In my quest to stimulate bench chemists to think like industrialists, I like to bring examples of chemistry from the literature to highlight a point I’m trying to make. The literature is full of transformations and research that serve as positive and negative examples of good scale-up thinking.

There are examples, however, that are less than choice in terms of green processing or good scale-up thinking. As I have said previously, green chemistry and good scale-up principles may not be equivalent concepts, but they can and often do run in parallel.

An interesting transformation is featured in the recent article entitled Efficient 1,2-Addition of Aryl and Alkenylboronic Acids to Aldehydes Catalyzed by the Palladium/Thioether-Imidazolinium Chloride System, by Kuriyama, Shimazawa, and Shirai, J. Org. Chem., 2008, 73, 1597-1600. [My apologies to the authors for their unanticipated role in this analysis.]

In this article a bond forming reaction between 1.5 eq of a boronic acid and 1.0 eq of an aldehyde is described affording a secondary alcohol. The transformation is catalyzed by 0.5 % Palladium allyl chloride dimer with 1 % of a custom imidazole carbene precursor in the presence of 2 eq CsF as base. The reaction mixture is heated to 80 C in dioxane and the chemistry is reported to be over in ca 20 minutes.

I am somewhat reluctant to be critical of chemistry that is done catalytically and is high yielding. But this transformation, solid science though it may be, would be difficult to justify taking to scale-up without an examination of alternative schemes.  Let me explain my thinking.

First, on the basis of atom efficiency alone, this process requires that a lot of different elements find their way into the pot. The tally is C, H, N, O, Cl, B, Pd, Cs, F, and S to just make a C-C bond to produce a benzyl alcohol. A scale-up chemist would have to ask, why not use a Grignard and the aldehyde? Granted, there may be incompatible functional groups on either Ar1 or Ar2 that would not tolerate a Grignard reagent. However, it is worth pointing out that the conventional way of making boronic acids is by addition of a boronic ester or fluoride to RMgX or RLi followed by hydrolysis. Compatibility is an issue there as well.

One might object that many of the diverse atoms used in the reaction are at a catalytic level and as such may not constitute a major cost or environmental insult. True enough for the user of the process. But the metal complex must be manufactured somewhere at a larger scale for distribution. Pd mining and beneficiation requires energy inputs and generates wastes. The same idea applies to the imidazolinium salt.

The reaction does seem to require 1.5 equivalents of boronic acid and 2 equivalents of cesium fluoride. Boronic acids are specialty synthetic intermediates whose manufacture generates its own waste stream. Furthermore, boronic acids can be on the expensive side. The use of a boronic acid as a latent nucleophile for a straightforward addition to an aldehyde seems somewhat extravagant.

Cesium fluoride residues (2 equivalents) will find their way into the aqueous waste stream and possibly to an incinerator where the solids may end up in roadway pavement or a landfill. While fluoride is an efficient base in this case, common sense suggests that carbonate may have a more benign fate in the environment owing to the fact that it decomposes to water and CO2. Unfortunately, the best yields are with cesium as cation.

Chemists seeking to apply this kind of coupling chemistry would be well advised to be extra careful in their IP diligence. The use of metal catalyzed coupling reactions may already be patented or applications may be pending for patents. The same comment applies to the use of imidazolinium carbenes. Industrial chemists would be well advised to look deeply into the carbene species for process and composition of matter claims. Ever since the Bayh-Dole Act, university patents have been popping up like dandelions.

I do not want to be too critical of this chemistry. It is an interesting transformation and certainly may be of use for some kind of product. But for scale-up, at first pass it seems too far from earth, air, fire, and water. I would say that for maximum profit, this process is more of a Plan B or Plan C scheme.