Daniel R. Carcanague

Solvent effects in molecular recognition

Synthetic cyclophane hosts form stable and highly structured inclusion complexes with organic molecules in aqueous solutions. The solution geometries of these complexes are determined in a conformational analysis using Monte Car10 methods. Solvation-desolvation processes are a central factor in determining the stability of apolar inclusion complexes. The tight binding of small aromatic solutes in water is entropically unfavorable and is predominantly enthalpy-driven. A large part of the favorable enthalpy term for strong complexation in water results from its specific contributions. Electron donor-acceptor interactions stabilize complexes between electron-rich cyclophane hosts and electron-deficient aromatic substrates; however, they may be masked by specific solvation effects. Computer liquid phase simulations are undertaken to evaluate at a microscopic level the origin of such solvation effects. The progress in the modeling studies is described. Apolar complexation also occurs in organic solvents. Solvents like 2,2,2-trifluoroethanol and ethylene glycol come close to water in their ability to promote apolar complexation. Binding strength decreases from water to polar protic to dipolar aprotic and to apolar solvents. Complexation strength in solvents of all polarity including water and in binary aqueous solvent mixtures is predictable according to a linear free energy relationship between the complexation free energy and the empirical solvent polarity parameter ET(30).

Steroid complexation by cyclophane receptors in aqueous solution: Substrate selectivity, enthalpic driving force for cavity inclusion, and enthalpy-entropy compensation

Abstract The synthesis, characterization, and steroid binding properties of two novel cyclophane receptors shaped by two naphthylphenylmethane spacers are reported. Cyclophane 1 forms inclusion complexes with bile acids, corticoids, and androgenic steroids in D 2 O CD 3 OD 1:1 Specific functional group solvation effects generate high binding selectivity in the series of structurally similar bile acid derivatives: the complex of lithocholic acid is ≈ 2 kcal/mol more stable than the complex of deoxycholic acid. Steroid complexation by 1 is enthalpically driven, and complexation thermodynamics follows a strong enthalpy-entropy compensation relationship. Cyclophane 2 with 4 quaternary ammonium centers shows a much higher non-aggregated water-solubility than 1 with its two quaternary centers and forms stable steroid inclusion complexes in pure water. Complexes of anionic steroids with 2 are stabilized by both apolar interactions and ion pairing.