Requirements for Analytical Instruments

Analytical methods used in process development are typically chromatographic methods such as gas-liquid chromatography (GLC) and HPLC, or in some cases TLC or mass spectrometry. These methods can be used for different projects and can be adapted to new tasks using standard methodology.

The number of samples increases rapidly after introducing parallelization, and then analysis becomes a likely bottleneck in the complete workflow. In general, two strategies to avoid this may be used:

• Installing an online analysis. The analytical system needs to be fast enough, i.e. the run time for one sample has to be the 1/nth part of the required time resolution for all reactors. Usually, this requires more than one analytical instrument (e.g. 2-4 GLCs) for one multiple reactor, or simplified analytical methods, or both. Online analysis may give fast data, but it is more difficult to set up and has to run reliably and stably to offer a real advantage.

• Analyzing the samples offline. This feature provides more flexibility and makes the system less complex to run. Sample preparation may be performed by a robotic system which additionally transfers the samples to a standard format that may be directly introduced into the chromatograph.

For every project a new decision has to be made as to whether time and money should be invested in a better performing high-throughput method or whether slow standard methods should be applied.

Quality and type of analytical method depends, on one hand, on the analytical problem, but, on the other hand, they also depend on the stage of development and the type of information required. Whereas in a process screening a simple yes/no answer determined by TLC may be all that is required to eliminate 70-80% of inactive catalysts, the requirements will rise with the progress of the development until, finally, elaborate, high-precision quantitative methods will be required to allow the setting up of mass and mole balances and the specification of trace amounts of side products.

Important contributions in the development of new methods for high-throughput testing and analysis in the primary screening have been made recently by researchers working in combinatorial catalysis. Maier and coworkers and Reetz and coworkers showed infrared (IR) thermography to be a feasible screening tool for analyzing the catalytic activity of heterogeneous catalysts in hydrogenations or oxidations [25], homogeneous catalysts in enantioselective reactions, ring-closing metathesis, and even enzyme-catalyzed reactions [26, 27].

Another issue of increasing importance is the high-throughput determination of enantiomeric excess; here, the adaptation of parallelization techniques from other disciplines is a tremendously fruitful approach. By parallel capillary electrophoresis, Reetz et al. were able to analyze the ee values of 7000 samples per day [28]. Mi-kami et al. combined a synthesis robot with an HPLC circular dichroism system to screen their library of chiral ligands in the asymmetric addition of diethyl zinc to aldehydes [29]. In the future, one can expect new methods in this field to be developed.

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