In the pharmaceutical and partly also in the fine chemicals industry many chemical conversions require stoichiometric amounts of reagents, and thus generate large amounts of waste [1, 2]. This is in contrast to the production of bulk chemicals which mostly relies on catalysis. This difference can be explained by the higher complexity of pharmaceuticals and fine chemicals which makes catalysis more demanding and process development more expensive.
According to Sheldon’s classification , most vitamins are typical fine chemicals with production volumes of about 100 to 10'000 tons per year. Some vitamins can be placed in the class of bulk chemicals. Typically these compounds have been produced industrially for decades in multi-step syntheses with high overall yields. The application of catalytic methods in the highly competitive field of vitamins has increased significantly in recent years because of price pressure on these products. Research and development is thus driven by the necessity to reduce waste, use less toxic reagents and solvents, improve energy efficiency, recycle catalysts and reagents, and combine unit operations to reduce costs and achieve more sustainable processes. These goals are mostly in accordance with the twelve principles of “green chemistry”[4,5,6].
Catalytic hydrogenation is certainly the most widely applicable method for the reduction of organic compounds and belongs to the most important transformations in chemical industry. Catalytic hydrogenations in the fine chemicals industry are usually carried out with heterogeneous catalysts. Homogeneous catalysts are typically applied for highly selective transformations, particularly enantioselective reductions. In the case of full recycling of heterogeneous or homogeneous catalysts, hydrogenation with molecular hydrogen is an atom economic transformation and undoubtedly the cleanest possible method for reducing a compound. Alternatively, hydrogen donors such as isopropanol or formic acid can be applied in transfer hydrogenations. In the field of catalytic hydrogenation reactions several significant inventions have been reported in the last 150 years. Sabatier and co-worker investigated the application of highly dispersed metals, e.g. nickel, in the hydrogenation of organic compounds [7,8]. The elective semi-hydrogenation of C≡C-bonds in presence of lead-doped palladium on calcium carbonate catalysts found by Lindlar was a further milestone in the field of catalytic hydrogenation reactions [9-11]. During the last decades asymmetric hydrogenations, pioneered by W.S. Knowles and R. Noyori, were a further highlight in the field of hydrogenation applied in organic synthesis [12,13].
Catalytic hydrogenations can be carried out in a variety of ways, either in the liquid or gas phase and in batch-wise or continuous mode. In continuous processes usually fixed-bed reactors or fluidized-bed reactors are used. The suitable choice of a reactor system depends on various factors such as, in particular, the choice of catalyst, the reaction conditions, heat formation, space-time-yield, residence time, hydrogen pressure, mass-transport phenomena, temperature, solvent and economic reasons.
In this contribution we will focus on industrially important catalytic hydrogenation reactions which are of interest for DSM Nutritional Products concerning the manufacture of vitamins, carotenoids and nutraceuticals. The various hydrogenations are organized by reaction types, rather than by the products prepared: hydrogenations of C=C double bonds, selective semi-hydrogenations of C≡C triple bonds, hydrogenations of C=X/C≡X multiple bonds (X = oxygen or nitrogen), and stereoselective hydrogenations.
2. Hydrogenation of C=C double bonds
Probably the most common hydrogenation reaction performed in industry is the hydrogenation of carbon-carbon double bonds. A wide variety of catalysts are available from commercial suppliers and this transformation is considered a robust and atom-economical reaction. Even so, careful optimisation of the reaction conditions can be required to obtain full conversion and reduce or eliminate by-products. This is also important in the synthesis of vitamins and fine chemicals.
Final steps of the chemical production of vitamin E.
The synthesis of isophytol can be carried out starting from acetone (
Synthesis of isophytol (
The other key intermediate for the synthesis of vitamin E, TMHQ (1), is accessible
Catalytic hydrogenation of TMQ to TMHQ.
The hydrogenation is usually carried out in a continuous mode at medium to low pressure and elevated temperature to prevent crystallization of the product from the reaction mixture. Yields are generally quantitative.
