Editorial: Toward a Few Good Reactions: Celebrating Click Chemistry’s First Decade

Ten years ago, at the vortex of “Click Chemistry”, many people on the campus of the Scripps Research Institute at La Jolla had already heard the term “Click Chemistry” before the historic manuscript by Kolb, Finn, and Sharpless appeared in Angewandte Chemie: “Click Chemistry: Diverse Chemical Function from A Few Good Reactions”.1 However, if someone claimed that click chemistry would become one of the most important concepts in chemistry in the next decade (so important that the term no longer requires apostrophes or capitalization), you would not find many supporters, despite the father of the idea already having a track record that won him a Nobel Prize later the same year. In the Acknowledgements of that Angewandte Chemie paper, the authors wrote: “We are very grateful to the following co-workers for their willingness to sail the click chemistry waters, and especially to those who have waited as long as several years to see their efforts reach the printed page.”1 Indeed, it was extremely difficult to deliver the click chemistry concept to many traditional chemists in the early years of its development. Today, we are ecstatic to find how the concept has garnered the attention of thousands of chemists and biochemists from all fields in one short decade. According to the Web of ScienceSM, the original paper was cited more than 2,700 times in the past ten years2, and it’s still on Angewandte Chemie’s most-cited list. Through mid-2007, Sharpless’s group updated a website of selected click-related papers (http://www.scripps.edu/chem/sharpless/click.html). But, as indicated in one of his recent correspondences: “I′ve given up collecting everything click, it’s completely out of control. What interests me most right now is how Invitrogen’s Click-ItTM kits are being used to label and light up the DNA of brand new cells. But even the applications in this area are becoming overwhelming.”3 The essence of chemistry is to create new function through the formation of different linkages (i.e. bonds or supramolecular interactions). Click chemistry, conceived by Sharpless early in the ‘90s (and coined by him in about 1995), revisits this fundamental. It represents some highly reliable chemical reactions which can link individual units together. Therefore, a click reaction is a modular approach which must be of broad scope, giving high transformation efficiency under non-exotic reaction conditions with trivial product-isolation protocols. To date, the concept of click chemistry and certain types of reactions have been welcomed by all disciplines of chemistry and related fields, including organic synthesis, medicinal chemistry, supramolecular chemistry, polymer synthesis, nanochemistry, surface chemistry (indeed, all the materials sciences), analytical chemistry, petroleum chemistry, nuclear chemistry, sensor development, biochemistry, and cell biology. In this issue of Chemistry An Asian Journal, we try our best to include original research papers and focus reviews by many of the active players in these fields. As one winds through the maze of the enormous knowledge base of organic reactions, significantly, only a handful can be claimed as click reactions. Since click-quality reactions need to be highly exothermic, most click components contain carboncarbon multiple bonds, and the reactions often involve the formation of carbonheteroatom (e.g. N, O, and S) linkages. Among them, the copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction is regarded as the “jewel in the crown” of click chemistry. Both azides and alkynes are high in chemical potential energy, yet unreactive toward most nucleophiles, electrophiles, and solvents common to standard organic reaction conditions. They are small, relatively nonpolar, and incapable of strong hydrogen bonding, thus unlikely to significantly change the properties of structures (big or small, bio- or nonbio-, molecules or surfaces) to which they are attached. More importantly, both azido and alkynyl groups can be readily introduced into different substrates. Pioneered by Huisgen in the 1950s and 60s,4 the 1,3-dipolar cycloaddition reaction between alkynes and azides to form 1,2,3-triazoles is well documented in the literature. However, not until the discovery of CuAAC, the reaction’s copper(I)-catalyzed version,5,6 did research scientists launch its renaissance, enabling thousands of applications across the full spectrum of molecular science. As readers can find from many of the articles in this issue, CuAAC’s existence (and its variants) became the primary engine driving click chemistry’s explosive growth. Due to the CuAAC reaction’s ubiquity, it is often incorrectly called “the click reaction” or even “click chemistry” itself. However, Click Chemistry ≠ CuAAC reaction!!! No question, “click reaction” is a snappier brand name than the correct term, “CuAAC reaction”, which is the acronym for a long, tongue-twisting term: copper-catalyzed azide–alkyne cycloaddition, and requires an understanding of organic chemistry to make sense. To make the reaction’s correct name as handy as it is, it is our privilege (with the enthusiastic support of Professors Fokin, Finn, and Sharpless) to propose a solution, that CuAAC hereafter be pronounced “Cue-AAC”. This will eliminate the way the inaccurate term diminishes the central and universal ideal behind the philosophy of click chemistry, which is to use only the best reactions available in the search for substances with desired functions. In fact, the 2011 concept paper by Sharpless and co-authors was a “look-back” exercise, picking the best half-dozen known reactions and awarding them the label, benchmarking the ideal. But above all, that paper proclaimed the certainty that many more click reactions were just waiting to be discovered, and defined a strategy for searching for them. Already over the past decade two more powerful click reactions have emerged: the CuAAC (“Cue-AAC”) reaction—a discovery—and the thiol-ene reaction—a re-discovery. Both processes were immediately recognized and embraced as first rank click reactions. Clearly, the onging challenge for chemists is finding more and more work-horse reactions that deserve the click label. By editing this themed issue of Chemistry-An Asian Journal, it is the editors’ intention to advocate such exciting research endeavor. We would like to thank Professors K. Barry Sharpless and M. G. Finn for their support and suggestions to this themed issue. We would like to thank Jan and Barry Sharpless for their suggestions and proofreading of this editorial. Also, we wish to acknowledge the Editors of Chemistry An Asian Journal and Angewandte Chemie, Brian Johnson and Peter Gölitz, respectively, for their help and guidance. Finally, and most important, we express our appreciation to the authors for their creativity, their significant contributions to science and their cooperation with this project. 1 Qian Wang Department of Chemistry and Biochemistry University of South Carolina Columbia, SC 29208 (USA) E-mail: wang@mail.chem.sc.edu 1 Craig Hawker Department of Chemistry and Biochemistry University of California at Santa Barbara Santa Barbara, CA 93106 (USA) E-mail: hawker@mrl.ucsb.edu