Light-Activated Phosphorus Does What Platinum Does - and Could Reduce Drug Costs

Nearly every drug contains nitrogen. The carbon-nitrogen bonds that link nitrogen into organic molecules are among the most important structures in pharmaceutical chemistry - present in analgesics, antibiotics, antidepressants, antivirals, and dozens of other drug classes. Building those bonds reliably and efficiently has historically required precious transition metals: platinum, palladium, iridium.

These metals work because of how they handle electrons. Under the right conditions, they accept and donate electrons in ways that bring otherwise unreactive molecules together. The problem is cost and supply. Platinum and palladium are rare, expensive, and increasingly targeted by thieves who strip them from catalytic converters. Pharmaceutical manufacturers pay significant prices for these materials, and those costs flow through to drug prices.

Research published in Nature by UCLA chemistry professor Abigail Doyle and colleagues describes an unexpected finding in the search for alternatives.

Phosphorus Has a New Trick

Phosphorus is common, cheap, and already widely used in organic chemistry. Phosphines - phosphorus compounds bonded to three carbon atoms - are standard tools in synthesis. But no one had seen phosphorus behave the way transition metals behave in the specific type of electron transfer that makes precious metal catalysis so useful.

The Doyle lab was not looking for this. Doctoral student Flora Fan was experimenting with ways to form carbon-nitrogen bonds when the experiment produced high reactivity for a completely different product than expected. What was going on, the team eventually determined, was phosphorus acting like a metal. The key was a photocatalyst - a light-reactive molecule - that transformed the phosphine into a short-lived, highly reactive form capable of interacting with carbon-carbon double bonds through pathways that closely resemble those used by metal catalysts. This allows coupling nitrogen-containing compounds to carbon double bonds in a reaction called hydroamination - an effective route to building complex molecular structures found in drugs.

Similar to Metals, but Different in Crucial Ways

Transition metal catalysts in this reaction type most commonly transfer two electrons. The light-activated phosphine starts in a state that allows reactions involving both one and two electrons. That difference creates a distinct reaction pathway - one that enables more diverse nitrogen-containing compounds to participate than would typically be accessible with metal catalysts.

"We've discovered a new reactivity mode for phosphorus that mimics a mode that transition metals like palladium and iridium commonly perform in catalysis," Doyle said. "Carbon-nitrogen bonds are some of the most important kinds of bonds for drug discovery and manufacturing. Almost all medicines have nitrogen in them, but fixing that nitrogen into molecules is difficult, which is why we use precious transition metal catalysts."

What This Could Mean for Drug Costs

Phosphorus is abundant. If the chemistry can be developed into reliable industrial processes, manufacturers could potentially reduce dependence on platinum-group metals for at least some reaction classes. This is an early-stage finding - scaling laboratory chemistry into industrial processes is its own discipline, and the hydroamination reaction demonstrated here is one specific application. Whether the approach can be generalized across the full range of reactions currently requiring precious metals remains an open question the team plans to investigate.

In addition to Doyle and Fan, the paper's authors include UCLA doctoral student Alexander Maertens and Princeton Ph.D. Kassandra Sedillo. The research was funded by the National Institutes of Health.