Abstract:
A reactor plate comprises a substrate with an array of reaction cells and a permeable film covering at least one of the cells to selectively permit transport of a reactant gas into the one cell while preventing transport of a reaction product out of the cell. A method comprises providing a reactor plate comprising a substrate with an array of reaction cells, at one least one cell of the array comprising a cavity and a permeable film cover and conducting a combinatorial high throughput screening (CHTS) method with the reactor plate.

Description:
BACKGROUND OF THE INVENTION  
         [0001]    The present invention relates to a reactor plate and method for running multiple parallel screening reactions with multiphase reactant systems.  
           [0002]    In experimental reaction systems, each potential combination of reactant, catalyst and condition must be evaluated in a manner that provides correlation to performance in a production scale reactor. Combinatorial organic synthesis (COS) is a high throughput screening (HTS) methodology that was developed for pharmaceuticals. COS uses systematic and repetitive synthesis to produce diverse molecular entities formed from sets of chemical “building blocks.” As with traditional research, COS relies on experimental synthesis methodology. However instead of synthesizing a single compound, COS exploits automation and miniaturization to produce large libraries of compounds through successive stages, each of which produces a chemical modification of an existing molecule of a preceding stage. A library is a physical, trackable collection of samples resulting from a definable set of processes or reaction steps. The libraries comprise compounds that can be screened for various activities.  
           [0003]    The technique used to prepare such libraries involves a stepwise or sequential coupling of building blocks to form the compounds of interest. For example, Pirrung et al., U.S. Pat. 5,143,854 discloses a technique for generating arrays of peptides and other molecules using light-directed, spatially-addressable synthesis techniques. Pirrung et al. synthesizes polypeptide arrays on a substrate by attaching photoremovable groups to the surface of the substrate, exposing selected regions of the substrate to light to activate those regions, attaching an amino acid monomer with a photoremovable group to the activated region and repeating the steps of activation and attachment until polypeptides of desired lengths and sequences are synthesized.  
           [0004]    Combinatorial high throughput screening (CHTS) is an HTS methodology that incorporates characteristics of COS. The definition of the experimental space permits a CHTS investigation of highly complex systems. The method selects a best case set of factors of a chemical reaction. The method comprises defining a chemical experimental space by (i) identifying relationships between factors of a candidate chemical reaction space; and (ii) determining a chemical experimental space comprising a table of test cases for each of the factors based on the identified relationships between the factors with the identified relationships based on researcher specified n-tuple combinations between identities of the relationships. A CHTS method is effected on the chemical experimental space to select a best case set of factors.  
           [0005]    The methodology of COS is difficult to apply in certain reaction systems. For example up to now, COS has not been applied to systems that may produce vaporous products that may escape from respective cells of an array and contaminate the contents of adjacent or near-by cells. There is a need for improved reaction plate and method to permit rapid and effective investigation of vaporous product reaction systems.  
         BRIEF SUMMARY OF THE INVENTION  
         [0006]    The invention provides a reactor plate and method to investigate these types of systems. According to the invention, a reactor plate comprises a substrate with an array of reaction cells and a permeable film covering at least one of the cells to selectively permit transport of a reactant gas into the one cell while preventing transport of a reaction product out of the cell.  
           [0007]    A method comprises providing a reactor plate comprising a substrate with an array of reaction cells, at one least one cell of the array comprising a cavity and a permeable film cover and conducting a combinatorial high throughput screening (CHTS) method with the reactor plate. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0008]    [0008]FIG. 1 is a schematic representation of a top view of a reactor plate according to the invention;  
         [0009]    [0009]FIG. 2 is a schematic cut-away front view through line A-A of the reactor plate of FIG. 1;  
         [0010]    FIGS.  3  to  5  are schematic cut-away representations of various cell configurations;  
         [0011]    [0011]FIG. 6 is a graph of permeability versus film thickness;  
         [0012]    [0012]FIG. 7 is a graph of permeability versus temperature; and  
         [0013]    [0013]FIG. 8 is a 3-D column graph showing interations of transition metal cocatalysts with lanthanide metal cocatalysts. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0014]    In an embodiment, the invention is directed to a reactor plate and method for CHTS. The method and system of the present invention can be useful for parallel high-throughput screening of chemical reactants, catalysts, and related process conditions.  
