Barry Sharpless

K. Barry Sharpless
Born	Karl Barry Sharpless 28 4, 1941
Birthplace	Philadelphia, Pennsylvania, U.S.
Nationality	American
Occupation	Chemist, academic
Title	W. M. Keck Professor of Chemistry
Employer	Scripps Research
Known for	Asymmetric catalysis, click chemistry, Sharpless epoxidation
Education	Dartmouth College (A.B.), Stanford University (Ph.D.)
Awards	Nobel Prize in Chemistry (2001, 2022), Priestley Medal (2019)

Karl Barry Sharpless (born April 28, 1941) is an American chemist and professor at Scripps Research in La Jolla, California, who has made foundational contributions to two distinct areas of chemical science: asymmetric catalysis and click chemistry. In 2001, he was awarded the Nobel Prize in Chemistry for his work on chirally catalyzed oxidation reactions, sharing the prize with William S. Knowles and Ryōji Noyori. Twenty-one years later, in 2022, he received a second Nobel Prize in Chemistry for his development of click chemistry, making him only the fifth person in history to receive two Nobel Prizes and only the second individual — after Frederick Sanger — to win the Nobel Prize in Chemistry twice. Over the course of a career spanning more than five decades, Sharpless has developed chemical reactions — including the Sharpless epoxidation, the Sharpless asymmetric dihydroxylation, and the copper(I)-catalyzed azide–alkyne cycloaddition — that have transformed the practice of organic synthesis and had far-reaching impact in pharmaceutical development, materials science, and chemical biology.

Early Life

Karl Barry Sharpless was born on April 28, 1941, in Philadelphia, Pennsylvania. He grew up in the Philadelphia area, where his early years were marked by an outdoor, hands-on orientation rather than a bookish inclination. In his Nobel biographical sketch, Sharpless recalled a childhood spent largely outdoors, developing interests that were practical and experiential.

From sixth through twelfth grade, Sharpless attended a Quaker school on the Philadelphia city line. The school's culture included a tradition of Quaker Meetings, held twice a week, in which the entire student body participated. These meetings, characterized by communal silence and reflection, were part of the educational environment in which Sharpless came of age. While the school provided a strong general education, Sharpless's own accounts suggest he was not initially drawn to academic pursuits in a conventional sense, and his path toward chemistry emerged gradually rather than as a preordained calling.

His childhood interests were notably physical and nature-oriented. He spent considerable time fishing, an activity that remained an enduring passion throughout his life. This early engagement with the natural world may have contributed to the observational habits and comfort with unpredictability that later characterized his approach to laboratory research. Sharpless has spoken in interviews about the importance of being attuned to unexpected results in the laboratory — a disposition that aligns with his formative experiences exploring the outdoors.

Education

Sharpless enrolled at Dartmouth College in Hanover, New Hampshire, where he studied as an undergraduate. He graduated from Dartmouth with the Class of 1963, earning his Bachelor of Arts degree. Dartmouth would later celebrate Sharpless as one of its most distinguished alumni following his Nobel Prize recognitions.

After Dartmouth, Sharpless pursued graduate studies in chemistry at Stanford University, where he earned his Ph.D. His doctoral training at Stanford provided him with a rigorous foundation in organic chemistry and exposed him to the frontier research environment of one of the leading chemistry departments in the United States. Following his doctoral work, Sharpless undertook postdoctoral research before embarking on his independent academic career, a trajectory that would take him to several of the most prominent chemistry departments in the country.

Career

Early Academic Career and Asymmetric Catalysis

Sharpless began his independent academic career in the 1970s, during which period he focused on developing new methods for selective chemical transformations. His early work concentrated on oxidation reactions — chemical processes that are fundamental to organic synthesis but had long presented challenges in terms of controlling the three-dimensional arrangement of atoms in the products. Specifically, Sharpless became interested in the problem of chirality, the property by which molecules can exist as non-superimposable mirror images of each other, much as left and right hands are mirror images. Because biological systems are inherently chiral, the ability to selectively produce one mirror-image form (or enantiomer) of a molecule over the other is of paramount importance in pharmaceutical chemistry and many other fields.

In the early 1980s, Sharpless and his research group achieved a breakthrough that would reshape the field of organic chemistry. As described by Scripps Research, "It was 1980 and the experiments were going suspiciously well." The result of these experiments was the Sharpless epoxidation, a reaction that uses a titanium catalyst in combination with a chiral auxiliary to convert allylic alcohols into epoxides with high enantioselectivity. The reaction was notable not only for its selectivity but also for its broad applicability — it worked reliably across a wide range of substrates, making it a practical tool for synthetic chemists rather than merely an academic curiosity.

