In the quest for new drugs, chemists have found a way to assemble complex molecules with the ease of snapping building blocks together.
Imagine a world where scientists could assemble complex molecules as easily as children click together building blocks. This vision is becoming a reality through "click chemistry" – a revolutionary approach to chemical synthesis that prioritizes efficiency, reliability, and simplicity. Among the most powerful tools in this arsenal is a next-generation technique called Accelerated SuFEx Click Chemistry (ASCC), a method that is dramatically speeding up the search for new functional molecules, from life-saving drugs to advanced materials 1 4 .
The term "click chemistry" was coined to describe chemical reactions that are like molecular Velcro: they click molecular modules together quickly, selectively, and under simple conditions. The goal is to make the process of molecule building more modular and predictable, drastically accelerating the discovery of new compounds with useful properties 4 .
At the heart of our story is a specific click reaction known as Sulfur Fluoride Exchange (SuFEx). Introduced in 2014 and later honored with the 2022 Nobel Prize in Chemistry, SuFEx exploits the unique properties of sulfur-fluorine bonds to create stable linkages between molecular fragments 7 . These connections are remarkably robust, making them ideal for constructing functional molecules. SuFEx has found applications across nearly all areas of modern chemistry, from drug discovery to materials science 1 .
However, the original SuFEx method, while powerful, had room for improvement. Reactions sometimes required high concentrations of catalyst or lengthy reaction times, especially with bulky molecular fragments 2 4 . This is where the breakthrough of Accelerated SuFEx Click Chemistry comes in.
Accelerated SuFEx Click Chemistry (ASCC) represents a monumental leap forward. Developed to overcome the limitations of classical SuFEx, ASCC is an improved method for efficiently coupling alcohols with "SuFExable hubs" – key sulfur-fluoride containing building blocks 2 4 .
Reaction completion time with ASCC vs. hours with classical methods
Catalyst loading with ASCC, significantly lower than previous methods
What sets ASCC apart is its stunning efficiency. Where classical reactions might have taken hours or required large amounts of catalyst, ASCC often completes reactions in minutes with catalyst loadings as low as 1.0 mol% 2 . This dramatic enhancement not only saves time and resources but also simplifies the purification process, making it perfectly suited for the rapid synthesis and testing of large libraries of molecules 4 .
The magic of ASCC lies in the powerful synergy between two key reagents:
2-tert-butyl-1,1,3,3-tetramethylguanidine: This hindered guanidine base, also known as Barton's base, was identified as a superb catalyst for SuFEx reactions. It occupies a "sweet spot" of reactivity, effectively accelerating the exchange process without degrading 2 .
This powerful combination allows chemists to directly use common aryl and alkyl alcohols, bypassing the previously necessary step of first converting them into silyl ethers. This streamlines the synthetic workflow, making the entire process faster and more practical 2 .
Hover over the reaction to see the click process
The development of ASCC was not an accident; it was the result of meticulous experimentation aimed at solving the specific bottlenecks of classical SuFEx chemistry.
The research, as detailed in a pivotal 2022 paper, followed a clear, step-by-step process 2 :
The team began by screening various guanidine bases for a relatively sluggish SuFEx reaction between 8-quinolinesulfonyl fluoride and a hindered silyl ether. Among the candidates, BTMG was the standout, achieving >99% conversion in just 2 hours. In stark contrast, the commonly used catalyst DBU managed only 17% conversion in the same time 2 .
With BTMG identified, the next step was to see if a silicon additive could further enhance the reaction, allowing for even lower catalyst loads. The researchers tested the reaction between a sulfonyl fluoride and sesamol (an alcohol) with BTMG and different silicon reagents. HMDS was the superior choice, enabling quantitative conversion in just 1 minute with only 1.0 mol% BTMG 2 .
Source: Adapted from 2 . Reaction conditions: 20 mol% catalyst, 2 hours.
Source: Adapted from 2 .
The data from this key experiment was clear and compelling. The combination of BTMG and HMDS was transformative:
Reactions that once took hours were now finishing in minutes, or even under a minute 2 .
Purification can often be achieved through simple evaporation rather than complex chromatography 2 .
This experiment firmly established ASCC as a robust, practical, and highly efficient platform for modular synthesis, living up to the high ideals of a true click reaction.
| Reagent | Function | Role in the Reaction |
|---|---|---|
| Sulfonyl Fluoride Hubs (e.g., Ethenesulfonyl Fluoride/ESF) | SuFExable Electrophile | Acts as a core building block; the S-F bond is selectively replaced to form new S-O, S-N, or S-C linkages 5 7 . |
| BTMG (Barton's Base) | Catalyst | A hindered guanidine base that dramatically accelerates the SuFEx exchange process 2 4 . |
| HMDS (Hexamethyldisilazane) | Synergistic Additive | Activates the reaction and protects the catalyst by sequestering harmful fluoride ions 2 4 . |
| Aryl/Alkyl Alcohols | Nucleophilic Partners | Common, commercially available modules that are clicked onto the SuFEx hubs to build complexity 4 . |
R-OH + F-SO2-R' R-OSO2-R' + HF
(Alcohol + Sulfonyl Fluoride Sulfonate Ester + Hydrogen Fluoride)
The true power of ASCC is revealed in its practical applications, particularly in the high-stakes field of drug discovery. Its speed and reliability make it ideal for creating vast libraries of compounds that can be quickly screened for biological activity.
New compounds created in days using ASCC at Cold Spring Harbor Laboratory 8
Researchers at Cold Spring Harbor Laboratory, for example, have used ASCC to rapidly create over 150 new compounds in a matter of days – a task that could take months with traditional methods 8 . They synthesized these molecules in a 96-well plate array format, a standard in high-throughput screening, and directly tested them against cancer cells and drug-resistant bacteria 4 .
One striking success story involves the late-stage functionalization of the natural product Combretastatin A-4, an anticancer agent. By using a SuFEx approach to create a sulfonate-linked derivative, scientists achieved a 70-fold increase in potency against a drug-resistant colon cancer cell line 9 . This demonstrates how a simple "click" modification can breathe new life into existing drug candidates.
Rapid synthesis of drug candidates and optimization of existing therapeutics.
Labeling biomolecules for imaging, diagnostics, and targeted therapies.
Construction of polymers and advanced materials with tailored properties.
Probing biological systems and developing chemical tools for research.
Accelerated SuFEx Click Chemistry is more than just a laboratory technique; it is a fundamental shift in how chemists construct complex molecules. By providing a faster, more efficient, and incredibly reliable method for modular synthesis, ASCC is empowering scientists to explore chemical space more broadly than ever before.
As this technology is adopted by more research teams and integrated into diverse discovery platforms, it holds the potential to significantly accelerate the development of new treatments for diseases like cancer and antibiotic-resistant infections 8 . In the molecular construction game, ASCC provides the ultimate click, opening up a new world of possibilities for functional molecules and the technologies they enable.