         [0015]    Typically, a CHTS method is characterized by parallel reactions at a micro scale. In one aspect, CHTS can be described as a method comprising (A) an iteration of steps of (i) selecting a set of reactants; (ii) reacting the set and (iii) evaluating a set of products of the reacting step and (B) repeating the iteration of steps (i), (ii) and (iii) wherein a successive set of reactants selected for a step (i) is chosen as a result of an evaluating step (iii) of a preceding iteration.  
         [0016]    In another typical CHTS method, a multiplicity of tagged reactants is subjected to an iteration of steps of (A) (i) simultaneously reacting the reactants, (ii) identifying a multiplicity of tagged products of the reaction and (B) evaluating the identified products after completion of a single or repeated iteration (A).  
         [0017]    A typical CHTS can utilize advanced automated, robotic, computerized and controlled loading, reacting and evaluating procedures.  
         [0018]    These and other features will become apparent from the drawings and following detailed discussion, which by way of example without limitation describe preferred embodiments of the present invention.  
         [0019]    [0019]FIG. 1 shows a top view of a preferred reactor plate and FIG. 2 shows a cut-away front view through line A-A of the plate of FIG. 1. FIG. 1 and FIG. 2 show reactor plate  10  that includes an array  12  of reaction cells  14  embedded into a supporting substrate  16  of the plate  10 . Each cell  14  is shown covered with a permeable film  18 . Each cell  14  can be covered with the same film  18  or each cell can be covered with a different film to provide different reaction characteristics to different cells  14 . Further, in another embodiment, selected cells  14  can be covered with film while other cells  14  are left uncovered to provide still different reaction characteristics.  
         [0020]    [0020]FIGS. 3, 4 and  5  illustrate embodiments of the cell of the invention. FIG. 3 shows a shallow cell with permeable film cover. For example, the cell can have a volume of about 20 mm 3 , a film area of 20 mm 2 , a 1 mil film and a 1 mm deep cavity. FIG. 4 shows a cell with two opposing walls comprising permeable film. For example, the cell can have a volume of about 20 mm 3 , a film area of 40 mm 2 , a 1 mil film and a 1 mm deep cavity. FIG. 5 shows a concave bottomed cell with permeable film cover. For example, the cell can have a volume of about 40-50 mm 3 , a film area of 2-3 mm 2 , a 1 mil film and a 5 mm deep cavity. The respective cells and films are selected by considering permeability of the film and robustness and rate of the reaction. For example, the cells can be designed so that rate of diffusion of gas through the membrane is greater than the rate of gas uptake of the reaction. In this instance, the system would be “reaction-limited” rather than “diffusion-limited.” 
         [0021]    The film  18  can be any permeable film that will selectively admit transport of a reactant but will prohibit transport of a reaction product in a CHTS process. For example, the film can be a polycarbonate, perfluoroethylene, polyamide, polyester, polypropylene, polyethylene or a monofilm, coextrusion, composite or laminate.  
         [0022]    Polycarbonate, PET and polypropylene are preferred films. Relative humidity may affect permeability of many films. However, permeability of polycarbonate, PET and polypropylene is substantially unaffected by changes in humidity. Hence, these films are particularly advantageous to conduct reactions in humid conditions or to conduct moisture sensitive reactions such as a carbonylation reaction.  
         [0023]    In certain applications, the film can be characterized by a diffusion coefficient of about 5×10 −10  to about 5×10 −7 , desirably about 1×10 −9  to about 1×10 −7  and preferably about 2×10 −8  to about 2×10 −6  in units of cc(STP)-mm/cm 2 -sec-cmHg.  
