Combinatorial Chemistry: Synthesis and Purification

Automated workstations are generally configured specifically for either the organic synthesis step of combinatorial chemistry or for the subsequent purification steps.

Automating Organic Synthesis

An example of a benchtop synthesizer is the Quest™ synthesizer (Argonaut Technologies, San Carlos, California USA), which performs up to 20 reactions performed in flasks with hands-on control.

The Vanguard™ system (Advanced ChemTech, Louisville, KY USA) allows for semi-automated synthesis to eliminate extensive manual manipulation, frequent intervention, and reactor transfers. The Vanguard's unique design allows it to be used as a stand-alone synthesizer, or as an additional mixing station for a fully automated synthesizer. All synthesis functions (mix, heat, cool, wash, empty, cleave) have been incorporated into a single module that fits on the benchtop.

More examples of modular synthesizers include the SOPHAS (Zinsser Analytic, Frankfurt, Germany) and SK233 (Gilson, Middleton, WI USA). A multifunctional workstation is exemplified by the Neptune™ Workstation (Mettler Toledo BohdanMundelein, IL) that includes a RAM™ Synthesizer for solution phase chemistry and a heating/cooling/shaking station for off-line vortex mixing with temperature control. This workstation assists with the following functions: reagent preparation, reaction mapping, off-line reaction incubation, liquid-liquid extraction, compound dissolution, and compound aliquoting for analysis and screening. The addition of an analytical balance and vortex mixer on the workstation meet the requirements of automating synthetic chemistry conditions.

A multi-tasking robotic workstation for synthesis is exemplified by the Iliad Series (Charybdis Technologies, Carlsbad, California USA). Iliad features two independently controlled robotic arms that dispense reagents and solvents simultaneously, and can do so in inert environments. This series, as well as others such as the Myriad Discoverer (Mettler Toledo Bohdan), can be upgraded to perform additional tasks and interface with additional components of a core system for higher throughput and higher performance. An alternative to a commercial workstation, when exact synthesis needs remain unmet, is the custom configuration of a robotic workstation approach based on the Zymate XP robot.

Automating Purification Steps

Purification steps performed following organic synthesis include liquid-liquid extraction, solid-phase extraction and filtration with scavenger resins. The ALLEX (Mettler Toledo Bohdan) is an example a workstation system that detects liquid-liquid phase boundaries and performs automated liquid-liquid extraction. The same function has been demonstrated in a custom configuration using a Zymate laboratory robot (Zymark) to shuttle sample vials between loading racks, liquid-liquid extraction stations and a centrifuge.

Automated SPE for compound purification is performed by many varieties of instruments, depending on format (SPE cartridges or microplates). Some common examples of liquid handling workstations performing automated SPE in microplates are the Packard MultiPROBE II (Packard BioScience Company, Meriden CT USA), SPEEDY (Zinsser Analytic), and Quadra96 (Tomtec, Hamden, CT USA), while in cartridges two of many workstation choices include BenchMate™ (Zymark, Hopkinton, MA USA) and Microlab SPE (Hamilton, Reno, NV USA).

Filtration plates containing scavenger resins are automated in an identical manner to SPE in microplates. An example of a versatile sample processing workstation that automates reaction workup and purification by LLE, SPE and filtration with scavenger resins is the Trident Sample Processing Station (Argonaut). When combined with the Trident Workstation for solid- and solution-phase synthesis, a complete semi-automated synthesis and purification system of up to 48 compounds can be performed in parallel. Higher throughput is achieved by combining the sample processing station with the Trident Library Synthesizer, achieving automated synthesis of up to 192 compounds in parallel.

Note that automated liquid handling workstations are also used in combinatorial chemistry for sample reagent and preparation, e.g., weighing, dissolving and dispensing compounds into plates, blocks or vials prior to performing chemical reactions, e.g., CALLI (Zinsser Analytic). Additionally, weighing resin or scavengers into reaction vessels, plates or vials is a tedious procedure which is automated using the REDI x,y,z dispensing system (Zinsser Analytic) with a powder pipette to precisely distribute particles.