What if you could snap molecular building blocks together like Lego to create more complicated molecules? Click chemistry does just that.
Heena Cho | December 12, 2022
Pioneered by American chemist Barry Sharpless in the early 2000s, click chemistry is a form of functional chemistry that simplifies molecular assembly. Its name denotes the central idea of the technique and the convenience with which two molecules can be “snapped” together to form a linkage, producing a new molecule that can be useful in different ways.
Creating complicated molecules is no easy task. Existing industrial processes for synthesis are long, expensive, and waste-generating. The bulkiness of organic molecules — combinations of several cyclical structures attached to a single atom — makes them unstable and difficult to synthesize. Moreover, even if the molecules are synthesized successfully, the process may not yield a sufficient amount of the compound to be used for applications. Click chemistry reactions, on the other hand, are industrially fast, easy, selective, and high-yielding.
Just a few months ago, three chemists were awarded the Nobel Prize in Chemistry for their role in the development of click chemistry. Chair of the Nobel Committee for Chemistry Johan Johan Åqvist wrote: “This year’s Prize in Chemistry deals with not overcomplicating matters, instead working with what is easy and simple. Functional molecules can be built even by taking a straightforward route.” One of the award-winning chemists, Caroyln Bertozzi, applied click chemistry to living organisms and discovered a series of bioorthogonal reactions — chemical reactions that occur without disrupting regular cellular processes. The specific reactions that Bertozzi discovered allow for the tracking of important cell-surface molecules called glycans, which are now being used in cancer pharmaceutical research as a cellular target for drug delivery. While Bertozzi brought click chemistry to a new level, Barry Sharpless and Morten Meldal were recognized for their role as pioneers in developing click chemistry. Around a decade ago, Sharpless and Meldal discovered a reliable and efficient chemical reaction — copper catalyzed azide-alkyne cycloaddition (CuAAC) — that is now widely utilized in pharmaceutical research. Recognized as one of the premier examples of click chemistry, CuAAC joins building blocks with various functional groups, namely azide and alkyne, to form 1,2,3-triazole, a chemical compound with the formula C₂H₃N₃.
One of the most common applications of click chemistry can be found in drug research. For example, click chemistry is now being used to produce cellular receptors for the treatments of type II diabetes, and it also plays a significant role in the ongoing HIV-1 protease research. Vanderbilt engages in cutting-edge click chemistry research as well. Dr. Bradley Baker and Dr. Paul Laibinis at the Vanderbilt Institute of Nanoscale Science and Engineering developed a “one-step hydrosilylation synthesis of azide surfaces for click chemistry compatible surfaces.” Hydrosilylation is an important reaction that enables the addition of silicon hydrides across multiple C–C bonds. In their technology, an azide molecule is formed in one step on a hydrogen-terminated silicon support, creating a surface that can easily undergo click reactions. This promising technology can be used for efficient manufacturing of azide-terminated silicon substrates, which are used in click chemistry application areas such as materials science, drug delivery platforms, drug discovery, imaging, and biosensing.
Click chemistry is an incredibly versatile and promising toolbox that attracts increasing research interest. As researchers discover more click reactions, we will be able to create more chemical entities that can then be used in various fields more easily. As the American Chemical Society comments, “the success of click chemistry can be judged by how well it allows chemists and nonchemists alike to harness the power of molecular manipulation for the discovery and optimization of useful properties.”
Devaraj, N. K., & Finn, M. G. (2021). Introduction: Click chemistry. Chemical Reviews, 121(12), 6697–6698. https://doi.org/10.1021/acs.chemrev.1c00469
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Devaraj, N. K., & Finn, M. G. (2021). Introduction: Click chemistry. Chemical Reviews, 121(12), 6697–6698. https://doi.org/10.1021/acs.chemrev.1c00469
Click chemistry. Med Chem 101. (n.d.). Retrieved November 7, 2022, from http://medchem101.com/?page_id=142