WO2001034660A2 - Criblage et analyse radiographiques de polymeres, de specialites chimiques et de catalyseurs - Google Patents

Criblage et analyse radiographiques de polymeres, de specialites chimiques et de catalyseurs Download PDF

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WO2001034660A2
WO2001034660A2 PCT/US2000/030720 US0030720W WO0134660A2 WO 2001034660 A2 WO2001034660 A2 WO 2001034660A2 US 0030720 W US0030720 W US 0030720W WO 0134660 A2 WO0134660 A2 WO 0134660A2
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radiolabeled
reaction
catalysts
reaction regions
catalyst
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PCT/US2000/030720
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WO2001034660A3 (fr
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Christopher D. Tagge
Robert B. Wilson
Seajin Oh
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Sri International
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Publication of WO2001034660A2 publication Critical patent/WO2001034660A2/fr
Publication of WO2001034660A3 publication Critical patent/WO2001034660A3/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N25/00—Investigating or analyzing materials by the use of thermal means
    • G01N25/20—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity
    • G01N25/48—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity on solution, sorption, or a chemical reaction not involving combustion or catalytic oxidation
    • G01N25/4846—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity on solution, sorption, or a chemical reaction not involving combustion or catalytic oxidation for a motionless, e.g. solid sample
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
    • B01L3/50851—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates specially adapted for heating or cooling samples
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/08—Investigating permeability, pore-volume, or surface area of porous materials
    • G01N15/088—Investigating volume, surface area, size or distribution of pores; Porosimetry
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N5/00—Analysing materials by weighing, e.g. weighing small particles separated from a gas or liquid
    • G01N5/04—Analysing materials by weighing, e.g. weighing small particles separated from a gas or liquid by removing a component, e.g. by evaporation, and weighing the remainder
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00279—Features relating to reactor vessels
    • B01J2219/00306—Reactor vessels in a multiple arrangement
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00279—Features relating to reactor vessels
    • B01J2219/00306—Reactor vessels in a multiple arrangement
    • B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
    • B01J2219/00315—Microtiter plates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/0054—Means for coding or tagging the apparatus or the reagents
    • B01J2219/00572—Chemical means
    • B01J2219/00574—Chemical means radioactive
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00585—Parallel processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068—Means for controlling the apparatus of the process
    • B01J2219/00702—Processes involving means for analysing and characterising the products
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds
    • B01J2219/00722—Nucleotides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C40B40/14—Libraries containing macromolecular compounds and not covered by groups C40B40/06 - C40B40/12
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
    • C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N11/00—Investigating flow properties of materials, e.g. viscosity, plasticity; Analysing materials by determining flow properties
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N2035/00178—Special arrangements of analysers
    • G01N2035/00237—Handling microquantities of analyte, e.g. microvalves, capillary networks

Definitions

  • the invention relates to methods, using radiography, for the analysis of polymers, specialty chemicals, and catalysts.
  • the invention also relates to combinatorial and high- throughput techniques for the synthesis and characterization of polymers, specialty chemicals, and catalysts using radiography.
  • Radiolabels have been used as tracers and tags.
  • Radiolabels have also been used to investigate the number of active centers in Ziegler-Natta catalysts.
  • the number of active centers of a Ziegler-Natta catalyst has been determined using inhibition and kinetic studies employing a radioisotope; see Abu-Eid, M, Davies, S. and Tait, P.J.T.; Polymer. Prep. 24(1): 114-115 (1983).
  • the determination of the number of active centers of various Ziegler-type catalyst systems, using 14 CO radiolabels has been reported in Jaber, LA. and Fink, G.; Makromol. Chem., 190:2427-2436 (1989); Jaber, LA., Hauschild, K., and Fink, G.; Makromol.
  • radiography has generally not been adapted or extended to the characterization of an array of chemical compounds, such as polymers, catalysts or specialty chemicals, in a high- throughput manner.
  • Sequential techniques involve time-consuming and inefficient methods for the analysis of large libraries or arrays of chemical compounds.
  • Such methods preferably provide a qualitative and/or quantitative determination of properties such as comonomer content, amount of incorporation of a reagent into a final product, and/or various properties of catalysts. This invention answers this need.
  • the invention relates to methods, using radiography, for the analysis of chemical compounds.
  • the methods of the invention provide analytical methods, which may be carried out in a highly parallel manner, and which are useful in the synthesis and analysis of chemical compounds in a high-throughput or combinatorial manner. In a preferred embodiment, these methods may be used to analyze a variety of polymers, specialty chemicals, and catalysts.
  • the invention in a first embodiment, relates to a method for the synthesis and analysis of polymers.
  • This method involves providing a substrate having a plurality of reaction regions, and delivering a monomer or mixture of monomers to two or more reaction regions. At least one of the monomers is a radiolabeled monomer.
  • the monomer or mixture of monomers is polymerized. After the polymerization step, any unreacted radiolabeled monomer may be removed from the reaction region.
