Method and apparatus for rapid screening of multiphase reactions

that will maximize reaction kinetics while reproducing the conditions used in large scale batch reactors.

The method and apparatus of the present invention is generally useful for conducting simultaneous mixed phase reactions. Thus, in an embodiment, an apparatus includes a 5 substrate having a plurality of wells adapted to receive a reactant system at least partially embodied in a liquid; a first heating source to maintain the reactant system at a first temperature; and a head plate disposed adjacent the substrate to form a headspace above the wells. The head plate is 10 preferably maintained at a second temperature higher than the first temperature. The components of the apparatus are preferably formed of strong, durable materials such that the apparatus can accommodate elevated reaction pressures of at least about 50 atmosphere and reaction temperatures of at 15 least 200° C. Reactions can be conducted in glass vials which are compatible with a variety of analysis systems.

Thus, an aspect of the present invention is an apparatus, one embodiment of which comprises a reaction substrate comprising at least one substrate reservoir at a first tern- 2o perature; a thermal unit in communication with the reaction substrate; and a head plate at a second temperature positioned adjacent to the reaction substrate and forming a headspace adjacent to the substrate reservoir. The head plate may secure a sealed headspace stable to pressures up to 25 about 50 atmosphere. The substrate reservoir may comprise multiple reaction wells including, but not limited to, an array sized to accommodate reaction tubes. Preferably, the head plate includes a port for the entry of gas into the headspace. Additionally, temperature detectors may be included in the 30 head plate and the reaction substrate to enable precise control of reaction conditions by an external control system. In one embodiment, individual substrate reservoirs include a reactant system at least partially embodied in a liquid. In one embodiment, the headspace includes a second reactant 35 introduced as a gas.

Another aspect of the invention is a method, one embodiment of which includes the steps of providing a reaction substrate having a plurality of wells and introducing a reactant system at least partially embodied in a liquid into 40 the wells. The reactant system is maintained at a first temperature. The method further includes providing a headspace above the wells which enables introduction of additional reactants in a gas phase while substantially preventing condensation outside of the wells. The liquid reactant is 45 preferably maintained at a level such that the reaction is essentially independent of mass transport of a second gaseous reactant into the liquid reactant.

In an alternative embodiment, the method comprises the steps of: providing a reaction substrate comprising at least 50 one substrate reservoir; introducing a reactant system at least partially embodied in a liquid into the substrate reservoir; providing an enclosed headspace above the substrate reservoir; maintaining the substrate reservoir at a defined temperature; and maintaining the headspace at a defined atmo- 55 sphere and pressure. In one embodiment the head plate is heated at a temperature greater than the temperature of the reaction substrate to prevent condensation outside of the substrate reservoir. Temperature detectors enable the precise control of the reaction substrate and head plate temperature 60 by an external control system. The substrate reservoir may include, but is not limited to, an array of reaction tubes comprising a septum. The method may include heating the headspace and providing a gas to the headspace at pressures up to about 50 atmosphere. In one embodiment, the method 65 comprises a gaseous reactant in the headspace. Thus, the liquid reactant may further comprise a thickness L which is

sufficient to allow the reaction to be independent of mass transport rates of reactants in the gas phase.

Referring now to FIG. 1, a reactor 2 for the rapid screening of potential reactants, catalysts and reaction conditions is shown. In one embodiment, reactor 2 includes a thermally-controllable reaction substrate 4 having at least one, but preferably many, substrate reservoir(s) 6 for receiving separate samples or reactant systems to be analyzed. The reactor 2 additionally includes a thermally-controllable head plate 10 positioned adjacent to the substrate reservoir 6 of reaction substrate 4. Head plate 10 includes walls that define a sealed headspace 12 adjacent to substrate reservoir 6. Preferably, headspace 12 forms a channel between a gas inlet port 36 in head plate 10 and the substrate reservoir 6 in reaction substrate 4. The port 36 delivers one gas or a combination of reactant gases 46 from a gas supply 38 into headspace 12. The headspace 12 is sealed such that the desired reactant gas 46 can be delivered to the substrate reservoir 6 at a pressure. Thus, by reacting multiple reactant systems in the substrate reservoirs 6, under controlled temperatures, with the reactant gas 46, at a controlled pressure, the reactor 2 enables the study of multiple reactants simultaneously.

