Array reactors for parallel synthesis.

The development of high-throughput screening (HTS) in the past decade generated the capacity to quickly evaluate large numbers of compounds in a variety of assay methodologies.1 In many organizations, this capacity easily exceeded the size of internal compound collections. Efficient utilization of this HTS resource drove the need for an analogous increase in the rate of compound synthesis. This, in turn, drove the development of technologies and processes, with the goal of multiplying the capacity of classical one-at-atime organic synthesis.2 One approach, which utilizes both combinatorial and parallel efficiencies, is to run reactions in an array. Over the past few years, we have worked to develop a solution-phase array reactor, which mimics the simplicity but can accommodate the functionality of the classic round-bottom flask. In other words, it should be simple but, with the addition of optional pieces, gain functionality. Although there are a number of commercial apparatuses3 approaching this ideal, we felt that a better (lighter, simpler, and less expensive) solution could be devised. We describe here the current incarnation of our development efforts. While developing an array reactor, we adhered to a few useful guiding design constraints to enforce simplicity and flexibility. The device should be lightweight, should use commodity, disposable glass for reaction vessels, should fit a microtiter4 footprint, and should enable a wide range of reaction conditions. The general design principles should allow construction of devices with numerous small reaction vessels or fewer large reaction vessels. Finally, the device should integrate well with standard laboratory equipment, such as hotplate/stirrers, in addition to equipment more associated with parallel processes, such as filter plates or liquid handling robots. We have developed three array reactors that adhere to these design constraints; the SynthArray-96, the SynthArray24, and the SynthArray-6, which have 96 2-mL, 24 8-mL, and 6 40-mL reaction vessels, respectively. The following description will focus on the SynthArray-24, since this reactor has been most thoroughly developed, tested, and used. The SynthArray-24 consists of six pieces. Shown5 in Figure 1 are (1) the tube holder, (2) the sleeve, (3) the solid top, (4) the top with holes, (5) the heater block/alignment guide, and (6) the heat transfer block. The tube holder 1 is machined from Teflon, and the other parts are made from aluminum. Drawings with measurements are included as Supporting Information. The central piece of the SynthArray-24 is the Teflon tube holder 1. The holder has a centered 4 × 6 array of 24 holes (18-mm spacing) with embedded O-rings that hold reaction tubes6 and provide a gastight seal. There are also four holes at the corners through which screws can pass. The reaction vessels are 13 × 100 mm screw-cap culture tubes. The tubes can be inserted into the holder by hand or, more conveniently, by pressing the holder onto the tubes with an arbor press. This (Figure 2a) is the simplest configuration and is adequate for many reactions. Addition of 24 stir bars provides ample stirring when the reactor is placed on a conventional laboratory magnetic stirrer. Caps can be placed on the tubes during a reaction and for storage. For a controlled atmosphere, an aluminum sleeve, 2, with a Leur gas inlet in the side, is snapped onto the top side of the Teflon holder, and a solid plate top, 3, held in place with four screws and nuts is added (Figure 2b). If needle access to the tubes is needed to allow addition of reagents under inert atmosphere, a Teflon-faced silicone sheet and a plate with 24 holes, 4, aligned with the tubes is placed on top instead (Figure 3a). One advantage of holding the tubes at the top is that, analogous to a round-bottom flask, one is not limited in the way temperature is controlled at the bottom of the reactor. Thus, the reactor can be easily placed in a variety of heating or cooling baths or blocks. Another advantage is that, because the reactor is not coupled to the heater, the reactor can be quickly removed from the heat source. Our preferred method of heating is to place the reactor in a heater block/alignment guide, 5, on a thermostatically controlled hotplate (Figure 3b). The heater block is a half-inch aluminum block with 24 holes drilled through for the reactor tubes as well as a hole for insertion of a thermocouple probe. The aluminum heater block/alignment guide can serve two other purposes. The block has four tapped screw holes on the corners so that it can slide up the tubes and act as a rigid receptor for the screws holding down the top. This forms a tighter seal, which is useful for reactions requiring better atmospheric integrity. Atmospheric hydrogenations (balloon pressure) have been accomplished using this configuration (Figure 4a), which allows for alternate vacuum and gas purging. In addition, because the block has the outside dimensions of a microtiter plate, it is used to align the reactor block precisely when placed on a liquid handling robot. Another optional piece of the reactor is the heat transfer block, 6. This is an aluminum block similar to the heater block except that a channel runs around the perimeter of the block with access at the four corners. By sealing one pair of * Corresponding author address: InnovaSyn LLC, 627 Arlington Street, Chapel Hill, NC, 27514. E-mail: [email protected]. † Current address: Department of Chemistry, University of Pittsburgh, 234 Chevron Science Center, Pittsburgh, PA 15260. ‡ Current address: Amphora Discovery Corporation, PO Box 12169, Research Triangle Park, NC 27709-2169. 308 J. Comb. Chem. 2004, 6, 308-311