The high cost of energy has an unexpected benefit, says Derek Lowe - it forces us to be more efficient

This issue’s energy theme is a difficult one to apply to pharmaceutical topics. On the discovery and manufacturing end, we are nothing but energy sinks. Both our processes and our materials are energy-intensive: think of those distilled solvents and purified powders, along with all those waste disposal issues. And, of course, the ultimate feedstock for many organic chemicals is petroleum, but only after it’s had even more energy spent on it. 

Now, it’s true that there’s been a huge rise over the last few years in ’green chemistry’. Actually, let me rephrase that: there’s been a huge rise in the number of things labelled as green chemistry, but I suspect that some of these were pasted on in order to please granting agencies and journal editors. Much of this work is very far from making an impact on the industrial scale - I’m yet to be convinced about the large-scale benefits of ionic liquids, for example, no matter how many publication lists they’ve lengthened. As things stand, a large-scale chemist’s idea of a green solvent is still something like toluene. It’s comparatively nontoxic, it can be recovered without much vapour loss, and it can even be re-used after you evaporate it away from your product. 

So while we still live in our solvent-soaked energy-intensive world, we have a responsibility to make the best of it. One useful goal is the concept of atom efficiency, which has been a part of chemistry for some years now. The idea is to use as few extraneous atoms in the chemical steps as you can. That’s simply stated, but it’s a challenge to live up to. 

Protecting groups, for example, applied to and removed from reactive functional groups during a synthesis, aren’t very atom-efficient at all. It doesn’t help that some of the more popular ones are huge, bristling with phenyl and tert-butyl groups. We try to avoid these things, but sometimes our hands are forced. 

Many other popular reactions also look less appealing from the atom-sparing viewpoint. For example, some old named-reaction favourites like the Wittig and Mitsunobu depend on the oxidation of triphenylphosphine, which on the atom-counting level is roughly the size of a barn. Huge counterions like tetrabutylammonium or highly functionalised leaving groups don’t come out too well, either. 

This helps to explain why one of the biggest areas of chemical research these days is in catalytic processes. It’s one of the places we can really improve our processes, especially when you count the waste stream (as you should) as part of the total energy bill. And there’s competition among these reactions for atom efficiency as well: if your slick transition-metal-driven coupling reaction only works on some large, unwieldy functional group, it’s not as slick as you think it is. Oxidation reactions are another example: over the last 25 years, they’ve been moving from stoichiometric amounts of metal reagents to catalytic systems where the reagent is regenerated by something small and cheap, like bleach or even atmospheric oxygen. Don’t forget that compared to a molar excess of chromium, hypochlorite bleach looks very green indeed. 

There are other efficiency considerations beyond the reagents involved, of course. But a common theme emerges as you deal with all of them: profit. The drive for efficient processes in industry isn’t motivated as much by idealism as it’s motivated by money. And frankly, as an industry-employed chemist (and as a free-market capitalist type), I have no problem with this at all. 

Over the years, the prospect of gain has been shown to be a very effective catalyst in its own right - the whole point is to harness it for something beneficial. In the advanced industrial nations, we’ve been doing that by removing the short-circuit incentive to use cheap-but-dirty chemical methods by making the cleanup cost part of the equation. Simply put, I think that if we can keep it profitable to be more efficient, we’re going to become more efficient. If we remove that financial motivation, we’re sunk. 

Looked at that way, higher energy costs have a hidden benefit to them, since they stimulate new ideas and give investors reason to fund them. We’re a resourceful species, but generally only when we have to be. 

Derek Lowe is a medicinal chemist working in preclinical drug discovery in the US