Though the Priestley Medal is for “services to chemistry,” my services have always been for chemists: to give you more reliable portals to the bond-making universe and molecular properties and function. I’m just a researcher, and one whose methods are uncommon, so the honor of my being here tonight could not be felt or appreciated more deeply.
I want this talk to be a service too. I’m the product of an upper-middle-class home that wasn’t always a happy one. My house, my schools, and my father’s surgery practice were in Philadelphia, but when asked “Where’s home?” I would say, “Manasquan, New Jersey.”
My mother grew up there, and she took my sister and me to the Jersey shore summers and weekends. On a wooded bluff above the Manasquan River, our parents bought a Sears Roebuck prefab cottage—four tiny bedrooms surrounded a big gathering area and kitchen that were often filled with my mother’s friends and their kids. Mom thrived when she had good companionship, but she was bipolar and sometimes couldn’t cope—in general, or with me—and my father usually couldn’t join us on weekends.
I need thrills and constant stimulation. With inattentive but indulgent parents, I did what I wanted. My self-education and growing up started when I was 6 years old and I got an 8 ft dinghy with an outboard motor. On the Manasquan, I cruised by myself up the estuary, down miles of river, and before long, out to sea. Still in grade school, yet entirely on my own, I became a competent seaman, commercial eel and crab trapper, fisherman, and a keenly curious observer and experimentalist. Not yet out of grade school, I’d become a self-reliant and fearless autodidact.
In fact, the first time my parents met my wife, Jan, my mom said, “Good luck. I’ve never been able to teach him anything.”
At 14, I became the youngest mate on a Brielle Basin charter fishing boat. We devoted every bit of energy to our captain’s boat having the happiest customers and best dockside display of fish at day’s end. Competitively attracting and catching fish makes you decisive. Maintaining the boat requires conscientious thoroughness. Working for tips, you learn how to please and, in my case, to overcome some shyness and camouflage the rest.
High school didn’t engage me—I was just a “good enough” student. When my dad shopped for medical texts, I’d go, too, bringing home mostly chemistry or oceanography books. I got passionate about evolution after reading Darwin’s The Voyage of the Beagle, but my favorite book was on sterol biosynthesis. When I saw how those three methyl groups disappeared from lanosterol and came out as CO₂, it was amazing—and a great introduction to oxidation chemistry.
Everyone’s different; I’m really different. But things I wouldn’t wish on anyone have contributed a lot to my chemistry. I’ve learned lessons I believe others can benefit from, so I’m going to describe my personal baggage now in the hope that it’s helpful.
Legendary Swiss organic chemist Albert Eschenmoser said this about me: “[Barry is] absolutely unpredictable in what he is going to say. With many normal people, you can predict what a discussion is going to be. Not with Barry.”
Being nonlinear is probably my most conspicuous, confusing, and annoying characteristic. I like the definition of nonlinear: “human thought characterized by expansion in multiple directions, rather than in one.”
At the same time, I need stimulation, thrills, scary things, inspiration, strangeness—these make me feel alive.
At Dartmouth, my first English composition got an F, and that was a shock. Fear transformed me into a zealot, studying until there was no question I couldn’t answer. With chemistry, things were easier. I inherited enough of my dad’s photographic memory to learn reactions for life, so science classes were easy, and I had time to quickly acquire the classroom skills good students already had. Fear got me going, but superb teaching and the pleasure of knowing I could be top of my class turned me into an enthusiastic learner who especially loved literature. I was fond of the ineluctable modality of James Joyce’s Ulysses!
I was a pre-med but joined assistant professor Tom Spencer’s informal arrow-pushing group. Chemists know what that is, and once I got into solving his weekly problems, I went overboard and prepped by learning, mostly by smell, the personalities of all the chemicals I could find. After pushing electrons, we hung around chalk talking, which became and remains one of my top pleasures. Meanwhile I fell in love with the periodic table.
Not having spent a summer on campus, I didn’t get to experience extended research projects, so Tom Spencer (whom I owe everything) counseled me to put off medical school and try a year of graduate school in chemistry. He sent me to Stanford University and his mentor, Eugene E. van Tamelen.
My project was the selective oxidation of polyolefins, but I flunked the biannual physical chemistry qualifying exam, so I spent 6 months tearing up the chemistry library learning about my project. When I did get in the lab, I’d become knowledgeable enough to settle into daily dialogues with postdocs and, often, van Tamelen.
Luck had me assigned to work with Bob Coates, who was a postdoc in van Tamelen’s lab and is now emeritus faculty at the University of Illinois, Urbana-Champaign.
Under his careful guidance, my first big insight: The faster you knock down “apparent” successes, the faster you move on and find new ones. I called it “killing.” Later, when my own students brought good results, I said, “Go try to kill them off. Develop multiple next moves while doing so. Promote the survivors quickly. Always look for reactivity’s clues and devise ways to interrogate them.”
The Massachusetts Institute of Technology indulged their new assistant professor as much as my parents had, allowing my fear and loathing of writing to ignore having to apply for a grant from the National Institutes of Health (NIH). After well over 2 years with no grants, the Chemistry Department chair, Glenn Berchtold, gave me two choices: dive to the Andrea Doria wreck for its gold treasure, or write a grant application.
