studies of substitution reactions with aquapentacyanoferrate(II) in aqueous solution enabled the determination of pentacyano(PAM)ferrate(II) formation and dissociation rate constants, coordination modes, pKa values of the coordinated ligands, complex stability constants, and σ-donating capabilities. The DFT-based analysis of atomic charge distribution transcended experimental limitations, offering a new perspective on electronic structure-related properties. This study presents the first side-by-side, internally consistent structure–reactivity map across PAM2, PAM3, and PAM4 isomers that triangulates crystallography, UV–Vis-derived pKa values, substitution kinetics, and DFT descriptors in a single framework.