A team led by Maria José Calhorda, researcher, along with Paulo J. Costa, Principal Investigator, both from BioISI’s Chemistry for Biological Systems (CBS) Group, at Ciências ULisboa, and Frederico Martins, at the time an MsC student from the same group, published a new paper with Xiuling Cui, Researcher, from Zhengzhou and Xiamen Universities and collaborators from the Zhengzhou University (China) in the journal Physical Chemistry Chemical Physics. The paper is featured in a themed collection entitled Computational Modelling as a Tool in Catalytic Science and addresses the C–H functionalization of quinoline N-oxides catalyzed by Pd(II) complexes using computational methods. In this BioISI Digest, you will get to know how important these reactions are and what they are used for.

What was the starting point that led to the current research?

This research was conducted on the framework of a Bilateral FCT Project between China and Portugal. Our Chinese colleagues were interested in quinolines, which are versatile and important heterocyclic molecules found in many natural products, and relevant in pharmaceuticals or agrochemicals. In their experimental studies of catalyst development for the activation of the C-H bond, they came across a curious system that was able to catalyze very selectively the C–H functionalization of quinolines, a very important reaction for the industry. Well-known Pd(II) acetate catalysts promoted the cleavage (C-H activation)of the C-H bond of quinoline N-oxides at the C2 position of the ring, but the new Pd(II)chloride catalyst, with chloride instead of acetate, made the reaction occur at the C8 position, originating different organic products. More interestingly, in the presence of water C8–H activation was accompanied by the formation of 2-quinolinones. These facts prompted us to unveil the reasons behind this reactivity using computational methods, namely, DFT calculations.

What is the main finding reported in this paper?

Using DFT calculations, we were able to propose a mechanism that explains the observed experimental reactivity (C8 vs. C2 activation) and may inspire new experimental studies. Indeed, we identified the intermediate responsible for the selectivity of the reaction. This intermediate can adopt the form of a σ-metallacycle, leading to C8 activation whereas the formation of a π-complex promotes C2 activation. The different energies of these σ vs. π complexes when the ligand changes from acetate to chloride dictate the observed reactivity.

If you had to explain the main finding to a 5-year-old child, how would you do it? 

Using a computer program we were able to understand why the same molecule is transformed into two different molecules when we change one condition.

Why is it important for the scientific community and for society at large?

As mentioned earlier, quinolines are very versatile heterocyclic systems found in many natural products and used in pharmaceuticals or agrochemicals. The functionalization of quinoline derivatives in specific positions is paramount for the creation of new drugs or other bioactive molecules. Our work helped to understand the general mechanism of the C-H activation and therefore, it could be decisive to a better and more efficient rational design of these molecules.

What are the next steps?

The same Chinese team is also expanding the studies of the reactivity of cyclopropenones with chosen amides using rhodium(III) catalysts. The resulting molecules are very interesting owing to their biological properties, namely the anti-HIV-1 1 and the anti-cancer activity and could become alternative precursors for more efficient drugs. We are currently using computational methods to complete the mechanisms based on the experimental data of our Chinese co-workers.

From left to right: Frederico Martins, Paulo J. Costa and Maria José Calhorda [images provided by the researchers]

From left to right:Paulo J. Costa,  Maria José Calhorda and Xiuling Cui [image provided by the researchers]

Find out more about CBS Group  here

Read the full paper here.