  • the radioactivity of the polymer in the reactor regions is then measured. The radioactivity provides a means for determining the yield of the polymerization reaction in the reaction region. Further, in cases where a copolymer is formed, the copolymer content may be determined, e.g.
  • the invention provides a method for determining the productivity of the catalysts, either in parallel or sequentially.
  • the productivity of a catalyst during the polymerization may be monitored by measuring the heat produced during the reaction, for instance, using calorimetry or thermography. According to the invention, the productivity of the catalyst may also be determined from the same polymerization, based on the radioactivity of the resulting polymer.
  • the amount of incorporation of a reagent into a specialty chemical is measured using radiography.
  • a substrate having a plurality of reaction regions is provided. The method involves delivering a reagent or mixture of reagents, where at least one reagent is a radiolabeled reagent.
  • a catalyst, co-catalyst, activator, or reaction solvent may also be added to the reaction regions.
  • the reaction may be conducted either in parallel or sequentially.
  • any unreacted radiolabeled reagent may optionally be removed from the reaction regions. The radioactivity of the products is measured, either during the reaction or after the reaction.
  • This embodiment provides a method for determining the conversion of the reactants. Also, according to the invention, it is possible to determine the amount of radiolabeled reagent incorporated in the product. Moreover, in another embodiment, a catalyst may be provided to the reaction region, and the productivity of the catalyst may be determined. For example, the catalyst productivity may be determined by monitoring the heat emitted or absorbed during the reaction, e.g. using calorimetry or thermography, or by determining the radioactivity of the resulting chemical compound and correlating the radioactivity to the productivity of the catalyst.
  • Also according to the invention is a method for the analysis of chemical and physical properties of porous catalysts.
  • a substrate having a plurality of reaction regions is provided, and then a porous catalyst is provided to two or more reaction regions.
  • a radiolabeled compound is provided to the reaction regions under conditions sufficient for the radiolabeled compound to be adsorbed by the porous catalyst.
  • the radioactivity of the catalyst after adsorption of the radiolabeled porous catalyst is measured. The radioactivity may be correlated to the surface area, the number of active sites of a porous catalyst, and/or the number of acidic or basic sites of a porous catalyst.
  • the invention also relates to a method for analysis of the pore size distribution of porous catalysts, comprising the steps of first providing a porous catalyst to a reaction region on a substrate, as described above.
  • a mixture of radiolabeled compounds is provided to the reaction regions under conditions sufficient for the radiolabeled compound to be adsorbed by the porous catalyst.
  • the mixture of radiolabeled compounds comprises compounds having different molecular sizes, where compounds of different molecular sizes are uniquely labeled with different radiolabels.
  • a method for measuring, either in parallel or sequentially, the exchange rate between different adsorbed species for a porous catalyst is provided.
  • the exchange rate is the rate of displacement of a first adsorbed species by a second adsorbed species from the porous catalyst, as monitored over time.
  • an array comprising a plurality of reaction regions is provided.
  • a porous catalyst is provided to two or more reaction regions, wherein the porous catalyst has a first adsorbed species, which is radiolabeled.
  • a second radiolabeled adsorbed species is provided to the reaction regions.
  • the invention relates to various methods, using radiography, for the analysis and characterization of chemical compounds, such as polymers, specialty chemicals, and porous catalysts. While any equipment or apparatus designed for high- throughput or combinatorial chemistry may be used, the methods of the invention employ a substrate having a plurality (i.e. two or more) of reaction regions.
  • a substrate having a plurality of reaction regions is employed.
  • polymerization, synthesis or adsorption steps are carried out with one or more radiolabeled reagents, or with radiolabeled starting materials.
  • the amount of the radiolabeled reagent or starting material incorporated into the resulting chemical product may be monitored using radiography.
  • the starting material is radiolabeled, it is also possible to monitor the loss of radioactivity, i.e. in a decomposition reaction. In either case, the change in the radioactivity is measured or monitored over time using radiography. The amount of radioactivity in the resulting product may then be used to determine various physical and chemical properties.
  • the methods of the invention are used to determine the comonomer content of polymers, the productivity of catalysts and/or the incorporation of a reagent in a specialty chemical.
  • the invention provides means for determining a variety of properties of porous catalysts, including surface area, the number of active sites, the number of acidic or basic sites, pore size distribution, and chemisorption.
  • the substrate used in the invention may be any material having a rigid or semi-rigid surface, and may be in any shape that is convenient and practical, e.g. an array comprising several wells, a spot plate, or a test tube rack.
  • the substrate may be fabricated from any material which is compatible with the reaction conditions and reagents to be used.
  • the substrate typically comprises one or more materials selected from silicon, doped silicon, silicon dioxide, doped silicon dioxide, steel, sapphire, glass materials, ceramic materials, plastic materials, and mixtures thereof.
  • Acceptable materials for the substrate include a variety of materials, including but not limited to: Pyrex, quartz, resins, carbon, metals, or inorganic crystals.
  • suitable materials for the array include steel and steel alloys, including materials such as stainless steel.
