E/Z Energetics for Molecular Modeling and Design

Abstract

Thermochemical data have been obtained from G3B3 quantum mechanical calculations for 18 prototypical organic molecules, which exhibit E/Z conformational equilibria. The results are fundamentally important for molecular design including evaluation of structures from protein-ligand docking. For the 18 E/Z pairs, relative energies, enthalpies, free energies, and dipole moments are reported; the E – Z free-energy differences at 298 K range from +8.2 kcal/mol for 1,3-dimethyl carbamate to −6.4 kcal/mol for acetone oxime. A combination of steric and electronic effects can rationalize the variations. Free energies of hydration were also estimated using the GB/SA continuum solvent model. These results indicate that differential hydration is unlikely to qualitatively change the preferred direction of the E/Z equilibria, though further study with free-energy methods using explicit solvent is desirable.

Hydrogen-Tunneling in Biologically Relevant Small Molecules: The Rotamerizations of α-Ketocarboxylic Acids

“…In the case of 4d, the broader barrier is compensated by the slightly lower potential barrier. Note that, contrary to our (and perhaps common) expectations, the pronounced π-donating capability of the cyclopropyl moiety does not exert a distinctive influence on the tunneling half-life of (5,4)-4c compared to 4b or 4d, unlike its effect on hydrogen tunneling in the [1,2]H-migration in cyclopropylhydroxycarbene. 43 Although our computed tunneling rates vary quite substantially among one another and do not reproduce the experimental tunneling half-lives quantitatively, the observed trend among 4a−d is essentially reflected by the theoretical results.…”

“…These relative orientations are commonly referred to as (Z) and (E), respectively, with the (Z)-orientation being the energetically favorable. 1 The (E)-conformer is sometimes accessible by either thermal annealing, or, given the presence of a suitable chromophore, by irradiation with UV light. Recently, also the wavelength-selective nearinfrared (NIR) overtone excitation of the OH-stretching vibrational mode using a tunable NIR laser source has seen more widespread use for this purpose.…”

Virtual Screening and Optimization Yield Low-Nanomolar Inhibitors of the Tautomerase Activity of Plasmodium falciparum Macrophage Migration Inhibitory Factor

“…From the top scoring compounds, hydrazones, hydrazides, hydrazines, α,ß-unsaturated ketones, catechols, imines, thiohydrazones, and compounds having four or more fused rings were eliminated as undesirable for reactivity concerns or complexity. Compounds whose poses had features associated with high internal energy, such as twisted ester or carboxylic acid groups, overly short non-bonded contacts, or energetically unfavorable E / Z isomers, 24 were also removed from consideration.…”

Intramolecular O–H···O═C Hydrogen Bond Energy via the Molecular Tailoring Approach to RAHB Structures

“…77 The electron-withdrawing character of the CN group lowers the electron charge density at the oxygen atoms involved, which in turn causes the enolic proton to be more acidic, therefore increasing the hydrogen bond strength. For structures 131a and 131b, the difference of approximately 2 kcal/mol of the E HB value depends on the syn-pentane effect 80 between the C2 and C3 substituents in the 131a conformer. When the substituent withdrawing electrons is bonded to the C3 enolic carbon atom (135-137), the E HB decreases slightly; however, when the extra hydroxyl group bonded with the C2 carbon atom can act with this C3 substituent in an anticooperative manner, each E HB value decreases by 3.8 kcal/mol (135-138a) or by 3.6 kcal/mol (136-139a), respectively, for the given pairs.…”