Transfer hydrogenation

Transfer hydrogenation is the addition of hydrogen (H2; dihydrogen in inorganic and organometallic chemistry) to a molecule from a source other than gaseous H2. It is applied in industry and in organic synthesis, in part because of the inconvenience and expense of using gaseous H2. One large scale application of transfer hydrogenation is coal liquefaction using "donor solvents" such as tetralin.[1][2]

Organometallic catalysts

In the area of organic synthesis, a useful family of hydrogen-transfer catalysts have been developed based on ruthenium and rhodium complexes, often with diamine and phosphine ligands.[3] A representative catalyst precursor is derived from (cymene)ruthenium dichloride dimer and the tosylated diphenylethylenediamine. These catalysts are mainly employed for the reduction of ketones and imines to alcohols and amines, respectively. The hydrogen-donor (transfer agent) is typically isopropanol, which converts to acetone upon donation of hydrogen. Transfer hydrogenations can proceed with high enantioselectivities when the starting material is prochiral:

RR'C=O + Me2CHOH → RR'C*H-OH + Me2C=O

where RR'C*H-OH is a chiral product. A typical catalyst is (cymene)R,R-HNCHPhCHPhNTs, where Ts = SO2C6H4Me and R,R refers to the absolute configuration of the two chiral carbon centers. This work was recognized with the 2001 Nobel Prize in Chemistry to Ryōji Noyori.[4]

Another family of hydrogen-transfer agents are those based on aluminium alkoxides, such as aluminium isopropoxide in the MPV reduction; however their activities are relatively low by comparison with the transition metal-based systems.

Transfer hydrogenation catalyzed by transition metal complexes proceeds by an "outer sphere mechanism."

Metal-free routes

Prior to the development of catalytic hydrogenation, many methods were developed for the hydrogenation of unsaturated substrates. Many of these methods are only of historical and pedagogical interest. One prominent transfer hydrogenation agent is diimide, which becomes oxidized to the very stable N2:

The diimide is generated from hydrazine. Two hydrocarbons that can serve as hydrogen donors are cyclohexene or cyclohexadiene. In this case an alkane is formed along with the formation of benzene. The driving force of the reaction being the gain of aromatic stabilization energy when benzene is formed. Pd can be used as a catalyst and a temperature of 100 °C is employed. More exotic transfer hydrogenations have been reported, including this intramolecular one:

Many reactions exist with alcohol or amines as the proton donors and alkali metals and electron donors. Of continuing value is the sodium metal mediated Birch reduction of arenes. Less important presently is the Bouveault–Blanc reduction of esters. The combination of magnesium and methanol is used in alkene reductions, e.g. the synthesis of asenapine:[5]

Organocatalytic transfer hydrogenation

Organocatalytic transfer hydrogenation has been described by the group of List in 2004 in a system with a Hantzsch ester as hydride donor and an amine catalyst:[6]

In this particular reaction the substrate is an α,β-unsaturated carbonyl compound. The proton donor is oxidized to the pyridine form and resembles the biochemically relevant coenzyme NADH. In the catalytic cycle for this reaction the amine and the aldehyde first form an iminium ion, then proton transfer is followed by hydrolysis of the iminium bond regenerating the catalyst. By adopting a chiral imidazolidinone MacMillan organocatalyst an enantioselectivity of 81% ee was obtained:

The group of MacMillan independently published a very similar asymmetric reaction in 2005:[7]

In an interesting case of stereoconvergence, both the E-isomer and the Z-isomer in this reaction yield the (S)-enantiomer.

Extending the scope of this reaction towards ketones or rather enones requires fine tuning of the catalyst (add a benzyl group and replace the t-butyl group by a furan) and of the Hantzsch ester (add more bulky t-butyl groups):[8]

With a different organocatalyst altogether, hydrogenation can also be accomplished for imines. In one particular reaction the catalysts is a BINOL based phosphoric acid, the substrate a quinoline and the product a chiral tetradehydroquinoline in a 1,4-addition, isomerization and 1,2-addition cascade reaction:[9]

The first step in this reaction is protonation of the quinoline nitrogen atom by the phosphoric acid forming a transient chiral iminium ion. It is noted that with most traditional metal based catalysts, hydrogenation of aromatic or heteroaromatic substrates tend to fail.

References

  1. ↑ Speight, J. G. "The Chemistry and Technology of Coal" Marcel Dekker; New York, 1983; p. 226 ff. ISBN 0-8247-1915-8.
  2. ↑ Muñiz, Kilian (2005). "Bifunctional Metal-Ligand Catalysis: Hydrogenations and New Reactions within the Metal-(Di)amine Scaffold13". Angewandte Chemie International Edition. 44 (41): 6622–6627. doi:10.1002/anie.200501787. PMID 16187395.
  3. ↑ T. Ikariya, K. Murata, R. Noyori "Bifunctional Transition Metal-Based Molecular Catalysts for Asymmetric Syntheses" Org. Biomol. Chem., 2006, volume 4, 393-406.
  4. ↑ Shimizu, H., Nagasaki, I., Matsumura, K., Sayo, N., and Saito, T. "Developments in Asymmetric Hydrogenation from an Industrial Perspective" Acc. Chem. Res. 2007, vol. 40, pp. 1385-1393. doi:10.1021/ar700101x
  5. ↑ Linden, M. V. D.; Roeters, T.; Harting, R.; Stokkingreef, E.; Gelpke, A. S.; Kemperman, G. (2008). "Debottlenecking the Synthesis Route of Asenapine". Organic Process Research & Development. 12 (2): 196–201. doi:10.1021/op700240c.
  6. ↑ Yang; Hechavarria Fonseca, M.; List, B. (2004). "A metal-free transfer hydrogenation: organocatalytic conjugate reduction of alpha,beta-unsaturated aldehydes". Angewandte Chemie International Edition in English. 43 (48): 6660–6662. doi:10.1002/anie.200461816. PMID 15540245.
  7. ↑ Ouellet; Tuttle, J.; MacMillan, D. (2005). "Enantioselective organocatalytic hydride reduction". Journal of the American Chemical Society. 127 (1): 32–33. doi:10.1021/ja043834g. PMID 15631434.
  8. ↑ Tuttle; Ouellet, S.; MacMillan, D. (2006). "Organocatalytic transfer hydrogenation of cyclic enones". Journal of the American Chemical Society. 128 (39): 12662–12663. doi:10.1021/ja0653066. PMID 17002356.
  9. ↑ Rueping; Antonchick, A.; Theissmann, T. (2006). "A highly enantioselective Brønsted acid catalyzed cascade reaction: organocatalytic transfer hydrogenation of quinolines and their application in the synthesis of alkaloids". Angewandte Chemie International Edition in English. 45 (22): 3683–3686. doi:10.1002/anie.200600191. PMID 16639754.

See also

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