All of you must have heard that “pressure makes diamonds”. This quote comes from General George S. Patton Jr. who used it as a motivational and inspirational tool for his troops. For a chemist “pressure makes diamonds” has quite a literal meaning since diamonds could indeed be formed in nature from various carbon-containing sources under extremely high pressure of around 50000 atm and at temperatures exceeding 1000 °C. One of the commercial methods to make synthetic diamonds uses such pressure and temperature of about 1500 °C.
For an organic chemist making diamonds is not really the goal, is it? The history of research on the influence of high pressure on chemical reactions goes back to the end of XIX century when W. C Roentgen found a small effect of high pressure (then “high” meant 500 atm) on the sugar inversion rate under the influence of hydrochloric acid. Research into the effects of high pressure on chemical reaction rates continued with V. Rothmund but it really expanded with the advancement in high pressure technology thanks to the works of P. Bridgman, an American physicist, who received the 1946 Nobel Prize in Physics for his work on the physics of high pressures. For instance, he and J. B. Conant were able to determine in 1929 that the pressures as high as 12000 atmospheres cause complete polymerization of isoprene within 50 hours whereas only traces of the polymer are formed after 68 hours if the reaction is carried out under 3000 atm.
To understand the effect of high pressure on the reaction rates one needs to introduce the “volume of activation” term, commonly denoted as DV≠. It is defined as the difference in molar volumes between the transition state and that of the reactants. Simply speaking, if the transition state is more “compact” than the reactants (a negative DV≠ term), “squeezing” the reaction mixture will make it much easier for the reactants to form the transition state and the reaction will be accelerated. There are quite a lot of reactions characterized by negative DV≠, for instance, Diels-Alder cycloadditions, conjugate additions, a variety of condensations, palladium-catalysed coupling reactions, peptide couplings, the Wittig reaction and many, many more.
The main benefits of using high pressure chemistry are not just about making the reactions somewhat faster. The differences between the reactions run at high and normal pressures can be spectacular. In many cases, one can synthesise compounds, which are not formed at normal pressure at all or in a very low yield (Example 1).
Sometimes the higher temperatures required to run the reaction at normal pressure are not acceptable as the substrates may decompose. Accelerating the reaction by using high pressure allows keeping the temperature low and prevents sensitive substrate degradation (Example 2).
High pressure may also affect the preferred stereochemistry if several isomers of the product can be formed. Furthermore, cyclization reactions leading to macrocycles can be facilitated by high pressure thus avoiding the need to use high dilutions. Last but not least reactions run under high pressure may produce very sterically congested structures like the Michael addition product shown in Example 3.
The reactions can be run using neat reagents or more often in a solution. Since the solvent freezing points depend on the pressure, one has to be careful which solvent is used. At very high pressures virtually all common solvents solidify and one needs to maintain sufficiently high temperature, usually room temperature and above, to keep the solvent in liquid state and the reactants in solution.
The main disadvantage of this technology is the requirement to run the reactions in small batches, volume of which is determined by the volume of the reaction vessel (say, 10 – 100 mL). This might explain why the high-pressure technology (up to 6000 atm) has not been adopted on an industrial scale, yet. However, there is light in the tunnel and it was lit by Polish scientists.
They have been at the forefront of high-pressure chemistry for over 40 years. Some of the most important contributions to the area came from the group of Professor Janusz Jurczak at the Institute of Organic Chemistry Polish Academy of Sciences. Their first paper on stereochemistry of the Diels-Alder reactions under high pressure was published in 1978. This group is still very active in the area, although the focus has expanded from the chemistry itself to making it safer and scalable. For instance, high pressure helped them to synthesize and functionalize unclosed cryptands, which may serve as potential phase-transfer catalysts. Very recently they solved the problem of scale by creating a flow equipment for high-pressure processing in continuous mode. It is worth adding that Poland may become the only place in the world where chemistry can be run in a flow mode under 6000 atm pressure.
Selvita is interested in using such high-pressure technology. We think it will help expand the range of chemistries and products we offer to our Clients. We are going to adopt the high-pressure technology while collaborating with the Institute of Organic Chemistry, Polish Academy of Sciences. Will it produce precious hard diamonds for us? Perhaps not, but some profits in the form of hard currency will probably be generated.
- Piotr Graczyk, Ph.D.