Catalytic Hydrogenation

Directed Homogeneous Hydrogenation,
   Brown, J. M. Angew. Chem. I. E. 1987, 26, 190.
Ammonium Formate in Organic Synthesis. A Versatile Agent for Catalytic Hydrogen Transfer Reductions,
   Ram, S. Synthesis 1988, 91.

Catalytic Asymmetric Hydrogenation:
Homogeneous Asymmetric Hydrogenation,
   Caplar, V.; Comisso, G.; Sunjic, V. Synthesis 1981, 85.
BINAP - An Efficient Chiral Element for Asymmetric Catalysis,
   Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345.
Enantioselective Transition Metal-Catalyzed Hydrogenation for the Asymmetric Synthesis of Amines,
   Bolm, C. Angew. Chem. Int. Ed. Engl. 1993, 32, 232.
Asymmetric Transfer Hydrogenation Catalyzed by Chiral Ruthenium Complexes,
   Noyori, R.; Hashiguchi, S.; Iwasawa, Y. Acc. Chem. Res. 1997, 30, 97-102.
Asymmetric Transfer Hydrogenation of C:O and C:N Bonds,
   Palmer, M. J.; Wills, M. Tet.: Assym. 1999, 10, 2045-61.
Asymmetric Catalysis by Functional Molecular Engineering: Practical Chemo- and Stereoselective Hydrogenation of Ketones,
   Noyori, R.; Okhuma, T. Angew. Chem. Int. Ed. Engl 2001, 40, 40-73.
Ru- and Rh-Catalyzed Asymmetric Hydrogenations: Recent Surprises from an Old Reaction,
   Rossen, K. Angew. Chem. Int. Ed. 2001, 40, 4611-3.

  Hydrogen itself is not reactive towards organic molecules, all useful reactions involve transition metal catalysts. The most used ones for hydrogenation and hydrogenolysis reaction are (in that order) Pd, Pt, Rh, Ni, Ru. Many kinds of functional groups can be reduced with H2 and a suitable catalyst, and this is the preferred method for large scale industrial reductions. However, because of the inconvenience of using a hydrogenation apparatus or pressure bottle for small scale laboratory use, hydrogenations are usually used only when other more convenient reagents are not up to the task (for example, carbonyl reductions are usually done using boron or aluminum hydride reagents). There are three main types of reductions where H2/cat is usually the preferred method: (1) hydrogenation of double bonds; (2) partial reduction of acetylenes (Lindlar); (3) hydrogenolysis of benzyl protecting groups.

  Below is a rough reactivity order of functional groups towards catalytic hydrogenation. Note that the details of substrate structure as well as the metal used, ligands, presence of acid or base catalysts, and solvents can alter this sequence in specific cases.

 

Alkene Hydrogenations

  Double bonds are hydrogenated faster than most carbonyl compounds are reduced (the exceptions are acid chlorides and sometimes aldehydes). The ease of hydrogenation is very sensitive to the number of substituents, with monosubstituted alkenes reacting most rapidly, and tetrasubstituted alkenes sometimes being very difficult to reduce. The activated hydrogen is in the form of Pt-H or Pd-H bonds on the surface of metal particles, and hindered alkenes can't approach the M-H bonds easily.

 

  Catalytic hydrogenation will usually cleanly reduce only the double bond of α,β-unsaturated carbonyl compounds. This is in contrast to most metal hydride (B-H, Al-H) reagents, which usually selectively reduce the carbonyl group. Oleocanthal: Smith, A. B.; Han, Q.; Breslin, P. A. S.; Beauchamp. G. K. Org. Let. 2005, 7, 5075.

 

Asymmetric Hydrogenation

  Catalytic asymmetric hydrogenations have been developed extensively, especially for the large-scale preparation of optically pure materials such as amino acids. William Knowles (along with Noyori and Sharpless) won the Nobel Prize in chemistry in 2001 for developments in this area.

The Monsanto process for synthesis of L-DOPA developed by Knowles and coworkers (Knowles, W. S. Acc. Chem. Res. 1983, 16, 106-112) DOI, Nobel Lecture

 

  A powerful method for the asymmetric hydrogenation of β-keto esters was developed by Noyori using BINAP-Ru complexes (Acc. Chem. Res. 1990, 23, 345), in which asymmetric reduction accompanied by dynamic kinetic resolution was achieved (Noyori J. Am. Chem. Soc. 1989, 111, 9134).

 

Semi-reduction of Alkynes

  There are several procedures for reducing triple bonds selectively to cis-double bonds in addition to catalytic hydrogenation (diimide reduction, hydroboration-protonation, hydroalumination-protonation), but the classical Lindlar hydrogenation (using a catalyst consisting of Pd on CaCO3, poisoned with lead and/or quinoline) is still the most widely used method. Benzyl protecting groups usually survive Lindlar hydrogenations

Acutiphycin: Smith, A. B.; Chen, S. S.-Y.; Nelsom, F.; Reichert, J. M.; Salvatore, B. A. J. Am. Chem. Soc. 1997, 119, 10935. DOI


 

Endiandric acids: Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E. J. Am. Chem. Soc. 1982, 104, 5558, 5560

 

Hydrogenolysis of Benzyl Protecting Groups

  Benzyl ethers are sturdy protecting groups which are readily removed by catalytic hydrogenation.They are stable to reaction conditions (acid, base, oxidants, hydride reductants, and fluoride ion) that are used to remove other orthogonal protecting groups. The principal interferences are easily hydrogenated functions like unhindered alkenes, aldehydes, acetylenes, or some alkyl halides. In the example below, note that the O-Bn group can be removed in the presence of a β-lactone, an alkyl chloride, and even an N-benzyl group (PMB = p-methoxybenzyl). Salinosporamide A: Ma, G.; Nguyen, H.; Romo, D. Org. Lett. 2007, 9, 2143. DOI

 

Hydrogenolysis of Cyclopropanes

 Cyclopropanes undergo relatively facile C-C bond hydrogenolysis, a reaction which has found some use in the introduction of gem-dimethyl groups from ketones, as in the example below. Spongian-16-one: Pattenden, G.; Roberts, L. Tetrahedron Lett. 1996, 37, 4191.

 

© 2019 Hans J. Reich, All Rights Reserved
Web page created by WINPLT.