DE10125126A1 - Integrated miniaturized chemical laboratory used in chemical and biochemical research, has a device for acquiring the detection of the material on a detector surface or detector volume - Google Patents

Abstract

Integrated miniaturized chemical laboratory comprises reactors for carrying out parallel reaction processes; analyzing devices each having a detector surface or detector volume for detecting a material in the reaction product; and a device (54) for acquiring the detection of the material on the detector surface or detector volume. An Independent claim is also included for a process for analyzing the reaction products obtained in the miniaturized chemical laboratory.

Description

Background of the Invention

The invention relates to an integrated miniaturized chemical laboratory with a A large number of reactors for carrying out parallel reaction processes and one Analysis device for analyzing at least one emerging Reaction product that a detector area or a detector volume to Detecting at least one substance in the reaction product. Further The invention relates to a method for analyzing a reaction product, which in an integrated miniaturized chemical laboratory with a parallel one The reaction process is created in a large number of reactors, with the step: feeding of the reaction product to a detector surface or a detector volume for Detect at least one substance in the reaction product.

Chemical and biochemical research and development includes complex ones Operations that often involve a high proportion of manual and specialized activities Require skills. So a typical synthesis contains in a traditional one Laboratory operations such as weighing, building equipment, filtration or distillation. The same applies to the determination of chemical and biological Properties of newly obtained reaction products. So both are Making new compounds or new catalysts with useful ones Properties as well as their chemical analysis are long and tedious expensive.

Attempts have been made for some time to deal with the complexes mentioned above Activities of traditional laboratories in miniaturized and automated form to integrate on a planar substrate. The facilities formed are a laboratory integrated on a microchip, "lab-on-the-chip", chip laboratory or microfluidic device.  

Another area where chemical information is efficiently obtained combinatorial materials and catalysis research.

The complex process of robots has recently been tried with the help of robots Material and catalyst development up to characterization too automate.

From WO 99 41 005 it is known e.g. B. known, a larger number at the same time Microreactors in one block under certain reaction conditions operate. The reaction conditions in such reactors can be those get quite close to conventional reactors. Both in the chemical and biochemical research and development as well as in combinatorial However, materials and catalysis research exists especially at chemical analysis very high requirements that have not yet been solved.

WO 00 29 844 describes the analysis of a product with a screened Mass spectrometer known. From US 5,959,297 A it is known that this type of Combine analytics with laser heating of a planar catalyst field. Methods with rastered mass spectrometers are restricted that a certain amount of product has to be taken in for analysis. This serial method of working goes a long way in a complex analysis cycle Lost time. Typical measuring times per microreactor have so far been at least 5 to 30 seconds. In addition, it allows the in US 5,959,297 A. described method does not, the catalyst field longer with reactants act to the temporal development of the reaction processes investigate. Many organic products produce overlapping Fragmentation pattern. Simple, so-called quadrupole Mass spectrometers limited in their mass resolution. A clear analysis Organic product mixtures in particular are therefore considerably more difficult.  

Gas chromatographic separation processes are known, which are flexible enable the analysis of product mixtures. These procedures are described in Devices that are used individually and serially product streams of different Reactors are metered supplied. This is complicated and wear-prone valves necessary, currently a maximum of 16 flows each can switch. Gas chromatographs have a relatively long life Analysis time, for example at least 3 to 5 minutes per reactor for Hydrocarbon mixtures, which due to serial processing too undesirably long analysis times of several hours per analysis cycle can lead.

From WO 97 32 208 and US 6,063,633 A different types of Activity determination in heat-producing reaction processes known. The reaction processes themselves are really parallel with an infrared camera displayed. With this method, however, only a relative statement about the Heat emission of reactive areas of the reaction process are made, but not about the product range of the reaction process.

From WO 00 29 844 it is also known to use product-specific information to obtain a resonant multiphoton ionization by means of laser (REMPI). However, this method is based on very few substances, such as. B. restricted to benzene show a suitable ionization behavior in laser light. So it can be done in parallel are analyzed, but only for a few molecules.

DE 196 32 779 A1 is a serial spectral product analysis in one Gas phase known by means of infrared spectroscopy in a reactor block. With this Art analysis makes it difficult to mix individual products from a product mix identify so that the scope is based on very simple product mixtures remains limited.

From EP 0 971 225 A2, which is considered the closest prior art, is a method for the detection of a product in the downstream of a catalytic  Materials known in a reactor block. In doing so, all product flows are based on carried an adsorbent which selectively reacts selectively with the product, z. B. by color change. This procedure relates to the detection of a each known product and is therefore for comprehensive analysis typical product mixtures not suitable.

Underlying task

The object of the invention is to overcome the disadvantages mentioned above overcome and in particular an integrated miniaturized chemical laboratory and a method for analyzing at least one reaction product create with which a simplified analysis of reaction products possible is.

Solution according to the invention

This task is according to the invention with an integrated device mentioned at the beginning miniaturized chemical laboratory solved in which an image processing Device for determining the detection of the substance on the detector surface or the detector volume is provided. Furthermore, the task with one described method solved, in which the detection of the substance with a image processing facility is determined.

In principle, any type of reactor is for the miniaturized laboratory according to the invention suitable in which chemical processes take place and from which small amounts of gaseous or liquid reaction product can be removed. In In this context, the term reaction process is used regularly understood a large number of reactions, for example in the form of a Chain reaction take place. Image processing equipment means in this Context that the establishment is one or more individual and / or one Sequence of image recordings with regard to their information content and / or one Can detect and evaluate changes in the information content. This  means that in addition to a corresponding camera system also a Evaluation system, usually in the form of an appropriately programmed Computers, is provided.

It is particularly important in the invention that the reaction product and not only the reaction processes themselves are observed. The reaction product is fed to a detector surface or a detector volume, on which or which uses an optical method to detect at least one substance is determined. For this purpose, the detector surface is advantageously designed such that it is on the substance to be analyzed by changing an optically recognizable property responding. In particular, the response behavior of the detector surfaces is designed that parallel image processing is also possible for a large number of detectors. The image processing is optionally done by direct imaging of the optical Behavior of the detectors mentioned or by multispectral analysis of the respective detector surfaces. For example, a CCD Camera are used.

