NUS-A*STAR Breakthrough: De-Saturated Copper Single-Atom Catalysts Achieve 94% Yields in Drug Synthesis

Unlocking New Possibilities in Nanoscale Catalysis: The NUS-A*STAR Breakthrough

In a groundbreaking advancement published in Advanced Materials on March 5, 2026, researchers from the National University of Singapore (NUS) and the Agency for Science, Technology and Research (A*STAR) have introduced de-saturated copper single-atom catalysts (De-sat Cu SACs). These innovative catalysts achieve remarkable 94% yields in propargylic substitution reactions crucial for pharmaceutical synthesis, addressing longstanding limitations in traditional single-atom catalysts (SACs). Led by Dean's Chair Professor Jiong Lu from NUS Department of Chemistry and Senior Scientist II Shibo Xi from A*STAR's Institute of Sustainability for Chemicals, Energy and Environment (ISCE²), this collaboration exemplifies Singapore's thriving research ecosystem. The discovery not only boosts efficiency but also paves the way for greener, more sustainable drug manufacturing processes.

Single-atom catalysts represent the pinnacle of atomic precision in catalysis, where individual metal atoms are anchored on a support material to maximize utilization—approaching 100% atom economy. Yet, their fully coordinated structures often hinder substrate access, limiting reactivity. The NUS-A*STAR team's KOH-mediated Joule thermal shock method transforms stable CuN₄ SACs into under-coordinated CuN₃ variants, exposing active sites for superior performance.

Understanding Single-Atom Catalysts: From Concept to Reality

Single-atom catalysts (SACs) emerged around 2011 with early examples like Pt₁/ZnO for CO oxidation, marking a paradigm shift from nanoparticle catalysts. Since then, SACs have revolutionized fields like electrocatalysis for oxygen reduction reaction (ORR) and CO₂ reduction, thanks to their unique electronic properties and high selectivity. In chemistry, SACs disperse isolated metal atoms (e.g., Cu, Pt, Fe) on supports like nitrogen-doped carbon (NC), mimicking enzymatic active sites but with enhanced stability.

The global catalyst market, valued at over $43 billion in 2025, underscores their importance, with pharmaceutical applications driving demand as catalysis underpins 90% of chemical processes, including fine chemical synthesis for drugs. Singapore, investing S$37 billion in RIE2030 (Research, Innovation and Enterprise 2030)—equivalent to 1% of GDP—positions itself as a hub, with NUS ranking 7th globally in QS Chemistry 2025.

The Challenge: Saturation in SACs Limits Catalytic Potential

Conventional SACs feature metal atoms in nearly saturated coordination environments (e.g., CuN₄), providing thermodynamic stability but restricting flexibility. This 'stiff hand' analogy—stable yet poor at grasping substrates—results in low turnover frequencies (TOFs) for complex reactions like propargylic substitutions, where propargylic carbonates react with nucleophiles to form C-N, C-C, or C-O bonds essential for pharmaceuticals.

• Symmetric coordination blocks substrate approach, reducing activation energy barriers.
• Homogeneous catalysts used traditionally suffer from separation issues and metal residues in drugs.
• Need for tunable, stable heterogeneous SACs to scale green synthesis.

Professor Lu's team at NUS, known for atomic-precision catalysis (h-index 66, 16k citations), targeted de-saturation to create asymmetric, accessible sites.

The Innovation: KOH-Mediated Joule Thermal Shock for De-Saturation

The method starts with CuN₄-NC precursors. A millisecond electrical pulse (Joule heating) reaches ultra-high temperatures (~2000°C), combined with KOH etching, selectively removes one N ligand, yielding stable CuN₃-NC. Synchrotron X-ray absorption fine structure (XAFS) by Shibo Xi confirmed the under-coordinated structure, raising Cu d_z² orbital energy for better π-back donation to alkynes.

Step-by-step:

1. Prepare Cu SACs via impregnation-pyrolysis on NC.
2. Coat with KOH solution.
3. Apply 1000V pulse for 10 ms.
4. Wash and activate—ready De-sat Cu SACs.

Photo by Mari Ganesh Kumar on Unsplash

Performance Highlights: 94% Yields and Exceptional Stability

De-sat Cu SACs catalyzed propargylic substitutions with TOFs up to thousands per hour, yields 90-94% for diverse nucleophiles. Piperidine substrates for clopidogrel (antiplatelet), donepezil (Alzheimer's), desloratadine (antihistamine) excelled. No degradation after 5 cycles, vs. drop in saturated counterparts.

• 94% yield for fluoxetine fragment (Prozac® precursor).
• 93% for maprotiline (antidepressant).
• 92% for naftifine (antifungal).
• Broad tolerance: amines, alcohols, carbons.

Shibo Xi notes: “The result is a stable metal atom that is more exposed, making it easier for reactants to reach.”

Pharmaceutical Applications: Transforming Drug Synthesis

Propargylic substitutions build complex scaffolds in APIs. Global pharma market ($1.6T by 2025) relies on efficient C-C/N formation; this SAC minimizes waste, metals. Singapore's pharma sector ($3.19B 2026) benefits, with catalysts key to 80% processes.

Examples:

NUS-A*STAR Synergy: A Legacy of Collaborative Excellence

NUS (QS #8 world 2026) and A*STAR partner via SSLS synchrotron, shared facilities. Past: green catalysts, GACs for pharma. Jiong Lu (nanocatalysis expert) + Shibo Xi (synchrotron catalysis) = atomic insights. Singapore's 2% GDP R&D fuels such innovations.

For aspiring chemists, explore research jobs at NUS or A*STAR.

Singapore's Catalysis Research Ecosystem and Economic Impact

With RIE2030 S$37B, Singapore leads Asia in chem R&D. Pharma manufacturing hub: 50+ firms, biocatalyst market $250M by 2028. This breakthrough boosts Singapore higher ed output, attracting talent.

Photo by Andy Wang on Unsplash

Challenges Ahead and Path to Industrial Scale-Up

• Scaling Joule heating for kg-scale.
• Cost of synchrotron validation.
• Tailoring for other metals/reactions.

Outlook: Pilot plants by 2028, per Xi: “Great promise for challenging transformations.”

Career Opportunities in Catalysis and Higher Education

This advances fields like academic CV building in catalysis. Jobs in faculty, research. Rate profs at Rate My Professor.

In conclusion, the NUS-A*STAR de-saturated Cu SACs herald a new era. Explore higher ed jobs, university jobs, career advice, or rate professors.