Three-dimensional docking of alcohols to ketones: an experimental benchmark based on acetophenone solvation energy balances

• Published in: Physical chemistry chemical physics : PCCP 2020-02, Vol.22 (5), p.287-2877
• Main Authors: Zimmermann, C, Gottschalk, H. C, Suhm, M. A
• Format: Article
• Language: English
• Subjects: Acetophenone; Alkylation; Benchmarks; Butanol; Carbonyl groups; Carbonyls; Docking; Electronic structure; Energy gap; Hydrogen bonds; Ketones; Low temperature; Predictions; Solvation; Zero point energy
• ISSN: 1463-9076; 1463-9084
• DOI: 10.1039/c9cp06128b

The two hydrogen bond solvation sites exhibited by the carbonyl group in acetophenone are influenced by alkylation of the methyl group in both the acetophenone and in the prototype solvent methanol, largely due to London dispersion forces. Phenyl docking and alkyl docking preferences can be realized at will by appropriate substitution. In particular, cyclopropylation helps to stabilize the opposite phenyl docking site. In all cases, the energy gap is small enough to allow for a simultaneous detection even under low temperature conditions. This density functional prediction is checked experimentally by jet FTIR spectroscopy and largely confirmed. A spurious out-of-plane solvation preference predicted for cyclopropylphenylketone with tert -butyl alcohol by B3LYP-D3 calculations is not confirmed experimentally. It is unlikely that this discrepancy is due to zero-point energy effects. Instead, the second most stable alkyl-side solvation motif predicted with a more in-plane coordination is found in the jet expansion. Overall, the ability of carbonyl solvation balances to benchmark subtle electronic structure effects for non-covalent interactions without major nuclear motion corrections is supported. Jet FTIR spectroscopy of acetophenone-methanol balances reveals subtle solvation energy preferences by dispersion-tuning of the alkyl groups.