The device according to the invention and the method are distinguished by that no complex between the detectors and an evaluation circuit and fault-prone electrical connections are required. This reduces costs while increasing the reliability of the miniaturized laboratories according to the invention. In selected cases it is possible, detectors with detector areas or detector volume for single use to use.

In the laboratory according to the invention, detectors can be exchanged very easily which also significantly increases the time to prepare the analysis shortened. This is particularly useful for detector areas that age quickly, such as z. B. highly selective organic or biological detector surfaces.

Furthermore, the laboratory according to the invention allows that as an image processing system conventional hardware and software can be used. this means  a huge advantage in terms of the cost of evaluating the optically determined data.

The miniaturized laboratory described here enables more efficient analysis parallel reactions. The laboratory requires only a very small amount of energy and no hydrogen or oxygen like flame ionization detectors, so that in principle mobile concepts can also be realized.

Advantageous developments of the invention

In an advantageous development of the invention, there are a large number Analysis devices are provided, each of which is individually assigned to a reactor, This is real parallel analysis with an identification of Reaction products possible. In particular, the detector surfaces or Detector volume of the large number of analysis devices in total image processing facility captured. Thus, with a single image processing facility with regard to a miniaturized laboratory as a whole the analysis of the resulting reaction product can be evaluated. by virtue of of today's commercially available image processing facilities existing extremely high number of pixels (for example 500 × 500 Pixels), the reaction product streams can in principle exceed 10,000 Reactors are tracked simultaneously. This means an enormous advantage compared to the approximately 100 reactors used in conventional high-throughput Analysis methods usually have to be examined serially. The frame rates Today's image processing facilities easily leave more than 5 images per second too. Through the method further developed according to the invention, the Efficiency in analytics can easily be increased by a factor of 10,000.

The detector surfaces mentioned are advantageously designed as adsorption surfaces, each with a receptor for adsorbing a substance from the reaction product. Adsorption binds the substance to be analyzed from the reaction product to the detector surface at least for a short time, the adsorption surface being designed in such a way that an optically determinable property changes. A short optical signal is produced which is registered by the image processing device at the corresponding location on the detector surface. The chemical selectivity of the analysis devices can be further increased by providing several chemically differently selective detector surfaces on the individual detectors. The number of pixels of today's image processing devices is sufficient to direct a larger number of pixels onto a single detector. For example, a CCD camera with 500 × 500 pixels with 400 reactors and corresponding 400 associated detectors can observe each individual detector with 20 × 20 pixels. These 20 × 20 pixels can easily represent, for example, 6 × 6 chemically and structurally different types of detector surfaces. Each detector can therefore have 36 different detector areas. By appropriately selecting differently selective materials of the detector surfaces and appropriately designed image processing software, sufficient selective detectors are made available for a large number of catalytic analyzes. The enormous advantages in terms of the efficiency of the analysis compared to conventional methods are obvious.

With regard to the construction of the detector, the composition is particularly important of the material of the detector surface is crucial. Advantageously, the Detector surface a molecular, inorganic, organic and / or biological receptor, the material of the receptor in particular flowing reaction product interacts. Alternatively or in combination the detector surface has a polymer and / or a porous host, in particular Zeolite, and / or a microporous and / or a mesoporous host. Zeolites have ion exchange properties and molecular sieve behavior. Zeolites and other porous hosts also have a defined one crystalline pore structure, the size of the pores being adjusted in this way can be molecularly selective. This also results in molecular selective receptor properties.  

In an advantageous development of the invention, the polymer or mentioned host a dye, in particular a salvatochromic dye introduced, its optical behavior by changing the surrounding molecular phase is changed. In particular, several different ones Pore structures with encapsulated dyes can be provided so that chemical and shape-selective molecular sieves can be used. Organic or organometallic dyes are used here as salvatochromic dyes Dyes (e.g. Nile Red or Porphyrins) understood the salvatochrome effects produce. These dyes are characterized in that their absorption or fluorescence spectra strongly influenced by the nature of a solvent become. So the spectral shift of the solvatochromic dyes exceeds when changing from non-polar to polar media in some cases 100 nm Absorption or fluorescence spectra of these dyes are also then by the presence of an analyte, e.g. B. influenced by analyte vapors, if they are located in the nanoscale channels or cages of porous hosts. In particular, the local environment at the host is designed so that adsorbed analyte, for example solvent, the dye molecule as well as possible can solvate so that the analyte-dye solvation via the host Dye interaction dominates. With zeolites, this is certain Cases advantageous if preferably unloaded grids are used, such as they z. B. occur in silicon-exchanged faujasite. The special form of the Adsorption isotherms of the nanoporous materials already leads to a relatively low external partial pressure Adsorption can be demonstrated. With the detector, this means that the dyes stored in the host are surrounded by the analyte. So it results high sensitivity of the detector. Additionally or alternatively you can fluorochrome effects and fluorescence quenching of fluorescent dyes, such as z. B. from the Coumarin family.

The dyes can be applied to or on the detector surfaces be chemically bound. Alternatively or additionally, they can be integrated into one Polymer film embedded or introduced into the porous film as a host. On  The advantage of introducing the dyes into a porous host lies in the additional available molecular selectivity. The pore size of the host limits that Type of molecules that diffuse into the host and with the dye can interact. So it's additionally a selectivity regarding certain molecular sizes possible. This is particularly the case with complicated ones Reaction products useful, of which only certain molecules are of interest.

Even higher demands are placed on the chemical selectivity of the detectors by combining several detector areas with different dyes and different responses or embedding the same Dye in various materials, such as. B. different swellable Polymers or different pore zeolites, met in a detector field. On Such a detector field has, for example, 64 detector areas, so-called Miniature pixels, which are then used individually to identify and quantify the Reaction products serve. Using appropriate image processing software this also makes it possible to quantify complex reaction products.

