Jadhav Vinod D, Herdtweck Eberhardt, Schmidtchen Franz P
Department of Chemistry, Technical University of Munich, Lichtenbergstrasse 4, 85747 Garching, Germany.
Chemistry. 2008;14(20):6098-107. doi: 10.1002/chem.200702036.
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.
双环六氢嘧啶并[1,2a]嘧啶阳离子骨架具有与多种含氧阴离子（磷酸盐、羧酸盐、方酸盐、次膦酸盐）结合的众所周知的能力。基于这一特性，在母体主体上引入仲羧酰胺取代基以生成化合物1 - 3，旨在提高阴离子结合亲和力和选择性，并了解熵因素的作用和大小。双环胍化合物通过相应的四酯22采用汇聚策略制备，随后进行催化酰胺化反应。在乙腈中用等温滴定量热法进行的主客体结合研究，探究了人工主体1 - 3与四烯丙基胍化合物4相比，在结合对硝基苯甲酸盐、磷酸二氢盐和2,2'-双酚环磷酸酯客体时的行为，这些客体在10⁵ - 10⁶ M⁻¹范围内显示出增强的亲和力。与预期相反，更好的结合源于更正的缔合熵，而非更强的焓相互作用（氢键）。在DMSO中的核磁共振光谱滴定中，邻苯二甲酸盐碱性足够强，能从胍官能团夺取一个质子，产物的X射线晶体结构证实了这一点。新型的 appended 羧酰胺锚定基团在甲醇中也能结合羧酸盐和磷酸盐，但不能结合硫酸氢盐，亲和力超过10⁴ M⁻¹。甲醇中络合的能量特征相对于乙腈溶剂是相反的，显示出一般离子对的模式，强正熵补偿了吸热的结合焓。这项研究提供了一个例子，即母体胍锚定官能团用额外的结合官能团进行真正的修饰可能会提供所需主客体亲和力的增强，但原因与标准分子建模指导下设计所实现的不同。