Alternatively, a range of different Pd-catalyzed hydrogenation conditions can be found in the literature, e.g. using Pd/C in solvents like carboxylic esters  or acetone , or palladium on acidic [23,24] or basic oxides  in lower alcohols. Also a Pt-catalyzed hydrogenation has been described using platinum nitrate and aluminium oxide in
An alternative access to TMHQ (
Synthesis of TMHQ from 2,6-DMQ
The K-vitamins are a group of substituted 2-methyl-1,4-naphthoquinones with (or without) a prenyl chain of different length in C-3 position (Figure 1). The core unit of all K-vitamins is menadione (vitamin K3,
After esterification, condensation with isophytol (
A remarkable stereoselective hydrogenation of a trisubstituted olefinic C=C double bond was used in several total synthesis routes to the water-soluble vitamin (+)-biotin (
Chemical production of vitamin K1.
Stereoselective heterogeneous hydrogenation in routes towards (+)-biotin.
3. Semi-hydrogenation of C≡C triple bonds (Lindlar type)
The semi-hydrogenation of carbon-carbon triple bonds to alkenes is one of the most useful hydrogenations for the production of vitamins, however careful choice of catalyst and reaction conditions are required to obtain high selectivity. In general, hydrogenation of acetylenes with a metal catalyst results in the formation of the fully saturated alkane product, since the second hydrogenation (alkene to alkane) is generally faster than the first (alkyne to alkene). However, as long as some of the starting alkyne remains in the reaction mixture, selectivity can be high since the alkynes bind more strongly to the metal surface. The selectivity can be enhanced by the use of suitable catalyst poisons which modify the activity of the metal catalyst.
One of the most widely used and most selective catalysts is the one originally developed by Lindlar [9,11]. With this catalyst, the palladium supported on calcium carbonate is doped with a lead acetate solution during manufacture. This catalyst can then be used either directly in the hydrogenation or modified further by an organic compound such as an amine. Since the hydrogen is delivered from the metal surface to the alkyne, usually high selectivity is obtained for the
One of the earliest uses of the catalyst developed by Lindlar was the semi-hydrogenation of a vitamin A key intermediate (27, Scheme 7) to give tetraene 28. Whilst this could be achieved with poisoned palladium on charcoal or palladium on calcium carbonate , selectivities were significantly higher with the lead-doped catalyst and the reaction could easily be stopped after the uptake of just one equivalent of hydrogen gas.
Semi-hydrogenation of a vitamin A intermediate.
Since this early success the “Lindlar catalyst” (as it has become known) has been used in many different production processes. It is of particular importance in the synthesis of vitamins A & E and also intermediates for the fragrance industry. An important starting material in DSM Nutritional Products’s production of such compounds is methylbutenol (MBE, 30, Scheme 8). MBE is synthesised by the partial hydrogenation of the corresponding alkyne MBY (29) in a batch-wise process. Selectivity is very high (>98%) and the catalyst can be recycled multiple times.
Semi-hydrogenation of MBY.
From MBE, the chain is extended in a sequential manner to obtain dehydroisophytol (31, Scheme 9). This is then reduced in another semi-hydrogenation to give isophytol (2, cf. Scheme 2) . Isophytol can then be coupled with TMHQ (1), as described previously, to form α-tocopherol (cf. Scheme 1). As with MBY-MBE, the hydrogenation is carried out in a batch-wise process at 2-5 bar hydrogen pressure.
Preparation of isophytol by semi-hydrogenation.
Two compounds of interest to the fragrance industry are linalool (11) and linalyl acetate (33, Scheme 10). Both have pleasant floral and spicy odours and are found in a wide range of natural flowers and spice plants. Their main uses are as perfume components in soaps, shampoos and lotions. They can both be synthesised by semi-hydrogenation of 8 and 32 using Lindlar catalysts, however the reaction conditions had to be optimised independently since even minor changes to the substrate structure can significantly affect the hydrogenation selectivity.
Production of linalool and linalyl acetate by semi-hydrogenation.
As an extension to the work above, another fragrance compound, dimethyloctenol (DMOE,
New approaches for the application of Lindlar-type catalysts are the use of supported palladium nanoparticles. By carefully controlling their preparation, a narrow range of diameters can be obtained and deposited on a carbon support [37,38]. These catalysts allow the hydrogenation of C≡C bonds with low metal loadings and in several cases with a high selectivity, e.g. hex-3-yne can be hydrogenated to hex-3-ene in high selectivity at full conversion, however to the best of our knowledge, these have not yet been applied on an industrial scale for the production of vitamins and fine chemicals.
Synthesis of DMOE by combination of two different kinds of hydrogenation.
