Fred van Rantwijk

Biocatalysis in ionic liquids

Roger Sheldon (1942) received a PhD in organic chemistry from the University of Leicester (UK) in 1967. This was followed by post-doctoral studies with Prof. Jay Kochi in the U.S. From 1969 to 1980 he was with Shell Research in Amsterdam and from 1980 to 1990 he was R&D Director of DSM Andeno. In 1991 he moved to his present position as Professor of organic chemistry and catalysis at the Delft University of Technology (The Netherlands). His primary research interests are in the application of catalytic methodologies—homogeneous, heterogeneous and enzymatic—in organic synthesis, particularly in relation to fine chemicals production. He developed the concepts of E factors and atom utilization for assessing the environmental impact of chemical processes.

Biocatalytic transformations in ionic liquids

Room temperature ionic liquids are non-volatile, thermally stable and highly polar; they are also moderately hydrophilic solvents. Here, we discuss their use as reaction media for biocatalysis. Enzymes of widely diverging types are catalytically active in ionic liquids or aqueous biphasic ionic liquid systems. Lipases, in particular, maintain their activity in anhydrous ionic liquid media; the (enantio)selectivity and operational stability are often better than in traditional media. The unconventional solvent properties of ionic liquids have been exploited in biocatalyst recycling and product recovery schemes that are not feasible with traditional solvent systems.

Room-temperature ionic liquids that dissolve carbohydrates in high concentrations

Carbohydrates are only sparingly soluble in common organic solvents as well as in weakly coordinating ionic liquids, such as [BMIm][BF4]. Ionic liquids that contain the dicyanamide anion, in contrast, dissolve approx. 200 g L−1 of glucose, sucrose, lactose and cyclodextrin. Candida antarctica lipase B mediated the esterification of sucrose with dodecanoic acid in [BMIm][dca].

Dissolution of Candida antarctica lipase B in ionic liquids: effects on structure and activity

The effects of ionic liquid media on the activity of Candida antarctica lipase B in a simple transesterification reaction were studied. In ionic liquids containing alkylsulfate, nitrate and lactate anions, which dissolved CaLB, the reaction was at least ten times slower than in [BMIm][BF4]. Only [Et3MeN][MeSO4] was an exception, as dissolved CaLB maintained its activity in this solvent. By means of FT-IR spectroscopy, denaturation of CaLB was observed upon dissolution in ionic liquids in which the activity was low, whereas the conformation of enzyme dissolved in [Et3MeN][MeSO4] closely resembled the native one.

Towards Biocatalytic Synthesis of β-Lactam Antibiotics

This review describes the remarkable transition in the manufacture of β-lactam antibiotics, which is driven by the desire to reduce or eliminate the production of waste and the dependence on organic solvents. To this effect, traditional chemical procedures are gradually being replaced by biotransformations. The β-lactam antibiotics industry has led the way in the introduction of biocatalysis in the fine chemicals industry by replacing the chemical multi-step process for the penicillin nucleus 6-aminopenicillanic acid (6-APA) by an enzymatic one in the early 1990s. Recently, bioprocesses have been developed for the synthesis of the cephalosporin nucleus, 7-aminodeacetoxycephalosporanic acid (7-ADCA) from a penicillin precursor and will shortly be commercialized. Thirty years of research have now resulted in viable enzymatic procedures for coupling the β-lactam nuclei with D-phenylglycine side-chains. The necessary adaptations in the synthesis of the side-chain donors have likewise resulted in more efficient procedures. 1 Introduction 2 Semi-Synthetic β-Lactam Antibiotics: Industrial Production Prior to 1985 3 Biocatalytic Synthesis of β-Lactam Nuclei 3.1 6-Aminopenicillanic Acid 3.2 7-Aminodeacetoxycephalosporanic Acid 4 Biocatalytic Routes to Side-Chains 4.1 Synthesis of the Side-Chain Building Blocks 4.2 Synthesis of Activated Side-Chain Donors 5 Enzymatic Coupling of the Side-Chains to the β-Lactam Nuclei 5.1 Chemical Procedures 5.2 Enzymatic Coupling 5.3 Practical Procedures for Enzymatic Coupling6 Conclusion and Future Outlook

Regioselective acylation of disaccharides in tert-butyl alcohol catalyzed by Candida antarctica lipase.