  • a variety of ceramic materials such as silicon nitride, silicon oxynitride, aluminum nitride, boron nitride, aluminum oxide, zirconium oxide, silicon carbide, lithium aluminum silicate and mixtures thereof may also be used.
  • plastic materials are also well suited for the fabrication of the array. Typical plastic materials comprise at least one of polyethylene, polypropylene, polystyrene, polycarbonates, polyimides, poly(vinyl chloride), fluorinated polymers (for example, such as tetrafluoroethylene fluorocarbon polymers and fluorinated ethylene- propylene resins), acrylic, and poly(ethylene terephthalate).
  • the substrate may be a hybrid substrate, with different sections made from different materials. For instance, it may be desirable to bond together a glass plate having wells and channels machined and/or etched therein, with a silicon wafer that forms the bottom of the wells. Other suitable materials are known in the art.
  • the array When the array is made from a silicon wafer, the array has the additional feature and advantage of being well adapted for single-use applications.
  • the array may be disposable or archivable. By batch-fabricating the array, the array may be produced at a cost such that it is cost-effective to dispose of the array after use, which avoids time-consuming cleaning operations and the risk of contamination.
  • the array may be archived for future studies or characterization.
  • the reaction regions on the substrate may be in the form of wells, dimples, or raised regions, which permit reactions to occur in separate areas or compartments. There may be a physical barrier between the reaction regions, or the reactions may be conducted in physically separate compartments or containers, and assembled together into a substrate or an array, i.e. a test tube rack, or an array made up of individual blocks or containers each having reaction regions.
  • the reaction regions may be of any size and volume that is practical.
  • the reactions may be run on small scale or microscale.
  • Advantages of the microscale include smaller reactor volume, lower costs for reagents and labor, generally higher throughput, and compatibility with commercially available radiographs.
  • the reaction regions may have a volume of less than about 1 ⁇ L.
  • the array may comprise wells having a volume of from about lnL to about 500 ⁇ L, from about 0.1 ⁇ L to about 100 ⁇ L, or from about 0.25 ⁇ L to about 10 ⁇ L.
  • the substrate is an array, such as described in co- pending U.S. Provisional Application Nos. 60/164,342 filed November 9, 1999 and 60/167,227 filed November 24, 1999, as well as U.S. Application "Array for the High- Throughput Synthesis, Screening, and Characterization of Combinatorial Libraries” and "Workstation, Apparatus, and Methods for the High-Throughput Synthesis, Screening, and Characterization of Combinatorial Libraries” both filed on November 9, 2000; the disclosure of all these applications is hereby incorporated in their entirety by reference.
  • the array as described in these applications, contains wells (typically used as reaction regions), and/or thermal channels which may be used to regulate or monitor the temperature of the reactions in the reaction regions.
  • the wells and thermal channels may be in the form of dimples, wells, raised regions or etched trenches in the substrate.
  • substrates typically have a plurality (i.e. two or more) reaction regions, and may have rows and columns in arrangements of about 8 x 12, and multiples thereof (i.e. 16 x 24, 32 x 48, etc.), or arrays of about 10 x 10, and multiples thereof (i.e. 100 x 100, 1000 x 1000, etc.).
  • the number and arrangement of the reaction regions depends upon the particular application involved, and are known or easily determined by one of ordinary skill in the art.
  • the substrate may be part of an apparatus optionally comprising an array cover, an array, a reaction stage, and/or means for attaching the array cover, the array, and the reaction stage.
  • the array cover may comprise one or more gas manifolds.
  • the array cover may have an array of gas manifolds, disposed over each of the individual reaction regions.
  • the gas manifolds may be used to introduce a gaseous reagent or other gas into the wells of the array, provide an inert atmosphere, remove gaseous side-products from the wells and/or provide a vacuum to the wells.
  • the apparatus may further comprise means for controlling the temperature of the wells.
  • means for controlling the temperature of the wells may be incorporated into any combination of the array cover, the array, or the stage.
  • the reaction stage may comprise means for heating, such as individual thermocouples or a heating block.
  • the array may further comprise one or more thermal channels, or an array of thermal channels, which are used to regulate the temperature inside the wells.
  • the thermal channels may be metalized for resistive heating, or doped with a material selected from the group consisting of boron, phosphorus, or arsenic, among others.
  • the thermal channels may contain a fluid or gas, which is used to regulate the temperature.
  • the thermal channels contain a coolant, such as nitrogen, air, water, methanol, hydrocarbons, or halogenated hydrocarbons, which permits the reactions within the wells to be run at a desired temperature.
  • the reactions within each well can run under isothermal conditions.
  • the thermal channels allow for the study of different reaction temperatures in different reaction regions of the same substrate.
  • the thermal channels may be aligned parallel to at least one row or column, or may define a checkerboard pattern around the wells of the array.
  • the array can be easily interchanged between different stations or analytical instruments without requiring transfer of compounds or components of the library from the array. This feature of the array reduces sample preparation and sample transfer steps.
