Stimuli-responsive disassembly of the mechanical bond: Synthesis and properties of ring-opening 2,2'-bipyridine macrocycles

Abstract

The development of template-directed methodologies have facilitated the synthesis of structurally-diverse mechanically interlocked molecules (MIMs) and prompted investigations into their unique chemical properties. In doing so, MIMs have been transformed from mere synthetic curiosities to functional materials with applications in a range of fields, such as molecular machines, materials, and catalysis. Although often overlooked among the plethora of application-based MIM literature, the use of MIMs in biological applications is a flourishing field. The introductory chapter provides a scoping review of current literature on synthetic interlocked molecules used for biological applications. By analysing the MIMs with respect to the properties of the mechanical bond, the chemical behaviour underpinning their biological function is elucidated. Chapter 2 details the synthesis of a ring-opening 2,2'-bipyridine macrocycle, which mediated AT-CuAAC rotaxination with high efficiency. Upon exposure to UVB light, the photolabile diethylaminobenzyl (DEABn) within the macrocycle backbone was cleaved, resulting in the ring-opening and release of the corresponding axle. In lieu of the expected photocleavage pathway, a surprising intramolecular photo-induced rearrangement was instead found to dominate. The photocleavable macrocycle was successfully incorporated into a dinucleotide rotaxane and later into a model oligonucleotide rotaxane structure. In Chapter 3, the development of a modular platform approach for the generation of ring-opening 2,2'-bipyridine macrocycles is described. A series of macrocycles designed to cleave in response to several different stimuli (pH, chemical, UV, light) were rapidly and conveniently synthesised, and shown to mediate AT-CuAAC rotaxination with high efficiency. Cleavage of the trigger unit in response to the appropriate stimulus generated an intermediate rotaxane species which underwent ring-opening to liberate the axle from the interlocked structure with varying degrees of success. Tailoring the electronic properties of the self-immolative spacer within the macrocycle backbone through judicious structural modification was later shown to significantly improve the ring-opening capability of the macrocycle.

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Identifiers

ORCID for Stephen Goldup: orcid.org/0000-0003-3781-0464

ORCID for Ali Tavassoli: orcid.org/0000-0002-7420-5063

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