Catalysis and inhibition of ester hydrolysis in the presence of resorcinarene hosts functionalized with dimethylamino groups y Giorgio Cevasco, 1 Sergio Thea, 1 * Daniele Vigo, 1z Andrew Williams 2 and Flora Zaman 2 1 Dipartimento di Chimica e Chimica Industriale dell’Universita ` di Genova, C.N.R., Consiglio Nazionale delle Ricerche, Via Dodecaneso, 31,16146 Genova, Italy 2 University Chemical Laboratory, Canterbury, Kent CT2 7NH, UK Received 15 February 2006; revised 18 May 2006; accepted 29 May 2006 ABSTRACT: Complexation and catalysis of two calixresorcinarene (RES) derivatives with nucleophilic N,N-dimethylamino functions attached to their upper rims in the hydrolysis of carboxylate and sulfonate esters of 4-nitrophenol and 2,4-dinitrophenol have been investigated. Rate constants obey the complexation equation: k obs ¼ k b  K S þ k c ½Host K S þ½Host Values of the dissociation constant (K s ) of the complexes are within the range exhibited by other systems such as cyclodextrins–ester complexes. The reactions of sulfonate esters only exhibit inhibition by the macrocyclic hosts. The reactions of the carboxylate esters exhibit catalysis and inhibition depending on the pH of the system. It is proposed that the dimethylamino function in RES3 and RES5 behaves as a nucleophile to form a reactive acylammonium species which subsequently decomposes and regenerates the catalytic amine. In the reaction of substituted phenyl acetates with RES3 the effective charge on the leaving oxygen in the complexed state (þ0.88) is slightly more positive than that in the free ester (þ0.70). The effective charge on the leaving oxygen in the transition structure is substantially more positive (þ0.04 units) than in a model intramolecular reaction of tertiary dimethylamines with aryl esters (0.53 units). The influence of the host on the reaction in the complex includes an electronic component which is ascribed to solvation of the transition structure of the rate-limiting step by water molecules located within the cavity of the host. It is suggested that this solvation is stronger than that occurring in the transition state for the model intramolecular reaction. Copyright # 2006 John Wiley & Sons, Ltd. Supplementary electronic material for this paper is available in Wiley Interscience at http://www.interscience. wiley.com/jpages/0894–3230/supplmat/ KEYWORDS: calixresorcinarenes; molecular receptors; catalysis; esterolysis INTRODUCTION The study of concave, macrocyclic molecules as host analogs of enzymes has enjoyed considerable success, particularly of those derived from cyclodextrins 1 and calixarenes. 2 In this paper we describe the synthesis of water soluble cyclophane derivatives, that is, calixresor- cinarenes RES3 and RES5, which possess a concave region suitable to act as a receptor for substrate complexation and hold functions which are potential nucleophilic catalysts, and their employment in structure- reactivity investigations. The reason for choosing this cyclophane structure is that it has the potential of being modified easily on its rims with a variety of catalytic and binding groups which could be useful in a future combinatorial approach. Moreover, it can be cheaply and easily prepared in large quantity. We believe that design of highly active and selective artificial enzymes could in future be assisted by combinatorial studies of structural libraries of potential catalysts and identification of the structure giving optimum activity. The scope of the catalytic activity of RES3 and RES5 (structures are shown in Chart 1 together with those of their precursors RES1, RES2, and RES4) is measured against the fission of the carboxylate and sulfonate esters displayed in Chart 2 (identity of substituted phenyl acetates is shown in Table 3). JOURNAL OF PHYSICAL ORGANIC CHEMISTRY J. Phys. Org. Chem. 2006; 19: 630–636 Published online 6 November 2006 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/poc.1101 *Correspondence to: S. Thea, Dipartimento di Chimica e Chimica Industriale dell’Universita ` di Genova, C.N.R., Consiglio Nazionale delle Ricerche, Via Dodecaneso, 31,16146 Genova, Italy. E-mail: sergio.thea@chimica.unige.it y Dedicated to the memory of Professor Carlo Dell’Erba (1933–2005). z In partial fulfillment of his PhD thesis. Copyright # 2006 John Wiley & Sons, Ltd. J. Phys. Org. Chem. 2006; 19: 630–636