Conformational, calorimetric and NMR spectroscopic studies on inclusion complexes of cyclodextrins with substituted phenyl and adamantane derivatives

Inclusion modes in complexes with α- and β-cyclodextrins in water have been investigated by NMR spectroscopy at 400 or 500 MHz, and compared with structures obtained by computer-aided molecular modelling and with calorimetric data. The NOEs observed on o- and m-aryl protons upon irradiation of either H3 or H5 inside the CD cavity indicate for all phenols an inclusion mode with the hydroxy group at the wide cavity end, and an increasingly deep immersion for phenol or phenolate with iodine compared with this nitro group, as para-substituent. This is found to be in line with the complexation-induced NMR shifts. Adamantane-1-carboxylate is indicated by distinct NOEs to be fully immersed into the β-CD cavity; the corresponding complex with α-CD shows contact only at the wider rim and a tilted conformation which allows formation of a hydrogen bond between the guest COO– and the 2-OH group of the CD. The same conformation is found by CHARMm calculations, including simulations in a water box. The results, together with some ΔGo values derived from NMR titrations, are in line with data from calorimetric studies. These show for complexes with tight fit (in α-CD) large enthalpies of up to 43 kJ mol–1 as the predominating driving force against sizeable entropy disadvantages (TΔSo⩽–24 kJ mol–1), particularly for guest molecules of higher electron density and/or polarizibility. These observations point to predominating dispersive interactions. In contrast, inclusion in the wider β-CD cavity suffers less from entropy disadvantage (TΔSo⩽–11 kJ mol-1); the binding, however, is still dominated by ΔHo, pointing to predominant cohesive and not entropic hydrophobic forces.

[1]  Henry S. Frank,et al.  Free Volume and Entropy in Condensed Systems III. Entropy in Binary Liquid Mixtures; Partial Molal Entropy in Dilute Solutions; Structure and Thermodynamics in Aqueous Electrolytes , 1945 .

[2]  H. Dugas.  Bioorganic Chemistry Frontiers , 1991 .

[3]  Wolfram Saenger,et al.  Cyclodextrin Inclusion Compounds in Research and Industry , 1980 .

[4]  J. J. Hoeven,et al.  Spectators in the cleavage of p-nitrophenyl acetate by cyclodextrins in basic solution. Catalysis by potential inhibitors , 1993 .

[5]  G. Wenz.  Cyclodextrins as Building Blocks for Supramolecular Structures and Functional Units , 1994 .

[6]  F. Djedaïni-Pilard,et al.  High field NMR techniques and molecular modelling study of the inclusion complexes of the nootropic drug tenilsetam (CAS-997) in cyclodextrins , 1992 .

[7]  C. Yoder,et al.  Inclusion complexes of alcohols with α-cyclodextrin , 1995 .

[8]  R. Bergeron,et al.  The molecular disposition of sodium p-nitrophenolate in the cavities of cycloheptaamylose and cyclohexaamylose in solution , 1976 .

[9]  D. Stauffer,et al.  Concerning the thermodynamics of molecular recognition in aqueous and organic media. Evidence for significant heat capacity effects , 1990 .

[10]  H. Schneider,et al.  EMPIRICAL CALCULATIONS OF 1H-NMR SHIELDING IN CYCLOPHANES , 1995 .

[11]  J. J. O'Dea,et al.  Kinetics and thermodynamics of inclusion of p-nitrophenolate with .alpha.-cyclodextrin measured with pulse voltammetry , 1991 .

[12]  J. B. Giorgi,et al.  The binding of alkyl chains to β-cyclodextrin and ‘hydroxypropyl-β-cyclodextrin’ , 1993 .

[13]  Nuclear Overhauser Effect , 2011 .

[14]  S. Andini,et al.  Inclusion compounds in water: Calorimetric and spectroscopic studies of the interaction of cyclomaltohexaose (α-cyclodextrin) with alkanols at 25° , 1991 .

[15]  F. Diederich,et al.  Enthalpically driven cyclophane-arene inclusion complexation: solvent-dependent calorimetric studies , 1991 .

[16]  Maurice R. Eftink,et al.  Cyclodextrin-adamantanecarboxylate inclusion complexes: studies of the variation in cavity size , 1985 .

[17]  E. Siimer,et al.  Thermochemical study of cyclodextrin inclusion complexes , 1990 .

[18]  K. A. Connors,et al.  Stability Constants for Complex Formation Between α-Cyclodextrin and Some Amines , 1983 .

