The conceptually novel active template (AT) approach to mechanically interlocked molecules recently introduced by Leigh and co-workers relies on a catalytically active metal center, bound within the cavity of macrocycle, which mediates the formation of a new covalent bond through the ring. [1] Much as the development of passive template methods over the last three decades has allowed the realization of increasingly complex interlocked molecular architectures [2] as well as prototypical molecular machines [3] such as switches, [4] motors, [5] and ratchets, [6] the AT approach has the potential to significantly increase the diversity of synthetically accessible interlocked structures. The AT approach is particularly synthetically powerful as, in principle, any metal-mediated bond formation can be adapted for use in the key bond forming step. Indeed in the six years since the first ATreaction was reported, [1a] based on the Sharpless-Huisgen-MeldalFokin copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, [7] the concept has been extended to nine other metal-mediated bond forming reactions, and applied to the synthesis of molecular shuttles, [1d,e,g,l] catenanes, [1h,i] and molecules with multiple mechanical bonds. [1d,k] However, although a number of different combinations of metal and ligand motif have been investigated and shown to effectively mediate rotaxane synthesis, all AT reactions disclosed have employed macrocycles with relatively large cavities, mandating the use of half-threads bearing extremely bulky stoppering units (typically substituted trityl moieties). [1] This prohibits the use of simple derivatives of commercially available materials and places limitations on the structure and properties of the rotaxane products, undermining the synthetic utility of the approach. Further, in some applications, including those where the macrocycle mechanically protects the thread from the local environment (prodrugs, [8] insulated molecular wires, [9] and mechanically protected dyes [10] ) and situations in which information transfer between the thread and macrocycle is desirable (sensing [11] and mechanically interlocked chiral catalysts [12] ), a "tight" fit between macrocycle and thread is required.Thus, we set out to ascertain the effect of macrocycle size in the active template synthesis of rotaxanes using the CuAAC-AT reaction as a model. The results obtained indicate that, although size matters, bigger macrocycles are not always better. Indeed, we demonstrate that this approach allows ready access to "small" functionalized rotaxanes based on commercially available materials in consistently excellent yields.The size of the macrocyclic cavity was varied by modifying the length of the alkyl linker between the phenolic oxygens in bipyridine macrocycles 3, and their efficacy in the CuAAC-AT reaction was assessed (Scheme 1, Table 1). In the case of Scheme 1. Variation of macrocycle size in the bipyridine-mediated CuAAC-AT reaction.

Although the central role that zinc plays in many biological processes and important disease states is now well-established, there remains a pressing need to develop an absolute understanding of the underlying biology of zinc trafficking in terms of its dynamic and quantitative processing in specific organelles. Here we describe the modular synthesis of zinc sensors using a 'click' approach and demonstrate the applicability of our new sensors in vivo using a zebrafish model.

Although metal‐ion‐binding interlocked molecules have been under intense investigation for over three decades, their application as scaffolds for the development of sensors for metal ions remains underexplored. In this work, we demonstrate the potential of simple rotaxanes as metal‐ion‐responsive ligand scaffolds through the development of a proof‐of‐concept selective sensor for Zn2+.

We report a high yielding, one-pot method for the synthesis of zinc responsive probes targeted to specific organelles and examine selected sensors in pancreatic islet cells.

The conceptually novel active template (AT) approach to mechanically interlocked molecules recently introduced by Leigh and co-workers relies on a catalytically active metal center, bound within the cavity of macrocycle, which mediates the formation of a new covalent bond through the ring. [1] Much as the development of passive template methods over the last three decades has allowed the realization of increasingly complex interlocked molecular architectures [2] as well as prototypical molecular machines [3] such as switches, [4] motors, [5] and ratchets, [6] the AT approach has the potential to significantly increase the diversity of synthetically accessible interlocked structures. The AT approach is particularly synthetically powerful as, in principle, any metal-mediated bond formation can be adapted for use in the key bond forming step. Indeed in the six years since the first ATreaction was reported, [1a] based on the Sharpless-Huisgen-MeldalFokin copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, [7] the concept has been extended to nine other metal-mediated bond forming reactions, and applied to the synthesis of molecular shuttles, [1d,e,g,l] catenanes, [1h,i] and molecules with multiple mechanical bonds. [1d,k] However, although a number of different combinations of metal and ligand motif have been investigated and shown to effectively mediate rotaxane synthesis, all AT reactions disclosed have employed macrocycles with relatively large cavities, mandating the use of half-threads bearing extremely bulky stoppering units (typically substituted trityl moieties). [1] This prohibits the use of simple derivatives of commercially available materials and places limitations on the structure and properties of the rotaxane products, undermining the synthetic utility of the approach. Further, in some applications, including those where the macrocycle mechanically protects the thread from the local environment (prodrugs, [8] insulated molecular wires, [9] and mechanically protected dyes [10] ) and situations in which information transfer between the thread and macrocycle is desirable (sensing [11] and mechanically interlocked chiral catalysts [12] ), a "tight" fit between macrocycle and thread is required.Thus, we set out to ascertain the effect of macrocycle size in the active template synthesis of rotaxanes using the CuAAC-AT reaction as a model. The results obtained indicate that, although size matters, bigger macrocycles are not always better. Indeed, we demonstrate that this approach allows ready access to "small" functionalized rotaxanes based on commercially available materials in consistently excellent yields.The size of the macrocyclic cavity was varied by modifying the length of the alkyl linker between the phenolic oxygens in bipyridine macrocycles 3, and their efficacy in the CuAAC-AT reaction was assessed (Scheme 1, Table 1). In the case of Scheme 1. Variation of macrocycle size in the bipyridine-mediated CuAAC-AT reaction.