         [0024]    The permeability of a film will vary with thickness. In this invention, the film can be of any thickness that will admit transport of a reactant, usually a gas or vapor, but that will prohibit transport of a reaction product. The thickness of the film can be about 0.0002 to about 0.05 mm, desirably about 0.005 to about 0.04 mm and preferably about 0.01 to about 0.025 mm. FIG. 6 shows CO 2  permeability of a polycarbonate film with thickness at 75° F. and 0% relative humidity, where permeability (P) equals cc/100 in 2 ·atm·day  
         [0025]    Temperature is another variable that can affect film permeability. FIG. 7 shows the effect of temperature on the permeability of 1 mil blown polycarbonate film at constant relative humidity (RH). FIG. 7 shows permeability versus thickness at 75° F. and 0% relative humidity where P equals cc/100 in 2 ·atm·day. Accordingly, the CHTS method can comprise reacting a reactant at a temperature of about 0 to about 150° C., desirably about 50 to about 140° C. and preferably about 75 to about 125° C.  
         [0026]    In one embodiment, the invention is applied to study a process for preparing diaryl carbonates. Diaryl carbonates such as diphenyl carbonate can be prepared by reaction of hydroxyaromatic compounds such as phenol with oxygen and carbon monoxide in the presence of a catalyst composition comprising a Group VIIIB metal such as palladium or a compound thereof, a bromide source such as a quaternary ammonium or hexaalkylguanidinium bromide and a polyaniline in partially oxidized and partially reduced form. The invention can be applied to screen for a catalyst to prepare a diaryl carbonate by carbonylation.  
         [0027]    Various methods for the preparation of diaryl carbonates by a carbonylation reaction of hydroxyaromatic compounds with carbon monoxide and oxygen have been disclosed. The carbonylation reaction requires a rather complex catalyst. Reference is made, for example, to Chaudhari et al., U.S. Pat. 5,917,077. The catalyst compositions described therein comprise a Group VIIIB metal (i.e., a metal selected from the group consisting of ruthenium, rhodium, palladium, osmium, iridium and platinum) or a complex thereof.  
         [0028]    The catalyst material also includes a bromide source. This may be a quaternary ammonium or quaternary phosphonium bromide or a hexaalkylguanidinium bromide. The guanidinium salts are often preferred; they include the α,ω-bis(pentaalkylguanidinium)alkane salts. Salts in which the alkyl groups contain 2-6 carbon atoms and especially tetra-n-butylammonium bromide and hexaethylguanidinium bromide are particularly preferred.  
         [0029]    Other catalytic constituents are necessary in accordance with Chaudhari et al. The constituents include inorganic cocatalysts, typically complexes of cobalt(II) salts with organic compounds capable of forming complexes, especially pentadentate complexes. Illustrative organic compounds of this type are nitrogen-heterocyclic compounds including pyridines, bipyridines, terpyridines, quinolines, isoquinolines and biquinolines; aliphatic polyamines such as ethylenediamine and tetraalkylethylenediamines; crown ethers; aromatic or aliphatic amine ethers such as cryptanes; and Schiff bases. The especially preferred inorganic cocatalyst in many instances is a cobalt(II) complex with bis-3-(salicylalamino)propylmethylamine.  
         [0030]    Organic cocatalysts may be present. These cocatalysts include various terpyridine, phenanthroline, quinoline and isoquinoline compounds including 2,2′:6′,2″ -terpyridine, 4-methylthio-2,2′:6′,2″ -terpyridine and 2,2′:6′,2″ -terpyridine N-oxide, 1,10-phenanthroline, 2,4,7,8-tetramethyl-1,1 0-phenanthroline, 4,7-diphenyl-1,10, phenanthroline and 3,4,7,8-tetramethy-1,1 0-phenanthroline. The terpyridines and especially 2,2′:6′,2″ -terpyridine are preferred.  
