Monitoring device for temperature-regulated capillary guidance with nested hoses and delivery capillary for an NMR flow cell

Abstract

The invention relates to a monitoring device (100) for measuring a reaction liquid (102) produced in a reaction vessel (101) in an NMR spectrometer (103), the monitoring device having the following components: a hollow NMR sample probe (104) for receiving the reaction liquid to be measured; an inlet transport capillary (105) for receiving the reaction liquid from the reaction vessel and for transporting it from the reaction vessel via a pump device (106) towards the sample probe; an outlet transport capillary (108) for transporting the reaction liquid from the sample probe back to the reaction vessel; a device (10) for guiding a temperature control fluid (25) around the inlet and outlet transport capillaries, the device for guiding the temperature control fluid having a hose section (23) which is configured in a double-walled manner from two radially closed sub-hoses which are arranged one inside the other, the sub-hoses comprising an outer sub-hose (19) and an inner sub-hose (21), the temperature control fluid flowing between the outer and inner sub-hoses and the inlet or outlet transport capillary being arranged radially inside the inner sub-hose, characterized in that the monitoring device has a closed temperature control circuit for the temperature control fluid which is designed in terms of its geometry such that the temperature control fluid always only flows in one predefined direction in each spatial region of the temperature control circuit and no reverse flow of the temperature control fluid occurs directly adjacent to the spatial region. As a result, the reaction liquid is always and completely uniformly temperature-controlled over its entire transport path.

Description

Technical Field

[0001] This invention relates to a monitoring device for measuring reaction liquids generated in a reaction vessel in an NMR spectrometer, particularly for examining chemical reactions by means of NMR spectroscopy, wherein the monitoring device has at least the following components:

[0002] A hollow NMR sample probe used to receive the reaction liquid to be measured in an NMR spectrometer.

[0003] An inlet delivery capillary for receiving the reaction liquid from the reaction vessel and for conveying the reaction liquid from the reaction vessel toward the sample probe via a pumping device;

[0004] A discharge delivery capillary used to return the reaction liquid from the sample probe to the reaction vessel;

[0005] A device for guiding temperature-regulating fluids around the inlet and outlet of the delivery capillary.

[0006] The device for guiding the temperature-regulating fluid around the inlet and outlet delivery capillary has a hose section, each hose section being double-walled and constructed of two nested, radially closed sub-hose sections, each sub-hose including an outer sub-hose and an inner sub-hose, wherein the temperature-regulating fluid flows between the outer and inner sub-hose, and the inlet or outlet delivery capillary is arranged radially within the inner sub-hose.

[0007] Such monitoring devices are known from the publication "NMR flow tube for online NMR reaction monitoring" by FOLEY, David A. et al., Analytical Chemistry, 2014, Vol. 86, No. 24, pp. 12008-12013 (=Reference [0]). Background Technology

[0008] This invention relates in its entirety to the field of nuclear magnetic resonance (NMR), and more particularly to a monitoring device for real-time NMR measurements of reaction liquids under temperature-controlled conditions.

[0009] NMR spectroscopy is a common and effective method in instrumental analysis. It allows the study of the electronic environment of individual atoms and the interactions between these atoms and their neighbors in a substance under investigation (e.g., hydrocarbons or bioinorganic complexes). This can, for example, elucidate the composition, structure, and kinetics of the substance under investigation, and also determine its concentration.

[0010] Typically, when measuring substances in liquid form, the substance to be studied is filled into an NMR tube. For measurement purposes, the filled NMR tube is placed in the measurement region of the NMR sample head of the NMR spectrometer. The substance is subjected there to a strong, static, uniform magnetic field B0, thereby orienting the nuclear spins within the substance. A high-frequency electromagnetic pulse is then injected into the substance under study. The same high-frequency electromagnetic field generated here is detected in the NMR spectrometer. Information about the properties of the substance under study can then be obtained.

[0011] Measurements of substances in liquid form can be performed as standalone measurements, in which the substance is individually loaded into an NMR tube, measured, and then removed. However, applications utilizing so-called NMR flow cells are also of particular interest.