The Sharpless epoxidation was followed by the development of the Sharpless asymmetric dihydroxylation, which allows the selective addition of two hydroxyl groups to an alkene, again with high control over the chirality of the product. Together, these reactions — along with the Sharpless aminohydroxylation — constituted a toolkit for asymmetric oxidation that found widespread use in both academic research and industrial pharmaceutical synthesis.

These contributions were recognized in 2001 when Sharpless was awarded the Nobel Prize in Chemistry "for his work on chirally catalyzed oxidation reactions." He shared the prize with William S. Knowles and Ryōji Noyori, who were recognized for their own contributions to asymmetric catalysis involving hydrogenation reactions. In his Nobel biographical sketch for the 2001 prize, Sharpless reflected on the trajectory of his career and the intellectual motivations that had driven his research.

Move to Scripps Research

Sharpless joined the faculty of Scripps Research (formerly The Scripps Research Institute) in La Jolla, California, where he held the position of W. M. Keck Professor of Chemistry. The institution provided an environment conducive to the kind of ambitious, curiosity-driven research for which Sharpless had become known. At Scripps, Sharpless continued to pursue his interest in developing new chemical reactions of broad utility, but the direction of his research underwent a significant shift in the late 1990s and early 2000s.

Click Chemistry

By the time Sharpless received his first Nobel Prize in 2001, he had already begun to articulate a new philosophy of chemical synthesis that would become known as click chemistry. The term, coined by Sharpless himself, refers to a set of principles for identifying and exploiting chemical reactions that are highly reliable, selective, and easy to perform — reactions that, in Sharpless's formulation, "click" together molecular building blocks with the same reliability and simplicity as snapping together the two halves of a seat belt buckle.

The click chemistry concept was formally introduced in a landmark 2001 publication in which Sharpless and colleagues outlined the criteria that a reaction must meet to qualify as a "click" reaction: it should be modular, wide in scope, give high yields, produce only inoffensive byproducts, and be stereospecific (though not necessarily enantioselective). The reaction should also be performable under simple conditions, ideally using readily available starting materials and reagents, and should require no solvent or use only benign solvents such as water.

The most prominent example of a click reaction, and the one that became virtually synonymous with the click chemistry concept, is the copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC). This reaction, developed independently by Sharpless and by the Danish chemist Morten Meldal, involves the coupling of an azide with a terminal alkyne in the presence of a copper(I) catalyst to form a 1,2,3-triazole. The reaction is remarkably reliable, works in water, tolerates a vast array of functional groups, and proceeds at or near room temperature — characteristics that made it immediately useful across a wide range of chemical disciplines.

In his Nobel Lecture for the 2022 prize, published in Angewandte Chemie International Edition under the title "Click Chemistry: The Certainty of Chance," Sharpless described how the development of click chemistry had been guided by a combination of deliberate design and serendipitous discovery. He noted that "the most important certainty-of-chance outcome of click chemistry was the realization that perfect reactions" could be identified and harnessed for practical purposes.

Click chemistry found applications that extended far beyond traditional organic synthesis. The CuAAC reaction and related click reactions became standard tools in chemical biology, where they are used to label and track biomolecules in living cells; in materials science, where they facilitate the construction of polymers and surface modifications; in drug discovery, where they enable the rapid assembly and screening of molecular libraries; and in bioconjugation, where they allow the precise attachment of functional groups to proteins, nucleic acids, and other biomolecules.

Sharpless continued to develop the click chemistry paradigm beyond CuAAC. He and his collaborators explored sulfur(VI) fluoride exchange (SuFEx) chemistry, which he proposed as a new generation of click reactions. SuFEx reactions involve the creation and exchange of bonds to sulfur(VI) fluoride groups and exhibit many of the same desirable properties — reliability, selectivity, and broad applicability — that characterize the original CuAAC click reaction.

Second Nobel Prize (2022)

On October 5, 2022, the Royal Swedish Academy of Sciences announced that Sharpless had been awarded the 2022 Nobel Prize in Chemistry, shared with Morten Meldal and Carolyn Bertozzi, "for the development of click chemistry and bioorthogonal chemistry." The Nobel Committee recognized Sharpless for laying the intellectual and experimental foundations of click chemistry, Meldal for independently developing the CuAAC reaction, and Bertozzi for extending click chemistry principles into bioorthogonal chemistry — reactions that can proceed inside living organisms without interfering with native biochemical processes.

