Click Chemistry: The Certainty of Chance (Nobel Lecture)**

The click chemist's playground: The most important certainty-of-chance outcome of click chemistry was the realization that perfect reactions can exist. Chemistry is about bond-making and bond-breaking reactions between atoms and molecules. So, the emergence of "perfect reaction" status promises to be transformative to the very heart of chemistry, and thence to the range of benefits for mankind that its future evolution may hold. If one is fortunate, one can spend time and effort trying to figure out how the world works. Since my college days, I have been obsessed with trying to understand the properties and relationships of the elements. Focusing on Selenium chemistry early in my career,1 I quickly learned that exciting new reactivity can be found almost anywhere in the Table, among main group elements (Se, S) as well as transition metals (Ti, Os, Cu) (Figure 1).2-5 All these years later, I am still obsessed and still learning. The click chemist's playground. George S. Hammond's profound Norris Award lecture (1968) taught us that "The most fundamental and lasting objective of synthesis is not the production of new compounds, but production of properties." This resonated with me from the beginning of my career and has guided my research ever since. It is my lifelong mission to provide chemists everywhere with easy access to more power, more speed, more reliability. I have also always regarded simplicity and utility as being more appealing than "elegant" complexity, making me, in essence, a process chemist. In this long hunt for good reactions and interesting reactivity, which began at MIT in the 1970s, my idea was to go fishing in the Table with the help of some fearless colleagues. And so, over the years, beyond the common fare, several unknown "creatures" emerged before us, and some of these strangers even turned out to be keepers! I started out seeking general solutions to known goals – expanding selectivity in the construction of molecules – but realized in late 1996 that asymmetric catalytic synthesis had become quite unsatisfying for me. Therefore, I decided to act on my core belief that the best way to achieve powerful (functional) chemistry is through reliable methods of bond formation. Thus, it became my mission to provide the bond forming tools that would enable the discovery and production of new properties through process-chemistry driven discovery. We needed a memorable name for this new way of thinking, and after some consideration, my wife Jan came up with the term "Click Chemistry". There is so incredibly much to discover, and chemical space is big, really big! The estimable Derek Lowe in 2014 reflected on the "Enumeration of 166 Billion Organic Small Molecules in the Chemical Universe Database GDB-17," by J−L Reymond, U of Bern:6 "The best guess for the number of plausible compounds up to molecular weight 500…is around 1060 …a number that the human mind is not well equipped to handle. That collection, assembled into compound vials at, say, 10 mg per vial, would exceed the amount of ordinary matter in the entire universe." Consequently, given the tremendous size of the chemical universe and the countless opportunities within it, we felt that there was no time to waste with complex, multi-step syntheses. Instead, we were convinced from the beginning that click chemistry is the best method, because the better we can rapidly build molecules, the more efficient the exploration of diverse chemical space to find or improve function will be. Hartmuth C. Kolb, M.G. Finn and I laid out our vision in our 2001 Click Chemistry manifesto entitled "Diverse Chemical Function from a Few Good Reactions".7 Fast and reliable inter-molecular connections are the key. If you have them, you are best equipped to access the vast chemical space and take advantage of "the certainty of chance." What do we mean by "Certainty of Chance"? The obituary of writer and jazzman George Melly (The Economist, July 12, 2007) illustrates this very well:8 "But Mr Melly liked fishing for another reason. As a lifelong Surrealist, he was sure that the bizarre and marvelous lay in wait for him everywhere, and carried in his head a Surrealist motto, "the certainty of chance". Chance might give him a fish with the next cast…" In the unimaginably large sea that is chemical space, then, improving the rod and reel seemed a useful pursuit. Originally, – before the discovery of any perfect reactions – we took our cues from Nature, and her preference for making carbon-heteroatom bonds over carbon-carbon bonds to create her premier functional molecules (Figure 2). We therefore started by exploring spring-loaded reactions that made C−O, C−N, and C−S bonds, finding in the literature many that are "modular, wide in scope, give very high yields, generate only inoffensive byproducts that can be removed by nonchromatographic methods."7 Later, we added that they should work in (or on) water, since on this planet water and dioxygen are king! Uncannily, the best click chemistry reactions tend to