Wednesday, October 3, 2012

Process Wednesday: why not transfer hydrogenation?

Kilomentor asks a good question -- why don't we use transfer hydrogenation?:
...Transfer hydrogenation is here discussed as it relates to scaling up a hydrogenation step. Chemists who are more accustomed to working in the laboratory are overwhelmingly more familiar with reactions with hydrogen in the presence of a catalyst and much less with the transfer of hydrogen atoms from a donor reagent to a substrate under catalysis. Yet this latter, transfer hydrogenation, is cheaper and safer both because no free hydrogen is used and because it does not require a special reactor, special stirring, or special gas handling auxiliaries. Indeed, the benefits of transfer hydrogenation  seem to be well understood by seasoned process chemists from the evidence of descriptions in process chemistry monographs but still far  too unfamiliar to new graduates, university scientists, and discovery chemists. 
Since transfer hydrogenation most often use relatively expensive supported palladium catalyst, an important consideration is whether the hydrogenation using molecular hydrogen or the transfer hydrogenation using a donor  results in the higher catalyst expense. I can find no generalized finding comparing the methods on economic issue. A related question is whether there is any increased or decreased tendency for traces of noble metal catalyst to be trapped in the isolated products using or the other of the two methodologies. Again this would be important because a disadvantage of catalytic hydrogenation in all its forms is the risk of residues of toxic heavy metals that can tenaciously adhere to the isolated product. From what I have seen of the literature this difficulty is neither reduced or enhanced using transfer hydrogenation....
[snip] Although other useful reviews have been devoted to transfer hydrogenation these have not been from the perspective of scale-up advantages. I have seen little that answers the general question of what makes a hydrogenation convertible to transfer hydrogenation and how one might predict situations where it is unlikely to work? A tentative rule might be that if the hydrogenation cannot be done using either palladium or a soluble catalyst it is has a reduced likelihood to work with transfer hydrogenation.
I don't know why more people don't use transfer hydrogenation. I suspect that there are solubility issues involved (w/r/t cyclohexene concentrations). Also, is there a difference in speed between transfer hydrogenation and regular hydrogenation? There's gotta be, right?

Readers, what do you think?


  1. Transfer hydrogenation with ammonium formate is my go to reaction for nitro reduction on lab scale. See: Tetrahedron Letters 1984, 25(32), 3415-3418. Seems it should be safer than a process scale H2 reduction and definitely more amenable to scale than Fe/Sn/Zn based methods that generate all that nasty ppt.

  2. I've used ammonium formate and hydrazine as well for transfer hydrogenations (though i can see hydrazine not being popular on a process scale). The convenience of not having to walk to the specialist hood for hydrogenations is a huge advantage. Plus the nitro reduction I ran that way was done in an hour. I'd think they would be slower but for a lot of these reactions, reaction times aren't terribly long anyway.

  3. My guess is technique not that widely used largely because ChemEs are very familiar with and experienced in dealing with H2 and Pd conditions at scale and as Kilometer pointed out even most Chemists are not well versed in using this chemistry so remains under utilized in early development. Most such transformations stay Status Quo until face a particular problem that requires shifts to extreme or less routine solutions. The Merck Process Group (which Kilometer was part of?) formerly was a prime example of labs seen in many companies decades ago that often did stretch the boundaries however not clear if today have as much concentration of effort for advancements of Process Chemistry since long ago adopted the outsourcing paradigm that diluted expertise and halted training of new generations.

  4. I like to use transfer hydrogenation with cyclohexene and Pd/C to deprotect Cbz-protected amines on a large scale (0.5 to 1 mol). Way better than using hydrogen, very clean, mostly safe and very easy to work up.

  5. if you want to de-benzylate amines on Pearlman's catalyst, using hydrogen actually works much better (at room temperature, without any acid additives, even under baloon of H2 without Parr shaker) than transfer hydrogenation with ammonium formate. I was looking into reasons for hydrogenation stalling in the later case (and I initially suspected catalyst poisoning) and tried various acid additives and pre-activation protocols, but it turned out that the reflux reaction temperatures needed for transfer hydrogenation were the culprit - refluxing activated Pearman's catalyst even under H2 rapidly lowers its activity so that it becomes useless for N-debenzylation; my guess is that this is probably due to Pd nanoparticles leaching off the charcoal support and undergo colloid changes due to Oswald ripening, and heating accelerates this degradation process.

    1. Hi milkshake, I agree with your reasoning about catalyst degradation.
      I'm in such a problem: trying to debenzylate an amine (10 mmol) using Pearlman's cat. + HCO2NH4/HCO2H but after 8hr refluxing in EtoH the reaction doesn't proceed anymore. I tried also cylohexene + Pd/C without any particular improvement.
      Scaling-up got worse! Do you have any suggestion?

  6. Transfer hydrogenation comes along with potentially having to remove your hydrogen generating reagent or its byproducts. Molecular hydrogen does not have that concern.

    There is a commercial process here that was a transfer hydrogenation. It had to be run in a aqueous miscible alcohol solvent, then solvent switched to an aqueous immiscible solvent for an aqueous workup, then solvent switched back into an alcohol-based crystallization solvent (which was unfortunately an alcohol that gave poor performance when used for the transfer hydrogenation reaction).

    When the process was switched over to a traditional hydrogenation, the whole process could be run in the alcohol-based crystallization solvent - heat to react, filter off catalyst, cool to crystallize. This product is made on about a 100 metric ton scale per year, so the savings in cycle time and waste was well worth the cost of installing a hydrogenator.