         [0031]    Another catalyst constituent is a polyaniline in partially oxidized and partially reduced form.  
         [0032]    Any hydroxyaromatic compound may be employed. Monohydroxyaromatic compounds, such as phenol, the cresols, the xylenols and p-cumylphenol are preferred with phenol being most preferred. The method may be employed with dihydroxyaromatic compounds such as resorcinol, hydroquinone and 2,2-bis(4-hydroxyphenyl)propane or “bisphenol A,” whereupon the products are polyearbonates.  
         [0033]    Other reagents in the carbonylation process are oxygen and carbon monoxide, which react with the phenol to form the desired diaryl carbonate.  
         [0034]    These and other features will become apparent from the following detailed discussion, which by way of example without limitation describes a preferred embodiment of the present invention.  
       EXAMPLE  
       [0035]    This example illustrates the identification of an active and selective catalyst for the production of aromatic carbonates. The procedure identifies the best catalyst from within a complex chemical space, where the chemical space is defined as an assemblage of all possible experimental conditions defined by a set of variable parameters such as formulation ingredient identity or amount.  
         [0036]    In this Example, a reactor plate is designed to provide a rate of diffusion of reactant gas through a polymer membrane greater than the rate of reaction of the gas to form the desired product. The desired reaction rate of the catalyst is 1 gram-mole/liter-hour. Each cell in the array of the plate is 5 mm in diameter and 1 mm thick, with 0.01 mm film making up the top and bottom of each cell as illustrated in FIG. 4. This design provides a cell volume of 20 mm 3  and a film area of 40 mm 2 .  
         [0037]    The plate is prepared for reaction by providing a preformed 86×126 mm piece of 1 mm polycarbonate substrate with an 8×12 array of 5-mm holes and heat sealing a piece of 86×126 mm 0.01 mm thick polycarbonate film to the substrate bottom. Twenty (20) microliters of premixed catalyst solution is delivered to each cell. A second 86×126 mm piece of 0.01 mm polycarbonate film is heat sealed to the top of the plate substrate.  
         [0038]    The subsequent reaction is run at 100° C. and at a partial pressure of 10 atmospheres of O 2 . Permeability of the film to oxygen at 100° C. is calculated to be 5×10 −9  cc(STP)-mm/cm 2 -sec-cmHg. Oxygen flow through the film is calculated as 2.44×10 −05  gram/moles-hour to provide an oxygen delivery rate to the 20 mm 3  (2×10 −5  liters) reaction volume of 1.22 g-mols/liter-hour. Formulation parameters are given in TABLE 1.  
                                         TABLE 1                                   Formulation Type Parameter   Formulation Amount           Variation   Parameter Variation                                    Precious   Held Constant   Held Constant       metal       catalyst       Transition   Ti, V, Cr, Mn, Fe, Co, Ni,   5 (as molar ratios to       Metal   Cu (as their acetylacetonates)   precious metal catalyst)       Cocatalyst       (TM)       Lanthanide   La, Ce, Eu, Gd (as their   5 (as molar ratios to       Metal   acetylacetonates)   precious metal catalyst)       Cocatalyst       (LM)       Cosolvent   Dimethylformamide (DMFA),   500 (as molar ratios to       (CS)   Dimethylacetamide (DMAA),   precious metal catalyst)           Diethyl acetamide (DEAA)       Hydroxy-   Held constant   Sufficient added to achieve       aromatic       constant sample volume       compound                  
 
         [0039]    The size of the initial chemical space defined by the parameters of TABLE 1 is 96 possibilities. This is a large experimental space for a conventional technique. However, the experiment can be easily conducted according to the present invention to determine optimal compositions. The space is explored using a full factorial design. A full factorial design of experiment (DOE) measures the response of every possible combination of factors and factor levels. These responses can be analyzed to provide information about every main effect and every interaction effect. The design is given in TABLE 2, below.  