thrive in this terrestrial milieu (Figure 3).9 Nature is the original combinatorial chemist. She achieves an immense diversity with <40 building blocks; large diversity requires 'big molecules'. The best click chemistry reactions actually thrive in/on/under water.9 Right after I defined our process-chemistry driven mission back in 1997, which was based on some early "neat chemistry" experiments at Scripps in 1996 by postdoctoral co-worker Elizabeth Pease, my lab at Scripps and Hartmuth's group at Coelacanth Corporation got to work. We were a great team: while my lab focused on looking for reliable bond-forming reactions, Hartmuth's lab worked on using them to produce libraries of "drug like" building blocks and chemical libraries for pharma companies. Initially, Coelacanth was a nascent company, built inside an abandoned Mack truck factory (complete with pigeons and mice!) (Figure 4), so Hartmuth spent his first months with his laptop at a Starbucks in New Brunswick, NJ, to assemble these compounds virtually. Later, we made gram quantities in the lab, exactly as planned, which validated our strong belief that we were on the right track with this approach (Figure 5). The heavy lifting was done by notable Coelacanth chemists, Paul Richardson, David Boulton, Laxma Reddy-Kolla, Zhi-Min Wang, Zhi-Cai Shi, Jay Chiang, Koenraad Vanhessche, Alex Gontcharov, Michael Voronkov, Ram Kanamarlapudi, Ashok Rao Tunoori, Cullen Cavallaro, and many others. Click chemistry lab at Coelacanth Corporation in New Brunswick, NJ in 1997. Click Chemistry at Coelacanth – "Rapid Assembly of Drug-Like Molecules". In 1999, Hartmuth and I presented our adventures at the 217th ACS national meeting with a talk entitled "Click Chemistry: A Concept for Merging Process and Discovery Chemistry."10 This was followed by countless presentations around the globe. The Huisgen 1,3-dipolar cycloaddition of azides and alkynes to form disubstituted 1,2,3-triazoles played a prominent role already back then, well before its copper-catalyzed variant (Copper-catalyzed Azide Alkyne Cycloaddition, or CuAAC) emerged (cf. Figure 6). Initially, our views were not met with enthusiasm, and we were accused of just repurposing "old" reactions. What many chemists did not realize back then was that the "old" reactions were often the "best" reactions. Hartmuth and I started working on our click chemistry manifesto around that time, but it took the masterful touch of M.G. to clearly articulate the concepts. An early draft of our Click Chemistry manifesto (1999). The azide-alkyne Huisgen cycloaddition already played a prominent role. Click Chemistry wouldn't have happened without the support of Alfred & Isabel Bader and Richard & Nicky Lerner (Figure 7). The late Alfred Bader, the original "Chemist Collector" and Founder of the Aldrich Chemical Company was not only an angel investor in Coelacanth, but he continued to travel around the world to do what he so much loved doing: collect rare chemicals, which he then provided to us.11 The late Richard Lerner, then President of Scripps, provided me with all the support I needed to keep my group running and to search for better reactions.12 The people who helped launch click chemistry. In the late 1990s, M.G. Finn moved to Scripps Research and became the 3rd founding click chemist, and soon thereafter the three of us published our "click manifesto".7 Recently, the three of us joined forces again to summarize highlights of 20 years of click chemistry.13 How is this related to the "Certainty of Chance"? Nature herself is a master in utilizing the certainty of chance for developing properties, a lesson that was masterfully delivered by Kevin Kelly's book "Out of Control". Here, the author beautifully explains that when the simple elements of complex systems (e.g., beehives, cells, immune systems) interact, their functions change.14 Such systems are Out of [Our] Control – adapting but can't be directed or predicted (Figure 8). Kelly's key message to us was, "There's nothing more addictive than being a god. The great irony of god games is that letting go is the only way to win." "Out of Control",14 by Kevin Kelly – The leadership paradox. M.G. and I both read "Out of Control" in December 1999 and within days we walked the beach, discussing it, and ultimately decided to try to adapt the idea to the difficult chemical challenge of creating a potent enzyme inhibitor, but without designing it. Instead, we presented the enzyme acetylcholinesterase with a variety of azide/alkyne combinations and allowed the target to serve as a molecular-scale reaction vessel for producing its own potent inhibitor, giving birth to "In Situ Click Chemistry – Enzyme Inhibitors Made to Their Own Specifications" (Figure 9).15-17 This was the first indication that we were on the right track! It also illustrated a characteristic property of the boundary-crossing nature of click-enabled science, which was to bring us together with wonderful colleagues in a different discipline. In this case, Palmer Taylor (UCSD pharmacologist) and his team were instrumental in