Abstract
Advances in supramolecular chemistry are often underpinned by the development of fundamental building blocks and methods enabling their interconversion. In this work, we report the use of an underexplored dynamic covalent reaction for the synthesis of stimuli-responsive [2]rotaxanes. The formamidinium moiety lies at the heart of these mechanically interlocked architectures, because it enables both dynamic covalent exchange and the binding of simple crown ethers. We demonstrated that the rotaxane self-assembly follows a unique reaction pathway and that the complex interplay between crown ether and thread can be controlled in a transient fashion by addition of base and fuel acid. Dynamic combinatorial libraries, when exposed to diverse nucleophiles, revealed a profound stabilizing effect of the mechanical bond as well as intriguing reactivity differences between seemingly similar [2]rotaxanes.
Highlights
Over the past two decades, [2]rotaxanes have found diverse uses, ranging fromselective synthesis and catalysis[1] to molecular machines,[2] the stabilization of reactive groups,1c,2b,3 sequence-specific peptide synthesis,[4] supramolecular medicinal chemistry,[5] materials chemistry,[6] and optoelectronics.3i,7 Future progress on these frontiers will likely depend on the development of methods for the synthesis of new types of mechanically interlocked compounds.[8]
Dynamic covalent chemistry (DCvC)[14] has been employed extensively for the preparation of [2]rotaxanes, [2]catenanes, and more complex mechanically interlocked architectures (MIAs).3j,14e,15 Arguably the most popular reversible organic reaction for the preparation of MIAs has been the condensation of aldehydes with primary amines that gives rise to imines.15f,h,k,16 This dynamic covalent reaction has often been followed by a reduction step, giving rise to a classic pairing of rotaxane chemistry, namely the combination of a secondary ammonium ion thread with a crown ether-type ring.[17]
The mechanical bond between the crown ether and the N,N’-disubstituted formamidinium ion renders the latter much less susceptible to nucleophilic attack and dramatically slows down the interconversion between the two geometrical isomers (E,E and E,Z). We explored these features in depth by coupling the amidinium/ amidine acid−base equilibrium to the fuel acid trichloroacetic acid (TCA) and by coupling dynamic combinatorial libraries (DCL) comprising six rotaxanes with the irreversible action of N-nucleophiles that cause the disassembly of the rotaxanes
Summary
Over the past two decades, [2]rotaxanes have found diverse uses, ranging from (stereo)selective synthesis and catalysis[1] to molecular machines,[2] the stabilization of reactive groups,1c,2b,3 sequence-specific peptide synthesis,[4] supramolecular medicinal chemistry,[5] materials chemistry,[6] and optoelectronics.3i,7 Future progress on these frontiers will likely depend on the development of methods for the synthesis of new types of mechanically interlocked compounds.[8]. Upon addition of strong base NBu4OH to rotaxane 1a, we observed by 1H NMR spectroscopy that benzylic, tert-butyl, and crown ether signals turned into broad singlets, indicative of relatively fast exchange between possible configurational and (co)conformational isomers on the NMR time scale (Schemes S17 and S22, Figure S60). During the rotaxane self-assembly, 24C8 strongly binds to the unsubstituted formamidinium ion (Ka = 9.5 × 103 M−1 in CD3CN at 295 K; Supporting Information, Section 6.1; crystal structure, Figure 3D) and less strongly to the key reaction intermediate−half-thread 3 (Ka ≈ 102 M−1 in CD3CN at 295 K; Supporting Information, Section 6.2; for general structure, see Figure 2A) This leads to the decreased reactivity of the amidinium moiety toward amines, since 24C8 sterically hinders the electrophilic reaction center on the amidinium moiety and presumably reduces its electrophilicity due to hydrogen bonding. A similar DCL of the threads (State 1) did not reveal any selectivity toward reaction with an external, bulky nucleophile (Figure 7B, Figure S69), confirming that that the mechanical bond impacts the thermodynamic stability of the DCL members and their (kinetic) reactivity
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