The Red Cage: Implementation of pH-Responsiveness Within a Macrobicyclic Pyridinium-Based Molecular Host

[Abstract] We present herein the implementation of pH-responsiveness into a new polycationic macrobicyclic structure, namely what we have termed the “red cage”. The hydrolytically-stable cryptand-like compound has been prepared in a relatively high yield in aqueous media by a kinetically-controlled hydrazone-exchange reaction, promoted by the unusual high stability of the new hydrazone C[double bond, length as m-dash]N bonds formed. In organic media the macrobicycle was found not able to complex model aromatic substrates. In buffered aqueous solutions, as a comparison, the “red cage” was found able to recognize them, but the binding was observed to be more efficient in acidic form of the cyclophane compared with its conjugate base.We are thankful for the funding received from the Agencia Estatal de Investigación and FEDER (PID2019-105272GB-I00 and CTQ2017-89166-R), the Xunta de Galicia (ED431C 2018/39 and 508/2020), and the European Research Council (grant agreement no. 851179). I. N. and P. C. thank, respectively, the MECD (FPU program, FPU2016/02347) and Xunta de Galicia (Axudas de Apoio á Etapa de Formación Predoutoral, ED481A-2020/019) for financial support. A. B. G. thanks Xunta de Galicia for a Postdoctoral Fellowship (ED481B-2021-099). E. P. thanks the Agencia Estatal de Investigación for her Ramón y Cajal contract (RYC2019-027199-I). H. Li wants to thank the financial supports from the National Natural Science Foundation of China (no. 91856116, 21772173, and 21922108), and the Natural Science Foundation of Zhejiang Province (no. LR18B020001). The authors are deeply grateful to professor Jonathan L. Sessler, for promoting and encouraging the collaboration reported herein: "we should be competing with Mother Nature to extract her secrets, not with one another!"Xunta de Galicia; ED431C 2018/39Xunta de Galicia; ED431C 508/2020Xunta de Galicia; ED481A-2020/019Xunta de Galicia; ED481B-2021-099China. National Natural Science Foundation of China; 91856116China. National Natural Science Foundation of China; 21772173China. National Natural Science Foundation of China; 21922108China. Natural Science Foundation of Zhejiang Province; LR18B02000