2. Discussion of Related Art: The general evaluation of potential reactants and catalyst systems requires that each potential combination be subjected to reaction conditions that permit the appropriate reaction (s) to take place and that the products of the reaction (s) be determinable at a level that allows discrimination among the potential combinations under t conditions that would provide a meaningful correlation to performance in a production scale reactor. These requirements present unique issues in applying combinatorial techniques to multiphase reactant systems. Specifically, in multiphase reactant systems, mass transport often plays a significant role in reaction kinetics or is rate limiting, thereby requiring mechanical mixing of the phases. Therefore, although running multiple simultaneous reactions would be desirable, the screening of potential reactants and catalysts for such systems has traditionally been carried out one experiment at a time.

When some reagents are in a liquid phase and others in a gas phase, traditional chemical engineering practice demands that the two phases be well mixed during the reaction, typically by rapid stirring, sparging, and the like. At production scale, the reaction is typically carried out in a continuous flow reactor. However, the expense involved in constructing and operating production scale continuous reactors has led to the general practice of screening multiphase

reactant systems in batch mode. A continuous reactor differs from batch mode in that in the continuous reactor a compositional steady state mixture is typically obtained containing product, starting materials, by-products, fresh and degraded catalysts, and the like. Traditional batch mode reactors have incorporated rapid stirring or gas sparging to facilitate mixing of the phases, which can present difficulties in creating methods which permit running multiple simultaneous reactions. An effective combinatorial model would be capable of discriminating among potential reactants and catalyst systems under conditions that would provide a meaningful correlation to performance in a continuous flow reactor. However, the aforementioned mass transport considerations have limited the application of combinatorial techniques to multiphase systems As the demand for high performance materials has continued to grow, new and improved methods of providing products more economically are needed to supply the market. In this context, various reactant and catalyst combinations are constantly being evaluated ; however, the identities of chemically or economically superior reactant systems for multiphase processes continue to challenge the industry.

New and improved methods and devices are needed for rapid screening of multiphase reactant systems.

SUMMARY The present invention is directed to a method and apparatus for rapid screening of multiphase reactant systems. In one embodiment, the present invention provides a method of producing a homogeneous chemical reaction utilizing multiphase reactant systems. The method includes the steps of providing a first reactant system at least partially embodied in a liquid and contacting the liquid with a second reactant system at least partially embodied in a gas. The liquid forms a film having a thickness sufficient to allow the reaction rate of the

homogeneous chemical reaction to be essentially independent of the mass transport rate of the second reactant system into the liquid.

BRIEF DESCRIPTION OF THE DRAWINGS Various features, aspects, and advantages of the present invention will become more apparent with reference to the following description, appended claims, and accompanying drawings, wherein FIG. 1 is a side view of an aspect of an embodiment of the present invention; FIG. 2 is a partial perspective view of an aspect of an embodiment of the present invention; and FIG. 3 is a side view of an aspect of an alternative embodiment of the present invention.

DETAILED DESCRIPTION Terms used herein are employed in, their accepted sense or are defined. In this context, the present invention is directed to a method and apparatus for rapid screening of multiphase reactant systems.

In an exemplary embodiment, the method includes the steps of providing a first reactant system at least partially embodied in a liquid and contacting the liquid with a second reactant system at least partially embodied in a gas. The liquid forms a film having a thickness sufficient to allow the reaction rate of the homogeneous chemical reaction to be essentially independent of the mass transport rate of the second reactant system into the liquid.

The term"embodied"includes situations where reactant systems are dissolved, suspended, entrained, or submersed in a liquid or gas.

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, the liquid can itself

be a component of the first reactant system, and, likewise, the 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.

The thickness of the liquid film allows the reaction rate to be "essentially independent"of the mass transport rate of the second reactant system into the liquid. In this context,"essentially independent"means that in comparison with other possible rate limiting factors, mass transport limitations are sufficiently low to allow comparative evaluations of potential reactant system components.

Optimum film thickness values can vary based on reaction conditions and the identity of reactant system components. Those skilled in the art will readily realize that in various systems, a minimum film thickness may be required to overcome the effects of evaporation or the formation of micro amounts of precipitate and the like. As such, optimum film thickness may not equate to the thinnest possible film that can be formed in a given application.

