Differential Activation Entropy Research Articles

Enantioselective Isothiourea-Catalysed Michael–Michael–Lactonisation­ Cascade Reaction for the Synthesis of δ-Lactones and 1,2,3,4-Substituted Cyclopentanes

This manuscript describes the application of α,β-unsaturated acyl ammonium intermediates in a Michael–Michael–lactonisation cascade process to furnish δ-lactones. Generation of α,β-unsaturated acyl ammonium intermediates was achieved upon addition of isothiourea catalyst HyperBTM into α,β-unsaturated acid chlorides. Subsequent reaction with enone-malonates gave access to δ-lactones in 20–64% yield, 72.5:27.5 to 95:5 er and 81:19 to >95:5 dr. Additionally, application of a ring-opening protocol yielded 1,2,3,4-substituted cyclopentanes in 28–77% yield, 76:24 to 98:2 er and 86:14 to >95:5 dr. Interestingly, the highest er was observed at high reaction temperatures, with 70 °C proving optimal. This effect was investigated by conducting an Eyring analysis, which indicated that differential activation entropy rather than differential activation enthalpy is responsible for enantiodiscrimination in this process.

Entropy-Driven 1,2-Type Friedel-Crafts Reaction of Phenols with N-tert-Butoxycarbonyl Aldimines.

Differential activation entropy (ΔΔS(≠)) is revisited as an important parameter that governs catalytic stereodiscrimination processes by investigating temperature effects on the basis of the Eyring theory. However, correlating the ΔΔS(≠) effect and the molecular structure of the asymmetric catalyst is still an underdeveloped area. Efforts to identify factors (including catalyst structure, reactants, and reaction conditions) that contribute to the attainment of large ΔΔS(≠) values for enantioselective 1,2-type Friedel-Crafts reactions of phenols with N-tert-butoxycarbonyl aldimines catalyzed by conformationally flexible guanidine bisthioureas are described. First, we uncover an interesting property of the ΔΔS(≠)-driven stereodiscrimination process: maximum enantioselectivity is obtained at around room temperature. Second, a plausible transition-state model accounting for the characteristic ΔΔS(≠) effect and the structural dynamics of the conformationally flexible organocatalyst in the stereodiscrimination process is discussed.

Theoretical Insight into Stereoselective Reaction Mechanisms of 2,4-Pentanediol-Tethered Ketene-Olefin [2 + 2] Cycloaddition

We report ab initio molecular dynamics calculations based on density functional theory performed on an intramolecular [2 + 2] cycloaddition between ketene and olefin linked with a 2,4-pentanediol (PD) tether. We find that the encounter of the ketene and olefin moieties could be prearranged in the thermal equilibrated state before the cycloaddition. The reaction mechanism is found to be stepwise, similar to that of intermolecular ketene [2 + 2] cycloadditions with ordinary alkenes. A distinct feature of the reaction pathway for a major diastereoisomer is a differential activation free energy of about 1.5 kcal/mol, including 2.8 kcal/mol as the differential activation entropy, with a transition state consisting of a flexible nine-membered ring in the olefin-PD-ketene moiety. This theoretical study provides a reasonable explanation for the strict stereocontrollability of the PD-tethered ketene-olefin cycloaddition, irrespective of reaction types or conditions.

Linking Conformational Flexibility and Kinetics: Catalytic 1,4‐Type Friedel–Crafts Reactions of Phenols Utilizing 1,3‐Diamine‐Tethered Guanidine/Bisthiourea Organocatalysts

Herein, we present details of our conformationally flexible, 1,3-diamine-tethered guanidine/bisthiourea organocatalysts for chemo-, regio-, and enantioselective 1,4-type Friedel-Crafts reactions of phenols. These organocatalysts show a unique stereo-discrimination governed by the differential activation entropy (ΔΔS(≠)), rather than by the differential activation enthalpy (ΔΔH(≠)). Extensive kinetic analyses using Eyring plots for a series of guanidine/bisthiourea organocatalysts revealed the key structural motif in the catalysts associated with a large magnitude of differential activation entropy (ΔΔS(≠)). A plausible guanidine-thiourea cooperative mechanism for the enantioselective Friedel-Crafts reaction is proposed.

Dynamic Solvation Effects on the endo/exo Selectivity of the Diels—Alder Reaction.

Abstract The endo/exo stereoselectivity of the Diels–Alder cycloaddition between cyclopentadiene and 3-crotonoyl-2-oxazolidinone catalysed by Et2AlCl is temperature- and solvent-dependent. Eyring plots of ln(endo/exo) versus 1/T show different inversion temperatures (Tinv) depending on the reaction solvent. Using toluene-d8 we found a break temperature (TNMR) in a variable temperature 13C NMR experiment of the starting oxazolidinone, and this TNMR corresponded to the Tinv. In several cases the differential activation entropy manages the observed stereoselectivity.

Dynamic solvation effects on the endo/ exo selectivity of the Diels–Alder reaction

The endo/ exo stereoselectivity of the Diels–Alder cycloaddition between cyclopentadiene and 3-crotonoyl-2-oxazolidinone catalysed by Et 2AlCl is temperature- and solvent-dependent. Eyring plots of ln( endo/ exo) versus 1/ T show different inversion temperatures ( T inv) depending on the reaction solvent. Using toluene- d 8 we found a break temperature ( T NMR) in a variable temperature 13C NMR experiment of the starting oxazolidinone, and this T NMR corresponded to the T inv. In several cases the differential activation entropy manages the observed stereoselectivity.