The years before applying for a grant were life changers. Library deep diving at Stanford inspired an intense search at MIT for reactivity among the periodic table’s less-studied squares. The rigor of pre-mid-20th-century accounts let me “talk” to and compare molecules’ properties, including their color, shape, solubility, and stability.
Selenium’s strange properties, first noted at Dartmouth, beckoned, in part because it was essential for life and redox active. At MIT the subconscious background I gained from peripheral reading at Stanford sent me looking at published SeO₂ mechanisms. Indeed, they were impossible, so we investigated in the lab. Amazingly, the whole field was wide open; I had found my own gold treasure. We quickly made multiple significant contributions. Selenium became my NIH proposal topic, and I became well known.
We just took off. Our modus operandi was to go through the periodic table and look for voids in the literature. We capitalized on lots of phobias and scary dark places that others didn’t want to explore, and we significantly expanded the limits of synthetic chemistry with, for example, lots of useful olefin oxidations.
In hindsight, what’s so astonishing is how simplicity’s stigma was so great that my lab had years of exclusivity in sweeping phobias out of the periodic table.
Because braininess wasn’t measured on the Manasquan River, I never got my ego caught up in the complexity game—thinking complex chemistry was the only worthwhile chemistry. Without intending to, I’d become a process chemist, which was blue collar by the standards of pharma, where medicinal chemists were the elites.
Since writing was, for me, like getting a cavity filled without novocaine, it never occurred to me to publish work of inadequate significance, and with only the University of Wisconsin’s Hans Reich in noble competition, the pressure to publish even great results was lifted. And then time spent documenting and fleshing them out led to ever-more interesting opportunities. Our published new methods always described at least one hitherto impossible selective transformation of a complex natural product; detailed experimentals were always included.
By the mid-1970s we were inundated by usage citations, creating a dynamic feedback loop that accelerated both our enthusiasm and productivity.
A 1973 discovery by my postdoc, the late Bob Michaelson, and my love of olefin oxidation chemistry led to postdoc Tsutomu Katsuki’s discovery of the asymmetric epoxidation (AE) reaction in 1980.
Also in 1980, graduate student Steve Hentges’s perfect stoichiometric asymmetric osmylation made me confident there were more catalytic asymmetric reactions waiting for discovery, despite the consensus siding with its impossibility.
Once the AE was out there, I needed new thrills, so I was ready to move on.
About 2 years after the discovery of the AE, I had a life-changing conversation with famed organic chemist Sir Derek Barton. When I told him of my plans to leave asymmetric catalysis for something new, he asked sternly, “Do you think there are other catalytic asymmetric reactions to be discovered?” I said, “Yes, I know there are.” Sir Derek said that if I didn’t pursue it, the AE could be an orphan reaction, and Derek Barton was a very convincing man!
The AE kept us so busy we didn’t get back to Hentges’s discovery, but we struck gold again in publications led by postdocs Eric Jacobsen and the late Istvan Marko. Catalytic asymmetric dihydroxylation (AD) was a real triumph, a wonderful, general, high-utility reaction.
With the AD discovered, I could finally move on, but my group wasn’t ready. I had a lab full of incredibly talented postdocs who’d come to do asymmetric catalysis, but my poor communication and leadership skills had let me down again. How could I turn them away from entrenched beliefs and break a religion that I helped create to take on something new? Lab morale declined, and when I later switched everyone onto what became click chemistry, it bottomed out.
No management tips from me, but advice about discovery is a different matter: Always look for clues, and follow good ones, even at the expense of existing priorities. Don’t worry about what you might miss, because the only thing that counts is what you find. And there is so very much to find. Asking good questions is vital. Strong inference, a multitude of working hypotheses, and the periodic table will never let you down.
In 1982 I submitted an NIH grant proposal for linking unnatural modules together using amine openings of epoxides (the AE had signaled this possibility), then combining these building blocks to see if they exhibited interesting properties or function. It was not funded.
I moved to Scripps Research Institute California and started consulting for a combinatorial chemistry company. Meanwhile, I was focused on finding a method for the rapid, reliable discovery of new chemical reactivity and function. Running reactions neat, without solvent, and connecting modular blocks with the few, best reactions was the plan. My student Janet Elizabeth Pease tried it in 1996 or 1997 with the six reactions we deemed best. This first attempt at what later became click chemistry had excellent yields of up to 96%. We were off and running. We soon abandoned doing the reactions neat and turned to water as a solvent.
Out of many candidate names, Jan and I settled on calling the method click chemistry because it seemed to us the most descriptive term. I had the most success explaining our enterprise by using the seat belts in cars’ back seats as a metaphor. Only the intended partners can connect—a middle seat belt can’t buckle up to a side belt. A connection’s success is guaranteed and, once made, is permanent. In a car, the spring-latched buckling up makes an audible click.
