Alkynyl Crown Ethers as a Scaffold for Hyperconjugative Assistance in Noncatalyzed Azide-Alkyne Click Reactions: Ion Sensing through Enhanced Transition-State Stabilization Brian Gold, Paratchata Batsomboon, Gregory B. Dudley,* and Igor V. Alabugin* Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306-4390, United States * S Supporting Information ABSTRACT: Our recent work has provided an alternative strategy for acceleration of azide/alkyne cycloadditions via selective transition state (TS) stabilization. Optimization of hyperconjugative assistance, provided by the antiperiplanar arrangement of propargylic σ-acceptors relative to the forming bonds, is predicted to relieve strain in cyclooctynes while providing large acceleration to the cycloaddition. The present work investigates this strategy in alkynyl crown ethers, where propargylic C-O bonds contained within the macrocycle are constrained close to proper alignment for hyperconjugative assistance. Preorganization of σ-acceptors into the optimal arrangement for hyperconjugative interactions may alleviate a portion of the entropic penalty for reaching the TS. Optimal alignment can be reinforced, and transition-state stabilization can be further amplified by binding positively charged ions to the crown ether core, highlighting the potential for applications in ion sensing. ■ INTRODUCTION “Click chemistry” 1 is revolutionizing the molecular sciences, with applications ranging from drug design 2 and chemical biology 3 to materials science, 4 development of sensors, 5 and polymer chemistry, 6 among others. In vivo applications 7 of the prototypical “click reaction”, 8 the copper-catalyzed variant 9,10 of the Huisgen azide-alkyne cycloaddition (CuAAC), 11 are limited by the toxicity of copper salts. 12 CuAAC also presents a problem in the functionalization of quantum dots and other nanomaterials, as the copper salts negatively impact the luminescent properties of nanocrystals. 13,14 Metal-free alternatives to the CuAAC provided by Bertozzi, 15 Boons, 3b,16 and others 17 have harnessed the “explosive reactivity” of activated cyclooctynes (OCT) in strain- promoted 18 azide-alkyne cycloadditions (SPAAC). These advances have allowed for intracellular azide-cyclooctyne coupling within hours at room temperature, 3a,19 enabling in vivo biological imaging 20 and ultimately spawning a new field of bioorthogonal chemistry. 7 Still in the early stages of develop- ment, bioorthogonal techniques provide new methods for the study of biological processes. Such studies often utilize azide- functionalized sugars, etc., which can be incorporated into biomolecules via natural metabolic pathways. 21 The advantages provided by rapid reaction kinetics prompted the efforts to “brush against the line between stability and reactivity without crossing it,” where lactam-based biarylcyclooctyne (BARAC) provides a 10-fold increase in reactivity over dibenzocyclooc- tyne (DIBO), leading to intracellular coupling within minutes. 22 The initial breakthroughs in SPAAC, discussed above, clearly illustrate the utility of reactant destabilization in the design of reactive alkynes. 23 While strain activation has provided access to an arsenal of options for bioorthogonal applications, this approach cannot escape the inherent drawback of relatively unstable compounds, enhancing the reactivity at the cost of reactant ground-state stabilization. Glimpses of an alternative strategy, transition-state stabilization, appeared when Bertozzi et al. observed the reactivity of OCT can be enhanced >50-fold by incorporation of fluorine atoms at the propargylic position in difluorocyclooctyne (cf. DIFO). 24 The ∼2 kcal/mol decrease in the activation barrier for DIFO relative to cyclooctyne is reproduced by DFT computations, 25 yet specific orbital interactions and an understanding needed in order to fully utilize such an approach remained elusive until recently. 26 In our previous work, we were able to identify precise stereoelectronic interactions responsible for selective TS stabilization (Figure 1). Acceleration is provided via hyper- conjugative assistance for 1,4-addition and a CH···F interaction for 1,5-addition. The stereoelectronic nature of such TS stabilization 27 is revealed by the observation that a single antiperiplanar propargylic fluorine substituent in the acyclic substrate (1-fluorobut-2-yne) is greater than the TS stabilization provided by two gauche fluorines in DIFO. 26 The judicious placement of activating substituents becomes apparent in the recent analysis of electronic effects on BARAC, where the most Received: May 1, 2014 Published: June 13, 2014 Article pubs.acs.org/joc © 2014 American Chemical Society 6221 dx.doi.org/10.1021/jo500958n | J. Org. Chem. 2014, 79, 6221-6232