Prokopchuk pins Palladium's activity on increased C-H acidification compared to Nickel
Citation:
Lin, L.; Schramm, T. K.; Kucheryavy, P.; Lalancette, R. A.; Hansen, A.; Prokopchuk, D. E. J. Am. Chem. Soc. 2025, ASAP. https://pubs.acs.org/doi/10.1021/jacs.5c07649
Summary Figure:
Background:
C-H functionalization reactions take unactivated carbon-hydrogen bonds (i.e., not very acidic, so not your average enolate) and typically use a transition metal to pull off that hydrogen. Theoretically, "any reaction that activates a carbon-hydrogen bond and makes a product" is an immensely wide net, so for the purposes of analyzing this paper, we'll restrict that towards organometallic reactions that end up forming a carbon-metal bond from a carbon-hydrogen bond.
The paper has a really great introduction to the field, which I will briefly summarize, but I recommend reading through the second paragraph as it is well written. Palladium (and nickel, and other transition metals) often activate C-H bond through a directing group strategy. Not all C-H bonds are created equal, and it has been found that the C-H bond most likely to be activated is the one in close proximity with the metal center in space, so if you can design the metal's inner coordination sphere to be right next to the desired C-H bond, you can preferentially activate it. In the below example, the pyridyl directing group binds as a ligand to the ruthenium catalyst, then orients the metal right at the ortho C-H bond, leading to selective activation. Afterwards, the directing group can be cleaved to generate a useful intermediate, in this case an aryl boronic ester.
Example taken from: Davies, H. M. L.; Morton, D. Recent Advances in C-H Functionalization. J. Org. Chem. 2016, 81, 343-350. This is a great short review with examples of different types of C-H functionalization reactions.
Referencing: Kinuta, H.; Tobisu, M.; Chatani, N. Rhodium-catalyzed borylation of aryl 2-pyridyl ethers through cleavage of the carbon-oxygen bond: borylative removal of the directing group. J. Am. Chem. Soc. 2015, 137, 1593.
The way that the C-H bond is activated is usually through an initial agostic interaction, where the electrons in the C-H sigma bond act as a ligand and bind to the metal in a 3 center, 2 electron bond. For those unfamiliar with agostic interactions, this is similar to how a pi bond acts as a ligand towards a metal. At a stretch, this is similar to how a pi bond forms bromonium intermediates in alkene reactions with Br2. While a pi bond is significantly more nucleophilic than a sigma bond, in this case a sigma bond still contains 2 electrons that can overlap with an empty metal orbital.
After formation of this complex, one of the most common elementary steps is concerted metalation-deprotonation (or CMD), where the carbon forms a full bond to the metal while the hydrogen simultaneously forms a bond with an equivalent of base. This base usually starts bound to the metal as an inner sphere ligand. Examples of bases used are acetates, carbonates, or alkoxides.
Nickel and palladium are both group 10 metals, which means they share many properties, including the ability to do C-H functionalization reactions. However, nickel is a base metal and much more prone to 1 electron reactions. This is due to the decreased splitting between its d orbitals (from undergraduate inorganic chemistry, in octahedral complexes this would be deltaO). This means that understanding the differences in mechanism between the two can be difficult, as for theoretically similar reactions there may be major differences in mechanism.
The Prokopchuk lab has been working on methods to quantify the strength of the agostic interactions with different metals, which is an important measurement to improve the activity and selectivity for C-H functionalization reactions. In this case, they are using their method to analyze differences between activation by Pd vs. Ni.
How it works:
The Prokopchuk lab has developed a tridentate ligand with two dicyclohexylphosphine groups attached to an adamantane core. This ligand binds from both phosphorus atoms and one of the adamantyl carbons, forming a PCP core.
Protonation by a strong acid (in this case, the extremely strong [H(Et2O)2]+[B(C6F5)4]-) leads to cleavage of the M-C bond, and formation of an agostic interaction between the metal and the now saturated carbon center's C-H bond.
Notably, this complex can still do C-H activation, releasing H+. Therefore, the agostic complex is actually in equilibrium with the deprotonated complex:
For these extremely strong acids, you can't stick a pH probe in, so how do you say that one acid is stronger than another? You have to find some molecule to protonate that really doesn't want to be protonated and compare how much of the protonated compound forms based on different acids. In this case, they use electron deficient anilines. The Prokopchuk group started with the PCP-ligated catalyst, then introduced anilinium acids (anilines that are already protonated). Then they measured how much of the agostic compound formed as the aniliniums introduced H+ into the system. Note that the formation of large amounts of the agostic compounds means that the palladium is less acidifying, because if the palladium acidifies the agostic compound, it is more likely to release H+ and reform the anilinium.
I will note that there is some fairly complex math being done to account for the necessary equivalents of the different anilinium acids being added- this is not a straightforward titration. The end result is that the acidification of the C-H bond for the palladium complex is 5 orders of magnitude, or 100,000x that of the comparable nickel complex (pKa of -0.3 vs. 4.2).
Initial Questions and Key Findings:
1. Can you quantify the degree of activation for a C-H bond by a metal complex?
A. Yes, by designing a complex to almost trap the agostic intermediate, you can perform carefully controlled studies to interrogate the reactivity of that intermediate.
2. Which makes the C-H bond more acidic, palladium or nickel?
A. Palladium
3. Is the difference in acidification between palladium and nickel sizeable enough to make a difference for C-H reactions?
A. Yes! This provides justification for the observed phenomenon that often Ni-catalyzed C-H functionalization reactions require the use of stronger bases. The authors attribute this phenomenon to a more electrophilic Pd center (compared to Ni).
Key Takeaways:
This is a really nice platform to study C-H activation in a controlled fashion. One challenge is that this ligand system is not the same as other common ligand systems for C-H activation reactions. This ligand can likely be applied to other metals (which the authors mention in their conclusions as a future direction) and get some nice understanding of the differences between base metals and noble metals. Finally, the applications are fairly clear: when trying a nickel-catalyzed C-H activation reaction, screen some stronger bases!
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