Molecular Interactions of Pyridine With Water: A Combined DFT Benchmarking and QTAIM Analysis

Abstract

ABSTRACT The microsolvation of pyridine (C 5 H 5 N) by water molecules was investigated systematically through a comprehensive exploration of the conformational landscape of the PYR(H 2 O) clusters () at the MN12SX‐D3/def2‐TZVP level of density functional theory, selected between 26 functionals, including dispersion corrections, by benchmarking to the DLPNO‐CCSD(T1)/CBS. A total of 326 stationary points were characterized, ranging from 3 conformers at to 55 at . For small cluster sizes (), the global minimum is dominated by a single O–HN hydrogen bond between water and the pyridine nitrogen, in agreement with microwave spectroscopy data. From onwards, cooperative O–HO inter‐water networks emerge and the energy landscape flattens dramatically, yielding dense manifolds of quasi‐degenerate conformers. For , the water subcluster progressively adopts closed‐cage topologies characteristic of large water clusters. Temperature‐dependent Boltzmann populations ( K) reveal that the global minimum is the sole populated species only for , while a broad conformational distribution governs larger clusters at ambient temperature. The incremental clustering energies converge toward a bulk‐like plateau of approximately −10 kcal . mol beyond , and the incremental Gibbs free energy remains positive throughout the series, demonstrating that stepwise gas‐phase microsolvation is entropically disfavored at every hydration step. Quantum Theory of Atoms in Molecules (QTAIM) analysis of the global minima identifies five types of non‐covalent interactions: O–HN, O–HO, C–HO, OC, and O–H contacts, whose diversity and number grow systematically with cluster size, reflecting the progressive transition from a simple donor–acceptor complex to a three‐dimensional hydrogen‐bond network that partially encapsulates the aromatic ring. These results provide a unified picture of the sequential microsolvation of pyridine and establish a benchmark dataset for the development of force fields and solvation models for nitrogen‐containing heterocycles.