Miscellaneous

Sumitomo Chemical in Japan has developed a robotic workstation for automated organic synthesis. The system consists of a computer, a robot, and several other devices (including a reaction device, a separation device, dispensing device, etc). The reaction device has four temperature regulation units, each of which can freely change the reaction temperature between —30 °C and 160 °C. Since each of the four units can handle four reaction containers, 16 reactions under different conditions can be performed simultaneously. Reactions beyond the boiling points of solvents are possible using reflux condensers. The separation-processing device automatically performs solution extraction operations, based on the detected liquid levels and interface positions. The dispensing device can automatically pump various reagents and/or solvents at various speeds into the reaction containers by switching valves through a digital syringe pump. This system can automate all synthesis and analysis processes and can perform at least 3000 experiments per year

Lindsey and coworkers investigated the conditions for condensation of mesi-taldehyde and pyrrole to provide tetramesitylporphyrin (27) (TMP) using an automated chemistry workstation (Scheme 31.9) [32]. The automated chemistry workstation consists of a 60-vessel reaction station, a 264-sample vial rack, reagent and work-up reagent racks, a solvent inlet line, a reagent and sample transfer syringe, a washing station for syringes, a robotic arm, and an ultraviolet (UV)-visible absorption spectrophotometer. Each reaction vessel consists of a 10-mL glass vial fitted with a septum cap. The entire station is controlled by thermostats, and a magnetic stirrer individually stirs each vessel. The workstation also has a space for additional analytical instruments. Using this workstation and the proprietary algorithm, cata-lyst-cocatalyst [BF3O(Et)2/alcohol] combinations and concentrations were exam ined in 284 reactions over a 10-week period, yielding 1704 data points. Three efficient cocatalysts were identified and the rate and reactor volume productivity were optimized. The authors concluded that the comprehensive set of data accumulated from the automated experiments establishes the scope of BF3/ethanol cocatalysis in the synthesis of TMP and should be useful for planning syntheses as well as for studying the mechanism(s) of catalysis.

27 fTMP)

Scheme 31.9. Condensation of mesitaldehyde and pyrrole to provide tetramesitylporphyrin 27 (TMP) using an automated chemistry workstation.

27 fTMP)

Scheme 31.9. Condensation of mesitaldehyde and pyrrole to provide tetramesitylporphyrin 27 (TMP) using an automated chemistry workstation.

Otera and coworkers have developed a new type of automated synthesizer with the ability to conduct a variety of synthetic reactions [33]. Although not intended for the process development, their results suggest that the system will be useful for automated process development with some modification. The system consists of a control unit [automatic reaction system (ARS) and a sequencer], a jacketed glass reactor (50 or 130 mL), reservoirs, volumetric ceramic valveless piston pumps, a syringe for quenching the reaction, and a cooling unit. Reactions can be run under inert atmosphere at reaction temperatures from —78 °C to elevated temperatures. Using the synthesizer, air-sensitive organolithium and Grignard reagents as well as transition metal catalysts could be handled. Also, the dependence of chemical yields on the reaction temperature for Peterson alkene synthesis and on the addition rates of the aldehyde for aldol reactions were examined. Because the order of reagent addition is programmed and the reaction temperature is quickly tunable, sequential reactions can be conducted smoothly. An advanced control system was incorporated that allows a task to start immediately after the preceding one has finished, minimizing the time for completing the multistep process.

In the current environment of intense market competition, batch process industries stand to benefit from faster process development. Two batch process areas, operating procedure synthesis (OPS) and process hazards analysis (PHA), are time-consuming because they are often performed manually. Recently, a Purdue University Group developed two intelligent systems, iTOPS and Batch HAZOPExpert (BHE), to automate OPS and PHA. Two applications from the specialty chemical industry are presented to demonstrate the utility of the integrated system [34].

Resolution by forming diastereomeric salts is still an important method for obtaining enantiomerically pure chiral compounds. Generally, tedious trial-and-error experiments are required to identify the satisfactory combination of resolving agents. Researchers at Roche Discovery Welwyn described the use of differential scanning calorimetry (DSC) as a means to identify diastereomeric salts with a clear eutectic composition that is needed for effective resolution and for forming the basis of a resolving agent screening process. This work also included automated salt synthesis using the ACT robot in 96-well microtiter plate format. (ACT refers to the Advanced ChemTech synthesis robot, which is primarily used for solid-phase synthesis.) Automation showed good correlation with the nonautomated experiment, and is therefore suitable for future screening of resolving agents. Rapid data analysis was facilitated using the in-house software package Resolution Companion, which also enabled identification of the optimum crystallization conditions following a trial crystallization experiment. This software package enables (1) the construction of binary-phase diagrams using the Schroeder-van Laar equation, (2) the rapid analysis of data from DSC thermograms, and (3) the construction of ternary-phase diagrams for evaluation of optimal solution concentrations. The authors also point out that the method has some limitations: (1) a failure to crystallize under multiwell evaporation does not imply crystallization will not occur under other conditions, (2) polymorphism, degradation, and signal overlap can complicate DSC analysis, and (3) solvate formation can markedly alter the phase diagram. Nevertheless, the use of DSC to aid in the selection of a resolving agent has been demonstrated and forms the basis of an automated screening procedure [35].

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