Influence of the Macroring Size on the Self-Association Thermodynamics of Cyclodextrins with a Double-Linked Naphthalene at the Secondary Face M. Jose ́ Gonza ́ lez-A ́ lvarez, † Juan M. Benito, ‡ Jose ́ M. García Ferna ́ ndez, ‡ C. Ortiz Mellet, § and Francisco Mendicuti* ,† † Departamento de Química Física, Universidad de Alcala ́ , 28871 Alcala ́ de Henares Madrid, Spain ‡ Instituto de Investigaciones Químicas (IIQ), CSIC - Universidad de Sevilla, 41092 Sevilla, Spain § Departamento de Química Orga ́ nica, Facultad de Química, Universidad de Sevilla, 41071 Sevilla, Spain *S Supporting Information ABSTRACT: The conformational properties and aggregation behavior of two selectively modified cyclomaltooligosacchar- ides (cyclodextrins, CDs) containing a double-linked 1,8- dimethylnaphthalene cap-like moiety at the secondary face, namely, 2 I ,3 I -O-(1,8-dimetylnaphthalene-α,α′-diyl)-per-O-Me- α- and -γ-cyclodextrins (NmαCD and NmγCD, respectively), in water and in organic solvents were investigated. Both CD derivatives self-associated in water to form dimer species, but the characteristics of the dimerization process and of the resulting dimer strongly depended on the size of the macrocycle. Dimerization constants, thermodynamic parameters upon association, and information about the preferred conformations of the monomer and dimer CD structures were obtained by using NMR, UV−vis, steady-state and time-resolved fluorescence, and circular dichroism experimental techniques, as well as molecular mechanics (MM) and molecular dynamics (MD) simulations. The complexation of 1,8-di(methoxymethyl)naphathalene (oNy) and the heteroassociation of both NmCDs with their permethylated CD partners (mCDs), lacking the aromatic cap, were examined. In addition, the influence of the size of the chromophore moiety on the thermodynamics of self-association was also assessed by comparison of the results obtained for the new naphthalene derivatives with those of the 2 I ,3 I -O-(1,2-xylylene)- modified CD analogues (XmCDs). ■ INTRODUCTION Cyclodextrins (CDs) are natural cyclic oligosaccharides formed of α(1→4)-linked D-glucopyranoside units. The three most common CDs are the hexamer (α-cyclodextrin), heptamer (β- cyclodextrin), and octamer (γ-cyclodextrin). All of them are water-soluble, natural products featuring a basket-shaped architecture with two well differentiated faces bearing the primary (narrower) and secondary hydroxyls (wider), respec- tively, and a hydrophobic cavity that can include guest molecules of appropriate size, thereby acting as molecular containers. 1,2 Chemical modifications of the natural cyclo- dextrins have attracted widespread interest in order to increase their water solubility, improve their binding properties, and enhance their chiral selectivity, molecular recognition, and molecular self-assembling abilities. 3−6 In this context, CD conjugates bearing a chromophore substituent 7−9 are especially interesting due to their potential as chemo-sensors, 7,10 photochemical microreactors, 8,9 and antenna host mole- cules. 11−14 Within fluorescent CDs, naphthalene-modified cyclodextrins have been extensively investigated as light harvesting host molecules, 11,15 building blocks for functional supramolecular architectures, 16,17 catalysts, 18 and in sensing applications. 19−21 Fluorescently labeled CD derivatives and their complexes are also useful tools for real-time monitoring of events involving their interaction with biological receptors or biomacromole- cules. 22−24 Controlling the self-association properties through face-selective modification is a general prerequisite for those channels. 25 Thus, the installation of hydrophobic moieties at the secondary face of CDs facilitates the formation of head-to- head bilayers upon interaction with nucleic acids, which is critical to generate transfectious nanocomplexes. 26−29 Notably, the size of the cyclooligosaccharide ring has been shown to have a strong impact in this process. 30 In this context, the possibility to use naphthalene moieties to simultaneously endow the system with fluorescent and self-assembling properties seemed very appealing. The majority of the reports about naphthalene functionalized CDs focus on βCD architectures. Derivatives of α- and γ- modified CDs are very rarely described, despite the distinct inclusion properties of their cavities. 31,32 Thus, the smallest αCD cavity size is appropriate for forming favorable inclusion complexes with a wide variety of small molecules 31 and linear Received: January 23, 2013 Revised: April 1, 2013 Published: April 16, 2013 Article pubs.acs.org/JPCB © 2013 American Chemical Society 5472 dx.doi.org/10.1021/jp400784t | J. Phys. Chem. B 2013, 117, 5472−5485