YSM Issue 96.4

Chemistry
FEATURE
THIS METAL-FREE REACTION
CONTAINS . . . METAL
Eliminating Palladium from the Suzuki Reaction
BY LAWRENCE ZHAO
It was the right time for a breakthrough, but was it too good
to be true? In early 2021, a research group led by Professor
Hua-Jian Xu at the Hefei University of Technology claimed
to have found a new, nitrogen-based catalyst for the Suzuki
reaction. The Suzuki reaction is a popular method among
organic chemists to create new bonds between two carbon
atoms, and in the past, it has always involved a palladium
catalyst—a substance that speeds up a chemical reaction.
However, researchers want to stop using palladium because
the metal is toxic, difficult to recycle, and expensive, which
limits their ability to use the Suzuki reaction to synthesize
compounds in industry. Since 2003, scientists have promised
a metal-free Suzuki reaction, but each time, they’ve found
evidence of palladium contamination in their attempts. Mere
traces of palladium on a dirty stir bar could be enough to start a
Suzuki reaction, so researchers must be extra careful that there’s
no palladium at all.
So, when the scientific community heard about Xu’s claims
of a palladium-free Suzuki reaction, they were immediately
skeptical. Although the Xu group included safeguards to avoid
palladium contamination, scientists on X (formerly Twitter)
quickly pointed out that Xu had used a palladium compound
to make their Suzuki catalyst. Could palladium have somehow
snuck into Xu’s experiment, just like his predecessors’?
Chemistry professor Robin Bedford at the University of Bristol
has been working with catalysts for over 30 years. “I was one
hundred percent confident that it was palladium-catalyzed,
and I needed [more evidence] to be shifted from that position,”
Bedford said.
Bedford contacted other scientists who had doubted Xu’s
work on social media and asked if they would join him in
investigating his hunch that palladium contamination was at
fault. After assembling a team of investigators, Bedford tried to
figure out what might have gone wrong. To Bedford’s surprise,
everything Xu did was reproducible to a remarkable degree—
the numbers were within one to two percent of reported values,
which is an unusual feat for synthetic chemistry. However, the
main issue lay in what Xu didn’t do—a control experiment that
created the catalyst without using palladium. When Bedford
used a different, palladium-free route to make Xu’s catalyst, the
catalyst no longer worked as advertised. Bedford did further
testing which revealed that the metal was hiding in plain sight.
ART BY KARA TAO
Pd 3+
It turned out that palladium had nestled itself
in a stable compound that made it challenging
to detect. Xu used a process that was unable to
extract the palladium from these compounds,
leading him to believe there wasn’t any
palladium in the catalyst. However, when
Bedford and his collaborators subjected it
to hot, concentrated acid, the metal broke
free. Unfortunately, Xu’s palladiumfree
Suzuki coupling wasn’t so
palladium-free after all. Nine
months after Xu’s initial
announcement, Nature
Catalysis published
the concerns that
researchers like Bedford
had voiced. In response
to growing doubt, Xu
swiftly retracted his paper.
Although Xu failed to make a
metal-free Suzuki reaction, his story is actually
an example of success in the scientific method. “The scientific
method is predicated on failure,” Bedford said. Science tends to
fall in line with existing beliefs, but Xu pushed the boundary
of what was conventionally thought to be possible. Because Xu
had to retract his work, the research may seem to be, at first
glance, reprehensible. In reality, his effort to expand the breadth
of human knowledge is admirable. Retractions carry a negative
stigma in the scientific community because they often arise
from papers with manipulated data. To encourage scientists to
retract papers with errors made in good faith, Bedford suggests
creating a separate distinction for papers like Xu’s.
Bedford continues to search for new sustainable pathways
to synthesize organic molecules. He is currently in the midst
of publishing a proof-of-concept of an iron-catalyzed Suzuki
coupling. Backed by almost 400 pages of data, Bedford’s
efforts underscore just how difficult it has been to eliminate
palladium from the Suzuki reaction. While his work may not
be more efficient than currently available procedures, it’s a big
step towards replacing palladium once and for all. One day,
we might be able to cheaply make life-saving pharmaceuticals
using a metal-free Suzuki reaction. ■
Zn 2+
www.yalescientific.org
December 2023 Yale Scientific Magazine 27