figuring out what the enzyme did, and how. In situ click chemistry with acetylcholinesterase. The enzyme assembles its own inhibitors within its binding sites.15-17 In situ click chemistry has found numerous applications, such as for the generation of molecular imaging tracers in Hartmuth's lab,18 and for the identification of peptide-based affinity agents (protein-catalyzed capture agents, PCCs) in Jim Heath's lab through the use of single-generation in situ click chemistry screens against large peptide libraries.19 It has also been performed for screening a large number of azide/alkyne combinations in a micro-fluidics based "lab on a chip.20 When we wrote our Click Chemistry manifesto, our early dreams for click chemistry quickly ran into difficulty: not even the best reactions known in 2001 were good enough for our module connection steps!! Until one or more near perfect reactions were available, the idea of using even just a few sequential linkup steps with diverse building blocks was not realistic, since one quickly arrives at chaos in any serial linkage scenario if the intermolecular linking reactions are not very close to being perfect. In fact, if the average yield per step is "only" 99 % you will have created a mess in 5 or 6 steps (Figure 10). At that time, the only exception was the thiol ene polymer reaction from Charlie Hoyle's laboratory,21 which I learned about in a chance encounter with Craig Hawker at the inaugural Cornforth Symposium in 2002, in Sydney Australia, and which was later named a click reaction. It is the basis of Oleplex for hair care created by Craig Hawker, a striking example of commercial success enabled by reliable chemical bond formation. In order for sequential reactions to provide high yields, each individual step must have yields well over 99.9 %. In the in situ click chemistry by acetylcholinesterase, the triazole made by the enzyme turned out to be the pure syn isomer, whereas the thermal Huisgen azide-alkyne cycloaddition made both 1,4 (anti) and 1,5 (syn) structures. This inspired Luke Green in my lab to try a few metal catalysts, mostly those known to interact well with terminal alkynes. Copper was loud and clear the winner, and I remember being floored by Luke's report to me in the lab the next day, describing the quick completion of a reaction that ordinarily was almost nonexistent at room temperature. This was the birth of the CuAAC process, which was independently discovered by Medal and Tørnoe in Denmark.22, 23 Looking back, I do believe that our process chemistry driven way of thinking gave us the tools and necessary focus to go and find – as well as identify and name – such perfect reactions for the first time. Our two favorites – the CuAAC (2002, Figure 11)22 and SuFEx (2014, described below)24 processes – share a remarkable property: when performed iteratively, say 100 times, in a linear stepwise sequence, the overall yield is often close to quantitative! This realization brought us full circle, back to polymers as an original inspiration for click chemistry: one cannot cleanly make a polymer without extraordinary fidelity and activity in the polymerization reaction (which is why there are so few of them). So, when I met Craig Hawker at the Cornforth Symposium in 2002, sparks flew for both of us! As a world leader in polymer chemistry, Craig was instrumental in driving the adoption of click chemistry by the materials science and polymer communities virtually overnight.25 A key contribution was our collaboration with the Hawker lab to use the CuAAC process to prepare diverse triazole dendrimers in almost quantitative yield (Figure 12).26 Our first CuAAC publication in 2002: "By simply stirring in water, organic azides and terminal alkynes are readily and cleanly converted into 1,4-disubstituted 1,2,3-triazoles through a highly efficient and regioselective copper(I)-catalyzed process." Triazole dendrimers prepared in almost quantitative yield using the CuAAC process.26 Thus, experiencing CuAAC for a few years served as a key point in our own journey to recognizing what a "perfect" reaction was like, and what it could do. Some of the key characteristics are: Forging of inter-molecular connections with 99.9+% yields in a highly specific fashion, producing only one product/isomer; high driving force; works on Earth (in the presence of water and O2); and "always works" (other functional groups don't interfere). Ironically, the most important certainty-of-chance outcome of click chemistry was our realization that perfect reactions can exist! Chemistry is quintessentially about bond-making and bond-breaking reactions between atoms and molecules. So, the emergence of "perfect reaction" status promises to be transformative to the very heart of chemistry, and thence to the range of benefits for mankind that its future evolution may hold. There are only a few at the moment, but there must be more out there, and now that we know what they look like, they will surely be easier to find. The CuAAC reaction was a breakthrough success. We consider it a "magic forge" which hammers