How Boron Guides Simpler Sulfur Chemistry

An Emerging Solution for Sulfenate Selectivity

Complex molecules like pharmaceuticals are built by chemists that react and combine smaller molecules in just the right way. One type of reaction uses sulfur-containing molecules called sulfenate anions to make sulfoxides, which contain a sulfur atom bonded to one oxygen atom and two carbon-containing groups. Sulfoxides are useful molecules in drug design, even for common heartburn medications. For chemists, the challenge is that sulfenates are highly reactive entities that are generally unselective in their reaction partners, unless specifically directed. An emerging way for chemists to guide sulfenate anions to react at specific location is by including boron atoms in the molecule near the wanted reaction site.

Trivalent boron compounds attract molecules with more electrons, like the oxygen in sulfenate anions. When strategically placed near the wanted reaction site, the boron atom attracts and guides the sulfenate anion into place, acting like an air traffic controller directing an airplane to a specific gate. Once in the right spot on the target molecule, which is at a carbon atom holding a “leaving group”, the sulfenate anion undergoes an S-alkylation reaction where it attacks and bonds to the carbon, displacing the leaving group, and ultimately forming a sulfoxide. There have not been any studies investigating the specifics of this type of reaction in detail, until now.

Guiding Chemical Reactions with a Boron “Tag”

University of Guelph chemistry professor Dr. Adrian Schwan and PhD student Adam Riddell have explored these sulfenate anion reactions in detail to try to make them more time- and cost-efficient. Adam conducted 22 competition experiments to compare how the sulfenate anions reacted when exposed to a nearby boron-containing group and a non-borylated group. In most cases, sometimes exclusively, the sulfenate anion reacted at the site near the boron-containing group.

In fact, in the presence of the nearby boron, the sulfenate anion reacted selectively when it contained more electron-rich groups but did not react as selectively when the boron was moved farther away on the molecule, or when the sulfenate anion was missing its electron-rich oxygen. This confirms that including a boron atom near the wanted reaction site greatly influences and directs the reaction of the sulfenate anion.

To double check the theory and results, Adam used computer modelling and other visualization methods to show that there is a pre-reaction complex between boron and the sulfenate oxygen. This overall lowers the energy required for the S-alkylation reaction, making it an easier, faster and more selective reaction. Further, the boron group can do more than just guide the sulfoxide formation – the resulting products can be incorporated into larger molecules through reactions at the boron group.

Laying Broader Groundwork for Other Synthetic Applications

 

 

This new level of control over sulfenate chemistry could help make drug development more efficient and greener. It’s a great example of how understanding small chemical interactions and making tiny chemical tweaks can lead to smarter, more sustainable and more impactful improvements for products that use sulfoxides, like pharmaceuticals. This research also doesn’t just solve one niche problem but lays groundwork for broader synthetic chemistry applications.

“This research builds on what we know about how sulfur-based molecules can react,” says Schwan.

“We showed that adding a nearby boron group doesn’t just guide the S-alkylation reaction but can also help synthetic chemists in further molecule syntheses. That means the same boron tag that steers the S-alkylation reaction can also serve as a useful handle when making other complex molecules and products.”

This work was supported by a Natural Sciences and Engineering Research Council of Canada grant.

Riddell A.B. & Schwan A.L. Directing Influence of Proximal Boron Functionalities on the S-Alkylation of Sulfenic Acid Anions: An Experimental and Computational Study. J. Org. Chem. 2025 June 26. doi: 10.1021/acs.joc.5c00829

This story was written by Jamie Dawson as part of the Science Communicators: Research @ CCMPS initiative. Jamie is an M.Sc. candidate in the Chemistry Department under Dr. Mario A. Monteiro. Her research focus is on characterizing bacterial cell-surface carbohydrate structures to ultimately develop glycoconjugate vaccines.