In one embodiment, the substrate reservoir 6 is sized to receive glass reaction vials 24. For example, 1.8 ml vials commonly used for gas chromatograph autosamplers can be employed. Referring also to FIG. 2, in a preferred embodiment, reaction substrate 4 contains multiple wells 6 in an array 22. The embodiment in FIG. 2 shows an orthogonal (6x8) array, although arrays of other shapes and sizes may be utilized.

Preferably, reaction substrate 4 is formed of a substantially rigid, lightweight, thermally conductive material, such as aluminum or the like. Even more preferably, one or more resistance temperature detectors 26 are mounted at various locations within reaction substrate 4 in order to monitor temperature variations.

In a preferred embodiment, reaction substrate 4 is positioned adjacent to, and in thermal communication with, a thermal unit 8. Thermal unit 8 adjustably maintains reaction substrate 4 at one or a series of temperatures, thereby heating or cooling the samples or reactant systems within substrate reservoir 6. Thermal unit 8 includes a thermally conductive material and a heating source 30 and a cooling source 20 to maintain the reaction temperature within a desired range. Preferably, thermal unit 8 is adjacent to at least one surface of reaction substrate 4. For example, in the embodiment shown in FIG. 2, reaction substrate 4 sits directly on thermal unit 8. Thermal unit 8 is preferably formed of a thermally conductive material, such as copper or aluminum or other suitable materials. More preferably, thermal unit 8 is in thermal communication with reaction substrate 4 such that variations in the temperature of thermal unit 8 are quickly transmitted to the reaction zone 28 in substrate reservoir 6. Although shown as separate components, reaction substrate 4 and thermal unit 8 may be integrally formed. Heating source 30 includes cartridge resistance heaters 30 mounted horizontally within the thermal unit 8, although other heating sources may be utilized. Cooling source 20 includes a pump 18 delivering a cooling agent 34 such as water or freon through a serpentine channel 32 within thermal unit 8 (FIG. 2), although other cooling sources may be utilized. As described above for reaction substrate 4, multiple resistance temperature detectors 26 can be mounted at various locations within thermal unit 8 in order to monitor temperature variations.

Preferably, head plate 10 is formed of a substantially rigid and corrosion resistant material, such as stainless steel, 5

hastalloy, INCONELTM material, titanium, tantalum or other suitable materials. In a preferred embodiment, the thermallycontrollable head plate 10 includes a heating source 40 to maintain head plate 10 at a temperature higher than the reaction temperature in the substrate wells. Acceptable heat- 5 ing sources 40 include surface heaters mounted on the upper surface 42 of head plate 10, although other heating sources may be utilized. Differential heating of head plate 10 substantially reduces condensation of reaction solvent that may be present in a vapor phase 44 of reaction zone 28. Preferably, temperature detectors 26 are mounted in head plate 10 to control and monitor temperature within the head plate 10.

In the embodiment shown in FIG. 1, head plate 10 comprises a seal 48 for preventing reactants from being 15 expelled during operation. Preferably, seal 48 is positioned adjacent to lower surface 60 of head plate 10. Even more preferably, a groove 62 can be provided in the upper surface 64 of substrate reservoir 4 to receive seal 48. Seal 48 is preferably selected from an o-ring or high temperature 20 gasket or other appropriate seals. Suitable seals include VITON® o-ring seals available from E.I. DuPont de Nemours & Co., Inc., Wilmington, Del.

Further, the reactor 2 preferably includes a base plate 52 that supports the other components of the reactor. Base plate 25 52 is preferably formed of a rigid material such as carbon steel or stainless steel, or an appropriate alloy. The assembled reactor 2 can be held together with a plurality of bolts or studs 54. Preferably, studs 54 on base plate 52 are inserted through apertures 66 on head plate 10. In this 30 embodiment, fasteners 56 on studs 54 can be tightened to provide clamping force and maintain effective contact among reaction substrate 4, thermal unit 8 and head plate 10. As shown in FIGS. 2 and 3, clamping is preferably achieved through the use of multiple studs 54 arranged around the 35 perimeter of the head plate 10 and base plate 52. The clamping force is preferably sufficient to maintain the seal between head plate 10 and reaction substrate 4 and to ensure effective heat transfer between thermal unit 8, reaction substrate 4 and substrate reservoir 6. 40

During the reaction, headspace 12 is maintained at pressures greater than 1 atmosphere. Preferably, headspace 12 is maintained at a pressure of up to about 20 atmosphere. Even more preferably, headspace 12 is maintained at a pressure of up to about 45 atmosphere. Most preferably, headspace 12 is 45 maintained at a pressure of up to about 50 atmosphere.

