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

The microsolvation of pyridine (C5H5N) by water molecules was investigated systematically through a comprehensive exploration of the conformational landscape of the PYR(H2O) n clusters ( n = 1 - 10 ) 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 n = 1 to 55 at n = 9 . For small cluster sizes ( n = 1 - 2 ), the global minimum is dominated by a single O-H ⋯ N hydrogen bond between water and the pyridine nitrogen, in agreement with microwave spectroscopy data. From n = 3 onwards, cooperative O-H ⋯ O inter-water networks emerge and the energy landscape flattens dramatically, yielding dense manifolds of quasi-degenerate conformers. For n ≥ 7 , the water subcluster progressively adopts closed-cage topologies characteristic of large water clusters. Temperature-dependent Boltzmann populations ( 0 - 500 K) reveal that the global minimum is the sole populated species only for n ≤ 2 , 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 - 1 beyond n = 5 , 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-H ⋯ N, O-H ⋯ O, C-H ⋯ O, O ⋯ C, and O-H ⋯ π 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.