The acylation of several disaccharides by ethyl butanoate and ethyl dodecanoate was catalyzed by Candida antarctica lipase in tert‐butyl alcohol, at temperatures ranging from 40° to 82°C (reflux temperature). The relative reaction rates of the various disaccharides were directly related to their solubility. The primary products were the monoesters derived from acylation of the primary alcohol groups. At higher conversions diesters were formed, and the ratio of diester to monoester was markedly dependent on the structure of the disaccharide. Thus, reaction of maltose with ethyl dodecanoate in refluxing tert‐butyl alcohol afforded the 6′‐monododecanoate even at high conversions. Trehalose, in contrast, afforded the 6,6′‐diester. Acylation of the less soluble sucrose and lactose was much slower, but a moderate (37%) conversion of sucrose was observed after a prolonged reaction time (7 days). A number of other lipases and proteases were tested but C. antarctica lipase was unique in catalyzing the acylation of sucrose in refluxing tert‐butyl alcohol.

Structure and activity of Candida antarctica lipase B in ionic liquids

The effects of ionic liquid media on the activity of Candida antarctica lipase B in a simple transesterification reaction were studied. In ionic liquids containing dicyanimide, alkylsulfate, nitrate and lactate anions, which dissolved CaLB, the reaction was at least ten times slower than in [BMIm][BF4]. Only [Et3MeN][MeSO4] was an exception, as dissolved CaLB maintained its activity in this solvent. A cross-linked enzyme aggregate of CaLB was twice as active in [BMIm][dca] as in tert-butyl alcohol, whereas the free enzyme was irreversibly deactivated in this latter ionic liquid.

Improved operational stability of peroxidases by coimmobilization with glucose oxidase

The operational stability of peroxidases was considerably enhanced by generating hydrogen peroxide in situ from glucose and oxygen. For example, the total turnover number of microperoxidase-11 in the oxidation of thioanisole was increased sevenfold compared with that obtained with continuous addition of H(2)O(2). Coimmobilization of peroxidases with glucose oxidase into polyurethane foams afforded heterogeneous biocatalysts in which the hydrogen peroxide is formed inside the polymeric matrix from glucose and oxygen. The total turnover number of chloroperoxidase in the oxidation of thioanisole and cis-2-heptene was increased to new maxima of 250. 10(3) and 10. 10(3), respectively, upon coimmobilization with glucose oxidase. Soybean peroxidase, which normally shows only classical peroxidase activity, was transformed into an oxygen-transfer catalyst when coimmobilized with glucose oxidase. The combination catalyst mediated the enantioselective oxidation of thioanisole [50% ee (S)] with 210 catalyst turnovers.

Hydrothermal formation of 1,2,4-benzenetriol from 5-hydroxymethyl-2-furaldehyde and D-fructose

Thermolysis of 0.05 M aqueous 5-hydroxymethyl-2-furaldehyde (HMF) at 27.5 MPa and 290 to 400°C led to the formation of 1,2,4-benzenetriol in yields of up to 46% at 50% HMF conversion. The reaction temperature and water density have a significant effect on the product composition. Pseudo-first-order reaction rate constants for HMF conversion under these conditions range from 0.107 to 0.308 min−1. For the region 290 to 350°C, the activation energy for HMF conversion was found to be 47.7 kJ.mol−1. When subjecting d-fructose to hydrothermolysis, the main products are HMF, 1,2,4-benzenetriol, and furfural.

Improving the catalytic performance of peroxidases in organic synthesis

Peroxidases are ubiquitous enzymes that catalyze a variety of enantioselective oxygen-transfer reactions with hydrogen peroxide (H2O2). Although they have enormous potential, their industrial application is hampered by their high price and low operational stability. Recent developments, such as the controlled addition and in situ formation of the oxidant, protein engineering and the rational design of semi-synthetic peroxidases, aim to improve the operational stability of peroxidases.