in triazole links anytime, anyplace, anywhere. Its two key features has made it almost synonymous with the term click chemistry: the azide and alkyne reactive groups are "invisible" amongst most other organic functional groups, and the linkage reaction is close to unstoppable, with a combination of strong driving force and singular selective path. Such processes are very rare – biology has no need of them – but we do. Qian Wang in M.G.'s lab quickly demonstrated the power of this new reaction by decorating virus particles with dyes, proteins and other agents with complete conversion under very mild conditions (Figure 13).27 This discovery put us well into unprecedented territory! I could not think of any reaction except olefin polymerizations which could compete, but of course they couldn't be performed in the presence of water or O2. Publication of this work was delayed so Qian could prove to us in several ways that the outlandish yield implications were correct. To reach the observed 96 % yield over 60 linear steps the per-step yield had to be 99.93 % [(0.9993)60]. Thus, the border into 'perfect reaction' territory had been crossed! However, it took the discovery of another such process a decade later before we started talking specifically about perfect reactions. Bioconjugation on a virus using the Copper-catalyzed azide-alkyne cycloaddition.27 In 2003, Hartmuth and I summarized the "growing impact of click chemistry on drug discovery" (Figure 14), highlighting that "the copper-(I)-catalyzed 1,2,3-triazole formation from azides and terminal acetylenes is a particularly powerful linking reaction, due to its high degree of dependability, complete specificity, and the bio-compatibility of the reactants" with "applications [being] increasingly found in all aspects of drug discovery, ranging from lead finding through combinatorial chemistry and target-templated in situ chemistry, to proteomics and DNA research, using bioconjugation reactions."28 The growing impact of click chemistry on drug discovery (2003).28 Later we found that water, life's matrix, is also the best 'solvent' for click chemistry. We observed dramatic rate accelerations for insoluble reactants "on water", NOT in water (Figure 15)! Given the giant place for water on earth and click chemistry's happiness in, on, or under water, this late emergence of interfacial water magic is one of my personally most thrilling, and completely unexpected finds.9 Click chemistry "on" water.9 The success of click chemistry opened the flood gates for a variety of applications, all enabled by near-perfect inter-molecular connectivity. ThermoFisher Click-ITTM assays from Salic and Mitchison (2008):29 "A Chemical Method for Fast and Sensitive Detection of DNA Synthesis in vivo" Illumina ClickSeq from Routh, et al. (2015):30 "Fragmentation-Free Next-Generation Sequencing via Click Ligation of Adaptors to Stochastically Terminated 3'-Azido cDNAs" OLAPLEX using the thiol-ene click reaction,21 co-founded by UC Santa Barbara materials scientist and click chemist Craig Hawker Biomedical imaging by Hartmuth's group, utilizing ligand discovery based on intermolecular linkage builders, in situ click chemistry, and rapid radiolabeling by CuAAC (Figure 16 Molecular Imaging enabled by in situ & CuAAC Click Chemistry for Discovery and Radiolabeling. Example: Carbonic Anhydrase Ligands and PET tracer. ).18, 31, 32 The team developed the first (and only) FDA-approved imaging agent for Alzheimer's Disease Tau pathology, 18F−T807 (aka Flortaucipir).33, 34 Our second near-perfect click reaction, the SuFEx [Sulfur(VI) Fluoride Exchange] process, was discovered by Jiajia Dong (Figure 17).24 SuFEx is another "magic wand" that forms -SO2- linkages, the neutral form of Nature's favored -PO2−- linkage .24, 35 It has chameleon-like properties, very different than the triazole linkage made by azide-alkyne cycloaddition: stable but controllably reactive, surprisingly nonpolar but able to interact with other molecular fragments, and structurally flexible but thermodynamically strong. The SuFEx reaction.24 I am incredibly excited about the materials/polymer science opportunities offered by SuFEx because of the last of those characteristics. The making of new polymers (Figure 18) requires hundreds of successive intermolecular connecting steps to occur with extremely high yields in order to give homogeneous, highly pure products. A reaction with 99.999 % per step yield will provide 99 % yield over 1000 steps, but a small drop to 99.9 % per-step yield – which most chemists would consider an excellent reaction – will give an overall yield of just 36.8 %! A drop to 99 % per step will result in just trace amounts of final product. SuFEx meets this challenge and creates a very interesting type of linkage besides. SuFEx – another perfect click chemistry reaction. Thus, Suhua Li demonstrated that SuFEx polymerization proceeded with 99.998 % yield per step, which resulted in a 500-mer polymer with 99 % overall yield. This polymer's 1H and 19F NMR spectra showed only one set of sharp signals (Figure 