  • the invention comprises methods for the analysis and/or synthesis of polymers and catalysts.
  • a polymerization reaction is carried out by delivering a monomer or mixture of monomers to reaction regions on a substrate.
  • solvent, one or more catalysts, co-catalysts, activators, etc. may be delivered to the reaction regions as well.
  • the monomer or mixture of monomers is selected from any commercially or synthetically available monomer starting material. As discussed below, at least one of the monomers contains a radiolabel.
  • Monomers containing radiolabels may be either commercially available, or synthetically produced from commercially available reagents and/or starting materials containing a radiolabel.
  • the monomer or mixture of monomers used in the invention are typically selected from a variety of linear olefins, branched olefins, cyclic olefins, diolefins, and aromatic olefins.
  • Examples of these include, but are not limited to: ethylene, propylene, cis-2-butene, butadiene, 1-hexene, 1- octene, 1-butene, 3 -methyl- 1-butene, 1,3-butadiene, 1-pentene, 4-methyl-l-pentene, 1- hexene, 4-methyl- 1-hexene, 1,4-hexadiene, 1,5-hexadiene, 1-octene, 1,6-octadiene, 1- nonene, 1-decene, 1 ,4-dodecadiene, 1-hexadecene, 1-octadecene, cyclopentene, 3- vinylcyclohexene, 5-vinyl-2-norbornene, 5-ethylidene-2-norbornene, dicyclopentadiene, 4- vinylbenzocyclobutane, tetracyclododecene, dimethano-oct
  • the invention relates to methods for determining the amount of incorporation of a reagent into a specialty chemical, i.e. a fine chemical, or a performance chemical.
  • a fine chemical is a pure, single substance produced by a chemical reaction.
  • Fine chemicals encompass a broad category of chemicals, including but not limited to: basic building blocks, advanced intermediates, pharmaceuticals, standard bulk compounds, cosmetic ingredients, food additives, household chemicals, agricultural products, pesticides, analytical chemicals, dyes and stains, and photographic chemicals, for example.
  • Performance chemicals are typically mixtures of substances, proprietary products, and formulated with carriers or solvent. See Stinson, S.C., ''Pharmaceutical Fine Chemicals", Chemical &Engineering News, 78(28):63-80 (2000).
  • specialty chemical does not include large biomolecules, i.e. polynucleotides. However, pharmaceuticals including small molecule peptides are considered specialty chemicals.
  • specialty chemicals, fine chemicals and performance chemicals can also be synthesized and then analyzed using radiography.
  • commercially available fine chemicals are usually sold in a pure form as a single compound, for the purposes of this invention, it is permissible to perform analysis of the fine chemical, although there may be solvent, side products, or other compounds in the reaction region. Thus, the fine chemical does not necessarily have to be purified prior to the analysis step.
  • the invention comprises providing a substrate having a plurality of reaction regions, as described above.
  • a first reagent, and a second reagent are delivered to a reaction region, where at least one of the first reagent or second reagent is a radiolabeled reagent.
  • solvents, one or more catalysts, co-catalysts, activators, etc. may be added.
  • the reagents may be selected from any commercially available and/or synthetically available reagents. Appropriate reagents and reaction conditions are known to one of ordinary skill in the art, or may be determined by routine experimentation.
  • a radiolabel is an isotope which is radioactve.
  • a radioactive isotope will undergo nuclear transformation, emitting energy in the form of , ⁇ , or ⁇ rays. Radioactivity is generally not affected by the physical state, temperature, pressure, or chemical combination of the element.
  • the radioactivity of a nuclide is characterized by the nature of the radiation, the energy, and the half-life of the process, i.e. the time required for the activity to decrease to one half of the original. Half-lives vary from microseconds to millions of years. To be effectively used as a radiolabel, the radioisotope must display a half-life appropriate to the particular process being used.
  • the half-life must usually be long enough to complete the polymerization, reaction or adsorption steps, and the analysis steps.
  • Suitable radiolabels can be selected depending on the particular reaction or polymerization to be studied. Information regarding the half-lives of radioisotopes, modes of decay, decay energies, etc. may be found in various handbooks; see Robert C. Weast, Editor, CRC Handbook of Chemistry and Physics, 64th Edition, CRC Press, Boca Raton, Florida (1983), which is hereby incorporated in its entirety.
  • Typical radioisotopes which may be used as the radiolabel include, but are not limited to, 3 H, 14 C, 125 1, 85 Kr, 222 Rn, 125 1, 33 P, 32 P, 35 S, 36 C1, and combinations of these.
  • the radioisotope used as the radiolabel is 3 H and/or 14 C, which have half-lives of about 12.26 years and 5730 years respectively.
  • radiolabeled compounds In additional to commercially available reagents and starting materials, it is also possible to synthesize radiolabeled compounds, using commercially available starting materials and reagents. Standard organic chemistry techniques may be used to synthesize a variety of radiolabeled reagents from commercially available starting materials and reagents.