[0012] Chemical reactions can be observed in real time and under reaction conditions using an NMR flow cell. For this purpose, the substance under study (the “reaction liquid”) is rapidly and continuously guided from the reaction vessel (typically where the reaction liquid is generated) to and through a hollow NMR sample probe, which is housed in an NMR spectrometer. NMR measurements are performed simultaneously as the reaction liquid is guided through the NMR sample probe. In this way, continuous monitoring of the reaction liquid (and therefore the reaction progress in the reaction vessel) is achieved through NMR measurements.

[0013] In NMR flow cell applications, capillaries are typically used to transport the substance under study (“measurement medium”). Capillaries are usually made of plastic and have an outer diameter of 1 / 16” (≈0.16 cm) or 1 / 32” (≈0.08 cm). Typically, the entire system is configured such that the measurement medium is transported from the reactor (“reaction vessel”) to a pump. The pump then continues to guide the measurement medium to the NMR measuring apparatus and from there back to the reactor.

[0014] During measurements, a specific temperature is typically present in the reactor. Therefore, it is essential to ensure that the chemical reaction within the reaction vessel proceeds uniformly and in a controlled manner, and that subsequent NMR measurements are comparable to each other. To maintain the specific temperature of the measurement medium as constant as possible along the path of the measurement medium, the capillary tube can be at least partially temperature-controlled.

[0015] In high-field systems, for example, the “InsightMR” system from Brock Corporation in Billerica, Massachusetts, USA (=Reference [3]) is used. In this system, the capillary region between the pump and the NMR system and between the NMR system and the reactor is temperature-controlled. However, temperature control is not performed along the entire length. Furthermore, the section between the reactor and the pump is completely untemperature-controlled. The temperature-controlled region that guides the capillary is constructed as an insulated hose. The temperature-controlled medium circulates directly through the capillary in this insulated hose.

[0016] The disadvantage of this system is that it is specifically developed for high-field systems and works well only in this application. It cannot be adapted to different systems and environments in other fields. Furthermore, components in which the temperature-controlled capillary can be guided cannot be used. For example, in the event of blockage, the capillary cannot be easily replaced. Before the capillary can be replaced, the temperature-controlled liquid must first be drained from the entire insulating hose.

[0017] EP2407796B1 (=Reference [2]) describes a monitoring cell by which reaction liquid generated in a reaction vessel can be measured in an NMR spectrometer. The monitoring cell includes a hollow NMR sample probe and a housing having an inlet delivery capillary for receiving reaction liquid from the reaction vessel and an outlet delivery capillary for discharging the reaction liquid back into the reaction vessel. Furthermore, the housing of the monitoring cell includes means for guiding cooling liquid around the inlet and outlet delivery capillary. The inlet and outlet delivery capillary are guided through a cavity. The cavity is connected to the means for guiding the cooling liquid. During measurement, the cavity is traversed by cooling liquid.

[0018] If, for example, one of the capillaries becomes clogged, all the coolant must first be drained before the clogged capillary can be removed. In the event of a capillary leak or damage, reactant fluid may also spill and contaminate the coolant. This requires costly cleaning of the coolant guiding device and can result in expensive cleanup of the contaminated coolant. Furthermore, the coolant guiding device is specifically designed for this system and is not compatible with other systems.

[0019] DE102015206030B3 (=Reference [1]) also provides a monitoring cell by which reaction liquid generated in a reaction vessel can be measured in an NMR spectrometer. Similar to that described in Reference [2], the monitoring cell includes a hollow NMR sample probe and a housing having an inlet delivery capillary for receiving reaction liquid from the reaction vessel and an outlet delivery capillary for discharging the reaction liquid back into the reaction vessel. Furthermore, the housing of the monitoring cell includes a device for guiding a temperature-controlled fluid, having an input line and an output line for the temperature-controlled fluid into the monitoring cell. The delivery capillary is guided within the input line of the temperature-controlled fluid, and the input line is coaxially surrounded by the output line. During measurement, the delivery capillary is therefore also in direct contact with the temperature-controlled fluid here.

[0020] If, for example, one of the capillaries becomes clogged, the temperature-regulating medium must first be drained from this monitoring tank to remove the clogged capillary. In the event of a capillary leak or damage, the reaction liquid may also spill out and contaminate the temperature-regulating fluid. This, in turn, leads to costly cleaning of the device used to guide the temperature-regulating fluid and sometimes expensive cleaning of the contaminated fluid. Furthermore, the device used to guide the temperature-regulating fluid is specifically designed for this system and cannot be adapted to other systems.

