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

Abstract

Jet FTIR spectroscopy of acetophenone–methanol balances reveals subtle solvation energy preferences by dispersion-tuning of the alkyl groups.

Binding Site Switch by Dispersion Interactions: Rotational Signatures of Fenchone–Phenol and Fenchone–Benzene Complexes

“…This hasa lso been observed for alcohol docking to substituted acetophenone, but in this case the two carbonyl binding sites are very different, as one involves ap henyl and the other an alkyl group. [40] In other studies exploring the interactions of water and alcohols with ethers, changes in the preferred primary bonding, OÀH•••O versus OÀH•••p,w ere observed due to dispersion effects ands tructural flexibility. [41,42] The data presented here provideu seful experimental benchmarks forc omputationalm ethods, in particular for analysing and accurately describing the effects of dispersion and competing interactions.…”

Pinacolone-Alcohol Gas-Phase Solvation Balances as Experimental Dispersion Benchmarks

“…If at least one of these three diagnostics fails, the DFT functional performance can be proven to be poor down to a sub-kJ/mol accuracy threshold. This was the case for one out of six pairings of aromatic ketones with alcohols in the first systematic study [11], for the otherwise most successful B3LYP-D3 functional. By using the second-most stable and less compact predicted structure in this particular case, the performance could actually be rescued.…”

“…By using the second-most stable and less compact predicted structure in this particular case, the performance could actually be rescued. [11] This former systematic investigation thus suggests a mildly erroneous preference of the B3LYP-D3 functional (at least for a standard def2-TZVP basis set), and to a lesser extent also the TPSS-D3 approach, for compact structures. Other explored functionals such as M06-2X failed the aromatic ketone balance test in several aspects [11] and need not be considered further.…”

“…[12,13] The idea is to have two very comparable lone electron pairs available at the acetophenone oxygen, to which alcohols can either dock from the phenyl or from the alkyl side, with little difference in ZPVE. Besides the intrinsic preference of a docking alcohol for the methyl side due to the more favourable local hydrogen bond geometry [11], the alkyl group of the alcohol will interact dispersively (and by Pauli repulsion) with the two ketone substituents and thus contribute to the preference for one of the docking sides. These secondary interactions through space are able to tip the balance towards phenyl side docking.…”

“…These secondary interactions through space are able to tip the balance towards phenyl side docking. [11] The comparison of different alcohols and acetophenones thus provides information on London dispersion interactions competing with the electronic and zero-point vibrational local hydrogen bond effects, which still largely govern the position of the alcoholic OH vibration. The latter is used to spectrally discriminate the docking isomers and it also contains further information on the competition of forces, because hydrogen bonds can be distorted by distant interactions of the donor molecule.…”