19), highlighting both the supreme fidelity of each intermolecular connection reaction and the highly dynamic nature of the sulfur-based connectors. NMR spectra of SuFEx polymer showing only one set of sharp signals. Furthermore, we discovered that (a) the [−N=S(=O)F-O−] polymer backbone linkages are themselves SuFExable and undergo precise SuFEx-based post-modification with phenols or amines to yield branched functional polymers, and (b) that several of these new materials derived from thionyl tetrafluoride had helical polymer structures (Figure 20).36 Atomic force microscopy images of thionyl tetrafluoride-based SuFEx polymers, indicating helical coils.36 These discoveries have unlocked a whole new world of click chemistry applications in the field of high-temperature, high-field capacitive energy storage (Figure 21). In collaboration with the labs of Peng Wu (Scripps) and Yi Liu (Berkeley Lab), we found a polysulfate polymer that upon coating with ultrathin Al2O3 allowed us to produce capacitors that maintained their high electrostatic energy storage performance under thermal and electric extremes (≥150 °C and more than 700 million volts per meter!).37 Polysulfates for High-Temperature, High-Field Capacitive Energy Storage.37 This journey through the Certainty of Chance, enabled by Click Chemistry, leaves us with several key lessons. The discovery that perfect reactions actually exist (and more are out there waiting to be discovered) is probably the most fundamental certainty-of-chance observation so far enabled by click chemistry. The faster we can directly create new molecules for screening, the richer will be the flow of new or improved functions. Properties are more generally modified by control of inter-molecular bond connections, not intra-molecular ones. Consequently, fast and reliable inter-molecular connective reactions are the key ingredient in discovery of useful new substances – they enable enormous power in the diversity of modules. With just a few truly perfect linker reactions we can move extremely fast through structural space and have the best chance to uncover exciting function. Linkages matter! CuAAC and SuFEx both leave connective functional groups behind them: triazoles and S(VI) linkages. Beyond their stability under terrestrial conditions, they possess very different properties which are appropriate for diverse applications. Each new click reaction opens new worlds of discovery by chance. To our knowledge, there is at present no better method to quickly explore the universe of chemical properties for useful new functional opportunities. I am extraordinarily grateful to the many co-workers who have joined us on this search for molecular function and chemical reactivity. Most are listed in the table in the Supporting Information, with apologies to any who I may have inadvertently omitted. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. K. Barry Sharpless, an American chemist, is a two-time Nobel laureate in Chemistry. He received the 2001 prize for chirally catalyzed oxidation reactions and the 2022 prize, shared with Carolyn R. Bertozzi and Morten P. Meldal, for click chemistry and bioorthogonal chemistry. Sharpless earned his Ph.D. from Stanford University in 1968 and held faculty positions at MIT, Stanford, and Scripps Research. He pioneered stereoselective oxidation reactions, including asymmetric epoxidation and aminohydroxylation, and coined "click chemistry," transforming chemical synthesis. A recipient of numerous honors, including the Wolf Prize and Priestley Medal, Sharpless continues groundbreaking work at Scripps Research, advancing modern chemistry. Dr. Finn earned his PhD in 1986 from MIT, working with K. Barry Sharpless on the mechanism of the titanium-tartrate catalyzed asymmetric epoxidation. He joined the University of Virginia faculty in 1988, moved to The Scripps Research Institute in 1998, and to the Georgia Institute of Technology in 2013, where he was Chair of the School of Chemistry and Biochemistry until 2025, and also serves as CSO of the Georgia Tech Pediatric Innovation Network. Known for his work on Click Chemistry, the Finn laboratory uses ultra-reliable bond-forming and disconnection chemistries to develop functional materials for drug delivery and molecular separations, protein nanoparticles for chemical biology and immunology, immunologically active small molecules, and novel methods of molecular evolution. Hartmuth C. Kolb earned his PhD in Organic Chemistry from Imperial College London in 1991. From 1997, he worked with K. Barry Sharpless at Coelacanth Corporation on Click Chemistry, contributing to its first publication. Later, he employed Click Chemistry for PET tracer development, including FDA-approved [18F]-T807 ("Tauvid") for imaging tau pathology in Alzheimer's disease. He advanced PET tracers and precision medicine in neuroscience and developed a p217Tau blood test for Alzheimer's. He is a visiting professor at the University of Wisconsin, Madison. He holds 100+ publications and 40+ patents, and his awards include the 2015 Alzheimer Award.