Metallic Frame

Product Outlet

Fig. 32.37. Reactor module consisting of stacked metallic frames. The catalyst inlays are mounted and removed in the directions indicated by the arrow.

Fig. 32.38. Chip module for the catalysis-on-a-chip approach.

trometer. The detected amount of catalytic product in the noncatalytic zone was less than 2% of that found in the active position. A 52-catalyst methanol oxidation library used for further verification of the microreactor demonstrated excellent sensitivity and reproducibility.

32.10.5.3 Catalysis on a Chip

Claus and coworkers have created a set of microreactors for enabling catalysis on a chip [178]. The chip-based system allows for efficient thermal control and short response time (Fig. 32.38). Preliminary investigations of this new technology utilized parallel microchannels etched into silicon and glass with cross-sectional dimensions of 500 x 200 m. Similar to the micromachined metal reactors, each microchannel contains a different catalyst, which is micropipetted into the chips. Reactants are introduced through a single inlet in the chip, flowing through a prefabricated manifold to each of the catalyst-filled microchannels. The products are analyzed as they leave the chip at a series of outlets. The prototype chip modules contain eight or 16 parallel channels having different cross-sections and channel lengths.

32.10.6

Capillary Array Electrophoresis

Recently, capillary electrophoresis (CE) has taken a key role in the parallel screening of homogeneous catalysts, in addition to the ''classical'' methods such as GC or HPLC. Yeung and coworkers have used multiplexed capillary electrophoresis for the combinatorial screening of enzyme activity [197a] and homogeneous catalysis [197b]. In the latter case, this methodology was successfully implemented to opti mize, in a multidimensional screening approach, the regiochemistry of a Pd-cata-lyzed annulation reaction.

Reetz and coworkers have adapted a commercial 96-well capillary electrophoresis system for the determination of enantiomeric excess [198]. In their initial study, chiral amines, which are potentially accessible by catalytic reductive ammonation of ketones, Markovnikov addition of ammonia to olefins, or enzymatic hydrolysis of acetamides, were used as model substrates (Scheme 32.40). Various a- and b-cyclodextrin derivatives were used as chiral selectors, which were then modified with fluorescent compounds to enable laser-induced fluorescence (LIF) to be employed as a detection mechanism. Known enantiomeric mixtures of the amines (with the fluorescent tag added) were then analyzed by a commercial instrument and by a capillary array electrophoresis (CAE) system. Results from the CAE system initially suffered from unstable runs, but results improved with the addition of a higher viscosity electrolyte composed of 40 mM 2-(N-cyclohexylamino)-ethanesulfonic acid and 6.25 mM g-cyclodextrin diluted with a buffer containing polyacrylamide. The agreement between the ee values of the mixtures of the (R)-and (S)-amines measured with the conventional capillary electrophoresis system, the CAE system, and a conventional GC was excellent. Enantiomeric separation with these systems requires approximately 19 min.

Scheme 32.40. Test system for the high-throughput screening of enantioselective catalysts using capillary array electrophoresis (CAE).

32.11

Summary and Outlook

It is virtually certain that we find ourselves at the dawn of a new age of applying combinatorial methodologies to catalysts' discovery and optimization. As this chapter demonstrates, significant first steps in that direction have been taken in the area of catalyst research, and a multitude of tools are now available using combinatorial technologies to appropriately accommodate the new tasks and requirements for combinatorially accelerated materials and catalyst research. A common underlying theme associated with these technologies is miniaturization, parallel-

ization, and automation so that large numbers of samples can be synthesized and screened efficiently. Rapid serial and parallelized adaptations of conventional analytical techniques will become increasingly important in the assay of materials properties, as will the development and implementation of new and unconventional high-throughput screening tools. Software development and engineering support in the construction and design of synthesis and screening tools are as crucial as further advances in chemistry, even when appropriate tools or robots for synthesis and screening automation are commercially available. Finally, the combinatorial methodology generates data much faster than the conventional research employing ''empirical'' and ''rational'' approaches to materials discovery, and, inevitably, the proper data handling and storage should accompany the high-throughput synthesis and screening to maintain the integrity of research and development efforts. Full realization of the combinatorial methodology will require the integration of chemistry, physics, engineering, and informatics to greatly enhance the probability of finding a global reaction optimum of a catalyst for a targeted reaction or materials with desired properties. In the future, the scientist's intuition may be shifted, at least to some degree, toward optimally programming and setting up appropriate experiments and screens, as well as for the analysis of the obtained data and materials. All these efforts will require an enormous initial investment in all of these areas [235].

Acknowledgements

The authors are deeply indebted to Ms Silvia Lee (Symyx Technologies) and Ms Kathryn Boykin (XenoPort) for their invaluable support in reference and patent searches. The authors thank Mr Ron Krasnow (Symyx Technologies) for checking the manuscript.

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