How does active site water affect enzymatic stereorecognition?

The E value for ketone reduction catalyzed by a secondary alcohol dehydrogenase (SADH) from Thermoanaerobacter ethanolicus is temperature dependent, due to a relatively large activation entropy difference, ΔΔS‡, which favors the formation (or reaction) of the (R)-enantiomer of 2-butanol and 2-pentanol. In contrast, the activation enthalpy, ΔΔH‡, favors the formation of the (S)-enantiomer of 2-butanol and 2-pentanol. C295A mutant SADH shows very large reductions in ΔΔS‡ compared to wild-type SADH, in addition to the expected reductions in ΔΔH‡. The decrease in ΔΔH‡ can be readily explained on the basis of steric interaction and van der Waals contacts of the enantiomeric substrates in the active site. The comparison of ΔΔS‡ of the wild-type and C295A mutant SADH reduces the possible entropy contributions to those associated with the Cys-295 sulfhydryl group. Examination of the crystal structure shows an ordered water molecule in the small pocket, located at a distance of 4.1Å from the sulfur atom of Cys-295. Thus, the stereospecificity of SADH may be at least partly determined by the selective expulsion of this bound water from the small alkyl binding pocket upon binding of large substituents in the small alkyl pocket. The data obtained with wild-type, S39T and C295A SADH with NADP, SNADP and APADP show a reasonable enthalpy–entropy compensation relationship, suggesting a contribution of solvation. Our results suggest that selective release of bound solvent from the active site upon binding of enantiomeric substrates may contribute to the differential activation entropy, ΔΔS‡.

Substrate entropy in enzyme enantioselectivity: an experimental and molecular modeling study of a lipase.

The temperature dependence of the enantioselectivity of Candida antarctica lipase B for 3-hexanol, 2-butanol, 3-methyl-2-butanol, 3,3-dimethyl-2-butanol, and 1-bromo-2-butanol revealed that the differential activation entropy, deltaR-SdeltaS, was as significant as the differential activation enthalpy, DeltaR-SdeltaH, to the enantiomeric ratio, E. 1-Bromo-2-butanol, with isosteric substituents, displayed the largest deltaR-SdeltaS. 3-Hexanol displayed, contrary to other sec-alcohols, a positive deltaR-SdeltaS. In other words, for 3-hexanol the preferred R-enantiomer is not only favored by enthalpy but also by entropy. Molecular dynamics (MD) simulations and systematic search calculations of the substrate accessible volume within the active site revealed that the (R)-3-hexanol transition state (TS) accessed a larger volume within the active site than the (S)-3-hexanol TS. This correlates well with the higher TS entropy of (R)-3-hexanol. In addition, this enantiomer did also yield a higher number of allowed conformations, N, from the systematic search routines, than did the S-enantiomer. The substrate accessible volume was greater for the enantiomer preferred by entropy also for 2-butanol. For 3,3-dimethyl-2-butanol, however, neither MD-simulations nor systematic search calculations yielded substrate accessible volumes that correlate to TS entropy. Ambiguous results were achieved for 3-methyl-2-butanol.

Solvent and temperature effect in aldol condensation between the lithium enolate of tert-butyl acetate and 2-phenyl propanal: enthalpy and entropy contribution

An analysis of nucleophilic addition of the lithium enolate of tert-butyl acetate and 2-phenyl propanal in two different solvents, such as THF and n-hexane, revealed the great importance of solvent effect in determining the stereoselectivity. In particular, temperature-dependent measurements of diastereomeric ratio allow the evaluation of diastereoselectivity in terms of differential enthalpy and entropy of activation for this reaction. Either in THF or n-hexane we obtained a predominance of the anti isomer in all temperature ranges, but in THF the diastereoselection is controlled by the differential activation enthalpy, whereas in n-hexane it is the sole differential activation entropy that accounts for the anti predominance.

Entropy-controlled asymmetric synthesis. How differential activation entropy is induced in chiral tethered reactions.

[figure: see text] Kinetic measurements to determine effective molarities of intramolecular reactions using 2,4-pentanediol and related tethers showed that methyl groups on the tether accelerate the major diastereomeric process but decelerate the minor process. The efficient promotion of stereocontrol is suggested to be due to chiral perturbation of the reaction rate through the entropy term. The conformation of the encounter complex of the reagent and reactant moieties was deduced by stereochemical analysis of the intramolecular adducts.

Temperature-Independent Stereocontrolled [2+2] Cycloaddition. Potential of the 2,4-Pentanediol Tether in Asymmetric Reactions as a Differential Activation Entropy Promoter

Temperature-Independent Stereocontrolled [2+2] Cycloaddition. Potential of the 2,4-Pentanediol Tether in Asymmetric Reactions as a Differential Activation Entropy Promoter

Inverse temperature dependence of the dipolarophilic reactivity of carbonyl ylide photogenerated from trans-stilbene oxide

In methylcyclohexane at 295 – 353 K, cycloaddition reactions of carbonyl ylide photogenerated from trans-stilbene oxide have small or negative activation enthalpies. This behavior can be explained in terms of reversible formation of a bimolecular complex. The increase in reactivity from one dipolarophile to another is due to the increase in differential activation entropy for collapse and back-dissociation of the complex.