Experimental (FT‐ICR) and theoretical (DFT) estimation of the basic site preference for the bidentate molecule 2‐(β‐aminoethyl)‐pyridine: similarity with histamine

The gas‐phase basicity of 2‐(β‐aminoethyl)‐pyridine (AEP)—an agonist of the histamine H 1 receptor—containing two potential basic sites (the ring N‐aza and the chain N‐amino) was obtained from proton‐transfer equilibrium constant measurements using Fourier transform ion cyclotron resonance mass spectrometry (FT‐ICR). Comparison of the experimental gas‐phase basicity found for AEP with those reported for monobasic model compounds indicates that the ring N‐aza is the favoured site of protonation, as with histamine. The gas‐phase basicity of AEP is lower than that of histamine by only 1.3 kcal mol −1 . DFT(B3LYP)/6–31G* calculations performed for AEP, histamine and their protonated forms confirm this interpretation. The energy barriers calculated at the DFT(B3LYP)/6–31G* level for internal transfer of the proton (ITP) between the ring N‐aza and the chain N‐amino in AEP and histamine are extremely low, and vanish when thermal corrections are applied to obtain the enthalpies or Gibbs energies of activation for the proton transfer. This indicates that the quantum‐chemical ITPs in AEP and histamine have a single‐well character, similar to that proposed for the previously studied dibasic nitrogen ligand, N 1 , N 1 ‐dimethyl‐ N 2 ‐β‐(2‐pyridylethyl)‐formamidine, where two potential nitrogen basic sites (both nitrogen atoms in sp 2 hybridization) are separated by the ethylene group. Enlarging the basis set to 6‐311G(2d,p) has no influence on this finding. A change of the basicity centre preference in AEP from the ring N‐aza to the chain N‐amino on going from the gas phase to aqueous solution was predicted using the polarizable continuum model applied to the DFT(B3LYP)/6–31G* optimized geometries of the N‐aza and N‐amino monoprotonated forms. This behaviour is similar to that observed for histamine. Copyright © 2005 John Wiley & Sons, Ltd.