[19]  I. Wadsö,et al.  The binding of alkane-α,ω-diols to α-cyclodextrin. A microcalorimetric study , 1990 .

[20]  W. Saenger,et al.  A molecular dynamics simulation of crystalline α-cyclodextrin hexahydrate , 1987, European Biophysics Journal.

[21]  J. Márquez,et al.  Thermodynamic study of the β-cyclodextrin benzyl-2-pyridyl ketone 2-pyridyl hydrazone inclusion process , 1990 .

[22]  G. Bruni,et al.  Solid-state microcalorimetry on drug-cyclodextrin binary systems , 1992 .

[23]  H. Schneider,et al.  Host guest chemistry. 26. NMR and fluorescence studies of cyclodextrin complexes with guest molecules containing both phenyl and naphthyl units , 1991 .

[24]  W. König,et al.  A Molecular‐Dynamics Simulation of the Complex Formation between Methyl (R)/(S)‐2‐Chloropropionate and Heptakis(3‐O‐acetyl‐2,6‐di‐O‐pentyl)‐β‐cyclodextrin , 1994 .

[25]  M. Eftink,et al.  Calorimetric studies of p-nitrophenol binding to α- and β-cyclodextrin , 1981 .

[26]  E. Siimer,et al.  Calorimetric studies of benzoic acid-cyclodextrin inclusion complexes , 1989 .

[27]  G. Barone,et al.  Inclusion compounds in water: Thermodynamics of the interaction of cyclomaltohexaose with amino acids at 25°☆ , 1989 .

[28]  S. Lincoln,et al.  Inclusion Complexes of the Cyclomalto-Oligosaccharides (Cyclodextrins) , 1988 .

[29]  C. Jaime,et al.  Modelling of the inclusion process of α-, β-, and γ-cyclodextrins with 1-bromoadamantane. A comparative molecular mechanics study accounting for the solvent , 1996 .

[30]  John Burgess,et al.  Titration calorimetric and spectrophotometric studies of micelle formation by alkyltrimethylammonium bromide in aqueous solution , 1995 .

[31]  R. Bergeron,et al.  Dependence of cycloamylose-substrate binding on charge , 1978 .

[32]  D. Fessas,et al.  Thermodynamics of the interaction of cyclodextrins with aromatic and α, ω-amino acids in aqueous solutions: a calorimetric study at 25°C , 1995 .

[33]  Yoshihisa Inoue,et al.  Calorimetric titration of inclusion complexation with modified .beta.-cyclodextrins. Enthalpy-entropy compensation in host-guest complexation: from ionophore to cyclodextrin and cyclophane , 1993 .

[34]  J. Szafranek,et al.  Thermogravimetric properties of inclusion complexes ofβ-cyclodextrin with benzene, acetylsalicylic acid and methyl salicylate , 1993 .

[35]  D. F. Lewis,et al.  Host properties of cyclodextrins towards anion constituents of antigenic determinants. A thermodynamic study in water and in N,N-dimethylformamide , 1990 .

[36]  K. Tawarah.  A thermodynamic study of the inclusion processes of α- andβ-cyclodextrins with the acid forms of methyl orange and methyl yellow , 1992 .

[37]  D. Kristol,et al.  Cyclodextrin inclusion complexes: studies of the variation in the size of alicyclic guests , 1989 .

[38]  R. Goldberg,et al.  Thermodynamic and NMR Study of the Interactions of Cyclodextrins with Cyclohexane Derivatives , 1994 .

[39]  W F van Gunsteren,et al.  On the occurrence of three-center hydrogen bonds in cyclodextrins in crystalline form and in aqueous solution: comparison of neutron diffraction and molecular dynamics results. , 1988, Journal of biomolecular structure & dynamics.

[40]  I. Gómez-Orellana,et al.  The thermodynamics of the binding of benzene to β-cyclodextrin in aqueous solution , 1993 .

[41]  H. Schneider,et al.  Host-guest chemistry. 14. Solvent and salt effects on binding constants of organic substrates in macrocyclic host compounds. A general equation measuring hydrophobic binding contributions , 1988 .

[42]  K. A. Connors,et al.  Complexing of .alpha.-cyclodextrin with sym-4,4'-disubstituted biphenyls , 1988 .

[43]  K. A. Connors,et al.  Complex formation between alpha-cyclodextrin and 4-substituted phenols studied by potentiometric and competitive spectrophotometric methods. , 1983, Journal of pharmaceutical sciences.