[0021] Reference [0] cited at the beginning describes a monitoring cell that is general for the present invention and has all the combination of features defined in paragraph 1 of the first page of the above specification. The monitoring cell is operated in a flow-through manner (“NMR flow tube for online NMR reaction monitoring”). However, here, the temperature-regulating liquid does not flow in only one direction, but is transported back and forth in three coaxial hoses. Therefore, it cannot be ensured that the liquid NMR sample is subjected to truly uniform temperature regulation throughout the entire transport path from the reaction vessel to the NMR spectrometer and back. Summary of the Invention

[0022] In contrast, the object of the present invention is to design, in a monitoring device of the type described at the beginning for measuring the reaction liquid generated in a reaction vessel in an NMR spectrometer, the means for guiding the temperature-regulating fluid around the inlet and outlet delivery capillaries in such a way that the inlet and outlet delivery capillaries can be replaced without problems at any time, the means for guiding the temperature-regulating fluid can also be used universally in other operating environments, and the inlet and outlet delivery capillaries are always and completely uniformly temperature-regulated during operation.

[0023] Brief description of the invention

[0024] The task is solved by the present invention in a surprisingly simple and effective manner by having a closed temperature control loop for a temperature-controlled fluid, the temperature control loop being geometrically designed such that the temperature-controlled fluid always flows in only one predetermined direction in each spatial region of the temperature control loop and that no reverse flow of the temperature-controlled fluid occurs at the direct adjacency of the spatial regions.

[0025] Therefore, the present invention proposes, instead of transporting liquid NMR samples from the reaction vessel to the NMR spectrometer and back in three coaxial hoses (as disclosed in reference [0]), to modify the apparatus such that the reaction liquid and the temperature-regulating fluid always flow in only one flow direction at every point in the apparatus. This is achieved by a coolant circuit according to the invention, the hoses of which are also constructed radially to be significantly more compact and technically less expensive than the triple hoses proposed in reference [0]. The circuit guidance of the liquid according to the invention means that the temperature-regulating fluid flowing from the reaction vessel to the NMR spectrometer is spatially separated from the temperature-regulating fluid flowing from the NMR spectrometer back to the reaction vessel. Thus, it is now possible to ensure completely uniform temperature regulation of the reaction liquid throughout the entire transport path.

[0026] Furthermore, a strict separation is established between the inlet and outlet of the delivery capillary (“delivery capillary”) and the temperature-regulating fluid. For this purpose, a double-walled hose section is provided, each section consisting of an outer sub-hose and an inner sub-hose disposed within the outer sub-hose. The temperature-regulating fluid flows in the intermediate region between the outer and inner sub-hose. No temperature-regulating fluid flows within the inner sub-hose. The delivery capillary is disposed within the inner sub-hose, which contains no temperature-regulating fluid.

[0027] With this configuration according to the invention, the delivery capillary can be easily and quickly inserted into or removed from the double-walled hose section, for example, by simply pressing the corresponding delivery capillary into the inner sub-hose. This eliminates the need for the cumbersome disassembly and assembly that has been largely necessary for guiding the temperature-controlled fluid.

[0028] Because the temperature-regulating fluid is spatially separated through the structural design of the double-walled hose section and the delivery capillary, the device for guiding the temperature-regulating fluid can be used with extreme flexibility. In other words, the device for guiding the temperature-regulating fluid designed according to the present invention can be used in situations where the structure of the monitoring equipment is completely different and is not limited to special, specialized structures.

[0029] If problems arise with the delivery capillary during the measurement of the reaction liquid, such as blockage or damage, it can be easily and smoothly pulled out of the inner sub-capillary. In particular, the temperature-regulating fluid does not need to be drained before the corresponding delivery capillary can be removed. Therefore, the delivery capillary can be removed without problems while the temperature-regulating fluid continues to flow in the intermediate region between the outer and inner sub-capillary. Contaminants in the inner sub-capillary can be removed very effectively and simply, for example, by guiding the solvent through the inner region of the inner sub-capillary.