  • radiolabeled comonomers may be prepared from commercially available isotopically enriched alcohols, as shown in the following scheme, where the radiolabeled carbon is indicated by the asterisk (*):
  • the catalyst may be any chemical compound that accelerates or initiates chemical reactions.
  • Typical catalysts may be inorganic, organic, or a complex of organic groups and metal halides.
  • the catalyst may be selected from a wide variety of catalysts including, but not limited to: acids, bases, mixed metal oxides, mixed metal nitrides, mixed metal sulfides, mixed metal carbides, mixed metal fluorides, mixed metal silicates, mixed metal aluminates, mixed metal phosphates, noble metals, zeolites, metal alloys, intermetallic compounds, inorganic mixtures, inorganic compounds, inorganic salts, radical catalysts, cationic catalysts, anionic catalysts, anionic coordination catalysts, and mixtures thereof. See Richard J. Lewis, Sr., Hawley's Condensed Chemical Dictionary, Thirteenth
  • Typical catalysts which may be used in the invention, include but are not limited to: Ziegler-Natta catalysts, metallocene catalysts, stereospecific catalysts, constrained geometry catalysts, single-site catalysts, late transition metal single-site catalysts, free radial initiators, living free radical initiators, cationic initiators, anionic initiators, co-ordination complexes and mixtures thereof.
  • the catalysts are supported catalysts.
  • the solid support material may include any material known to one of ordinary skill in the art.
  • Typical supported catalysts, and methods of making and using precipitated catalyst supports in polymerization processes are known to those of ordinary skill in the art, and are described, for example, in U. S. Patent Nos. 5,747,407; 5,206,314; 5,081,090; 4,946,816;
  • Typical solid support materials include, but are not limited to: porous resinous materials selected from the group consisting of copolymers of styrene-divinylbenzene, or solid inorganic oxides, selected from the group consisting of silica, alumina, magnesium oxide, magnesium chloride, titanium oxide, thorium oxide, mixed oxides of silica and one or more Group 2 or 13 metal oxides.
  • the solid support material is selected from the group consisting of silica-magnesia and silica-alumina mixed oxides, or from the group consisting of silica, alumina, and mixed oxides of silica and one or more Group 2 or 13 metal oxides.
  • the invention also provides methods for analysis of the catalysts in the polymerization and synthesis reactions. For instance, the productivity and/or activity of the catalyst may be also measured.
  • the productivity of the catalyst is the polymer or product per unit of catalyst.
  • Activity is polymer per unit of active catalyst sites.
  • the invention provides a convenient means for determining the productivity and/or activity of catalysts.
  • the catalysts may be analyzed based on the heat produced during the reaction, i.e. monitoring the reaction using calorimetry or thermography.
  • the catalysts may also be studied, based on the amount of heat absorbed during the reaction; for a discussion of IR- thermographic screening of thermoneutral or endothermic transformations, see Reetz, M. T. et al., Angew. Chem. Int. Ed. 39(7): 1236-1239 (2000).
  • the activity and productivity of the catalysts may also be determined by the radioactivity of the final product.
  • the radioactivity is directly correlated to the activity of the catalyst.
  • the invention may be used to study whether different catalysts incorporate different ratios of reagents or starting materials.
  • different ratios of reagents may be incorporated in the final product.
  • each catalyst may incorporate different proportions of monomer or comonomer in the resulting polymer.
  • the total amount of the specialty chemical or polymer product is determined, and the amount of radioactivity is measured. By measuring the radioactivity of the product, it is possible to determine the relative amount of radiolabeled reagent that is incorporated into a specialty chemical, or in the case of polymerization reactions, it is possible to determine co-monomer content.
  • radiolabeled monomers or reagents by using two or more different radiolabeled monomers or reagents, it is also possible to determine co-monomer content in a copolymer, or the ratio of reagents incorporated in a specialty chemical.
  • different reagents or monomers comprise a different radiolabel. By measuring the radioactivity corresponding to each radiolabel, it is possible to determine the relative amounts of each corresponding monomer or reagent in the resulting product, i.e. the polymer or specialty chemical.
  • the reagent or monomer including the radiolabeled reagent or monomer, may be delivered to the reaction regions by any means known in the art.
  • any catalyst, co-catalyst, activator, solvent, etc. as required may be delivered to each of the reaction regions, either manually or through an automated system. Typical delivery systems include pipette and other dispensers.
  • the reagent may be delivered by one or more gas manifolds, positioned over the reaction regions.
  • the monomer or mixture of monomers are polymerized under conditions sufficient to form a polymer.
  • the polymerization step may be carried out under suitable reaction conditions, as known to one of ordinary skill in the art, e.g. a gas phase polymerization, a slurry phase polymerization, solution polymerization, or an emulsion polymerization.
  • the polymerization reaction may typically require initiators, activators, heat and/or light.
  • the polymerization reaction may be run under high pressure.