Further trends in the research on Lindlar hydrogenations are focusing on the addition of FeCl2 and tetramethylammonium chloride to the catalyst, and the use of palladium on metal sintered fibers. This allows the hydrogenation of triple bonds in a continuous reaction mode, also with low Pd loadings, in which Pb doping is not necessary [39-42].
An alternative approach to resveratrol uses the selective hydrogenation of tolan derivatives
Synthesis of combretastatin and resveratrol via Sonagashira coupling and semi-hydrogenation.
Semi-hydrogenation of butynediol for vitamin B6.
As described above, Lindlar hydrogenations are usually carried out in a batch-wise mode in presence of a Pb-doped Pd catalyst on a calcium carbonate carrier. However, new trends in the selective semi-hydrogenation of C≡C bonds are continuous processing and the application of environmentally friendly solvents. The application of supercritical fluids (sc-fluids) in fine chemical processes, e.g. extractions or as process solvent is well documented .
Lindlar-type hydrogenations in supercritical fluids, e.g. sc-CO2, can be carried out in a continuous manner applying a plug-flow reactor set-up. The set-up allows the usage of a new type of Pd-catalyst, amorphous Pd81Si19 in a Pb-free system .
4. Hydrogenation of C=O and C≡N functional groups
As well as the hydrogenation of C-C multiple bonds, the hydrogenation of C-X multiple bonds is used extensively in the production of vitamins and fine chemicals.
L-Ascorbic acid (vitamin C,
Reduction of D-glucose to D-sorbitol in the Reichstein process for the synthesis of vitamin C.
Vitamin B1 (thiamine chloride,
Modern industrial syntheses still use the same basic process, although optimisation has improved the reaction significantly, further reducing the unwanted by-products. Reactions proceed in a batch-wise process with a solvent saturated with ammonia at moderate (>10 bar) hydrogen pressure to ensure high activity and throughput. The catalyst can be recycled multiple times and usually remains in the reaction after batch. The choice of nickel catalyst is also important and recently nickel-alloy catalysts (Centoprime®) have been developed that reduce amine by-products further [57-60].
Production of Grewe diamine for vitamin B1.
Hydrogenation of a ketone for the synthesis of resveratrol.
5. Stereoselective hydrogenation of C=C double bonds
Stereoselective processes, in particular the asymmetric hydrogenation of C=C double bonds, play an increasingly important role in the total synthesis of isomerically pure biologically active products. The naturally occurring fat soluble antioxidant (2
Asymmetric hydrogenation reactions of allylic alcohols in isoprenoid chemistry.
The homogeneous asymmetric hydrogenation of allylic alcohols catalyzed by ruthenium complexes could be performed on pilot scale with substrate-to-catalyst ratios of up to 150’000 (Scheme 17). The C10-building block (
Even two chiral centers can be introduced by the one-pot reduction of unfunctionalized trialkyl substituted olefins in the presence of Ir-BArF complexes containing chiral P,N-ligands (Scheme 18). By applying this novel retrosynthetic concept, an (all-
Asymmetric hydrogenation reactions of unfunctionalized trisubstituted olefinic double bonds.
A Rh(I)-catalysed highly diastereoselective hydrogenation is the basis for a very short synthesis of (+)-biotin (
Diastereoselective hydrogenation in the Lonza procedure to (+)-biotin.
The chiral D-lactone
A breakthrough was achieved in an inter-company cooperation, between DSM Nutritional Products and the catalysis group of Solvias [66,67]. The asymmetric hydrogenation of anhydride
Synthetic strategies for the introduction of optical activity into (+)-biotin.
Preparation of an optically active lactone by catalytic asymmetric hydrogenation.
Enantioselective hydrogenation of 2-oxopantolactone in the synthesis of pantothenic acid.
While the heterogeneous nickel catalyzed hydrogenation of (
Asymmetric transfer hydrogenation of (
Various types of hydrogenation reactions are indispensable parts of economically and ecologically beneficial manufacturing processes towards valuable products in the vitamins and fine chemicals industry. The increasing importance of environmentally benign production methods is addressed by developing concepts for improving the efficiency of transformations, continuous processing and recycling, and achieving high chemo- and stereoselectivities, thus avoiding laborious separation protocols and waste formation. The examples presented and discussed in detail show many achievements in this field during recent decades, but also the necessity to further search for alternative solutions.