Complexation of neutral guest molecules by synthetic macroheterocyclic hosts

Macroheterocyclic molecules can be used to organize the binding sites required for selective molecular recognition and/or molecular catalysis. Although most work in the literature deals with recognition of ionic species, there is an increasing interest in the selective complexation of neutral molecules. Based on X‐ray analysis of solid complexes and NMR in solution, hydrogen bonding of host to guest and/or vice versa determines the structure, and very likely also the stability of these complexes between neutral host and guests. This paper describes an NMR method to determine the (weak) association constants of such complexes. Subsequently, two strategies are described for the enhancement of the thermodynamic stability, viz. the introduction of (intraannular) acidic groups in the molecular cavity and the use of metallomacrocyclic hosts in which a ‘soft’ cavity is combined with a ‘hard’ macrocyclic moiety. For both approaches novel synthetic methodology has been designed and for the first approach, the pKa values of acidic groups present in molecular cavities have been studied. Finally we have used the novel metallomacrocycles to organize two (or more) different metal centres in molecular cavities.