Study challenges notion that solution-phase organic reactions are unfeasible at high temperatures

Chemists have used sealed glass capillaries to perform pyrazole isomerisation reactions at temperatures as hot as 500°C. By demonstrating that capillary synthesis is a viable way to perform solution-phase reactions at high temperatures, the researchers behind the work say they hope to use their method to unlock entirely new synthetic pathways and significantly simplify the preparation of complex molecules.

Solution-phase organic reactions form the backbone of organic synthesis. Compared to solid-phase and gas-phase methods, solution-phase chemistry allows greater control over reaction conditions and molecular interactions.

However, a key factor limiting their versatility is temperature. In fact, ‘chemists have long considered performing solution-phase reactions at high temperatures, such as 400–500°C, almost impossible,’ says Valentine Ananikov from the Zelinsky Institute of Organic Chemistry in Russia. ‘They believed that these conditions would lead to the thermal degradation of both solvents and substrates.’ As such, researchers have mainly performed solution-phase synthesis at temperatures below 250°C. ‘Under these conditions, the maximum activation energy that can be overcome is typically around 40–45kcal/mol, restricting the reaction space to a set of well-known and largely explored chemical transformations,’ explains Ananikov.

Now, Ananikov and his team have developed a way to perform organic synthesis up to 500°C and overcome activation barriers of 50–70kcal/mol. The method uses Pasteur pipettes as reaction vessels. A small volume of solvent and reactant is confined within the glass pipettes, before they are sealed and then heated by either induction heating, microwaves or in a muffle furnace. The team identified that solvents such as water, dimethylsulfoxide and pyridine caused the capillaries to rupture at high temperatures, whereas aromatic or saturated hydrocarbons were more compatible, with p-xylene being the optimal solvent.

So far, the team has tested their method on the isomerisation of N-substituted pyrazoles, including those with aryl, fluoroalkyl and phenol functional groups. Such reactions typically require multiple steps, making them time-consuming. But by heating capillaries containing 1,5-disubstituted pyrazoles in p-xylene to 500°C, it’s possible to overcome the significant activation energy barrier and complete the reaction within five minutes.

‘Although synthesis at such high temperatures is not a favourable condition and is atypical at the laboratory level due to high energetic waste or availability of appropriate equipment, it is only for five minutes,’ comments Jaime Portilla, an expert in pyrazole derivatives synthesis from the University of the Andes in Colombia. Portilla does, however, note that the reactions the team has tested its technique on are ‘very specific’.

In the future, Ananikov says he hopes to scale-up the method, and ‘continue expanding the boundaries of high-temperature organic chemistry by discovering new reactions and making previously inaccessible transformations possible.’