Hydrogen‐Bond Interactions of Nicotine and Acetylcholine Salts: A Combined Crystallographic, Spectroscopic, Thermodynamic and Theoretical Study

Abstract

The hydrogen-bond (HB) interactions of the monocharged active forms of nicotine and acetylcholine (ACh) have been compared theoretically by using density functional theory (DFT) calculations and experimentally on the basis of crystallographic observations and the measurement of equilibrium constants in solution. The 2,4,6-trinitrophenolate (picrate) counterion was used to determine the experimental HB basicity of the cations despite its potential multisite HB acceptor properties. The preferred HB interaction site of the ammonium picrate salts was determined from a survey of crystallographic data found in the Cambridge Structural Database (CSD) and is supported by theoretical calculations. Two distinct classes of ammonium groups were characterised depending on the absence (quaternary ammonium) or presence (tertiary, secondary and primary ammoniums) of an N(+)HO hydrogen bond linking the two ions. The crystal structure of nicotinium picrate was determined and compared with that of ACh. This analysis revealed the peculiar behaviour of the ammonium moiety of nicotinic acetylcholine receptor (nAChR) ligands towards the picrate anion. Dedicated methods have been developed to separate the individual contributions of the anion and cation accepting sites to the overall HB basicity of the ion pairs measured in solution. The HB basicities of the picrate anions associated with the two different ammonium classes were determined in dichloromethane solution by using several model ion pairs with non-basic ammonium cations. The experimental and theoretical studies performed on the nicotine and ACh cations consistently show the significant HB ability of the acceptor site of nAChR agonists in their charged form. Both the greater HB basicity of the pyridinic nitrogen over the carbonyl oxygen and the greater HB acidity of the N(+)H unit relative to N(+)CH could contribute to the higher affinity for nAChRs of nicotine-like ligands relative to ACh-like ligands.

A Theoretical Evaluation of the pKHBand Δ$H{{{\,\ominus}\hfill \atop {\rm HB}\hfill}}}$ Hydrogen‐Bond Scales of Nitrogen Bases

“…Complex conformations: Following the work of Lamarche and Platts, [19,21] we have recently confirmed that [10,23,34] if a separate treatment is carried out for different families of bases, hydrogen fluoride (HF) can be selected as a convenient model of hydrogen-bond donor with the double benefit that it requires the minimum of computing time and limits the number of stereoisomeric complexes around the accepting centre. In the initial geometries of the complexes, the HF molecule was placed in the direction of the nitrogen lone pair and the interaction energetics-the interaction energy (D ðHFÞ 0 ), the theoretical enthalpy of the complexation reaction with hydrogen fluoride (DH A(HF) ) and the free energy of the complexation reaction with hydrogen fluoride (DG A(HF) )-were calculated from Equations (5)- (7) …”

I5–polymers with a layered arrangement: synthesis, spectroscopy, and structure of a new polyiodide salt in the nicotine/HI/I2system

“…The geometric parameters of the title dication are similar to those known from the literature (Table 1). However, it is surprising that only three doubly protonated [31-33] and a handful of singly protonated nicotine cation-containing salts [34][35][36][37][38] have structurally been characterised so far.…”

Lewis Basicity and Affinity Measurement: Definitions and Context

“…[118], carbonyls [119], pyridines [119] and amines [120]. The other terms correspond to the intermolecular interactions already described between two molecules and generalized here to solute/solvent interactions.…”