For example, in a homogeneous liquid-phase reaction in which the availability of oxygen in the liquid phase is the rate limiting factor, mass transport can be expressed in the following manner. First, it is assumed that the reaction is a first order liquid-phase homogeneous reaction with respect to the limiting gaseous reactant (dissolved in the liquid), oxygen, or is limited by this reaction. Second, oxygen mass transport effects in the gas phase are ignored, since the transport rate in the gas phase is significantly higher than the transport rate in the liquid phase. Third, it is assumed that the gas contacts the liquid film only on the top surface of the film and that the film has uniform thickness. It is noted that the amount of oxygen available at the gas/liquid interface can also be increased by increasing the pressure of the gas in the reaction vessel. With these assumptions in mind, the steady state relationship among the liquid film thickness (L), the rate

constant (k), and the diffusivity (D) of dissolved oxygen in the liquid can be expressed as follows : It is noted that k denotes a first order reaction rate constant of the homogeneous chemical reaction with respect to the dissolved form of the second reactant system in the liquid The rates themselves should be substantial enough to be accurately measurable, so that differences among rates can be evaluated, thus allowing comparison among potential reactants and catalysts. In this context, it is preferred that b has a value between 0 and 5. This defines a minimum average-to-surface dissolved oxygen concentration ratio (or reaction rate) of approximately 20% (b=5). More preferably, bhas a value between 0 and 2, which defines a minimum average-to-surface concentration ratio of approximately 48% (b=2). In various applications, other acceptable values for b can be determined with reference to the following relationship between the film thickness and the concentration profile: CALZ) = cosh-zu CAO cosh b In the preceding relationship, the value of z is 0 at one surface of the film (i. e., the top), and, if the reaction is carried out in a vessel that supports the film from the bottom, the value of z is L at the opposing surface of the film (i. e., the bottom). It is further noted that the film may be supported on its sides (e. g., in a capillary tube or the like) or may be suspended in another manner that allows gas to be presented to both the bottom and top surfaces of the film simultaneously. In this situation, the value of z is L at the midpoint of the film (only half of the film is considered, since the other half is a mirror image).

As noted, mass transport in the gaseous phase may be increased by pressurizing the gas; therefore, it is preferred that the gas be maintained at a pressure greater than 1 atm while in contact with the liquid. Many homogeneous reactions respond favorably to increased temperature; therefore, in altemative embodiments, the liquid can be maintained at temperatures above 0° C while in contact with the gas.

An altemative embodiment of the present invention provides a method of performing simultaneous homogeneous chemical reactions utilizing multiphase reactant systems. The method includes the steps of providing a combinatorial micro-reactor comprising a first vessel and a second vessel ; placing a first reactant system at least partially embodied in a first liquid into the first vessel ; and placing a second reactant system at least partially embodied in a second liquid into the second vessel. The first liquid is contacted with a third reactant system at least partially embodied in a first gas, and the first liquid forms a film having a thickness sufficient to allow the reaction rate of the homogeneous chemical reaction to be essentially independent of the mass transport rate of the third reactant system into the first liquid. The second liquid is contacted with a fourth reactant system at least partially embodied in a second gas, and the second liquid forms a film having a thickness sufficient to allow the reaction rate of the homogeneous chemical reaction to be essentially independent of the mass transport rate of the fourth reactant system into the second liquid.

Additional vessels can be added to the combinatorial micro-reactor as needed.

This embodiment of the present invention is useful for rapid parallel screening of reactant system components. Accordingly, depending upon the purpose of the reactions, the first reactant system and the second reactant system can include identical compounds in the same or differing quantities. Likewise, the third reactant system and the fourth reactant system can include identical compounds in the

same or differing quantities. Furthermore, the first liquid and the second liquid can be chemically identical, and the first gas and the second gas can be chemically identical. Those skilled in the art will realize that the present method can be used to isolate the effects of changes in the identity of reactant system components, component ratios, and reaction conditions in order to optimize a desired characteristic of a given reaction.

