Structural & Supramolecular Chemistry Research Group – Research – Structure and intermolecular interactions of host-guest complexes

B. Structure and intermolecular interactions of host-guest complexes

Supramolecular systems involving cyclodextrins (CDs), macrocyclic carbohydrates of varying size (α, β, γ-CD) comprises one of the main topics of the laboratory. CDs have a hydrophobic cavity in which a plethora of hydrophobic molecules can be encapsulated (Scheme B1). The laboratory has a long experience in structural studies of CD inclusion complexes in the crystalline state and in aqueous solution. Aspects of complex formation regarding self assembly in the solid sate, strongly influenced by the structure of the guest molecule, complexation variants in solution, enantioselectivity and enantiospecificity issues have been studied.

Scheme B1. An inclusion complex is formed by a cyclodextrin (green) and a guest molecule (pink).

B1. Crystal structures by X-ray analysis: influence of the guest on the self assembly of hosts in the crystal

Structural studies of β-CD have revealed that the majority of complexes form dimers in the crystalline state (Figure 1a,b, c), which pack in four major packing arrangements,B1-B3 however interesting exceptions (trimers) are also observed (Figure 1d).B4

Figure B1. Packing modes of βCD complexes (a) dimers with tridecanoic acid, host:guest, 2:1 (channel); (b) tridecanedioic acid, 2:1 complex and (c) N-acetyl-L-tryptophan, 2:2 complex (broken channel); (d) Trimers of the βCD-pyridinealdazine 3:2 complex.

B2. Crystal and solution structures of bioactive compounds molecularly enclosed into cyclodextrin hosts

Comparative studies in the solid state and in aqueous solution (mainly by X-ray crystallography and NMR spectroscopy) of CD complexes with guests (Figure 2), such as drugs (acemetacin,B5 triclosan,B6 sulfonylurea anti-diabetic drugs, B7 penicillinsB8), pheromones (dacus B9-B10 and prays oleaeB11 sex pheromonesB11), nucleotidesB12, amino acidsB13 and various model systemsB14-B17 that allow to study self-organization, B18,B19 guest recognition and enantioselectivity in binding.B9-11, B13, B20

Figure B2. (a) A βCD dimer enclosing the anti-diabetic drug, tolazamide in the crystal; (b) the complex of βCD dimer with the antibacterial agent triclosan; (c) mode of inclusion of deoxyadenosine monophosphate into the cavity of a guanidinylated β-CD dimer in solution.

B3. Enantioselectivity in the crystal and in solution

The inherent chirality of the cyclodextrin hosts frequently impacts the selectivity of binding of a chiral guest. Depending on the size and the flexibility of the host molecule, the manifestation of enantioselectivity toward a specific chiral guest can be impressive (Figure B3). In aqueous solution either preference or no preference toward one of the enantiomers can be observed, however upon crystallization the numerous soft host-guest interactions that determine preference in solution are magnified by the imposed crystallographic order and crystallization of only one of the enantiomers may be observed. Characteristic examplesB9-10 are permethylated α-CD that forms crystalline inclusion complex with only the (R)-enantiomer of the olive tree fly Bactrocera oleae (Dacus) pheromone, whereas permethylated β-CD with only the (S)-enantiomer (Figure B3a,b).

Figure B3. (a) In the crystal only the (R)-enantiomer of a Dacus insect pheromone is encapsulated by per-2,3,6-O-methyl-α-CD (enantiospecificity);B9 (b) In the crystal primarily the (S)-enantiomer of the same insect pheromone is encapsulated by per-2,3,6-O-methyl-β-CD (enantioselectivity); B10 (c) β-CD forms a crystalline complex only with N-Acetyl-L-tryptophan (the crystalline complex of the D-enantiomer cannot be obtained).B11