         [0040]    In this experiment, each metal acetylacetonate and each cosolvent were made up as stock solutions in phenol. Ten ml of each stock solution are produced by manual weighing and mixing. For each sample, an appropriate quantity of each stock solution is then combined using a Hamilton MicroLab 4000 laboratory robot into a single 2-ml vial. The mixture is stirred using a miniature magnetic stirrer. Then 20 microliter aliquots are measured out by the robot to individual cells in the array. After the aliquots are distributed, the upper film is heat sealed to the substrate.  
         [0041]    The assembled reactor plate is then placed in an Autoclave Engineers 1-gallon autoclave, which is then pressurized to 1500 psi (100 atm) with a 10% O 2  in CO mixture. This provides a 10 atm oxygen partial pressure. the autoclave is heated to 100° C. for two hours, cooled, depressurized and the array removed. Raman spectrum of each product is taken by focussing an argon ion laser  38  (Spectra Physics 2058) on a cell and detecting the inelastically scattered light with an Acton Spectra-Pro 3001 spectrophotometer  36 .  
         [0042]    Performance in this example is expressed numerically as a catalyst turnover number or TON. TON is defined as the number of moles of aromatic carbonate produced per mole of charged palladium catalyst. The performance of each of the runs is given in the column “TON” of TABLE 2.  
                                                     TABLE 2                           Transition   Lanthanide                   Metal (TM)   Metal (LM)   Cosolvent       Run   Cocatalyst   Cocatalyst   (CS)   TON                                 1   Mn   Gd   DEAA   555.1078        2   Cu   La   DMAA   456.5777        3   Mn   Ce   DMAA   513.6325        4   Ti   Gd   DEAA   400.5089        5   V   Eu   DMFA   587.5912        6   Mn   La   DMAA   1750.03        7   Ti   Ce   DEAA   292.4069        8   Cr   Eu   DMAA   625.9431        9   V   Ce   DMFA   665.1948       10   Fe   Eu   DMFA   332.9006       11   Ti   Eu   DMFA   679.5486       12   Fe   La   DEAA   468.5033       13   Co   Ce   DEAA   257.2479       14   Cu   Eu   DMAA   468.7711       15   Ni   Ce   DMFA   433.6684       16   Co   Gd   DMAA   485.2293       17   Cu   Gd   DEAA   342.2256       18   Cu   Gd   DMFA   506.5736       19   Mn   Eu   DMFA   356.3573       20   Co   La   DMFA   545.6339       21   Ni   Gd   DMFA   483.2507       22   V   Gd   DMFA   590.907       23   Ti   La   DEAA   885.7548       24   Cr   Eu   DEAA   344.2193       25   Mn   Gd   DMFA   338.4866       26   Fe   Ce   DMFA   474.0333       27   Ni   Eu   DMFA   758.6696       28   Mn   Ce   DMFA   625.6508       29   Cr   Gd   DMFA   603.5539       30   Cr   Eu   DMFA   249.9745       31   Co   Eu   DEAA   431.0617       32   Mn   Gd   DMAA   372.3904       33   Ni   Gd   DMAA   652.7145       34   Cu   Ce   DMAA   352.7221       35   Ni   Eu   DEAA   459.774       36   Co   Gd   DEAA   472.6578       37   Fe   La   DMFA   472.984       38   V   La   DMAA   858.9171       39   V   Eu   DMAA   416.1047       40   Cu   La   DEAA   345.512       41   Cr   La   DMFA   552.11       42   Cu   Eu   DEAA   250.3933       43   Cr   La   DEAA   417.1977       44   Mn   La   DEAA   1291.111       45   V   Gd   DEAA   490.6305       46   Co   Gd   DMFA   452.9355       47   V   Gd   DMAA   413.9911       48   Cu   Gd   DMAA   683.2233       49   Fe   Ce   DEAA   276.7799       50   Co   La   DEAA   390.3853       51   Ti   Gd   DMAA   390.6338       52   Ni   La   DMAA   673.2558       53   Mn   Ce   DEAA   360.0271       