As noted, the present invention is also directed to an apparatus for rapid screening of multiphase reactant systems. An exemplary embodiment is shown in FIG. 1 in which a vessel 10 contains a first reactant system at least partially embodied in a liquid 12 and a second reactant system at least partially embodied in a gas 14. Liquid 12 forms a film having a thickness L sufficient to allow the reaction rate of the resulting homogeneous chemical reaction to be essentially independent of the mass transport rate of the second reactant system into liquid 12. Acceptable values for L can, be readily determined by using the relationships discussed supra or by routine experimentation.

Vessel 10 is preferably formed of a rigid material that is chemically inert in the reaction environment. An example of an acceptable vessel for many reactions is a glass vial. When dealing with liquids with low vapor pressures or with lengthy reactions, it may be desirable to provide a covering, such as a selectively permeable cap 16 or a septum (not shown) incorporating a feed tube or needle disposed on vessel 10 such that gas 14 is allowed to move freely into and out of vessel 10 while depletion of liquid 12 by evaporation is minimized. This arrangement allows an external pressure source to act upon gas 14 while limiting the evaporation of liquid 12. In most applications, suitable materials for the cap include polytetrafluoroethylene (PTFE) and expanded PTFE. A suitable cap for use with 2 ml glass vials is"Clear Snap Cap, PTFE/Silicone/PTFE with Starburst, 11 mm", part no. 27428, available from Supelco, Inc., Bellefonte, Pennsylvania.

As shown in FIG. 2, the present invention is also directed to a combinatorial micro-reactor comprising a first vessel 10 and a second vessel 20. First vessel 10 contains a first reactant system at least partially embodied in a first liquid 12 and a second reactant system at least partially embodied in a first gas 14. First liquid 12 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 the second reactant system into first liquid 12.

Second vessel 20 contains a third reactant system at least partially embodied in a second liquid 22 and a fourth reactant system at least partially embodied in a second gas 24. Second liquid 22 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 the fourth reactant system into second liquid 22.

The combinatorial micro-reactor can further include a substrate 36 having a plurality of discrete wells 38 adapted to receive vessels 10, 20 therein. Substrate 36 can be formed of any material capable of supporting and separating vessels 10,20 provided that the material does not adversely affect the reactions. In various applications, desired reaction conditions can include elevated temperatures within liquid 12, 22. In these circumstances it may be desirable to form substrate 36 of a thermally conductive material so that temperature within the liquid can be more easily controlled with an extemal device. In applications that require elevated temperatures and pressures, substrate 36 can be placed in an autoclave (not shown) or other device capable of maintaining these reaction conditions in preferred ranges. If additional capacity is needed, multiple vessels can be inserted into each well by linearly stacking the vessels.

In order to provide a film having a substantially uniform thickness, it is preferable to utilize vessels with substantially planar bottom sections, such as those depicted in FIG. 1 and FIG. 2.

However, most commercially available small vials are geometrically

similar to the vial shown in FIG. 3, where the bottom section 40 is concave. It is noted that the method of the present invention can be performed in such a vial and that the teachings of the present application provide guidance in choosing workable ranges for film thickness when employing these reaction vessels.

EXAMPLES The following examples are provided in order that those skilled in the art will be better able to understand and practice the present invention. These examples are intended to serve as illustrations and not as limitations of the present invention as defined in the claims herein.

Diphenyl carbonate (DPC) is useful, inter alia, as an intermediate in the preparation of polycarbonates. One method for producing DPC involves the carbonylation of a hydroxyaromatic compound (e. g., phenol) in the presence of. a catalyst system. A carbonylation catalyst system typically includes a Group Vlil B metal (e. g., palladium), a halide composition, and a combination of inorganic co-catalysts (IOCCs). This one step reaction is typically carried out in a continuous reactor at high temperature and pressure with gas sparging. Insufficient gas/liquid mixing can result in low yields of DPC.

Generally, testing of new catalyst systems has been accomplished at macro-scale and, because the mechanism of this carbonylation reaction is not fully understood, the identity of additional effective IOCCs has eluded practitioners. An embodiment of the present invention allows this homogeneous carbonylation reaction to be carried out in parallel with various potential catalyst systems and, consequently, this embodiment has been used to identify effective IOCCs for the carbonylation of phenol.