As already indicated above, the image processing device according to the invention works Establishment advantageous on the principle of direct mapping or Spectral analysis of the detector area or the detector volume, wherein in particular, a light guide can be used to transmit light radiation can. The light guide is attached to the detector surfaces in a suitable manner Detector volume brought up, so that both absorption and Fluorescence spectra can be recorded. In addition, the image processing device can be combined with color filters.

In a further embodiment, the invention determines image processing device a vibration spectrum, in particular a Raman and / or infrared spectrum, the detector area and the Detector volume. In particular, for Raman spectroscopy substances adsorbed or flowing past the detector surfaces with laser light stimulated. The emitted by the detector surfaces or the detector volume  Raman scattering is either applied directly to a CCD after a filter process Imaged camera, or through light guides, such as. B. glass fibers, to the gap one Monochromators guided and for each detector area or each detector volume spectrally split. Infrared light is used for infrared spectroscopy Infrared-transparent light guide to the detector surface or the detector volume introduced and either the diffusely scattered light or that after transmission light remaining through the detector surface or the detector volume a two-dimensional infrared detector of a camera is detected. For analysis of the spectral properties of the detected infrared light Light guides emerging light guide advantageously on the gap of a monochromator mapped and spectrally decomposed before it is detected on the infrared detector. Alternatively, the infrared light can also be modulated and adjusted by an interferometer Interaction with the detectors in parallel in a two-dimensional IR Detector can be detected.

If the reaction products to be examined are liquids acts, these can be separated by liquid chromatography. Because of the In this case there is no high density of liquids on the detector surfaces porous host required. Raman spectroscopic or infrared spectroscopic the liquid itself, which is currently on the detector, is examined.

Raman spectroscopy has the advantage that biomolecules can easily be found in water can be determined and that because of the typical excitation with visible Light also simple materials, such as B. Glass for windows and substrates can be used. This enables inexpensive disposable detectors and in addition, simple measurements even at high temperatures. Will continue a relatively good one because of the shorter wavelength of the excitation light Local resolution reached. There are two for spatially resolved Raman spectroscopy Approaches: On the one hand, the Raman scattering from a broadly radiating sample are imaged on a CCD area detector after Rayleigh radiation filtered out with an interference filter and a very narrow desired Band range with another filter has been selected. On the other hand  a bundle of optical fibers that carries the spatially resolved information is lined up and the light of the individual fibers in a monochromator is spatially resolved spectrally to be analyzed. With the largest CCD area detectors currently available can at least several hundred detectors or channels simultaneously to be analyzed.

According to the invention, light guides can advantageously be used in Raman spectroscopy be used in such a way that they each on the detector surfaces or Detector volume and at the same time excitation light by others, tightly coupled light guides are supplied to the surface. The scattered Raman light is preferably recorded in backscatter geometry, but also other geometries are possible if required. Alternatively, excitation light can also be used in an integrated chip using lithographically or otherwise defined light guides be brought up to the surfaces. With the help of miniature lens systems or the excitation light can be applied to the surfaces by light guides with index gradients are imaged and the Raman light is recorded in detector fibers. The Scattered light can, if desired, also be integrated into the light guide optical surface detectors are included. The excitation light can be at Needs can be varied over a wide frequency range. There are lasers today and CCD area detectors in the range from ultraviolet to near infrared Light available. The excitation energy transmitted with the light has significant impact on analytical capabilities. With ultraviolet light can often suppress disruptive fluorescence and with higher sensitivity be measured. In visible light, the detection of the Raman resonance high sensitivity. Excitation with near-infrared light in turn helps to avoid fluorescence.

In a very similar way to Raman spectroscopy, infrared Spectroscopy infrared light through light guides to the detector surface or that Detector volume brought up and either the diffusely scattered light or the light transmitted in transmission through the surface or volume with a two-dimensional infrared detector. To the spectral properties of the  Analyzing detected infrared light becomes that from the detector light guides emerging light is mapped onto the slit of a monochromator and spectrally split before it is detected on the infrared detector. Alternatively, it can Infrared light also modulated by an interferometer and after interacting with it the detectors are detected in parallel in a two-dimensional IR detector become. In contrast to Raman spectroscopy, infrared Spectroscopy on the detector infrared transmissive windows, e.g. B. made of germanium or silicon. On the other hand, there is none for infrared spectroscopy Excitation lasers are required and the process offers a high overall Sensitivity.

The image processing device can be used with a conventional CCD camera be designed particularly inexpensively if these are in the range of visible and / or ultraviolet and / or infrared light works. Such a camera has a high resolution and low energy consumption.

Alternatively or additionally, the detector surfaces can be more porous on the principle and / or swellable adsorbents are based. The adsorption leads in particular gaseous reaction products for a drastic enrichment of the analytes on the detector surface and thus to a significant increase in Sensitivity of the detector compared to the direct analysis in the Gas phase. In particular, the optical behavior can also be caused by the adsorption of a substance on the detector surface. At a Spectroscopic analysis of the detector area should include spectral interference the adsorbents are taken into account. This interference can be caused by suitable data processing, e.g. B. so-called spectral subtraction is eliminated become. Suitable adsorbents on the detector surfaces are thin Polymer films with different swelling behavior, amorphous porous materials, e.g. B. Silica, clays, carbon as well as anodically etched porous aluminum, silicon or germanium, still microporous materials as well as combinations of the called adsorbents.  

The Raman spectroscopy described above can advantageously be used for detection the reaction in the reactor room itself can be used. this happens for example with light guides that end at the respective reactor space.

In a further embodiment of the integrated miniaturized chemical laboratories each analysis device has one Injection device to put a small amount of reaction product into one to inject gaseous or liquid carrier stream, the Injection devices in particular combined to form an injection block are. The injection turns the reaction product into a sample, so to speak removed and supplied to the carrier stream. The number and amount of Samples are usually constant. The carrier current also preferably flows evenly, so that from the sample obtained on the composition of the Reaction product can be concluded. The carrier current is then conveyed to the detector, where the amount of reaction product is analyzed becomes.

