A November 2025 Journal of the American Chemical Society paper by researchers working with Prof. Alán Aspuru-Guzik has recently done a deep dive on the challenge of protodeboronation, looking to determine ways to decrease the waste of material in reactions that use the Suzuki-Miyaura cross-coupling reaction.
The Suzuki–Miyaura cross-coupling reaction is used in chemistry to join two carbon fragments together, a basic step that underlays the creation of useful products from pharmaceuticals, dyes, and plastics to fuels and electronic components. A key ingredient that enables the cross-coupling is the boronic reagent, but these reagents can be destroyed in the process when they react with water—in a side reaction called protodeboronation.
In Bulky Phosphine Ligands Promote Palladium-Catalyzed Protodeboronation, Cher-Tian Ser, Han Hao, Sergío Pablo-García, Kjell Jorner, Shangyu Li, Robert Pollice and Alán Aspuru-Guzik explore whether protodeboronation is an inevitable byproduct of using the Suzuki–Miyaura cross-coupling reaction, or if the catalyst involved—the palladium-phosphine complex—also affects the rate of loss of the boronic reagent.
Graduate Student Cher-Tian Ser answered a few questions for Chemistry Stories about how The Matter Lab used self-driving labs to perform multiple experiments with combinations of ligands—molecules or ions that bind to metal atoms—to explore the rate of palladium-catalyzed protodeboronation in these reactions.
Bio: I grew up in Singapore and did my Bachelor's in Chemistry at the National University of Singapore, working on computational physical organic chemistry for my research. I moved to Toronto for my PhD with Alán, working to combine machine learning approaches with computational chemistry, and am currently in my final year. I enjoy hiking and backcountry camping -- but don't do it nearly enough!
Why is the Suzuki-Miyaura reaction so important?
In terms of impact on the general population, pharmaceuticals are probably the most relevant. Drugs are typically molecules with complex structures -- and to make them it is typical to build them up from smaller, simpler chemical building blocks. These blocks are typically joined together using a cross-coupling reaction, and the Suzuki-Miyaura is the most used carbon-carbon cross-coupling reaction in industry. The Suzuki-Miyaura cross-coupling is ideal for industrial purposes due to its low toxicity, which matters for health applications as contamination risks are significantly reduced. Additionally, the reagents associated with these reactions are easy to handle as the boronic reagents are typically solids, which is desirable especially at large scales for industrial synthesis.
There are quite a few other uses as well, isn’t that right?
Yes. For our lab, we were primarily thinking about using the Suzuki-Miyaura cross-coupling for the synthesis of organic lasers, following the same idea of joining smaller building blocks together. Since we were screening many molecules—formed by enumerating building blocks and combining them together—we needed a reaction that had the highest chance of working across a wide variety of building blocks. But as reactions and reagents get more complex, we cannot determine beforehand if a reaction will work just by looking at the reagents used!
Given the fact that we were also using a self-driving lab and automated setups to perform these experiments, a reaction that has easy-to-handle reagents would be robot-friendly as well, and the Suzuki-Miyaura cross-coupling reaction satisfies many of these desirables.
Finding a way to lessen protodeboronation would be very beneficial, then?
Indeed – boronic reagents are typically very expensive! While strategies to protect the boronic reagent or make the cross-coupling faster than the side reaction—by increasing catalyst activity—have been applied with varying levels of success, it is also common to treat this as an inevitable side reaction, in which an excess of this expensive organoboron reagent is used in order to ensure high product yields. Reducing protodeboronation would mean that reagents are being put to use more effectively.
So the usual approaches to reducing protodeboronation have minimal impact?
Protodeboronation is widely considered to be base-catalyzed and this version of the reaction described in our paper received a lot of attention, given that the Suzuki-Miyaura cross-coupling requires some form of base to work. A wide variety of strategies have been developed to prevent base-catalyzed protodeboronation, but when we used such resistant versions of the boronic reagent, we still detected that the undesirable reaction with water was still happening. What we noticed was that when we removed the palladium catalyst from a reaction we were performing, we did not see any side reaction occurring—suggesting that, paradoxically, the palladium catalyst that drives the main reaction was also responsible for promoting the side reaction! This suggests that palladium-catalyzed protodeboronation can be more significant than the widely-considered base-catalyzed version, and steps need to be taken to prevent it from occurring for effective cross-coupling.
How were the Matter Lab’s Self Driving Labs involved?
A cool part of this research was definitely the automated experimentation—we would have robot arms dispense the solids into vials, and the reagents are pumped into these vials using an automated controller written using Python code.
We also performed a large number of computational calculations to understand the effects of every single phosphine ligand we experimentally tested on promoting this side reaction. It is more typical to try to understand by picking a few specific model systems to test.
Through these calculations, we were able to think of and suggest alternative mechanisms for protodeboronation to occur.
The Matter Lab work in this area provides important insight into inefficiencies in one of chemistry’s most widely used reactions. This research has broad implications, therefore, for reaction optimization across academic and industrial settings.
The Suzuki-Miyaura cross-coupling is ideal for industrial purposes due to its low toxicity, which matters for health applications as contamination risks are significantly reduced. -Cher-Tian Ser