The economics of producing DPC by the carbonylation process is partially dependent on the number of moles of DPC produced per mole of Group VIII B metal utilized. In the following examples, the

Group VIII B metal utilized is palladium. For convenience, the number of moles of DPC produced per mole of palladium utilized is referred to as the palladium turnover number (Pd TON). Unless otherwise specified, all parts are by weight; all equivalents are relative to palladium; and all reactions were carried out in 2 ml glass vials at 90- 100° C in a 10% 02 in CO atmosphere at an operating pressure of 95- 110 atm. Reaction time was generally 2-3 hours. Reaction products were verified by gas chromatography.

EXAMPLE 1 A liquid reactant system was prepared by adding 1,4- bis (diphenylphosphino) butane palladium (II) dichloride ("Pd (dppb) C12"), 240 equivalents of bromide in the form of tetraethylammonium bromide ("TEAB"), 56 equivalents of lead in the form of lead (II) oxide, and 8 equivalents of cerium in the form of cerium (ill) acetylacetonate to phenol. Assorted aliquots of the liquid reactant system were placed, at ambient conditions, in 2 mi glass vials. The vials were placed in individual wells in an aluminum substrate. The substrate was placed in an autoclave, where a 9% 02 in CO atmosphere was introduced into the vials at a pressure of 109 atm. The liquid was heated to a temperature of 100° C. These reaction conditions were maintained for 3 hours. The substrate was then removed from the autoclave ; the vials were removed from the substrate; and samples from each of the vials were analyzed to provide the following results : Sample No. Pd (dppb) C12 Sample Size DPC (wt %) Pd TON (mM) zip 1 0. 20 24 13. 8 3407 2 0. 20 27 14. 1 3487 3 0. 20 99 10. 2 2528 4 0. 20 101 13. 0 3213 5 0. 25 293 3. 0 593 6 0. 25 306 2. 9 569

The data show that sample size (and consequently film thickness) affects the reaction yield. For the carbonylation of phenol with the catalyst system, reaction vial size, and other reaction conditions used, the data show that a sample size of about 25 tL is preferred.

EXAMPLE 2 In order to determine whether results obtained using the thin film micro-reactor effectively correlate with results obtained from a macro- scale reactor, tests were conducted in discrete reactors. One set of tests was performed in a thin film micro-reactor according to the method of Example 1. The other set of tests was performed in a"batch- flow"reactor.

The batch-flow reactor allows a liquid reaction mixture to be fed into a reaction chamber. The system is then sealed, and pressurized gaseous reactants are continuously introduced into and removed from the reaction chamber. The reaction chamber and the entering gaseous reactants are heated to a desired temperature, In addition to the agitation caused by the continuous introduction of the gaseous reactants, the liquid reaction mixture is constantly stirred to effect mixing of the phases and to minimize settling of any precipitate.

Molecular sieves are disposed in the reaction chamber to function as desiccants. Aliquots of the reaction mixture can be periodically withdrawn and analyzed to monitor the reaction and to determine yield.

The correlation data was produced by reacting phenol with carbon monoxide in the presence of the following catalyst system: 0.25 mM palladium (II) acetylacetonate ("Pd (acac) 2"), 56 equivalents of PbO, various amounts of cerium (ill) acetylacetonate ("Ce (acac) 3") and various amounts of an organic bromide salt, either TEAB, tetramethylammonium bromide ("TMAB"), or hexaethylguanidinium bromide ("HegBr"). The reactions were carried out at 100° C in a 10%

Os in CO atmosphere. Product samples were obtained after 3 hours of reaction time and analyzed for Pd TON to produce the following data: BATCH-FLOW REACTOR Sample No. Ce (acac) 3 TEAB TMAB Pd TON Equivalents Equivalents Equivalents 1 0 160 0 878 2 8 80 0 2230 3 8 80 0 1828 4 8 160 0 2921 5 8 330 0 4466 6 8 0 320 5411 7 16 0 320 4234 THIN FILM MICRO-REACTOR Sample No. Ce (acac) 3 HegBr Pd TON Equivalents Equivalents 1 0 150 300 2 0 150 472 3 2 150 2655 4 4 150 3147 5 8 150 3191 6 16 150 2765 7 8 60 1554 Combinatorial Via is vs. the Batch Flow reactor 56 PbO + 8 Ce (acac) 3: PdTON vs. Br eq's Pd TON Combinatorial Vials vs. the Batch Flow reactor 56 Pbo + Ce (acac) 3: PdTON vs. Ce eq's Pd TON

