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 dendrimers in almost quantitative yield using the CuAAC Thus, CuAAC for a few years as a key in our own to what a reaction was and what it of the key of inter-molecular connections with yields in a highly producing only one high driving on the of water and and functional the most important certainty-of-chance outcome of click chemistry was our realization that perfect reactions can 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. There are only a few at the but there must be more out and that we what they they will be to The CuAAC reaction was a We it a which in triazole two key has made it almost with the term click chemistry: the and are most organic functional and the linkage reaction is close to with a of strong driving and Such processes are very rare – has no of them – but we in lab quickly the of this new reaction by with and agents with very (Figure This discovery us well into I not of any reaction which but of they be performed in the of water or of this work was so to us in several that the yield were the % yield over linear steps the yield had to be % Thus, the into had been it took the discovery of another such process a later before we started about perfect reactions. on a using the azide-alkyne In Hartmuth and I the of click chemistry on (Figure that “the from azides and terminal is a powerful linking to its high of and the of the with found in all of from finding through combinatorial chemistry and in situ chemistry, to and using The of click chemistry on discovery we found that water, is also the best for click chemistry. We for in water (Figure the for water on and click or water, this late emergence of water is one of my most and Click chemistry water.9 The success of click chemistry the for a variety of applications, all enabled by inter-molecular from and Chemical for Fast and of in from Click of to using the click by materials and click Craig Hawker imaging by Hartmuth's utilizing discovery based on intermolecular linkage in situ click chemistry, and by CuAAC (Figure enabled by in situ & CuAAC Click Chemistry for Discovery and and The team the first imaging for Our click the SuFEx process, was discovered by (Figure SuFEx is another that the form of linkage It has properties, very different than the triazole linkage made by azide-alkyne but but to interact with molecular and but The SuFEx I am incredibly about the science opportunities by SuFEx because of the of those The making of new polymers (Figure requires of intermolecular steps to with high yields in order to give highly pure A reaction with % per step yield will provide 99 % yield over but a to 99.9 % yield – which most chemists would an reaction – will give an overall yield of just A to 99 % per step will in just of SuFEx this challenge and a very interesting of linkage SuFEx – another perfect click chemistry reaction. Thus, that SuFEx polymerization with % yield per which in a polymer with 99 % overall This and only one of (Figure both the fidelity of each intermolecular connection reaction and the highly nature of the of SuFEx polymer only one of we discovered that the polymer are and with or to yield functional and that several of these new materials from had polymer (Figure of SuFEx have a new world of click chemistry in the of (Figure In collaboration with the of and we found a polymer that with allowed us to produce that their high thermal and and more than per for This through the of enabled by Click us with several key The discovery that perfect reactions actually more are out there to be is the most fundamental certainty-of-chance so enabled by click chemistry. The we can create new molecules for the will be the of new or are more by of inter-molecular bond not Consequently, and reliable inter-molecular reactions are the key in discovery of useful new – they enable in the diversity of just a few perfect reactions we can through space and have the best chance to exciting CuAAC and SuFEx both functional and their terrestrial they very different properties which are for diverse new click reaction new of discovery by our there is at no better to quickly the universe of chemical properties for useful new functional I am to the many who have joined us on this search for molecular function and chemical are in the in the with to any who I may have As a to our and this by the Such materials are and may be for but are not or support from than should be to the The is not for the or of any by the than should be directed to the author for the an chemist, is a in the 2001 for reactions and the with and for click chemistry and chemistry. his from in and at and Scripps reactions, asymmetric and and “click chemical A of numerous the and work at Scripps chemistry. Finn his in from working with on the of the asymmetric joined the of in moved to The Scripps Research in and to the of in he was of the of Chemistry and and also as of the for his work on Click the Finn bond-forming and to functional materials for and molecular for chemical and molecules, and methods of molecular Hartmuth C. his in Organic Chemistry from in 1997, he worked with at Coelacanth Corporation on Click to its first Later, he Click Chemistry for for imaging in tracers and in and a for is a at the of and and his the