An injection device which is described later in detail advantageously comes as an injection device Multi-channel valve according to the invention in the form of a disc or plate for Commitment. This has a large number of switching channels for metering one Sample volume from each reactor in a carrier stream, which then z. B. in a pressurized capillary system is fed. The material of the disc is chosen so that the best possible seal and a long service life are guaranteed. Advantageous materials are, for example, PEEK, polymer with Teflon, or hard materials with thin sliding layers such as polished Silicon. The pane is pressed between adjacent panes by kept tight on the outside.

Furthermore, the analysis device according to the invention advantageously has one Chromatograph, in particular a capillary chromatograph, with at least one separation column or capillary, in particular several Separation columns are combined to form a separation column block.  

Chromatographs are generally known. You enable it under It is possible to separate more than 100 substances in one separation. meanwhile succeeded by increasing the so-called column pressure Analysis speed even with complex separation to a few minutes reduce. The product or the substance to be analyzed is e.g. B. by comparison retention times or by spectral identification with infrared or Raman spectroscopy identified. The speed of analysis and the resolution can be achieved by miniaturization in fully or partially integrated chromatographs be increased on silicon chips. Individual gas chromatographic capillaries can be integrated in silicon chips with detectors. An important feature It is further developments according to the invention that such chromatographic Separation processes are integrated in the analysis on the chip laboratory, d. H. channels or capillaries defined by lithography are in a planar Substrate of the chip used. This allows a big increase in efficiency in the analysis of parallel reactions. Another advantage is just that little energy is consumed, so that in principle mobile concepts are also implemented can be. The inner surfaces of the capillaries can be advantageous be chemically treated. With chemical surface treatment Separation capacity of a capillary set, in particular increased. The For example, capillary is etched into the capillary block and its inner Surface then treated so that a desired separation performance is obtained. For etching the capillaries, such as. B. isotropic and anisotropic etching and Dry etching, silicon is suitable as a material for the capillary block. After Formation of the capillaries are caused by electrostatic bonding electrical voltage with glass or similar materials at around 350 to 450 ° C closed. Another method of making closed capillaries is a direct bonding of two silicon surfaces to each other with a much higher one Temperature of about 1100 ° C. Each capillary leads into a small detector or Sensor volume in which a detector is located. This detects that Appearance of the chromatographically separated peak values (peaks) of the analytes.  

The above-mentioned method developed according to the invention can also be used for Separation in the liquid phase can be used. However, a fluid medium points a higher viscosity, the possibly higher capillary or Channel cross sections required, as well as a higher pressure at the separation column and at the detector field. For reaction processes with liquid reaction products a simultaneous analysis of numerous substances in the reaction product with the help of so-called High Performance Liquid Chromatography (HPLC) possible. The Capillaries of the HPLC advantageously have walls with a meso- or microporous coating or such a filling on, causing the separation phase relatively tightly packed is available. The covering or the filling can be through different methods of growing up or by adsorption or Slurrying. Alternatively, the walls of the capillaries can be used directly the usual molecular layers. The surface of a porous separation phase can, if necessary, also with the in the Liquid chromatography known molecular layers, such as. B. Octadecyltrichlorosilane or chiral molecules can be modified to the to achieve the desired separation performance.

Detection of reaction products using liquid chromatography There may be separation at the outlet of the capillaries in a simple manner done directly spectroscopically by placing the capillaries in a detector block are led that a certain distance of the capillaries in transmission of light is irradiated. The capillaries lead to this with colinear light guidance for example, vertically through said detector block. The In this case, analytes can also be determined quantitatively if the spectroscopic signature of the molecules to be separated sufficiently from that of the Carrier current or the mobile phase differs.

In a further advantageous embodiment, the reactors and the Detectors combined into a laboratory block. So is a compact Laboratory structures created. As a material for the laboratory block z. B. metal, Silicon, ceramic or plastic can be used. The reactors of the  integrated miniaturized chemical laboratories according to the invention particularly advantageously combined into a reactor block, wherein in particular, the reactor spaces are particularly advantageously cylindrical. This enables a space-optimized arrangement with high stability of the laboratory block, good manufacturability and easy supply and discharge options for the reaction product. Alternatively, the reactor spaces can be cubic, with in particular square cross-section, or be spherical. The Integration of the described reactors and detectors with microscopic Structures are made using lithographic techniques, with a lateral resolution from approx. 1 to 10 µm is aimed for. In this laboratory block also the Injection devices, the chromatographs and / or the selection devices be integrated. Alternatively, these modules can also be separated from the Reactors can be arranged, which is useful if at the reactors special environmental conditions, such as very high temperatures, to rule.

The laboratory block is advantageously smaller than 50 cm along the longest axis, especially smaller than 20 cm. Alternatively, the laboratory according to the invention but also in a larger dimension with a laboratory trestle of up to about 10 m Length. The reactor rooms are also particularly advantageous less than 5 ml, preferably less than 100 µl. Alternatively, larger ones Reactor rooms are used, for example with a volume of up to 1 l or even up to 1000 l.

To achieve a high packing density in the laboratory and at the same time one It is up to the manageable number of reaction processes to run integrated miniaturized chemical laboratory according to the invention advantageous, between 16 and 20,000, especially between 48 and 1,000 reactors to summarize a block.

Brief description of the drawings

In the following, exemplary embodiments according to the invention are integrated miniaturized chemical laboratories using the attached schematic Drawings explained in more detail. It shows:

Fig. 1 is a longitudinal section of a first embodiment of an integrated miniaturized chemical laboratories according to the invention,

Fig. 2 shows the longitudinal section of FIG. 1 in a different operating state of the

Fig. 3 is a plan view of a second embodiment of an integrated miniaturized chemical laboratories according to the invention,

Fig. 4 shows the top view of FIG. 3 in a different operating condition of the laboratory,

Fig. 5 is a longitudinal section of a third embodiment of an integrated miniaturized chemical laboratories according to the invention for liquid reactions,

Fig. 6 is a perspective view of a first embodiment of a detector block and an image processing means,

Fig. 7 is a longitudinal section of the first embodiment of the detector block,

Fig. 8 is a longitudinal section of a second embodiment of a detector block, and

Fig. 9 is a longitudinal section of a third embodiment of a detector block.

