Introduction

Followup to part 1.

I encourage readers to read the papers fully and not just rely on the small summaries here. This tangentially relates to a reason I think that large language model (LLM) summarisation of papers just isn’t as valuable as people think it is. It is simply not the same as carefully reading and thinking deeply about work. Having an algorithm “decide” what is and isn’t important in a piece of work - a decision which has already been considered by the authors, the editor and the reviewers - skips an important part of the learning process.

When reading critically, one is (ought to be) doing more than collecting facts. A key step in building expertise is changing the way in which knowledge is grouped together mentally.

For more on this see:

Persky, Adam M., and Jennifer D. Robinson. “Moving from Novice to Expertise and Its Implications for Instruction.” American Journal of Pharmaceutical Education 81, no. 9 (November 1, 2017). https://doi.org/10.5688/ajpe6065)

and citations therein.

Papers 1 & 2

Citations:

Kwan, Eugene E., Yuwen Zeng, Harrison A. Besser, and Eric N. Jacobsen. “Concerted Nucleophilic Aromatic Substitutions.” Nature Chemistry 10, no. 9 (September 2018): 917–23. https://doi.org/10.1038/s41557-018-0079-7.

and

Kania, Matthew J., Albert Reyes, and Sharon R. Neufeldt. “Oxidative Addition of (Hetero)Aryl (Pseudo)Halides at Palladium(0): Origin and Significance of Divergent Mechanisms.” Journal of the American Chemical Society, July 3, 2024. https://doi.org/10.1021/jacs.4c04496.

The first publication is a landmark, as it provides strong experimental and computational evidence for concerted SnAr, which had been proposed in the past. This is contrary to the widely-prescribed addition-elimination mechanism in textbooks. As seen in the citations presentated in the introduction, this adds arenes to a long list of sp2 electrophiles which undergo concerted nucleophilic substitution.

The second paper is complementary; it provides, through its work and citations, a preponderance of experimental and computational evidence that concerted SnAr-like reactivity is observed in transition metal oxidative addition as well. The effects of ancillary ligands and substrates on the preferred pathway and the implications for selectivity are noteworthy and highly informative. They also serve as a reminder of the predictive power of mechanisms, though this prediction is not formalised here with a model.

Incidentally, model-based predictions for oxidative addition do exist:

Lu, Jingru, Sofia Donnecke, Irina Paci, and David C. Leitch. “A Reactivity Model for Oxidative Addition to Palladium Enables Quantitative Predictions for Catalytic Cross-Coupling Reactions.” Chemical Science 13, no. 12 (March 24, 2022): 3477–88. https://doi.org/10.1039/D2SC00174H.

The approach is not reliant on mechanistic considerations. I would argue that the observations from the computational studies on the competing pathways for oxidative addition can explain the discrepancies between model prediction and experiments in this publication.

Drawing a connection between the concerted SnAr and the mechanisms of oxidative addition, which appear seemingly disparate to someone new to the field, is the kind of mapping between concepts that is referred to in the introduction.

Paper 3

Citation:

Blokker, Eva, Willem-Jan van Zeist, Xiaobo Sun, Jordi Poater, J. Martijn van der Schuur, Trevor A. Hamlin, and F. Matthias Bickelhaupt. “Methyl Substitution Destabilizes Alkyl Radicals.” Angewandte Chemie International Edition 61, no. 36 (2022): e202207477. https://doi.org/10.1002/anie.202207477.

This work highlights a subtle but important point regarding alkyl radical stability. The canonical explanation for the trends in C-H bond dissociation energy (BDE) refers to differences in energy (stability) of the product radicals. This implicitly assumes that differences in the energies of the hydrocarbon starting materials are negligible. The computations presented illustrate that this explanation has it the wrong way around; the relative stability of the radicals is the opposite of what is proposed, but the differences in energies of the starting materials make up for this, leading to the observed trends in BDE.

A key takeaway is that it is imperative to identify implicit assumptions and evaluate them thoroughly.

Paper 4

Citations:

Moravskiy, A., and J. K. Stille. “Mechanisms of 1,1-Reductive Elimination from Palladium: Elimination of Ethane from Dimethylpalladium(II) and Trimethylpalladium(IV).” Journal of the American Chemical Society 103, no. 14 (July 1981): 4182–86. https://doi.org/10.1021/ja00404a034.

Elegant old-school experiments to illustrate how Pd(II) can undergo oxidative addition to simple electrophiles such as MeI. This reactivity is very similar to that observed with Pt(II), although the Pt(IV) complexes are much more resistant to reductive elimination.

Paper 5

Bloomer, Brandon J., Sean N. Natoli, Marc Garcia-Borràs, Jose H. Pereira, Derek B. Hu, Paul D. Adams, K. N. Houk, Douglas S. Clark, and John F. Hartwig. “Mechanistic and Structural Characterization of an Iridium-Containing Cytochrome Reveals Kinetically Relevant Cofactor Dynamics.” Nature Catalysis 6, no. 1 (January 2023): 39–51. https://doi.org/10.1038/s41929-022-00899-9.

An illustration of the power of kinetic analysis typically employed for investigating organometallic mechanisms and how it can be applied to non-natural enzymatic catalysis. The cofactor dynamics cannot really be teased out using any other method.