Journal Article Analysis:
Journal Article Analysis:
Dual Nickel-Photoredox Catalysis
Dual Nickel-Photoredox Catalysis
ARTICLE: Merging photoredox with nickel catalysis: Coupling of α-carboxyl sp³ -carbons with aryl halides
AUTHORS: Zhiwei Zuo, Derek T. Ahneman, Lingling Chu, Jack A. Terrett, Abigail G. Doyle, David W. C. Macmillan
PUBLICATION: Science 2014, 345 (6195), 437–440.
Note that this Science article follows an IRDAM structure, but, as is standard for chemistry papers, it is not clearly labeled as such. The Introduction, Results, and Discussion sections follow each other logically in the body of the article. Chemistry Science papers typically intersperse Discussion and Results segments. The Methods section is included in the article’s Supplementary Information section.
The article begins with an acknowledgement of the then-recent advances in the field of photochemistry that motivated the paper, as well as a discussion of the history of nickel cross-coupling catalysis. This history emphasized the types of substrates amenable to that methodology (“aryl or vinyl boronic acids, zinc halides, stannanes, or Grignard fragments”). Providing background information about these two branches of synthetic chemistry allowed the authors to highlight the limitations of the methods, specifically the low accessibility of alkyl carbon centers for cross-coupling reactions.
This introduction to nickel catalysis and photoredox as distinct fields allowed the authors to then transition into an introduction of their utility in dual nickel-photoredox catalysis. This paper, along with a paper from the Molander group,1 pioneered this type of dual catalysis. As such, a lengthy explanation of the proposed mechanism of the deal catalytic reaction is included in the introduction. Briefly: a photocatalyst is excited with light and generates a reactive species called a carbon-centered alpha-amino radical, an aryl halide (such as those used for conventional nickel catalysis) complexes to nickel, the radical species is intercepted by the nickel complex, the two coupling partners eliminate from the nickel complex, and the catalysts are returned to their original states for the cycle to begin again. This section describes only the proposed mechanism that generated the idea for the paper, so it is not included in the Results.
Dual nickel-photoredox was successfully realized over the course of the study. For the model alpha-amino acid, N-Boc proline, and its model coupling partner, para-iodotoluene, optimal conditions were found: “Ir[dF(CF3)ppy]2(dtbbpy)PF6 and NiCl2•glyme (glycol ether), dtbbpy, in the presence of 1.5 equivalents of Cs2CO3 base and white light from a 26-W compact fluorescent bulb.” With proof of concept in hand, various combinations of chemical species were tested. The aryl halide fragment (associated with conventional nickel catalysis) was varied, with 15 species tested in total; all species worked with the model amino acid coupling partner. The carboxylic acid species was then varied. Protected amino acids, including cyclic and acyclic species, could be used. Alpha-oxycarboxylic acids were also viable. Dimethylaniline, which does not have a carboxylic acid group, was also used as a substrate for the photocatalytic part of the study. This species was able to undergo coupling to aryl halides directly at its alkyl carbon center, replacing an alkyl C-H bond.
The viability of the predicted mechanism was discussed and confirmed in the context of empirical data. While this article does not include a full mechanistic study (and does not claim to), assertions were made about the likelihood of the proposed dual catalytic method based on reduction potential measurements taken during the study and confirmed by the literature. The relevance of the substrate scope reported was discussed, with emphasis on the successful coupling of fragments that could not have been put together via photocatalysis or nickel catalysis alone. Notably, alkyl carboxylic acids had not been used previously in transition metal catalysis, and alkyl C-H bonds typically cannot be replaced in coupling reactions. So, this method opens up a wide range of new chemical species to be used as starting materials for transition metal-catalyzed cross-coupling reactions.
Methods information such as the equipment models and purification procedures used were included here. The full results tables for the optimization studies, including the initial model reaction and dimethylaniline studies, were provided. Specifics were written out for the procedures of each reaction type: amounts of reagents used, equipment specifications, temperature and pH conditions and how they were achieved, reaction times, and purification procedures. There is enough information in this section for a knowledgeable chemist to replicate the experiments. Characterization data for every chemical species used in the study was also included in the Supplementary Information.
Is the topic of the paper somewhat original?
Yes. This study was conducted in the context of a surge in interest surrounding visible light photocatalysis initiated in part by David MacMillan, one of the corresponding authors on the paper, in 2008. This article, however, along with Gary Molander’s paper published in the same issue of Science in June 2014,1 was the first study of its kind. These two concurrently published papers are heralded as the initiators of a surge in research into dual nickel-photoredox catalysis, specifically. This methodology is exciting because it enables the coupling of alkyl carbon centers, which have only single bonds, with saturated carbons. Alkyl carbons are notoriously difficult to utilize in coupling reactions.
Do the authors have a solid track record?
Emphatically, yes. David MacMillan received the 2021 Nobel Prize in Chemistry, albeit for his work in a different area of research, asymmetric organocatalysis. He even developed a class of catalysts in that field that now bear his name: MacMillan catalysts. He is highly decorated within the scientific community beyond the Nobel Prize, as well. Moreover, he is a prolific researcher, with an h-index of 110 (indicating that he has published lots of highly-cited research). Abigail Doyle is likewise well-renowned, albeit to a level that corresponds to her earlier position in her career. She joined the faculty at Princeton in 2008 and was promoted to full Professor in 2017. She now works at UCLA and is Senior Editor of the journal Accounts of Chemical Research.