54   V   Ce   DMAA   650.6003       55   V   La   DMFA   848.4497       56   Cu   La   DMFA   476.2182       57   Cr   Gd   DMAA   427.1539       58   Co   Ce   DMFA   468.8664       59   V   La   DEAA   743.0518       60   Co   Eu   DMAA   364.7413       61   Fe   Eu   DMAA   572.7474       62   V   Eu   DEAA   459.1624       63   Ti   La   DMFA   778.1048       64   Ni   Gd   DEAA   522.5839       65   Fe   Gd   DMAA   340.3491       66   Ni   La   DMFA   733.7841       67   Cr   La   DMAA   613.4944       68   V   Ce   DEAA   295.7852       69   Ni   Eu   DMAA   868.0304       70   Fe   La   DMAA   559.6479       71   Fe   Gd   DMFA   592.372       72   Cr   Ce   DEAA   326.6567       73   Cr   Ce   DMAA   417.9809       74   Cu   Ce   DEAA   267.8915       75   Ni   Ce   DEAA   262.121       76   Ni   Ce   DMAA   554.9479       77   Cr   Ce   DMFA   495.3985       78   Ni   La   DEAA   451.5785       79   Ti   Eu   DMAA   877.8409       80   Fe   Ce   DMAA   612.9162       81   Mn   Eu   DMAA   644.8604       82   Fe   Gd   DEAA   521.141       83   Fe   Eu   DEAA   457.5463       84   Mn   La   DMFA   1650.954       85   Ti   Eu   DEAA   450.2065       86   Ti   Ce   DMAA   512.3347       87   Cu   Ce   DMFA   324.8884       88   Ti   Gd   DMFA   747.381       89   Co   Ce   DMAA   242.6424       90   Co   La   DMAA   366.3668       91   Co   Eu   DMFA   474.389       92   Ti   Ce   DMFA   374.0002       93   Cu   Eu   DMFA   549.2309       94   Cr   Gd   DEAA   279.3706       95   Ti   La   DMAA   634.0476       96   Mn   Eu   DEAA   350.5033                  
 
         [0043]    The results are analyzed using a “General Linear Model” routine in Minitab software. The routine is set to calculate an Analysis of Variance (ANOVA) for all main effects and 2-way interactions. The ANOVA is given in TABLE 3. In TABLE 3, Sources of Variation are potentially significant factors and interactions. Degrees of Freedom are a measure of the amount of information available for each source. Adjusted Sums of Squares are the squares of the deviations caused by each source. Adjusted Mean Squares are Adjusted Sums/Degrees of Freedom. The F Ratio is the Adjusted Mean Square for each Source/Adjusted Mean Square for Error. The F ratio is compared to a standard table to determine its statistical significance at a given probability (0.001 or 0.1% in this case).  
                                                             TABLE 3                       Source of   Degrees of   Adjusted Sums of   Adjusted Mean       Significant       Variation   Freedom   Squares   Squares   F Ratio   at P &lt; 0.001                                TM   7   1243723   177675   9.84   Yes       LM   3   973525   324508   17.98   Yes       CS   2   896969   448484   24.84   Yes       TM * LM   21   1754525   83549   4.63   Yes       TM * CS   14   353434   25245   1.4   No       LM * CS   6   205012   34169   1.89   No       Error   42   758191   18052       Total   95                  
 
         [0044]    The column “Significant at P&lt;0.001” indicates that a TM*LM (transition metal *lanthanide metal) interaction has a significant effect on TON. These interactions are also illustrated in FIG. 8, which shows that interaction of Mn and La have a strong positive influence on the TON.  
         [0045]    While preferred embodiments of the invention have been described, the present invention is capable of variation and modification and therefore should not be limited to the precise details of the Example. The invention includes changes and alterations that fall within the purview of the following claims.