Detailed description of the exemplary embodiments

An integrated miniaturized chemical laboratory 10 shown in FIG. 1 comprises, as an essential component, a reactor block 12 made of brass, which is composed, among other things, of an upper part 14 , a main part 16 and a lower part 18 . The components 14 , 16 and 18 enclose reactor spaces 20, two of which are shown in FIG. 1. In total, the reactor block 12 comprises 64 reactor rooms 20 , each of which is individually assigned to a reactor.

Lines, not shown, made of steel or copper lead to and away from the reactor block 12 , which can also be milled and / or etched in connection blocks. These lines extend in particular perpendicular to the upper and lower sides of the reactor block 12 shown in FIG. 1. The essential parts of the reactor block 12 and its connections are held together by flanges and screws, not shown, and are connected gas-tight by seals.

In the upper part 14 , two vertical inlet openings 22 are formed per reactor, through which solids, for. B. solid catalyst, and two different gases or gas products introduced into the associated reactor space 20 or a vacuum can be applied to this. A slide valve 24 is integrated in the upper part 14 , with which the inlet openings 22 can be opened or closed either individually and / or together. In an embodiment not shown, a hood is provided instead of the upper part 14 , so that all reactor spaces 20 can be filled with gas, for example, at the same time.

An outlet opening 26 is formed in the lower part 18 under each reactor chamber 20 . These outlet openings 26 are so narrow in relation to the inlet openings 22 that they have the greater flow resistance and thus define the main flow resistance. The outlet openings 26 thus determine the flow velocities in the reactor spaces 20 .

A frit 28 , ie a gas-permeable disk, is horizontally arranged in each reactor chamber 20 , on which a catalyst or a number of solid bodies 30 is stored as a bed. The main part 16 is penetrated at the level of the catalyst 30 by temperature sensors 32 , which each lead to one of the reactor rooms 20 from the outside. The temperature sensors 32 are used when controlling a heating and / or cooling (heating or coolant channels) of the reactor block 12 , not shown. Instead of the temperature sensors 32, optical fibers or light guides can optionally be provided, which enable a spectroscopic analysis of the substances present in the reactor space 20 . Both infrared spectroscopy (attenuated total reflection mode ATR with infrared light guides), electronic excitation spectroscopy with ultraviolet and visible light, near infrared spectroscopy and Raman spectroscopy are available. Due to the relative arrangement of the fibers to each other, all known geometries for exciting and recording the spectra can be set. For example, geometries with backscattering of 180 degrees are preferred for infrared, fluorescence and Raman spectroscopy (Raman and fluorescence spectroscopy also 90 degrees), while transmission geometries are preferred for electronic excitation spectroscopy and near-infrared spectroscopy. The signals on the optical fibers can be analyzed using optical detectors. In addition to or as an alternative to this detection, a further detection of substances, described below, is provided according to the invention in at least one reaction product emerging from the reactor spaces 20 .

The lower part 18 serves primarily to delimit the reactor spaces 20 downwards. At the same time, a slide valve 34 is also integrated in the lower part 18 , by means of which an injection of reaction product from the reactor spaces 20 takes place for a subsequent gas chromatographic separation. The lower part 18 thus also forms an injection block, which is described in more detail below.

In the exemplary embodiment shown in FIGS. 1 and 2, this injection block is integrated in the reactor block 12 .

The slide valve 34 is designed in the form of a disk or plate which can be pushed back and forth by means of an actuating or stepping motor, not shown. The slide valve 34 is guided by guides, not shown.

The slide valve 34 is penetrated by vertically continuous, in particular drilled, channels 36 , 38 and 40 , three of which are each assigned to a reactor or its outlet opening 26 . The channels 36 , 38 and 40 are evenly spaced from one another.

In the lower part 18 , an outlet channel 42 is formed on the side of the slide valve 34 opposite the outlet opening 26 , and two opposite carrier gas channels 44 are formed laterally at a certain distance which corresponds to the distances between the channels 36 , 38 and 40 .

The lower part 18 and the slide valve 34 interact in their function as an injection device as follows:
First of all, the slide valve 34 is in the rest position, as shown in FIG. 1, ie the channel 38 connects the outlet opening 26 to the outlet channel 42 , reaction product flows through it and thereby “charged”. During this time, carrier gas for the chromatographic separation flows through the channel 40 and the carrier gas channels 44 and is provided by a gas source (not shown). The channel 36 is closed at both ends by the lower part 18 .

By moving the slide valve 34 in the direction of arrow A, the channel 38 passes between the carrier gas channels 44 . This is shown in Fig. 2. The reaction product is injected into the carrier gas stream. The channel 36 in the meantime ensures the outflow of reaction product from the reaction space 20 to the outlet channel 42 . The channel 40 is closed by the lower part 18 .

After a short time of generally no longer than about 5 seconds, the slide valve 34 is moved back again, so that the idle and charging state is restored. In an embodiment not shown, the channel 36 is also flushed through by a gas in this rest position, for example a cleaning gas or else by a carrier gas of a second gas source, which enables a second, approximately simultaneous chromatographic separation of the same reaction product.

The slide valve 34 is designed in a non-illustrated embodiment as a circular disc in which the channels 36 , 38 and 40 are arranged in the form of concentric circles. This disc is guided on a journal. The switching logic when turning corresponds to that described above.

The injection volume for gas chromatographic separation is determined by the dimensions of channels 36 , 38 and 40 . In particular, the thickness of the slide valve 34 and the respective diameter of the channels 36 , 38 and 40 can be varied. The slide valve 34 is sensibly designed with a thickness of 4 to 10 mm and the channels 36 , 38 and 40 advantageously each have the same diameter, namely between 0.1 mm and 1.0 mm.

In an embodiment not shown, a flow divider is inserted between the main part 16 and the lower part 18 , so that sufficient flow velocities are achieved in the reactor and at the same time the channels 36 , 38 and 40 are not overloaded. The flow divider can be used as a branch in the main part 16 or the lower part 18 or be formed in one of these. The flow division is determined by the ratio of the flow resistances from the channels 36 , 38 or 40 and the flow divider.

