Click chemistry, 25 years on

Twenty-five years after its first description appeared in the pages of Angewandte Chemie,¹ click chemistry is now embedded throughout molecular sciences and engineering, but is nowhere near mature – if not in its infancy, then perhaps enjoying a highly active childhood.

Conceived by K Barry Sharpless, click chemistry’s simple idea got some organic chemists a wee bit upset when it was first articulated. It seemed only obvious: good bond-forming reactions are useful. Well, of course. But the heart of the matter is much more than that. When those reactions are not just good, but nearly perfect, they carry incalculable power. This was being elegantly demonstrated at the time by Carolyn Bertozzi and had always been at the root of polymer chemistry. Once you realise that, finding new reactions of this type becomes compelling. Sharpless showed chemistry users they didn’t need to fret about synthetic accessibility, and he gave chemistry discoverers a broader purpose. Both were freed by this incisive vision from a narrow focus on carbon-carbon bond-forming reactions and empowered to seek connectivity.

The concept of click chemistry enabled non-chemists to bring functional molecular designs to their worlds

Thus, click chemistry’s organising principles gave investigators from many different fields a conceptual framework to take advantage of outstanding chemical reactivity. I am reminded of a science fiction book I read in my youth (Babel-17 by Samuel R Delany). In one passage, residents of a planet with a very hot atmosphere – and therefore of a civilization that depends on its ability to control temperature – encounter a human spaceship. They are able to describe the entire heating and cooling system of that ship in enough detail to reproduce it exactly, using only three words of their language. The point, academically codified as ‘linguistic relativity’, is that language carries perspectives, information and assumptions that enable or constrain the ideas generated by its users. By introducing the concept of click chemistry into the language of modern science, Sharpless enabled many non-chemists to bring functional molecular designs to their worlds.

The applications of click chemistry will therefore continue to grow in a self-reinforcing loop that connects chemists to materials scientists, engineers, biologists, clinicians and many others. And for those who explore the fundamentals of chemical reactivity, click chemistry will also continue to grow in sophistication. We have seen many new reactions recently invented (or rediscovered) that meet click chemistry standards and become rapidly identified as useful by acquiring that label. Each is a treasure that adds to an ever-growing list of connector structures that can be selected to match the desired application. After all, click chemistry highlights the power of connectivity – biology’s signature method of generating molecular function – but also requires us to pay attention to what exactly is doing the connecting.

Click reactions will become increasingly integrated into the tools and practice of biological and engineered evolution

Furthermore, chemistries that go beyond universally reliable connectivity are becoming available, such as click reactions that trigger subsequent bond cleavage events. Another example is Sharpless’s SuFEx reaction and related processes that become flawless bond-forming engines only in a particular type of environment.² This allows the reaction itself to mark where in a complex biological mixture such an environment exists. Lastly, since function is the overall goal of click chemistry, I anticipate that click reactions will become increasingly integrated into the tools and practice of biological and engineered evolution, the most powerful creator of molecular function that we know of.

So perhaps the lasting value of click chemistry’s original description lies in its linguistic relativity, comprising a shift of the limits of molecular expectation: making the bonds you want to make, and avoiding making those you do not, is within our capabilities in many different settings. That’s worth thinking about.