Attaching Onto or Inserting Into an Intramolecular Hydrogen Bond: Exploring and Controlling a Chirality-Dependent Dilemma for Alcohols

Abstract

Prereactive complexes in noncovalent organocatalysis are sensitive to the relative chirality of the binding partners and to hydrogen bond isomerism. Both effects are present when a transiently chiral alcohol docks on a chiral α-hydroxy ester, turning such 1:1 complexes into elementary, non-reactive model systems for chirality induction in the gas phase. With the help of linear infrared and Raman spectroscopy in supersonic jet expansions, conformational preferences are investigated for benzyl alcohol in combination with methyl lactate, also exploring p-chlorination of the alcohol and the achiral homolog methyl glycolate to identify potential London dispersion and chirality effects on the energy sequence. Three of the four combinations prefer barrierless complexation via the hydroxy group of the ester (association). In contrast, the lightest complex predominantly shows insertion into the intramolecular hydrogen bond, such as the analogous lactate and glycolate complexes of methanol. The experimental findings are rationalized with computations, and a uniform helicality induction in the alcohol by the lactate is predicted, independent of insertion into or association with the internal lactate hydrogen bond. p-chlorination of benzyl alcohol has a stabilizing effect on association because the insertion motif prevents a close contact between the chlorine and the hydroxy ester. After simple anharmonicity and substitution corrections, the B3LYP-D3 approach offers a fairly systematic description of the known spectroscopic data on alcohol complexes with α-hydroxy esters.

London Dispersion-Assisted Low-Temperature Gas Phase Synthesis of Hydrogen Bond-Inserted Complexes

“…This does not affect the conclusions of this work, and we continue with the consistent B3LYP-D3(BJ)/def2-TZVP approach for optimized structures, electronic energies, harmonic zero-point corrections, and OH stretching wavenumbers. As shown before, 10 DLPNO-CCSD(T)/aug-cc-pVQZ 16 calculations also do not change the energetic picture significantly, but they tend to stabilize the attachment complexes by 1 to 3 kJ∙mol –1 (see SI, Tables S4 and S5).…”

“…Because the total energy includes deformation energy whereas the interaction energy does not do so, the trends in the curves are more significant than the absolute values. 10 The black curves show that the extra methyl group in L systematically destabilizes insertion over attachment, largely by increasing the hydrogen bond-accepting capability of the OH group. They also show that halogenation destabilizes insertion for G and L, and that this preference is almost the same for het (dashed, species not observed in experiment, because they are less stable independent on attachment or insertion) and hom pairings for L.…”

“…The experimental and quantum-chemical procedures employed in this work closely follow the initial investigation of the parent benzyl alcohol and its para-chlorinated derivative in combination with the simplest achiral and chiral -hydroxy esters. 10 We refer to that work for the details of the supersonic jet infrared and Raman spectroscopy techniques, and to the Supporting Information (SI) for the actual spectra obtained and for their assignment (see Figures S5-S8 for the spectra, Tables S8-S11 for the assigned band positions, and Table S12 for the experimental conditions), which is based on systematic harmonic shift predictions obtained at the B3LYP-D3(BJ)/def2-TZVP level 11,12 with the ORCA 4.0 program suite. 13 The experimental outcome is analyzed in terms of optimized transition states and reaction paths acquired with the Turbomole 7.3 package.…”

“…The quantification is carried out through predicted IR and Raman cross-sections. 10 When the energy calculations were repeated with the def2-QZVP basis set, 12 the relative energies of minima and connecting transition states changed by less than 0.6 kJ•mol -1 and the energies for dissociation into benzyl alcohol and hydroxy ester units (discussed later) rather uniformly dropped by less than 10% (see SI, Tables S6 and S7). This does not affect the conclusions of this work, and we continue with the consistent B3LYP-D3(BJ)/def2-TZVP approach for optimized structures, electronic energies, harmonic zero-point corrections,…”

“…Because the total energy includes deformation energy whereas the interaction energy does not do so, the trends in the curves are more significant than the absolute values. 10…”