Dissecting Solvent Effects on Hydrogen Bonding

Abstract

The experimental isolation of H-bond energetics from the typically dominant influence of the solvent remains challenging. Here we use synthetic molecular balances to quantify amine/amide H-bonds in competitive solvents. Over 200 conformational free energy differences were determined using 24 H-bonding balances in 9 solvents spanning a wide polarity range. The correlations between experimental interaction energies and gas-phase computed energies exhibited wild solvent-dependent variation. However, excellent correlations were found between the same computed energies and the experimental data following empirical dissection of solvent effects using Hunter's α/β solvation model. In addition to facilitating the direct comparison of experimental and computational data, changes in the fitted donor and acceptor constants reveal the energetics of secondary local interactions such as competing H-bonds.

Keywords: Electrostatic Interactions; Hydrogen Bonds; Noncovalent Interactions; Solvent Effects.

Figure 1

A) Molecular balance design employed in the present investigation to measure H‐bonding interactions in solution. All compound variants are depicted in Figure 2 and included a variable C _n linker (C₁=CH₂, or C₂=CH₂CH₂). B) Control compounds quantify steric and other secondary contributions to the position of the conformational equilibrium. Application of Hunter's solvation model enabled further dissection of the solvent‐independent H‐bond energy (ΔE _HB) and the difference between the H‐bond donor (α) and acceptor (β) abilities of the molecular balance in the folded and unfolded conformations (see Section S3.4, Supporting Information).

Figure 2

Experimental conformational free energies (ΔG _exp) were measured in nine different solvents by ¹⁹F{¹H} NMR spectroscopy (376.5 MHz, 298 K) for H‐bonding balance series A) 1‐C₁‐X, B) 1‐C₂‐X, C) 2‐C₁‐Y, D) 2‐C₂‐Y. Steric and secondary contributions to the conformational free energy differences were accounted for by subtracting the conformational free energies of the respective methylene (Control‐C₁) or ethylene‐linker (Control‐C₂) balances measured in each solvent (ΔG _control, Figure 1B) from the ΔG _exp values of the H‐bonding balances. Negative ΔG _exp values are defined as a preference for the folded (H‐bonded) conformation. All data and errors are tabulated in Section S3.1, Supporting Information.

Figure 3

A) Experimental measurements of the intramolecular H‐bonding interactions determined in nine solvents using balance series 1‐n‐X and 2‐n‐Y (approximated by ΔG _exp−ΔG _control) plotted against those determined by fitting against the Hunter solvation model ΔG _{α/β model}=Δα β_s+Δβ α_s+ΔE _HB, where α_s and β_s are the known H‐bond donor and acceptor constants of the solvent, Δα and Δβ are the changes in the H‐bond donor and acceptor constants of the balance upon forming the intramolecular H‐bond, and ΔE _HB is the solvent‐independent energy of the intramolecular H‐bond. B) Correlations of the empirically dissected solvent‐independent H‐bond energies, ΔE _HB with the gas‐phase energy difference between the folded and unfolded conformers calculated via a conformer distribution search (DFT/B3LYP/6‐31G*). C) Calculated electrostatic surface potentials (DFT/B3LYP/6‐31G*) at the 0.002 electron Å⁻³ isosurface along the N−H bond axis correlate strongly with D) the empirically dissected solvent‐independent H‐bond energies, ΔE _HB determined by fitting with the Hunter solvation model. All data and errors are tabulated in Tables S10–S32, Supporting Information.