Nature | Celebrating the 25th Anniversary of Click Chemistry: An Underappreciated Revolution in Chemical Reactions

In 2001, three chemists—Kolb, Finn, and Sharpless—published a seemingly 'idealized' review article in *Angewandte Chemie*, introducing an entirely new chemical concept: click chemistry. They proposed that ideal chemical reactions should be as simple, efficient, and reliable as clicking a mouse—rapidly joining two molecules together in water, without generating any harmful by-products. At the time, this vision was mocked by some peers as a 'misleading publicity stunt' and even criticized as 'superfluous and unwelcome hype'. Yet, 25 years later, click chemistry has not only become one of the cornerstones of synthetic chemistry but also helped Sharpless, Meldal, and Bertozzi jointly win the 2022 Nobel Prize in Chemistry. This article traces the quiet yet world-changing revolution sparked by this reaction paradigm. Carolyn Bertozzi, Morten Meldal, and Barry Sharpless (left to right) What is 'Click Chemistry'? — A Precise, Lego-Like Molecular Connection Technique The core idea of click chemistry is deceptively simple yet highly ambitious: reactions must be modular, broadly applicable, exceptionally high-yielding, generate only harmless by-products, and allow precise control over the three-dimensional structure of molecules. To meet these stringent criteria, Kolb et al. suggested that chemists should not blindly mimic nature’s biochemical carbon–carbon bond-forming reactions—processes with weak thermodynamic driving forces and difficult to control, which even modern enzymes have required billions of years of evolution to perform efficiently. Instead, click chemistry focuses on reactions with strong thermodynamic driving forces, especially those forming carbon–heteroatom bonds (e.g., with nitrogen or oxygen) in aqueous media. Such reactions are not only highly efficient but also environmentally benign, proceeding smoothly in water and drastically reducing reliance on organic solvents and waste generation. From Drug Discovery to Cross-Disciplinary Revolution: The Rise of Click Chemistry Click chemistry was originally conceived to address inefficiency and excessive waste in drug discovery. At the time, the pharmaceutical industry widely employed 'solid-phase synthesis', attaching molecules to microbeads for stepwise reactions. Although high-yielding, this method consumed vast quantities of reagents and involved lengthy procedures. Kolb et al.’s click chemistry concept encouraged chemists to revisit old yet highly efficient reactions—particularly those forming carbon–heteroatom bonds—to build compound libraries more creatively and with less waste. Despite initial skepticism and ridicule, Sharpless’s team reported, in 2002, the most iconic click reaction—the copper-catalyzed azide–alkyne cycloaddition (CuAAC). This reaction selectively couples azide and alkyne groups to form stable triazole rings; it is operationally simple and delivers near-quantitative yields, fulfilling virtually all click chemistry criteria. Almost simultaneously, Meldal’s team independently discovered the same reaction—earning both scientists shared credit for the Nobel Prize.

Spotlighting Ingenious 'Alchemical' Examples: Transforming Waste into Valuable New Materials

Relevant research findings were published in *Applied Catalysis B: Environmental* (DOI: 10.1016/j.apcatb.2018.02.010) (Wang Y, Cao H, Chen L, et al. Tailored synthesis of active reduced graphene oxides from waste graphite: Structural defects and pollutant-dependent reactive radicals in aqueous organics decontamination[J]. *Applied Catalysis B: Environmental*, 2018, 229: 71–80.) (V) A Dual-Waste Strategy: Converting Waste Cooking Oil and Red Mud into Composite Carbon Materials Red mud is a solid residue generated during the alkaline digestion of bauxite to produce alumina. Composed of fine particles of aluminum, iron, silicon, titanium, and other trace metal oxides, red mud exhibits a highly alkaline pH of 10–12.5. Due to its alkalinity and high metal content, uncontrolled dumping of red mud in landfills poses significant adverse impacts on adjacent soils and groundwater. In 2017, global red mud production reached 77 Mt yr⁻¹, prompting continuous efforts by industry and researchers to develop safe, permanent disposal strategies. Beyond disposal, red mud has been explored for various industrial and environmental applications—including as a component in construction bricks, asphalt pavement filler, coagulant producer, adsorbent for inorganic and organic compounds, and catalyst. Despite some progress, the majority of daily red mud output remains stockpiled in landfills. Thus, reliable methods are urgently needed to reduce its environmental burden and enable benign waste valorization. Researchers led by Kwangsuk Yoon at Sejong University developed a biochar composite material via co-pyrolysis of waste cooking oil and red mud, thereby stabilizing red mud. To further enhance sustainability, the team employed carbon dioxide (CO₂) as the reaction medium during co-pyrolysis. Using CO₂ in the co-pyrolysis of lipid waste and red mud enables controlled carbon distribution among pyrolytic products. CO₂ accelerates thermal cracking of lipid waste and further reacts with it during decomposition. The presence of mineral phases in red mud—especially Fe₂O₃—enhances these mechanistic effects of CO₂, boosting CO production by over 40-fold at 550°C. However, CO₂ suppresses lipid dehydrogenation (~50%), leading to an altered reduction pathway for iron oxide in red mud. As part of red mud modification, the catalytic performance of the resulting biochar composite was evaluated using biodiesel synthesis (FAMEs) as a model reaction. Graphical Abstract Experimental results demonstrate that the biochar composite serves as an effective catalyst for biodiesel synthesis.

Chemists Should Put Waste, Loss, and Defects to Work

1 day ago

C&EN contributor Seemesh Bhaskar argues that chemists should utilize waste, defects, and losses as resources through frugal innovation and circular economy principles rather than engineering them out.

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2026-10-28

Chemists Should Put Waste, Loss, and Defects to Work

Chemists Should Put Waste, Loss, and Defects to Work

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