  • the polymerization reaction may be carried out (1) in the gas phase, typically at high pressures and temperatures of greater than 50°C, (2) in solution at normal to high pressure and at normal to high temperatures, typically from about 0°C to about 70°C, (3) in slurry, typically at normal to high pressures, and at temperatures ranging from about 50°C to over 200°C, or (4) in emulsion form, typically at normal pressures, and at temperatures from about -20 to about 60°C. See Richard J.
  • the polymerization step in each reaction region may be carried out either in parallel, or sequentially.
  • the polymers produced may be transferred to a second array for analysis, or in a preferred embodiment, the array that was used for the polymerization step is also used for the analysis step, described below.
  • the invention also applies to an embodiment for the synthesis and analysis of specialty chemicals.
  • the first and second reagents, and optionally any catalysts, cocatalysts, activators, solvent, etc. as required are exposed to conditions sufficient to form a product. Suitable reaction conditions depend upon the reaction, and are apparent to one of ordinary skill in the art. The reaction steps may be carried out either in parallel or sequentially.
  • the specialty chemicals may be made by a variety of reactions known in the art, whereby at least one radiolabeled reagent is monitored, either by incorporation into a product, or by disappearance from a starting material.
  • Typical reactions include, but are not limited to the following: condensation, decomposition, oxidation, reduction, combination, replacement, hydrolysis, hydrogenation, hydro silylation, hydrocyanation, hydroformylation, carbonylation, metathesis, cross coupling, hydration, dimerization, enolization, saponification, covalent interactions, ligand binding, hydroboration, hydrohalogenation, and combinations of these.
  • addition reactions include hydrogenation, hydroboration, hydrohalogenation, hydroxylation, hydroformylation, halohydrination, alkylation, carbene addition, dihalo carbene addition, carbonylation, epoxidation, aziridination, and combinations of these.
  • Preferred reactions include catalytic hydrogenation, carbonylation, hydroformylation, epoxidation, and aziridination, as examples. This list is not meant to be exclusive. One of ordinary skill in the art can apply the methods of this invention to other suitable reactions.
  • the reactions may be conducted using any combinatorial and high-throughput processes known in the art.
  • the synthesis may create mixtures of compounds, or arrays of individual compounds in each reaction region of the substrate. In cases where mixtures of compounds are synthesized, screened and/or characterized, there is often also a method of identifying compounds of interest. These methods may be either spatial, (such as through spatially addressable synthesis or chemical encoding), or systematic, (such as through a series of deconvolutions).
  • Spatially addressable synthesis refers to the generation of an array of compounds where each reaction well comprises an individual reaction product or compound.
  • Chemical encoding may take the form of a number of inert chemical tags to identify each compound.
  • Iterative deconvolution involves the identification of the most active mixture, followed by fixing some specific part of the molecule and making a smaller library; this process is repeated until a single compound is identified.
  • Other deconvolution, positional scanning, and encoding methods are known in the art. See Wilson, S.R. and Czarnik, A. W., Eds., Combinatorial Chemistry, John Wiley & Sons, New York, 1997, which is hereby incorporated in its entirety.
  • radiolabeled reagents may be removed by any means known in the art, including applying a vacuum, or by flushing the reaction regions with an inert fluid (such as argon or helium gas) or using a solvent, until no radioactivity is detected in the exit gas or wash solution.
  • an inert fluid such as argon or helium gas
  • any volatile solvents, and unreacted starting materials or reagents may also be removed.
  • the invention may also be practiced without necessarily having to remove excess radiolabeled compounds.
  • the radioactivity is incorporated into the product in the reaction region, it is then possible to monitor, over time, the amount of radioactivity that is incorporated into the polymer, specialty chemical, or porous catalyst. Using this method, it is possible to monitor either an increase or decrease in the amount of radioactivity in the reaction regions over time.
  • the same array is used for both the synthesis and analysis steps, since this avoids time-consuming and possibly expensive transfer and handling steps.
  • one or more steps are automated.
  • the invention may be carried out in a workstation, where one or more of the materials, i.e. starting materials, catalysts, co-catalysts, activators, solvents, reagents, etc., is delivered using an automated system.
  • an automated system For example, a number of pipetters and robotically or computer controlled workstations are known in the art. Such systems may be also programmed to dispense specified quantities of compounds into certain reaction regions at certain times, over the course of the reaction.
  • the analysis of the products may also be carried out using an automated system.
  • the entire substrate may be transferred between a number of workstations, each designed for a different type of analysis technique.
  • This embodiment provides a method for characterizing many different properties of the products, in an efficient manner that does not involve sample handling or transfer steps.
  • Such a workstation has been described in co-pending U.S. Provisional Application No. 60/167,227 filed November 24, 1999; the disclosure of which is hereby incorporated by reference.
  • the compounds may be analyzed for radioactivity.
  • Radioactivity can also be detected and measured using a Geiger counter, where the ions and electrons produced by the ionizing radiation permit conduction of an electrical current, which can be correlated to the amount of radiation produced.
  • a scintillation counter may be used to detect and measure fluorescence caused by radiation, and thereby the radiation that causes it.