Hartmuth Kolb, my colleague at Scripps, became the engine driving click chemistry’s development from its inception; the first public lecture on the subject was given at the spring American Chemical Society national meeting in 1999: “Click Chemistry, a Concept for Merging Process and Discovery Chemistry.” It was a joyous event for me when M. G. Finn, my graduate student at MIT in the 1980s, joined the Scripps chemistry faculty. He got enlisted, becoming the scholar-philosopher who gave click chemistry its logical foundation. M. G. articulated the concepts over which Hartmuth and I had struggled.
We called ourselves “the three amigos,” and we called our manuscript on click chemistry “The Manifesto.” It was submitted to Angewandte Chemie in August 2000. Angewandte’s editor in chief, Peter Gölitz, was willing to override the negative reviews, but he was concerned about my being able to handle possibly becoming chemistry’s international fool. “Click Chemistry: Diverse Chemical Function from a Few Good Reactions” appeared online in May 2001.
Too much happened that year: prizes, including the Nobel Prize in Chemistry, and my 60th birthday celebration with 33 Sharpless group alumni speaking at the spring ACS national meeting in San Diego. At the banquet, I received the best present of my life! When MIT’s renowned George Büchi died, his young colleague (and my former student) Greg Fu inherited Büchi’s library. Greg regifted part of it to me: maybe a ton of Houben-Weyl Methoden der Organischen Chemie (all volumes, 1909–1986, but including literature back to 1834). Greg gave me chemical discovery’s golden age—what more would any chemist want!
Previously, during a walk on the beach with M. G. after we’d both just read Kevin Kelly’s Out of Control, we agreed our favorite part of the book was something Kelly called god games. To quote Kelly, “The great irony of god games is that letting go is the only way to win.” This later inspired us to let a much-studied enzyme’s reaction site choose two reactants to unite. With 98 possible products, picky acetylcholinesterase chose to make just one, an inhibitor tremendously more potent than any other, thereby creating in situ click chemistry. We did this in collaboration with University of California San Diego’s Palmer Taylor.
Postdoc Luke Green’s work on that enzyme reaction precipitated the discovery of CuAAC, the copper-catalyzed azide-alkyne cycloaddition. Albert Eschenmoser had the best quote again, calling CuAAC “an improvement in the efficiency and scope of a known reaction that was so dramatic, it clearly amounted to a discovery of the first order.” Both studies were published in 2002.
Several click-chemistry-based companies have been founded by others, the most intriguing being Olaplex. Its clicked hair repair lets Kim Kardashian change her hair color every few days and still look swell.
In 2002 I shared inaugural honors for the University of Sydney’s Cornforth Lectureships with Craig Hawker, a world-leading materials scientist at the University of California, Santa Barbara, and founder of multiple start-ups, including Olaplex. “The inspiration [for Olaplex],” he wrote to me, “goes back to your talk in Sydney many years ago, and changed my thought process. As you mentioned and in the words of Sir John Cornforth himself, ‘It does, for example, no good to offer an elegant, difficult and expensive process to an industrial manufacturing chemist, whose ideal is something to be carried out in a disused bathtub by a one-armed man who cannot read, the product being collected continuously through the drain hole in 100% purity and yield.’ Your key message of efficiency, simplicity, and orthogonality—hallmarks of all good click chemistry—resonate even more loudly today.”
M. G. Finn’s click bioconjugation, developed in 2003, was the next game changer, and the bioscientists who, daily, use kits based on it are probably unaware they’re even using click chemistry.
After numerous failures in our group to reproduce German chemist Wilhelm Steinkopf’s work from 1927 to 1930, and after several failures of his own, my research associate Jiajia Dong, now at the Shanghai Institute of Organic Chemistry, succeeded. After receiving a cylinder of sulfuryl fluoride from Dow, this led to SuFEx, the second near-perfect click reaction discovered in our lab. SuFEx unexpectedly opened up a whole sulfate connective world.
Now, Dong’s lab has another new, near-perfect click reaction. With four great click reactions, building bottom-up complexity with absolute certainty and precision will, I predict, explode.
So many people have made my presence today possible, and I thank them all. I also apologize to everyone whom I’ve not treated the way they deserved, the group members who didn’t get publications or whom I didn’t even talk to, and the many chemists who have never been thanked or acknowledged for dedicated papers, gifts, and other kindnesses. I am so sorry that I just utterly fail at doing so many things. A lot of people have made sacrifices while I’ve selfishly had so much fun being a chemist. I really appreciate you all with my every molecule.
I’m really grateful to be able to see simplicity and function coming into favor in my lifetime. I close with quotes from a letter I received in 2015 from MIT’s Stephen Buchwald, a reminder of the bravery it takes to strike out away from the pack, and so gratifying to me personally. He may have been my only convert in the previous century.
“Your influence on the chemistry carried out in my group has been profound—focusing on chemistry that can easily be used by others. Your efforts on my behalf were key to my success. Over and over again during the years I have resorted to WWBD: What would Barry do? in my quest for the best path forward. It was your philosophy of doing important things that also were practical that led me to where I am today. As I approach my 60th birthday, I just wanted to thank you.”