  1. The Crystal Structure of the 4-tert-Butylbenzyl Alkohol β -Cyclodextrin Complex. Common Features in the Geometry of the β-cyclodextrin Dimeric Complexes. Mentzafos, I. M. Mavridis, G. Le Bas and G.Tsoucaris, Acta Crystallogr. 1991, B47, 746-757. (review article)
  2. Molecular structures of the inclusion complexes β-Cyclodextrin/1,2-bis(4-aminophenyl)ethane and β-Cyclodextrin/4,4΄-diaminobiphenyl. Packing of dimeric β-Cyclodextrin inclusion complexes. P. Giastas, K. Yannakopoulou and M. Mavridis, Acta Crystallogr. 2003, B59, 287-299.
  3. Organization of long aliphatic monocarboxylic acids in β-cyclodextrin channels. S. Makedonopoulou, M. Mavridis, K. Yannakopoulou, J. Papaioannou J. Chem. Soc. Chem. Commun. 1998, 2133-2134.
  4. β-Cyclodextrin trimers enclosing an unusual organization of guest: The inclusion complex β-Cyclodextrin/4-pyridinealdazine. S. D. Chatziefthimiou, K. Yannakopoulou, M. Mavridis Cryst. Eng. Comm. 2007, 9, 976-979.
  5. The Self-Association of the Drug Acemetacin and its Intermolecular Interactions and Stability with β-Cyclodextrin in Aqueous Solution. An NMR and HPLC Study. D. Zouvelekis, K. Yannakopoulou, A. Antoniadou-Vyza, M. Mavridis, Carbohydr. Res. 2002, 337, 1387-1395.
  6. Crystal structure of the inclusion complex of the antibacterial agent triclosan in β-cyclodextrin and NMR study of its molecular encapsulation in positively and negatively charged cyclodextrins. A. Paulidou, D. Maffeo, K. Yannakopoulou, M. Mavridis, Carbohydr. Res. 2008, 343, 2634-2640.
  7. Similar modes of inclusion in complexes of β-cyclodextrin with sulfonylurea hypoglycemic drugs. A. Paulidou, D. Maffeo, K. Yannakopoulou, M. Mavridis Cryst. Eng. Comm. 2010, 12, 517-525.
  8. Positive Effect of Natural and Negatively Charged Cyclodextrins on the Stabilization of Penicillins towards β-Lactamase Degradation due to Inclusion and External Guest-Host Association. An NMR and MS Study. D. Maffeo, L. Leondiadis, M. Mavridis, K. Yannakopoulou Org. Biomol. Chem. 2006, 4, 1297-1304.
  9. Chiral Recognition of (R)-(-)-1,7-Dioxaspiro[5.5]undecane by Hexakis(2,3,6-tri-O-methyl)-α-Cyclodextrin. K. Yannakopoulou, D. Mentzafos, M. Mavridis and K. Dandika, Angew. Chem. Int. Ed. 1996, 35, 2480-2482.
  10. Non-covalent interactions in the crystallization of enantiomers of 1,7-dioxaspiro[5.5]undecane (olive fly sex pheromone) by enantiospecific cyclodextrin hosts, hexakis(2,3,6-tri-O-methyl)-α-cyclodextrin and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin. S. Makedonopoulou, K. Yannakopoulou, D. Mentzafos, V. Lamzin, A. Popov, I. M. Mavridis, Acta Crystallogr. 2001, B57, 399-409.
  11. Controlled Release of the Prays Oleae Pheromone, as a Consequence of Supramolecular Structure: Study of the Z-7-Tetradecenal/β-Cyclodextrin Complex in the Solid state and in Solution. K. Yannakopoulou, J. A. Ripmeester, M. Mavridis J. Chem. Soc. Perkin 2, 2002, 1639-1644.
  12. Binding of nucleotides and nucleosides to per(6-guanidino-6-deoxy)-cyclodextrins in solution. Ch. Aggelidou, M. Mavridis, K. Yannakopoulou Eur. J. Org. Chem. 2009, 2299-2305.
  13. Molecular recognition of N-acetyltryptophan enantiomers by β-cyclodextrin. S. D. Chatziefthimiou, M. Inclán, P. Giastas, A. Papakyriakou, K. Yannakopoulou, I. M. Mavridis Beilstein J. Org. Chem. 2017, 13, 1572-1582
  14. Threading of long end-functionalised organic molecules into cyclodextrins: Structural analysis in aqueous solution by NMR spectroscopy and in the solid state by X-ray crystallography. Yannakopoulou, I. M. Mavridis Current Org. Chem. 2004, 8, 25-34. (review article)
  15. Rotaxane and Catenane Structures Involving Cyclodextrins. K. Yannakopoulou, I. M. Mavridis, invited chapter in the Handbook “Cyclodextrins and their Complexes. Chemistry, Analytical Methods and Applications” H. Dodziuk, Ed., p. 356-369, ISBN 3-527-31280-3 Wiley-VCH, Weinheim, 2006. (review article)
  16. NMR detection of simultaneous formation of [2]- and [3]pseudorotaxanes in aqueous solution between α-cyclodextrin and linear aliphatic α,ω-aminoacids, an α,ω-diamine and an α,ω-diacid of similar length, and comparison with the solid state structures. K. Eliadou, K. Yannakopoulou, A. Rontoyianni, I. M. Mavridis, Org. Chem. 1999, 64, 6217-6226.
  17. Rotaxanation of Congo Red into γ-Cyclodextrin. Solution Structures and Thermodynamic Parameters of 1:1 and 2:2 Adducts, as Obtained from NMR Spectroscopy and Microcalorimetry. N. Mourtzis, G. Cordoyiannis, G. Nounesis, K. Yannakopoulou Chem. 2003, 15, 639-649.
  18. Synthesis of 6-Mono-6-deoxy-β-cyclodextrins substituted with isomeric aminobenzoic acids. Structural Characterization, Conformational Preferences and Self-inclusion, as Studied by NMR Spectroscopy in Aqueous Solution, and by X-Ray Crystallography in the Solid State. Eliadou, P. Giastas, K. Yannakopoulou, I. M. Mavridis, J. Org. Chem. 2003, 68, 8550-8557.
  19. Cooperative heterodimer formation between per-guadinylated and carboxylated or phoshphyorylated cyclodextrins in DMSO and DMSO-water studied by NMR spectroscopy and Microcalorimetry. K. Fotiadou, A. Thanassoulas, G. Nounesis, K. Yannakopoulou, Chem. 2011, 23, 493-500.
  20. Real time monitoring of nanomolar binding to a cyclodextrin monolayer immobilised on a Si/SiO2/Novolac surface using White Light Reflectance Spectroscopy: The case of triclosan. Maffeo, Z. Velkov, K. Misiakos, K. Mergia, A. Paulidou, M. Zavali, I. M. Mavridis, K. Yannakopoulou J. Colloid. Interface Sci. 2011, 358, 369–375.