  • radioactivity is measured using an autoradiograph. Digital autoradiography equipment is commercially available.
  • Typical autoradiographs which are used in this invention include those commercially available from sources such as EG&G Berthold, Gaithersburg, Maryland. Typical models used include, but are not limited to the LB 287 Digital autoradiograph, and LB 285 and LB 284 Linear Analyzers. Some recent advances are described in Lees, J. E., Fraser, G. W., Carthew, P., Nucl. Instr. Meth. A., 40 (1998).
  • the step of measuring the radioactivity of the product may be performed in parallel or sequentially, and/or may be automated.
  • the radioactivity provides a measure of the productivity and/or activity of the catalyst.
  • the productivity of the catalyst is the polymer or product per unit of catalyst.
  • Activity is polymer per unit of active catalyst sites.
  • the total radioactivity of the final product can provide a measure of the total amount of polymer or specialty chemical produced, i.e. the yield of the reaction. In an embodiment where the amount of catalyst in each reaction region is the known, the radioactivity can then also be correlated to the productivity of the catalyst.
  • the productivity of the catalyst activity or productivity may be monitored during the course of the reaction by measuring the amount of heat emitted or absorbed, e.g. using thermography or calorimetry.
  • the catalyst activity i.e. measured by reaction calorimetry or thermography, may then also be used to calculate the mass of the polymer or specialty chemical produced.
  • the change in radioactivity can be monitored over time, providing kinetic rate data, for example.
  • the total mass of the product is determined by methods known in the art, i.e. by calculations based on the catalyst activity or productivity, or by direct measurement of the product. Once both the radioactivity measurement, and the total mass of the product is known, the ratio of the radiolabeled comonomer in a copolymer (i.e. the comonomer content), or the ratio of the radiolabeled reagent incorporated into the product may also be determined.
  • the same amount of catalyst is provided to each reaction region, and the total amount of radioactivity in the final product provides a direct comparison of the productivity of the catalyst.
  • the autoradiograph will also show the relative amounts of radioactivity in each of the reaction conditions, which is particularly useful for optimizing reaction catalysts and/or reaction conditions.
  • radiolabeled monomers or reagents by using two or more different radiolabeled monomers or reagents, it is also possible to determine co-monomer content in a copolymer, or the ratio of reagents incorporated in a specialty chemical.
  • different reagents or monomers contain different radiolabels. By measuring the radioactivity corresponding to each radiolabel, it is possible to determine the relative amounts of each corresponding monomer or reagent in the resulting product, i.e. polymer or specialty chemical.
  • the substrate containing the products may be placed into one or more other instruments, for analysis of the products, either before or after measuring the radioactivity.
  • Several of these analytical methods may be performed before measuring the radioactivity, without affecting the measurement of the radioactivity.
  • the analytical instrument used may be selected from any analytical instrument that is known in the art, including but not limited to: a reaction calorimeter (i.e. used during a polymerization or reaction step), a differential scanning calorimeter, a viscosity sensor, or a mass spectrometer.
  • Typical techniques to be used with this invention include, but are not limited to: calorimetry, mass spectrometry, viscosity measurement, thermogravimetric analysis (TGA), polarimetry, imaging polarimetry, infrared spectroscopy, IR imaging, reflectance spectroscopy, uv-vis spectroscopy, chemisorption, surface area (BET) measurements, uv-vis fluorescence, phosphorescence, chemiluminescence, Raman spectroscopy, near IR spectroscopy, magnetic resonance imaging, NMR spectroscopy, Electron Spin Resonance (ESR) spectroscopy, gas chromatography, high performance liquid chromatography (HPLC), gel permeation chromatography (GPC), temperature rising elution fractionization (TREF), x-ray diffraction, neutron diffraction, refractometry, circular dichroism, turbidimetry, electron spectroscopy, scanning electron microscopy (SEM), transmitting electron microscopy (TEM),
  • the invention also relates to a method for the analysis of porous catalysts. For instance, according to the invention, the surface area, the number of active sites and/or metal sites, the number of acidic or basic sites, the pore size distribution, and the exchange rate of different adsorbed species and/or diffusion rates of adsorbed species can be determined.
  • This embodiment of the invention comprises the step of providing a substrate having a plurality of reaction regions, as described above. Next, a porous catalyst is delivered to the reaction regions.
  • the porous catalysts may be the same or different, depending on the process to be studied.
  • the invention provides a method for comparing properties of different porous catalysts. However, it is also possible to study the same catalyst, under different conditions in the reaction regions, i.e. different reagents, different amounts of activators or co-catalysts, different temperatures, etc.
  • the porous catalyst may be any supported catalyst, as discussed previously, which contains channels or open spaces.
  • the channels may be microscopic or macroscopic, and there may be a variety of different size pores.