The reaction product injected into the carrier channels 44 is subsequently separated chromatographically in capillaries (not shown). The capillaries are formed in a capillary block into which they are milled or etched. In an embodiment not shown, the capillaries are designed in a bundle of commercially available capillaries in the desired length. The separation performance of the capillaries is determined by their length and a filling or a wall covering. Their number is equal to that of the reactors, so in the embodiment shown in FIGS. 1 and 2 the number is 64.

A real parallel takes place in these parallel connected capillaries chromatographic, in the example shown gas chromatographic separation. The capillaries are arranged in a heatable housing, the Heating is controlled and separate heating programs for each separation can expire.

In FIGS. 3 and 4, an embodiment is shown in which a reactor block is used similarly to that shown in Figs. 1 and 2 shown. The reactor block is designed as a gas flow reactor block, ie a gas, a vapor or a mixture of these forms as a reaction product.

The main part of this reactor block is screwed onto a stainless steel block, which contains a milled channel system and a slide valve corresponding to the lower part 18 in FIGS. 1 and 2 and forms an injection block. The slide valve is designed here as a channel plate 34 a, in which channels 36 a, 38 a and 40 a are essentially designed to correspond to channels 36 , 38 and 40 , but here in a planar arrangement.

Fig. 3 shows the position of the channels 36 a, 38 a and 40 a when loading the channel 38 a with reaction product. FIG. 4 shows how the reaction product is subsequently injected into the carrier gas of a gas chromatograph (multichannel GC) which is connected downstream of the last-mentioned injection block.

At the exit of each capillary in the described exemplary embodiments a detector or sensor is arranged so that a detector field results. The Detectors are combined in a detector block, which is located on the Capillary block connects.

FIG. 5 shows an exemplary embodiment of a miniaturized laboratory in which a reactor block 12 for liquids with a dosage for liquid chromatographic separation is provided. The reactor block 12 is designed similarly to the embodiment shown in FIGS. 1 and 2. It also has an upper part 14 , a main part 16 and a lower part 18 . In the main part 16 , reactor spaces 20 are formed which have a conical shape and into which liquid, solid (for example resin beads) and gas can be introduced or a vacuum can be applied through inlet openings or cannulas 22 with a dosing robot 46 . The refer to Fig. 5, upper diameter of the conical reactor chambers 20 is 12 mm. A frit 28 is provided at the outlet opening 26 in order to retain any solids present in the reactor space 20 .

A block with conical spaces 47 is arranged under the lower part 18 and is provided for receiving and discharging the reaction product emerging from a reactor space 20 .

The substances of the reaction product which have been partially or completely separated in the chromatographic separation after the reactor spaces 20 are conducted into a field with detectors 48 which are arranged in a planar substrate or detector block 50 . Fig. 6 shows this detector block 50. In this exemplary embodiment, Raman spectroscopic detection without fiber optics takes place on these detectors.

The detector block 50 has capillaries 52 , one of which leads to and away from a detector 48 . The number of detectors 48 corresponds to the number of reactors, ie is 64. The detectors 48 are irradiated with monochromatic light from a laser and imaged with a CCD camera 54 as an image processing device. In front of the CCD camera are holographic filters to eliminate intense Rayleigh scattering, as well as filters to select certain desired frequency ranges of the Raman scattering. With this type of device, the Raman signal is recorded in a defined frequency range for all detectors 48 simultaneously, ie in parallel. This means that the presence of almost any substance can be detected over a wide frequency range of the filter (e.g. from 400 to 4000 wave numbers). Alternatively, the detection can be limited to certain substance groups by a narrower frequency range, for example to substances with carbonyl groups in the range around 1700 wave numbers.

FIG. 7 shows an exemplary embodiment with detectors 48 , which operate on the basis of the adsorption of a substance to be analyzed on a host and the image processing detection of a Raman spectrum after this adsorption. The individual detector 48 has a base plate 56 and an intermediate plate 64 above it, in which channels 58 and 60 for supplying and removing material flows to a recess 62 are formed. An optically transparent cover plate 66 made of glass or quartz is arranged on the intermediate plate 64 . The actual detector surface 68 , the so-called pixel, is located in the cutouts 64 . In an exemplary embodiment not shown, there is a reflective coating on the base plate 56 on the side of the recess 62 opposite the detector surface 68 , which is designed as a metallic mirror or as a diffusely reflecting white surface. The CCD camera 54 illustrated in FIG. 6 observes the detector surface 68 through the cover plate 66 in the direction of the arrows B.

The material of the detector surface 68 here is the mesoporous host SBA-15, in the pores of which analytes are adsorbed when reaction product flows through the channels 58 and 60 and the recess 62 . The material has been applied as a film by dip-coating a suspension of the host onto the transparent cover plate 66 , the pattern of the detector surfaces 68 on the detector block 50 being defined by an adhesive masking film. In one exemplary embodiment, which is not shown, the pattern was produced by means of lithography with photoresist, by screen printing, by spraying with a mask or by hydrothermal washing on areas left open by openings in a resist mask.

FIG. 8 shows an exemplary embodiment of detectors 48 which are constructed essentially the same as the detectors 48 shown in FIG. 7. However, the detectors 48 according to FIG. 8 are not scanned directly and indirectly with a combination of light guides or quartz fibers and corresponding transfer optics for a laser as an excitation light source, and quartz fibers for the radiation to be detected. The radiation to be detected is guided in a linear arrangement of the glass fibers to a monochromator for the dispersion of the light, where the light is analyzed in the CCD camera. In an embodiment not shown, the excitation takes place via a diffuse excitation source, while detection is carried out via individual light guides or individual glass fibers. Alternatively, excitation and detection can be carried out via branched light guides.

In the present exemplary embodiment, a UV laser is used for excitation, with which avoids the unwanted fluorescence and achieves high sensitivity becomes. Alternatively, other laser colors can be used for excitation, for example red diode lasers at around 780 nm. The big advantage here is that much higher information density on each detector surface, which is characterized by the spectral resolution of the Raman signals results.