Referring now to FIG. 4, the configuration of reactor 2 allows vials 24 containing previously prepared reactant systems to be inserted into substrate reservoir 6 of reaction substrate 4. The reactant systems, however, may be directly 50 added to the substrate reservoir 6. In the embodiment shown, head plate 10 is lowered onto reaction substrate 4 and a clamping force applied by fasteners 56 on studs 52. In a preferred embodiment, a counterweight system 60 is employed to facilitate movement of head plate 10 with 55 minimal effort. Thermal unit 8 can be adjusted to the appropriate temperature, and gas 46 pumped into sealed headspace 12. Preferably, reactor 2 incorporates a computerbased automated control system 70, which monitors and controls various operations such as the gas supply to and 60 venting of headspace 12, and the heating and cooling functions of the head plate 10, thermal unit 8 and reaction substrate 4. Preferably, temperature detectors 26 positioned on head plate 10, reaction substrate 4 and thermal unit 8 are in communication with control system 70. More preferably, 65 control system 70 automatically logs temperature and pressure data for each reaction.

6

In an alternative embodiment, the present invention is directed to a combinatorial method to perform multi-phase polymerization reactions using a micro-reactor having multiple reaction vessels. In one aspect of the invention, each vessel contains a first reactant system at least partially embodied in a liquid and a second reactant system at least partially embodied in a gas. Preferably, the liquid forms a film having a thickness L sufficient to allow the reaction rate of the homogeneous chemical reaction to be essentially independent of the mass transport rate of a second reactant system into the liquid. The reaction vessels are disposed within the wells of the reaction substrate. The head plate is clamped to the reaction substrate to form a sealed headspace above the reaction vessels. In a preferred embodiment, a second gaseous reactant system is provided to the reaction zone under pressure. The head plate is maintained at a temperature above the reaction temperature to prevent condensation outside the reaction vessels.

Thus, in one aspect, the invention comprises a method for rapid screening of potential reactants, catalysts and reaction conditions. As shown in FIG. 5, in one embodiment the method comprises the steps of: (1) providing a reaction substrate 4 having at least one substrate reservoir 6; (2) introducing a reactant system 28 at least partially embodied in a liquid into the substrate reservoir 6; (3) providing an enclosed headspace 12 above the substrate reservoir 6; (4) maintaining the substrate reservoir 6 at a defined temperature; (5) maintaining the headspace 12 at a defined atmosphere by pumping in gas 46 at a defined pressure from gas supply 38; and (6) substantially preventing condensation outside of the substrate reservoir 6 by heating heaters 40 on head plate 10 to a temperature greater than the temperature of reaction substrate 4.

Unless otherwise noted, the term "reactant system" can include reactants, solvents, carriers, catalysts, and chemically inert substances that are present to affect a physical property of one or more components of the reactant system. In this regard, a liquid can itself be a component of the first reactant system, and likewise, a gas can be a component of the second reactant system. In alternative embodiments, the first reactant system can be dissolved or suspended in the liquid and the second reactant system can be dissolved in the gas. In other embodiments, the first reactant system can be submersed or entrained in the liquid.

In a preferred embodiment and referring back to FIG. 4, substrate reservoir 6 comprises wells. More preferably, substrate reservoir 6 is sized to accommodate reaction tubes 24. Even more preferably, the tubes comprise a septum cap 72 at one end. Thus, the method contemplates that upon introduction of gas 46 into reactor headspace 12, elevated pressure in headspace 12 will drive gas 46 from headspace 12 outside reaction tubes 24 through an aperture 74 in septum cap 72 and into the headspace 76 inside reaction tubes 24. Preferably, the atmosphere in reactor headspace 12 will equilibrate with the headspace 76 inside reaction tubes 24.

Thus, in one embodiment, reactor headspace 12 comprises a high pressure seal which is stable to elevated pressure in the headspace 12. Preferably, reactor headspace 12 comprises pressure of greater than 1 atmosphere. More preferably, headspace 12 is maintained at a pressure of up to 20 atmosphere. Even more preferably, headspace 12 is maintained at a pressure of up to 45 atmosphere. Most preferably, headspace 12 is maintained at a pressure of up to 50 atmosphere.

Preferably, head plate 10 is heated to prevent condensation of gaseous reaction components. Thus, in one