As can be seen above, the micro-reactor correctly identified 8 equivalents as the preferred amount of cerium for the same reaction in the batch-flow reactor. Furthermore, results from the micro-reactor correctly predict that, for the reaction conditions used, Pd TON will increase as bromide concentration increases. Although the Pd TONs at a given concentration are not identical between the two reactors, it is evident that the correlation between the performances of the two reactors allows for meaningful discrimination among potential reactants using the thin film micro-reactor.

EXAMPLE 3 The method of Example 1 was repeated with the combination of palladium (II) acetylacetonate, HegBr, and manganese (lit) acetylacetonate as a catalyst system. The sample size for all samples was 25 gL. The vials were exposed to a 10% 02 in CO atmosphere at 100° C and 98 atm for 3 hours. The following results were observed: Sample No. Pd (acac) 2 Mn (acac) 3 HegBr Pd TON mM Equivalents Equivalents 1.25 2 10 104 2.25 2 600 423 3.25 6 150 440 4. 25 20 10 294 5. 20 20 600 40. 6 EXAMPLE 4 The method of Examples 1 and 3 was repeated with palladium (II) acetylacetonate, HegBr, and copper (II) acetylacetonate as an inorganic co-catalyst. The reactants were heated to 100° C for 3 hours in a 10% oxygen in carbon monoxide atmosphere. After the reaction, samples were analyzed for DPC by gas chromatography. The following results were observed: Sample No. Pd (acac) 2 Cu (acac) 2 HegBr Pd TON mM Equivalents Equivalents 1. 25 28 120 1320 2.25 28 30 318 3.25 20 600 1067 4.25 20 10 216 5.20 17. 5 750 1993 6.25 14 600 1850 7.25 14 120 1184 8.25 14 60 707 9. 25 14 30 424 .25 2 10 211

EXAMPLE 5 The method of Examples 1,3, and 4 was repeated with. 25 mM palladium (II) acetylacetonate, various amounts of bromide, and various amounts of manganese (III) acetylacetonate and bismuth (II) tetramethylhetptanedionate as IOCCs to provide the following results : Sample No. Mn (acac) 3 Bi (TMHD) 2 HegBr Pd TON Equivalents Equivalents Equivalents 1 14 2.8 120 645 2 14 2. 8 30 583 3 28 5. 6 120 728 4 28 5. 6 30 564 5 2. 8 14 120 818 6 2. 8 14 30 477 7 5. 6 28 120 1075 8 5. 6 28 30 556

EXAMPLE 6 The method of Examples 1 and 3-5 was repeated with. 25 mM palladium(II) acetylacetonate various amounts of HegBr, and various amounts of the IOCC combination of iron (Iil) acetylacetonate and bismuth (li) tetramethylheptanedionate. The following results were observed: Exmperiment Fe(acac)3 Bi(TMHD)2 HegBr PdTON No. Equivalents Equivalents lents 1 2. 8 14 120 372 2 2. 8 14 30 216 3 5. 6 28 120 368 4 5.6 28 30 231 5 14 2.8 120 208 6 14 2. 8 30 474 28 5.6 120 377 8 28 5. 6 30 732

Based on the results of these experiments, it is evident that the method and apparatus of the present invention can effectively discriminate among various reaction conditions in a homogeneous reaction utilizing multiphase reactants.

It will be understood that each of the elements described above, or two or more together, may also find utility in applications differing from the types described herein. While the invention has been illustrated and described as embodied in a method and apparatus for rapid screening of multiphase reactant systems, it is not intended to be limited to the details shown, since various modifications and substitutions can be made without departing in any way from the spirit of the present invention. For example, robotic equipment can be used to prepare the samples and various types of parallel screening methods can be incorporated. As such, further modifications and equivalents of the invention herein disclosed may occur to persons skilled in the art using no more than routine experimentation, and all such modifications and equivalents are believed to be within the spirit and scope of the invention as defined by the following claims.