Journal of Inclusion Phenomena and Molecular Recognition in Chemistry 14:205 215, 1992. 205 © 1992 Kluwer Academic Publishers. Printed in the Netherlands'. A New Ligand-Functionalized fi-Cyclodextrin as a Esterolytic Reagent at Neutral pH ROBERTO FORNASIER, ENNIO SCARPA, PAOLO SCRIMIN,* PAOLO TECILLA, and UMBERTO TONELLATO* Department of Organic" Chemistry and Centro CNR Meccanismi Reazioni Organiche, Universita' di Padova, Via Marzolo 1, 35131 Padova, Italy (Received: 1 June 1992; in final form: 30 September 1992) Abstract. The paper reports the synthesis of a fi-cyclodextrin (fl-CD) derivative (1) functionalized with a ligand subunit at the secondary-hydroxyl rim. The ligand subunit is 2-hydroxymethyl-6-thiomethyl pyridine connected to the macrocycle via a thioether bond. In the presence of Cu(II) ions 1 accelerates the cleavage of the p-nitrophenyl esters of picolinic acid (PNPP), quinaldic acid (PNPQ) and its 6-phenyl derivative (PNPQPh) via the nucleophilic attack of the hydroxyl of the pyridine subunit. However, the fi-CD derivative is less effective than the ligand 2-hydroxymethyl-6-methylthiomethyl pyridine (2), indicating no cooperation between the hydrophobic and metal ion recognition sites. However, in the case of PNPQPh, the observed rate constants in the presence of Cu(II) ions are close to that of model 2 and this suggests we are approaching a binding mode appropriate for taking advantage of the two binding sites of the metal receptor 1 • Cu(II). Interestingly, the most reactive derivative with native fl-CD is the p-nitrophenyl quinaldate (PNPQ) in accord with its mode of complexation to the macrocycle and the location of the actual nucleophile (one of the secondary hydroxyls of fl-CD). Key words. Cyclodextrin, transacylation, metal, Cu(II), catalysis, ester, supramolecule. 1. Introduction The synthesis of functionalized cyclodextrins (CDs) [1] provides new receptors with molecular recognition properties and catalytic behavior often quite different from those of native CDs. For instance, CD derivatives bearing a pendant imidazole [2] may act as catalysts in the cleavage of complexed esters in neutral aqueous solutions, in contrast to native CDs, which react at much higher pHs through a transacylation process [3]. The ability of transition metal ions to act as additional recognition and/or catalytic sites for several substrates [4] has stimulated the investigation of modified cyclodextrins bearing ligand subunits for transition metal ion complexation which may behave as polytopic receptors. Ligand modified CDs have been synthesized by Breslow [5], Tabushi [6], Willner [7], V6gtle [8], Czarnik [9], Schneider [10], and Rizzarelli [11]. Cooperativity between the hydrophobic CD cavity and the metal ion in binding proper substrates [6, 7] as well as catalysis of the hydrolysis of activated esters complexed within the cavity [5, 9, 10] have been reported. We address here the problem of the competition between the two binding sites of a ligand functionalized CD (i.e., the macrocycle's cavity and the metal ion * Authors for correspondence.