A new approach to general C(sp3)–H functionalization was recently developed in the group of Professor Abigail Doyle at UCLA.
The paper detailing this discovery, titled “A general strategy for C(sp3)–H functionalization with nucleophiles using methyl radical as a hydrogen atom abstractor” was published on November 29th in Nature Communications. Doyle is the Saul Winstein Chair of Organic Chemistry in the Department of Chemistry & Biochemistry at UCLA, having recently moved from Princeton University this past summer. The lead authors on this report are Isabelle Leibler, a fourth-year graduate student co-advised by Professor Robert R. Knowles at Princeton University, and Dr. Makeda Tekle-Smith, a postdoctoral fellow in the Doyle group at UCLA.
The development of catalytic approaches to C(sp3)–H functionalization has been a cornerstone of organic synthesis. These methodologies allow for direct manipulation of the most ubiquitous bond in organic molecules, enabling the construction of synthetic building blocks and the late-stage derivatization of complex molecules. Despite the rich history that surrounds C(sp3)–H functionalization, the activation and functionalization of this incredibly strong bond in a mild and general fashion has remained a challenge.
In this study, Leibler, Tekle-Smith, and Doyle designed a photocatalytic strategy for C(sp3)–H functionalization. Specifically, the authors aimed to develop a strategy that would allow a variety of nucleophile coupling partners to react with the C(sp3)–H partner, as nucleophiles represent an abundant and practical class of reagents by comparison to electrophiles, which, while commonly utilized in C(sp3)¬–H functionalization, are often either strong oxidants, expensive to purchase, or limited in synthetic accessibility. To do so, the C(sp3)–H partner is transformed to a carbocation via two consecutive steps – hydrogen atom transfer (HAT) followed by oxidative radical polar crossover (ORPC) – catalyzed by a photocatalyst and visible light.
One of the critical tasks in designing this methodology was identifying the ideal hydrogen atom abstractor. The authors discovered that N-acetoxyphthalimide, a redox-active precursor to the methyl radical, was the ideal reagent for this chemistry. Notably, the methyl radical has never before been utilized for photocatalytic C(sp3)–H functionalization, making this report the first synthetic and mechanistic investigation of methyl radical in this context. Furthermore, N-acetoxyphthalimide can be prepared on large-scale from feedstock chemicals, offering significant opportunity for broad reagent application in photocatalytic C(sp3)–H functionalization.
About the lead authors:
Professor Abigail G. Doyle (pictured above) received her A.B. and A.M. summa cum laude in Chemistry and Chemical Biology from Harvard University in 2002 and her PhD from the same department in 2008. Professor Doyle began her independent academic career in the Department of Chemistry at Princeton University in 2008. In 2021, she moved to UCLA as the Saul Winstein Chair in Organic Chemistry.
Isabelle Leibler is a fourth-year graduate student at Princeton University, co-advised by Professors Abigail G. Doyle and Robert R. Knowles. Her current research involves exploring new strategies for photocatalytic methodological development in organic synthesis, with a focus on nucleophilic C(sp3)–H functionalization and annulation chemistry.
Dr. Makeda Tekle-Smith is currently a postdoctoral fellow in Professor Abigail G. Doyle’s group at UCLA. Her current research involves developing new approaches to chemical synthesis, with a focus on Ni/photoredox catalysis and nucleophilic fluorination.
Article by Dr. Makeda Tekle-Smith, UCLA Department of Chemistry & Biochemistry, makedat@g.ucla.edu and Isabelle Liebler, Princeton University, ileibler@princeton.edu.
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