What was the aim of the study? What hypothesis did the researchers test? Are the conclusions reached (assuming they are valid) important to you and others (explain)?
The aim of the study was to demonstrate that the conditions used for nickel catalysis and photoredox catalysis could be combined to enable cross-coupling reactions that are not possible under either condition alone. The study described this as a dual-catalytic strategy and proposed a mechanism in line with that description, but did not and did not claim to confirm that the proposed new type of dual catalysis does in fact proceed by that mechanism. The hypothesis was tested this way; no characterization of reaction intermediates or quantum calculations were performed to examine the reaction mechanism. A range of substrates were tested under these conditions to demonstrate that various types of alpha-amino acids and aryl halides are amenable to the synthetic method. The high yields of these reactions are sufficient to show that the reaction conditions are effective in coupling the reactions, however the mechanism might actually proceed. This conclusion is indeed important, because substrates that could not be used with one type of catalysis or the other alone, and therefore could not be coupled under adjacent strategies in the past, were successfully coupled.
Were enough data obtained to reach valid conclusions?
Enough data were obtained to conclude that this catalytic strategy works. No mechanistic data were obtained in this study, so all discussions of the mechanism of the reaction are proposed statements. The strength of those statements were supported with information about the reagents used and their reactivity, but ultimately there is not evidence here to conclusively say that the proposed mechanism is correct. The paper does not purport to be a mechanistic study, however, so that is acceptable in this context. Moreover, enough substrates were tested in the scope of the study to conclude that this methodology can be used for various substrates. The authors’ claims are supported there. The substrate scope is a bit small in some cases, however. The authors claim that a “wide range of aryl iodides are amenable to this dual-catalysis strategy,” but only four aryl iodides were tested. The species tested do span the range of highly electron-rich to electron-poor monosubstituted species, so the claim is technically correct, but no modifications more complicated than that were made. Similarly, only four coupling partners were used with dimethylaniline: enough to demonstrate that it works, but not enough to support much beyond that. While substrate scope was not exceedingly diverse, the authors claim that these reaction conditions are effective is nonetheless supported.
Are the results consistent with those of other studies?
The results are consistent with those of other studies. As previously mentioned, the Molander group at the University of Pennsylvania independently published a similar study at the same time - in fact, in the same issue of Science.1 This study differed in that the Molander group used an organoboron reagent instead of a carboxylic acid for the photoredox cycle, which, unlike a carboxylic acid, does not require deprotonation. The mechanism proposed for the dual catalytic cycle is otherwise identical. For two studies on this topic to be published independently, both approaching the problem from a different angle, speaks to the validity of the proposed mechanism and the potential of this strategy to be applied in ways that had not been discovered at the time. Indeed, the Molander group later published an article examining the mechanism of the reaction,2 and a plethora of research utilizing this strategy has been conducted since its publication.
Have the authors discussed possible limitations of the study?
The authors do not discuss the limitations of the study. This is common for synthetic chemistry papers; if a substrate does not work under the reaction conditions described, it is usually not reported at all. This leaves the reader not knowing whether experiments with classes of substrates not discussed were simply not attempted, or whether they are omitted because they did not work. In this paper, specifically, it is not mentioned that neither enantioselectivity nor cross-coupling between two alkyl centers was yet achieved. The reader must infer from the omission of these details that those limitations exist or have not yet been studied. It is also obvious from reading the paper that no substrate other than dimethylaniline has been used for direct alkyl C-H coupling, but the authors do not draw attention to this.
Do the study’s findings have practical importance, regardless of whether they have statistical significance?
Yes! After this study was published, there was a surge in research into dual nickel-photoredox catalysis precisely because the transformations accomplished in the study are so useful. In the pharmaceutical industry, cross-coupling reactions are among the most-used reaction types by far. Billions of dollars and millions of lives depend on these reactions. Opening up new classes of substrates to transition metal coupling, especially cheap and unconventional ones, has an enormous effect on the way molecules can be put together. This is especially true in the case of alkyl C-H bonds. If further research can extend the substrate scope of this C-H functionalization beyond dimethylaniline, it would be tremendously helpful to medicinal chemists.
Tellis, J. C.; Primer, D. N.; Molander, G. A. Single-Electron Transmetalation in Organoboron Cross-Coupling by Photoredox/Nickel Dual Catalysis. Science 2014, 345 (6195), 433–436. https://doi.org/10.1126/science.1253647.
Gutierrez, O.; Tellis, J. C.; Primer, D. N.; Molander, G. A.; Kozlowski, M. C. Nickel-Catalyzed Cross-Coupling of Photoredox-Generated Radicals: Uncovering a General Manifold for Stereoconvergence in Nickel-Catalyzed Cross-Couplings. J. Am. Chem. Soc. 2015, 137 (15), 4896–4899. https://doi.org/10.1021/ja513079r.