When the detector surface 68 is excited by light guides, several excitation light guides can be grouped around a detection light guide or, conversely, several detection light guides can be grouped around one excitation light guide. The light guide and detector surface can be inserted by inserting optical elements, such as. B. Optically coupled lenses. In order to avoid stray light in neighboring detectors, each detector surface 68 or each pixel can be separated from the surrounding ones by an opaque partition. Furthermore, optical filters can be used at suitable points in the beam path to prevent unwanted radiation, such as. B. Rayleigh scatter.

In the exemplary embodiment shown in FIG. 8, the detector surface 68 comprises a mesoporous film, which after masking has been applied to the transparent cover plate 66 and calcined. These detector surfaces 68 are used for detecting organic substances which are briefly adsorbed in the mesopores of the detector surfaces 68 when a substance or a chromatographically separated substance peak flows past.

In an exemplary embodiment of a miniaturized laboratory, not shown, detectors according to FIG. 8 are used for the analysis of chromatographically separated liquids (HPLC). The detectors are modified in such a way that they do not have a mesoporous film, but rather that the Raman spectrum of the analyte that is briefly present in the sample volume is recorded directly. In contrast to gas chromatographic separation, the material of the carrier stream plays an important role in liquid chromatographic separation, because the Raman spectrum of the analyte must be distinguishable from the spectrum of the carrier stream. In particular, simple molecules with or without a few hydrogen atoms, such as e.g. B. carbon tetrachloride or supercritical carbon dioxide in question.

FIG. 9 shows detectors 48 which are provided for detecting an analyte in a flowing chromatographically separated reaction product via spectrally resolved infrared spectra and which operate on the basis of the transmission geometry. Alternatively, a detector working with direct or diffuse reflection geometry can be used, as is illustrated in FIGS. 7 and 8.

The detector 48 shown in FIG. 9 also has a base plate 56 , an intermediate plate 64 with channels 58 and 60 and with cutouts 62 , and finally a cover plate 66 . The base plate 56 and the cover plate 66 are both made of a material which is transparent to infrared radiation of the desired spectral range, for example germanium or silicon. Detector surfaces 68 are formed in the cutouts and are constructed with a mesoporous or microporous material analogously to the detectors 48 described above. On the one hand, the porous material should bind the reaction product flowing past for a short time in order to obtain sufficient spectral sensitivity, and on the other hand, if desired, select substances in the reaction product by means of molecular sieve effects.

The infrared radiation is guided via light guides (not shown) in Direction of arrows C. Of these, the detecting light guides, i. H. those Light guide into which the infrared radiation that has passed through the detector occurs in a linear arrangement in a monochromator with imaging quality coupled in and the radiation is after spectral dispersion on the grating or Prism imaged on a two-dimensional, spatially resolved infrared detector.

In exemplary embodiments that are not shown, the detectors 48 described above in connection with FIGS. 6 to 9 are used for direct imaging or a spectral analysis of adsorption surfaces, or for determining an absorption and / or fluorescence spectrum of the detector surfaces 68 . In this case, for example, the color change of the detector areas 68 can be determined by providing it with the solvatochrome dye Nile Red in the pores of a film of the mesoporous host SBA-15. Alternatively, a mesoporous film after masking can be applied to the transparent cover plate 66 , calcined and used for the detection of fluorescent substances which are briefly adsorbed in the mesopores of the detector surface 68 as a chromatographically separated peak flows past. The film is applied as with the detectors described above. Light guidance and analysis are also carried out with a monochromator and CCD camera in the same way as for the methods described above.

Finally, it should be noted that with the expression "block" used here not only a cubic body is meant, but that too disk-like or plate-like bodies are intended to be encompassed thereby.

Overall, the layering is consequently modular a reactor block, an injection block, a capillary block and Finally, a sensor block is particularly compact and at the same time cost-effective solution of a miniaturized chemical laboratory.  

LIST OF REFERENCE NUMBERS

10

laboratory

12

reactor block

14

top

16

Bulk

18

lower part

20

reactor chamber

22

inlet port

24

spool valve

26

outlet

28

frit

30

catalyst

32

temperature sensor

34

spool valve

34

a channel plate

36

channel

36

a channel

38

channel

38

a channel

40

channel

40

a channel

42

exhaust port

44

Carrier gas channel

46

Dispensing

47

conical space

48

detector

50

detector block

52

capillary

54

CCD camera

56

baseplate

58

channel

60

channel

62

recess

64

intermediate plate

66

cover

68

detector surface

Claims (33)

