Photoclick: twisted molecules remain reactive longer

A team from Ben Feringa’s group (University of Groningen), in collaboration with two Chinese research groups, has discovered how to increase the speed of photoclick reactions by a factor of 21. By adding bulky steric groups to the popular reactant 9,10-phenanthrenequinone (PQ), they altered how the molecule behaves when exposed to light. The researchers published their results in the Journal of the American Chemical Society (JACS). ‘I find it truly remarkable to see how much more we have come to understand about this photoclick reaction in recent years’, said co-first author Annemarie Doze, PhD student in the Feringa group.

Light-triggered click chemistry

Photoclick is a hybrid of photochemistry and click chemistry. It allows you to “click” two specific molecules together very quickly, efficiently, and precisely (and non-invasively) by using light to trigger the reaction. Photoclick often works in complex biological environments, making the technique widely used to attach labels, dyes, or other functional groups to proteins or other biomolecules, allowing you to track and study them in living cells.

For photoclick reactions, you typically use molecules that react quickly and whose reaction properties are easy to control and adjust. This allows researchers to tailor the reaction to different illumination conditions and precisely determine when and where the coupling occurs.

Twisted molecules

A now-popular photoclick reaction developed by Feringa and colleagues several years ago involves the organic compound 9,10-phenanthrenequinone (PQ) and electron-rich alkenes (ERA). It is fast, efficient, and biocompatible.

However, combining high efficiency with activation by visible light is not straightforward for this system. Originally, powerful light sources were required for efficient activation of PQ. Furthermore, the activation still occurred in the ultraviolet to violet range (around and below 400 nm). If the environment is exposed to this type of light for too long, undesirable side reactions can occur that may limit the application of such a system.

To address these issues, Doze and colleagues introduced steric hindrance to PQ. In other words, they modified the three-dimensional structure of PQ in such a way that it remains in an active state longer and can react more quickly with ERA. They did this by introducing methyl substituents (CH₃) in the ortho positions of the aryl rings, which altered the shape of the molecule. As a result, it becomes less flat and more “twisted,” and the molecules can stack less tightly on top of each other. Due to the change in shape, the lifetime of the triplet state increased from 0.33 μs to 6.9 μs.

Furthermore, the geometric distortion in PQ made the intersystem crossing from the first excited energy state (S1) to the reactive triplet state (T1) more efficient. As a result, the system loses less energy through unwanted pathways, and a larger proportion of the excited molecules are in the reactive triplet state, which increases the likelihood of successful photoclick reactions with ERA.

21 times faster

However, not all substituents lead to a faster photoclick reaction. The Groningen researchers discovered that strong electron-donating substituents can alter the electronic structure in such a way that intersystem crossing is disrupted, causing the reaction rate to actually decrease.

For PQ-o2CH₃ with N-Boc-2,3-dihydro-1H-pyrrolepyrrole (PY), the researchers achieved a second-order reaction rate of 11,300 M⁻¹ s⁻¹—approximately 21 times faster than the reference system PQ-H with the same alkene, PY.

The researchers also investigated how their system could write, read, and erase light-controlled “information” using fluorescence. They demonstrated that, under controlled 420-nm light, the system could generate a fluorescent signal, write patterns using a mask, read the signal with UV light, and erase it again through uniform illumination (420 nm).

Doze explains: ‘One of the major advantages of the PQ-ERA photoclick reaction is that the product is fluorescent, making it easy to see and allowing you to closely monitor the progress of the reaction. This offers many possibilities for using the reaction in, for example, smart materials. But you can also use the reaction for biological applications, such as labeling proteins in cells.’

Tumors and infections

‘The research may seem basic, but as we gain a better understanding of the mechanism behind the PQ-ERA reaction, we can also design better applications’, says Doze. ‘For example, we use the reaction to rapidly attach radioactive particles to drugs for PET scans, which allow tumors and infections to be accurately detected.’ To this end, they are collaborating closely with the University Medical Center Groningen.

Doze: ‘In addition, we are working on activating the PQs with red light, because it causes fewer side reactions and penetrates deeper into the body than blue or UV light. That is important if we eventually want to use the reactions for biological applications, for example first in animals and later possibly in humans. We are also trying to make PQ variants more soluble in water, which is also necessary for such applications.’

Y. Fu, J. Zhou, A.M. Doze, et al., Steric Engineering of Phenanthrenequinone for Ultrafast and Tunable Visible Light-Induced Photoclick Reaction, JACS (2026), doi:10.1021/jacs.5c21739