kilomentor | 29 September, 2012 17:53
I have a confession to make at the very outset of this blog article. I have
never performed a transfer hydrogenation in my entire career, even though I
have been involved developing many hydrogenation process steps using hydrogen
gas, often under pressure. How can this have transpired if transfer
hydrogenation is better known to process chemists and if it provides all the
benefits that I shall recite; benefits substantiated by the many transfer
hydrogenations reported in process chemistry books and journals? The reason is perhaps
that, once a site commits to having hydrogen handling technology as the
companies I worked for had, using it may
be important to justify that expenditure.
Certainly, catalytic reduction by the addition of hydrogen is a very convenient and atom efficient reaction step. The reagent, hydrogen, is easily removed even though used in large excess and an excess that drives reactions involving it to completion. Another important point to bear in mind is that hydrogenations are often mass transfer limited; that is, the rate of reaction is determined by how quickly hydrogen can be delivered to the surface of the catalyst rather how fast it will react with the substrate. Thus the reaction is often dependent upon the effectiveness of the stirring, which in turn affects the size and number of hydrogen bubbles created in the solvent mixture. Where it exists this dependency presents a particular concern as the process step is scaled up and the reactor equipment varied.
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.
Particularly surprising is that transfer hydrogenation has not been adopted more in academia particularly for undergraduate research since transfer hydrogenations are both safer and easier to sample for reaction completion. There is no flammable gaseous headspace and since there is no pressure sampling can be done with a septum and syringe needle. Indeed, essentially no free divalent hydrogen is present at any time during the reaction. Furthermore, unlike the reaction using hydrogen gas, it is not mass transfer limited by the rate the gas gets stirred into the solution. Thus, the reaction kinetics can be expected to be simpler.
As early as 1973 Chemical Reviews wrote “Certainly these catalytic
transfer reductions at the very least are a considerable technical improvement over the rather messy traditional reduction with metals and acid. The catalytic transfer reactions appear to be more selective than regular catalytic hydrogenation…… There is no question as to the greater experimental convenience with catalytic transfer hydrogenation, most reactions being complete after 1 or 2 hr at reflux, without the use of elaborate apparatus. It is surprising that routine use is not made of this process.”
Although the use of hydrogen gas is more atom economic if one bases the decision naively on the simple balanced equation, in practice a large excess of hydrogen is normally used as an atmosphere in the headspace. Also, the reactor is routinely repeatedly degassed, flushed, and vented to start, and all the excess hydrogen is lost when the step is worked up. With transfer hydrogenation, the hydrogen source is typically used in only a 4-5 times molar excess and these hydrogen sources are cheap and do not present any particular waste problems.
Vigorous boiling of reaction mixtures promotes the reaction rather and does not expel hydrogen. The catalyst makes possible transfer of hydrogen atoms from a suitable donor to a suitable substrate without hydrogen release making transfer hydrogenation compatible with any inerted plant reactor. There is no special venting requirement and no fire or explosion hazard and these advantages result in significant cost savings and flexibility of operations.
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.
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.
Hydrogen donors include cyclic ethers, benzyl alcohol, cyclohexanone, 2-propanol, ethylene glycol, 2,3-dihydroindole, 1,2,3,4-tetrahydroquinoline, cyclohexene, cyclohexadiene, limonene, hydrazine, ammonium formate, ammonium hypophosphite.
Takeshi Nishiguchi, Hideaki Imai, Yoshikazu Hirose, and Kazuo Fukuzumi in Journal of Catalysis, Volume 41, Issue 2, February 1976, Pages 249–257 report the hydrogen-donating ability of organic compounds in the hydrogen transfer reaction catalyzed by Pd-carbon decreasing in the order: indoline > formic acid > tetrahydroquinoline > piperidine > pyrrolidine > cyclohexene > N-methylpyrrolidine > di-n-propylamine > d,l-limonene > 1,2-dihydronaphthalene.
Cyclohexene and cyclohexadiene both produce benzene as co-product and so might be discouraging just to completely avoid the slightest health exposure question. Isopropanol is sufficiently volatile to be easily removed along with acetone produced. The heterocyclic compounds as well as their aromatic heterocyclic products can be removed by acid extraction of the reaction mixture making workup easier in the cases of neutral or acidic products. Hydrazine can be washed out and its oxidation product is a gas. The inorganic ammonium salts are also water soluble and the co-products are volatile. These formats are also the most active. Limonene which is said to be a good hydrogen source gives rise to by-product and co-product that are not always easily removed.
It would appear that the most convenient hydrogen atom source of all for transfer hydrogenations is ammonium formate. Unlike the organic molecules that can donate hydrogen it can easily be removed from the product either by washing with water or evaporation. Ammonium formate is completely and easily volatile. Ammonium formate is reported to be soluble in water, formic acid, acetic acid, methanol and somewhat surprisingly ethyl ether and apparently THF can be used as a cosolvent with methanol in these reactions. Sodium hypophosphie is another inorganic source of hydrogen atoms for reduction. The transfer hydrogenation can also be done by dissolving the substrate in ethanol, adding the 10% Pd/C, heating to the reaction temperature and adding an aqueous solution of sodium hypophosphite to the stirred solution. Sodium hypophosphite is reported to be soluble even in cold (ethyl?) alcohol.