1. Integrated miniaturized chemical laboratory ( 10 ) with a plurality of reactors ( 12 , 20 ) for carrying out parallel reaction processes and an analysis device for analyzing at least one emerging reaction product, which has a detector surface ( 68 ) or a detector volume for detecting at least one substance in the reaction product , characterized in that an image processing device ( 54 ) is provided for determining the detection of the substance on the detector surface ( 68 ) or the detector volume. 2. Integrated miniaturized chemical laboratory according to claim 1, characterized in that a plurality of analysis devices are provided, each of which is individually assigned to a reactor ( 12 , 20 ), in particular the detector surfaces ( 68 ) or the detector volumes of the plurality of analysis devices as a whole from the image processing unit Device ( 54 ) are detected. 3. Integrated miniaturized chemical laboratory according to claim 1 or 2, characterized in that the detector surface ( 68 ) is designed as an adsorption surface with a receptor for adsorbing at least one substance from the reaction product, and in particular several adsorption surfaces with different receptors are provided per analysis device. 4. Integrated miniaturized chemical laboratory according to claim 1, 2 or 3, characterized in that the detector surface ( 68 ) has a molecular, inorganic, organic and / or biological receptor, wherein the material of the receptor can interact in particular with the reaction product flowing past. 5. Integrated miniaturized chemical laboratory according to claim 4, characterized in that the material of the receptor is a polymer and / or a porous host, in particular zeolite, and / or a periodic one has mesoporous and / or a microporous host. 6. Integrated miniaturized chemical laboratory according to claim 5, characterized in that the polymer and / or the host one salvatochrome dye. 7. Integrated miniaturized chemical laboratory according to one of claims 1 to 6, characterized in that the image processing device ( 54 ) is based on the principle of direct imaging or spectral analysis of the detector surface ( 68 ) or the detector volume, in particular an optical fiber for transmission of light radiation is used. 8. Integrated miniaturized chemical laboratory according to one of claims 1 to 7, characterized in that the image processing device ( 54 ) determines an absorption and / or fluorescence spectrum of the detector surface ( 68 ) or the detector volume. 9. Integrated miniaturized chemical laboratory according to one of claims 1 to 8, characterized in that the image processing device ( 54 ) determines an oscillation spectrum, in particular a Raman and / or infrared spectrum, of the detector surface ( 68 ) or the detector volume. 10. Integrated miniaturized chemical laboratory according to one of claims 1 to 9, characterized in that the image processing device ( 54 ) operates in the range of visible and / or ultraviolet and / or infrared light. 11. Integrated miniaturized chemical laboratory according to one of claims 1 to 10, characterized in that the detector surface ( 68 ) is based on the principle of porous and / or swellable adsorbents, in particular their optical behavior being influenced by the adsorption of a substance. 12. Integrated miniaturized chemical laboratory according to one of claims 1 to 11, characterized in that the analysis device comprises an injection device ( 18 , 34 ) to a small amount of reaction product in a gaseous or liquid carrier stream towards an associated detector surface ( 68 ) or to inject a detector volume, in particular several injection devices ( 18 , 34 ) being combined to form an injection block. 13. Integrated miniaturized chemical laboratory according to one of claims 1 to 12, characterized in that the analysis device has a chromatograph, in particular a capillary chromatograph ( 18 , 20 ), with at least one separation column, in particular a plurality of separation columns being combined to form a separation column block. 14. Integrated miniaturized chemical laboratory according to one of claims 1 to 13, characterized in that the analysis device is a selection device has to select the reaction product for certain Molecular sizes. 15. Integrated miniaturized chemical laboratory according to one of claims 1 to 14, characterized in that the reactors ( 12 , 20 ) and the detectors ( 48 ), and in particular also the injection devices ( 18 , 34 ), chromatographs ( 16 , 20 ) and / or selection devices are combined in a laboratory block. 16. Integrated miniaturized chemical laboratory according to claim 15, characterized in that the laboratory block is smaller along the longest axis than 50 cm, in particular less than 20 cm. 17. Integrated miniaturized chemical laboratory according to one of claims 1 to 16, characterized in that between 16 and 20,000, in particular between 48 and 1000, reactors ( 12 , 20 ) are combined to form a reactor block ( 12 ). 18. A method for analyzing a reaction product which is produced in an integrated miniaturized chemical laboratory ( 10 ) in parallel reaction processes in a plurality of reactors ( 12 , 20 ), with the step: supplying the reaction product to a detector surface ( 68 ) or a detector volume for detection at least one substance in the reaction product, characterized by the step: determining the detection of the substance with an image processing device ( 54 ). 19. The method according to claim 18, characterized in that the reaction product from the plurality of reactors ( 12 , 20 ) is guided parallel to a plurality of detector surfaces ( 68 ), and the plurality of detector surfaces ( 68 ) or detector volume overall from the image processing device ( 54 ) be recorded. 20. The method according to claim 18 or 19, characterized in that the detector surfaces ( 68 ) adsorb at least one substance of the reaction product with a receptor, and in particular the reaction product of each reactor ( 12 , 20 ) leads to a plurality of detector surfaces ( 68 ) with different receptors becomes. 21. The method according to claim 18, 19 or 20, characterized in that the detection with a molecular, inorganic, organic and / or biological receptor takes place, the Material of the receptor, in particular with the reaction product flowing past interacts. 22. The method according to claim 21, characterized in that the detection with a polymer and / or a porous host, especially zeolite, and / or a periodic one mesoporous and / or a microporous host. 23. The method according to claim 22, characterized in that the polymer or the host has a salvatochromic Dye carries. 24. The method according to any one of claims 18 to 23, characterized in that the image processing device ( 54 ) works on the principle of direct imaging or spectral analysis of the detector surface ( 68 ) or the detector volume, in particular light radiation being transmitted with an optical fiber. 25. The method according to any one of claims 18 to 24, characterized in that the image processing device ( 54 ) determines an absorption and / or fluorescence spectrum of the detector surface ( 68 ) or the detector volume. 26. The method according to any one of claims 18 to 25, characterized in that the image processing device ( 54 ) determines an oscillation spectrum, in particular a Raman and / or infrared spectrum, of the detector surface ( 68 ) or the detector volume. 27. The method according to any one of claims 18 to 26, characterized in that the image processing device ( 54 ) operates in the range of visible and / or ultraviolet and / or infrared light. 28. The method according to any one of claims 18 to 27, characterized in that the detection with porous and / or swellable Adsorbents takes place, in particular by the adsorption of a substance optical behavior of the adsorption surface is influenced. 29. The method according to any one of claims 18 to 28, characterized in that the analysis comprises a parallel injection ( 18 , 34 ) of reaction product into a gaseous or liquid carrier stream in the direction of an associated detector surface ( 68 ) or a detector volume, wherein in particular the parallel injections ( 18 , 34 ) combined in one injection block. 30. The method according to any one of claims 18 to 29, characterized in that the analysis comprises a parallel chromatographic separation, in particular a capillary chromatographic separation ( 18 , 20 ), the parallel separation taking place in particular combined in a separation column block. 31. The method according to any one of claims 18 to 30, characterized in that the analyzing is a selection of the Reaction product includes certain molecular sizes. 32. The method according to any one of claims 18 to 31, characterized in that the reaction processes ( 12 , 20 ) and the detection on the detector surfaces ( 68 ) or the detector volume take place together in a laboratory block. 33. The method as claimed in one of claims 18 to 32, characterized in that between 16 and 20,000, in particular between 48 and 1000, reaction processes ( 12 , 20 ) are carried out in a reactor block ( 12 ).