Peter Schultz, president and CEO of Scripps Research, noted the significance of the award, and the institution celebrated Sharpless's achievement as a reflection of the depth and impact of his research program. At Dartmouth, Sharpless's undergraduate alma mater, the announcement was met with recognition of his longstanding connection to the college; the institution noted that the award celebrated the field of "click chemistry," a name Sharpless had coined.

The 2022 Nobel made Sharpless the fifth person in history to receive two Nobel Prizes, joining Marie Curie, Linus Pauling, John Bardeen, and Frederick Sanger. He became the second person, after Sanger, to win two Nobel Prizes in Chemistry specifically.

During the Nobel Week in Stockholm in December 2022, Sharpless participated in an interview in which he discussed his career, his philosophy of research, and the development of click chemistry.

Personal Life

Sharpless has been known for his love of fishing, an interest that dates back to his childhood in the Philadelphia area. In various interviews and biographical accounts, fishing has been mentioned as one of his most enduring personal pursuits, providing a counterpoint to the intensity of his laboratory research.

In 2018, Sharpless suffered a stroke, which affected his ability to speak. Despite this health challenge, he continued to be engaged with his research and his colleagues at Scripps Research. His presence at the 2022 Nobel ceremony in Stockholm, following his recovery, was noted by observers and colleagues.

Sharpless's personality and approach to research have been described by colleagues and in institutional profiles as marked by a distinctive combination of intuition, persistence, and willingness to pursue unexpected leads. His career has been characterized by long periods of focused work on specific problems, punctuated by moments of redirection when new opportunities or observations emerged.

Recognition

Sharpless has received numerous awards and honors over the course of his career, reflecting the breadth and impact of his contributions to chemistry.

His two Nobel Prizes in Chemistry, awarded in 2001 and 2022, are the most prominent of these recognitions. The 2001 prize honored his work on chirally catalyzed oxidation reactions, while the 2022 prize recognized his development of click chemistry.

In 2019, Sharpless was named the recipient of the Priestley Medal, the highest honor bestowed by the American Chemical Society. The award recognized his cumulative contributions to chemistry, spanning both asymmetric catalysis and click chemistry. An article in Chemical & Engineering News announcing the award noted that Sharpless "is a master at getting molecules to do his bidding" and described him as having "pioneered two influential areas of chemistry: asymmetric catalysis and click chemistry." The same article noted that when Sharpless won the 2001 Nobel Prize, he had written in his biographical sketch about the motivations and trajectory of his career, suggesting a reflective awareness of his own scientific journey.

Dartmouth College has recognized Sharpless as one of its most distinguished alumni. Following the 2022 Nobel announcement, the college published a celebratory article highlighting his connection to the institution and his achievements.

Legacy

The impact of Sharpless's work on the practice of chemistry is measurable in several dimensions. The reactions he developed for asymmetric oxidation — particularly the Sharpless epoxidation and the Sharpless asymmetric dihydroxylation — became standard tools in the synthetic chemist's repertoire within years of their publication. These reactions enabled the efficient production of single-enantiomer compounds, a capability that proved essential as pharmaceutical regulations increasingly required the separate evaluation of individual enantiomers of chiral drug candidates. The practical reliability of Sharpless's reactions, which worked across a broad range of substrates with predictable selectivity, was central to their adoption.

Click chemistry, and particularly the CuAAC reaction, has had an even broader impact, extending well beyond traditional organic synthesis. The click chemistry concept shifted the way chemists think about molecular assembly, emphasizing modularity, reliability, and functional-group tolerance over the elegance or complexity of the synthetic route. This philosophical shift, articulated by Sharpless in his foundational publications, influenced a generation of chemists who adopted click reactions as routine tools in fields as diverse as chemical biology, polymer science, and nanotechnology.

The fact that Sharpless's career encompassed two separately Nobel-recognized bodies of work, developed decades apart, is itself notable. His trajectory illustrates the possibility of sustained creativity and reinvention within a single scientific career. Rather than continuing to refine asymmetric catalysis — the field for which he was already celebrated — Sharpless chose to pursue an entirely new research direction, one that required him to articulate a fundamentally different set of values about what constitutes a useful chemical reaction. The success of both programs underscores the productivity of his approach to research, which combined deep chemical intuition with a willingness to follow unexpected experimental results wherever they led.

At Scripps Research, Sharpless's legacy is embedded in both the institutional culture and the ongoing research programs that build on his foundational work. His contributions have been recognized as central to the institute's identity as a leader in chemical research.