Addressing association entropy by reconstructing guanidinium anchor groups for anion binding: design, synthesis, and host-guest binding studies in polar and protic solutions.
The bicyclic hexahydropyrimidino[1,2a]pyrimidine cationic scaffold has a well-known capacity to bind a variety of oxoanions (phosphates, carboxylates, squarates, phosphinates). Based on this feature, the parent host was supplemented with sec-carboxamido substituents to generate compounds 1-3 in an effort to improve the anion-binding affinity and selectivity and to learn about the role and magnitude of entropic factors. Bicyclic guanidinium compounds were prepared by a convergent strategy via the corresponding tetraester 22 followed by catalytic amidation. Host-guest binding studies with isothermal titration calorimetry in acetonitrile probed the behavior of artificial hosts 1-3 in comparison with the tetraallylguanidinium compound 4 on binding p-nitrobenzoate, dihydrogenphosphate, and 2,2'-bisphenolcyclophosphate guests that showed enhanced affinities in the 10(5)-10(6) M(-1) range. Contrary to expectation, better binding emerges from more positive association entropies rather than from stronger enthalpic interactions (hydrogen bonding). In an NMR spectroscopy titration in DMSO, o-phthalate was sufficiently basic to abstract a proton from the guanidinium function, as confirmed by an X-ray crystal structure of the product. The novel carboxamide-appended anchor groups also bind carboxylates and phosphates, but not hydrogen sulfate in methanol with affinities in excess of 10(4) M(-1). The energetic signature of the complexation in methanol is inverted with respect to acetonitrile solvent and shows a pattern of general ion pairing with strong positive entropies overcompensating endothermic binding enthalpies. This study provides an example of the fact that bona fide decoration of a parent guanidinium anchor function with an additional binding functionality may provide the desired enhancement of the host-guest affinity, yet for a different reason than that implemented by design as guided by standard molecular modeling.
Department of Chemistry, Technical University of Munich, Lichtenbergstrasse 4, 85747 Garching, Germany.
Vinod D
VD
Jadhav
Eberhardt
E
Herdtweck
Franz P
FP
Schmidtchen
D000838:Anions / Q000737:chemistry; D002151:Calorimetry; D019277:Entropy; D019791:Guanidine / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D010100:Oxygen / Q000737:chemistry; D012996:Solutions
D000838:Anions; D012996:Solutions; D019791:Guanidine; D010100:Oxygen