Journal of Inclusion Phenomena and Molecular Recognition in Chemistry 27: 21–30, 1997. 21 c 1997 Kluwer Academic Publishers. Printed in the Netherlands. Synthesis of a Calix[4]arene Containing ‘Hard’ and ‘Soft’ Metal Ion Binding Sites BUNCHA PULPOKA, ZOUHAIR ASFARI and JACQUES VICENS E.C.P.M., Laboratoire de Chimie des Interactions Mol´ eculaires Sp´ ecifiques, associ´ e au C.N.R.S. 1 rue Blaise Pascal, F-67008, Strasbourg, France. (Received: 28 February 1996; in final form: 10 June 1996) Abstract. Co-receptor 1,3-calix[4]-di(aza-benzo)crown-crown-6 ( 1-H) designed with one cal- ix[4]arene in a 1,3-alternate conformation and ‘hard’ and ‘soft’ metal ion binding sites has been prepared according to three pathways ( A–C). Pathway B, consisting of two different 1 + 1 conden- sations with ditosylate derivatives, was shown to be the most efficient. Key words: Co-receptors, ‘hard’ and ‘soft’, calix[4]arene 1,3-alternate conformation, crown ether, diazabenzo crown-ether, Schiff base. 1. Introduction Co-receptors refer to polytopic receptor molecules combining two or more binding subunits within the same macropolycyclic architecture [1]. A recent review article reports the supramolecular chemistry of those co-receptors which contain com- binations of ‘hard’ and ‘soft’ metal cations in the same molecular structure [2]. When dissymetric, ‘hard’ and ‘soft’ receptors provide entries to molecular behav- ior such as cooperativity, allostery, regulation and transfer signal [1]. For example, the combination of two different polyether loops combining oxygen/sulfur donor atoms leads to ligands with a charge-differentiating effect of the binding compart- ments [3]. Lateral macrobicyclic cryptands have been designed by association of ‘hard’ azoxamacrocycles with ‘soft’ 2,6-dimethylthio pyridine. The resulting het- eroditopic cryptates are well suited for inducing processes of ‘push-pull’ dimetallic substrate activation [4]. Similarly, a lateral macrobicyclic ‘hard’ and ‘soft’ cryptand containing an -phenanthroline subunit and an aza-crown ether has been prepared for forming copper(I) and rhodium(I)-alkali complexes [5]. More recently, the synthesis of diazatetraoxacyclooctadecane derivatives bearing two catechol groups has been designed to bind simultaneously alkaline and transition metal cations [6]. ‘Hard-soft’ ditopic metal binding sites have been attached to a calix[4]arene in the cone conformation. It has been established that silver cation can coexist with sodium in the ionophoric cavity [7]. A metallomacrocycle has been designed from calix[4]arene in the l,3-alternate conformation with a salophene unit on one side Author for correspondence.