  • the porous catalyst may further comprise naturally occurring and synthetic zeolite materials, typically comprising aluminum and silicon, and additionally boron, gallium, zirconium, titanium and trivalent metals heavier than aluminum. Additional materials may be deposited on the porous catalyst using techniques known in the art, i.e. impregnation, precipitation techniques or ion exchange. In a wet impregnation technique, the support pellets are presaturated with a solvent and immersed in the agitated solution of an active component of a certain concentration.
  • the porous catalyst may comprise other clays, clay oxides, silica and/or metal oxides.
  • zeolites, pillared clays and molecular sieves are used.
  • inactive materials may be incorporated into the porous catalyst in order to control the rate of reaction.
  • a radiolabeled compound is delivered to said reaction regions under conditions sufficient for the radiolabeled compound to be adsorbed by the porous catalyst.
  • Typical radiolabeled reagents for such uses include Rn, Kr, and various radiolabeled hydrocarbons, such as methane, propane, ethane, cyclopropane, and others.
  • the radiolabeled compound may be delivered, either in parallel or sequentially.
  • the radioactivity of the catalyst in each region may be detected and/or measured.
  • the radioactivity of the catalyst can then be correlated to a number of physical properties, e.g., the surface area and/or the number of active sites of the porous catalyst may be determined.
  • the radioactivity may be detected using an autoradiograph, for instance, and the detection step may be conducted either in parallel, or sequentially.
  • the method may be automated.
  • the invention also relates to an embodiment for determining the pore size distribution.
  • This method comprises the steps of providing an array comprising a plurality of reaction regions, and providing a porous catalyst to the reaction regions.
  • a mixture of radiolabeled compounds is delivered to the reaction regions under conditions sufficient for said radiolabeled compound to be adsorbed by the porous catalyst.
  • the mixture of radiolabeled compounds comprises compounds having different molecular sizes, and wherein compounds of different molecular sizes have a different radiolabel.
  • mixtures of radiolabeled hydrocarbons of varying molecular size and shape, such as methane, ethane, propane, cyclohexane, etc. may be used. Volatile or gaseous compounds are generally preferred. Any excess radiolabled compounds are removed from the porous catalyst in the reaction regions.
  • a method for determining the exchange rate of an adsorbed species adsorbed to a porous catalyst is provided.
  • An array comprising a plurality of reaction regions is provided, and a porous catalyst is also provided to the reaction regions.
  • the porous catalyst has a first radiolabeled compound adsorbed by the porous catalyst.
  • the porous catalyst may either be delivered to the reaction region with the first radiolabeled compound already adsorbed, or the porous catalyst may first be delivered to the reaction region, and then the first radiolabeled compound will be delivered and, under appropriate conditions, adsorbed by the porous catalyst.
  • a second radiolabeled compound is provided to the reaction regions under conditions to allow a second radiolabeled compound to displace the first.
  • the increase or decrease in the amount of radiation associated with the first radiolabeled absorbed compound and/or the second absorbed species is measured.

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Abstract

L'invention porte sur des procédés recourant à la radiographie pour l'analyse de composés chimiques tels que des polymères, des spécialités chimiques et des catalyseurs, et en particulier sur des procédés exécutables en fort parallélisme en vue de la synthèse et de l'analyse de composés chimiques, avec un rendement élevé ou de manière combinatoire. L'invention prévoit à cet effet un substrat comportant plusieurs zones de réaction, puis des étapes de polymérisation, synthèses ou adsorption exécutées avec ou sans réactifs radiomarqués. La radioactivité des produits résultants fournit une mesure de différentes propriétés physiques. Le procédé de l'invention peut par exemple servir à déterminer la teneur en comonomères de polymères, la productivité de catalyseurs et/ou l'incorporation d'un réactif dans une spécialité chimique. En outre, l'invention prévoit des moyens de déterminer différentes propriétés chimiques et physiques de catalyseurs poreux dont la surface efficace, le nombre de sites actifs, le nombre de sites acides ou basiques, la distribution en taille des pores, et la chimiosorption.
PCT/US2000/030720 1999-11-09 2000-11-09 Criblage et analyse radiographiques de polymeres, de specialites chimiques et de catalyseurs WO2001034660A2 (fr)

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CN105116013A (zh) * 2015-04-23 2015-12-02 山东农业大学 一种确定金属离子对蛋白酶水解大豆分离蛋白影响的方法

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EP1336429B2 (fr) † 2002-02-19 2011-09-28 Basell Polyolefine GmbH Procédé à haut débit pour déterminer la qualité des catalyseurs de polymérisation
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US7998418B1 (en) 2006-06-01 2011-08-16 Nanotek, Llc Evaporator and concentrator in reactor and loading system
US7854902B2 (en) 2006-08-23 2010-12-21 Nanotek, Llc Modular and reconfigurable multi-stage high temperature microreactor cartridge apparatus and system for using same
US7797988B2 (en) 2007-03-23 2010-09-21 Advion Biosystems, Inc. Liquid chromatography-mass spectrometry
CN105116013A (zh) * 2015-04-23 2015-12-02 山东农业大学 一种确定金属离子对蛋白酶水解大豆分离蛋白影响的方法

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