[0030] By spatially separating the temperature-regulating fluid and the delivery capillary, contact between the temperature-regulating fluid and the reaction liquid due to leakage can be effectively prevented in the event of capillary damage. Therefore, the risk of undesirable reactions between the temperature-regulating fluid and the reaction liquid is eliminated. Contamination between the temperature-regulating fluid and the reaction liquid is also prevented. This approach offsets the typically costly cleanup of contaminated temperature-regulating fluid and / or contaminated reaction liquid.

[0031] When multiple delivery capillaries are used in the device for guiding the temperature-controlled fluid during measurement, if a delivery capillary malfunctions and requires replacement, the remaining delivery capillaries can continue to be temperature-controlled. Measurements of the reaction liquid in the remaining delivery capillaries can then be easily and uninterrupted.

[0032] The inner and outer sub-tubes are radially closed sub-tubes. The delivery capillary is arranged radially within the inner sub-tube. By achieving shape consistency between the radially inner sub-tube and the delivery capillary arranged radially within it, effective and uniform temperature control of the delivery capillary (and therefore the reaction liquid) using a temperature-regulating fluid can be achieved. The efficiency of temperature control can be further improved by reducing the distance between the inner sub-tube and the delivery capillary.

[0033] The hose section can be made of chemically inert plastic (e.g., PTFE). This prevents damage to the corresponding hose section due to spilled reactive liquid in the event of a capillary leak.

[0034] Depending on the required temperature range of the reaction liquid, deionized water (VE water), 2-propanol (isopropanol), or temperature-regulating oil can be used as the temperature-regulating fluid. The temperature-regulating fluid can be guided through a device for guiding the temperature-regulating fluid by means of a temperature-regulating fluid pump (“fluid pump”).

[0035] Preferred embodiments and improvements of the present invention

[0036] In a particularly preferred embodiment of the monitoring device according to the invention, the inner sub-hose and the outer sub-hose are arranged concentrically. This arrangement is easily implemented and has been established in practice. Through a uniform radial spacing between the inner and outer sub-hose, the temperature-regulating fluid can be uniformly distributed in the intermediate space between them. Therefore, uniform temperature regulation of the fluid entering and exiting the delivery capillary can be achieved.

[0037] An embodiment of a preferred category of the monitoring device according to the invention is characterized in that the internal sub-hose is geometrically configured such that the inlet and outlet delivery capillaries can be inserted into and pulled out of the internal sub-hose.

[0038] Therefore, the entry and exit capillaries can be replaced quickly and easily, for example, in the event of blockage or damage to the corresponding capillary. Thus, it is not necessary to first disassemble the device used to guide the temperature-regulating fluid in order to replace the corresponding capillary.

[0039] In a preferred improvement of this type of implementation, the inner diameter of the inner sub-tube is designed to be greater than or equal to the outer diameter of the corresponding inlet or outlet capillary. When the inner diameter of the inner sub-tube is greater than the outer diameter of the corresponding inlet or outlet capillary, the corresponding inlet or outlet capillary can be comfortably inserted into the inner sub-tube. When the inner diameter of the inner sub-tube is approximately equal to the outer diameter of the corresponding inlet or outlet capillary, the corresponding inlet or outlet capillary can be arranged flush within the inner sub-tube. The inner sub-tube and the corresponding inlet or outlet capillary are in direct contact with each other, thereby effectively transferring the temperature of the temperature-regulating fluid. Furthermore, it makes sliding of the corresponding inlet or outlet capillary difficult.

[0040] Furthermore, preferred extensions of these improvements are characterized in that at least the inner sub-tube is made of a material having a sliding material having a coefficient of friction μ≤1, preferably μ≤0.1, especially μ≤0.05, and / or at least the inner sub-tube is made of an expandable material.

[0041] Therefore, the corresponding inlet or outlet delivery capillary can be inserted into the inner sub-tube with particularly simple and comfortable low-friction operation. In the inner sub-tube made of an expandable material, the corresponding delivery capillary can be inserted into the inner sub-tube as the expandable material expands. Furthermore, the expandable material can be tightly placed around the corresponding delivery capillary. The temperature of the temperature-regulating fluid can then be transferred to the corresponding delivery capillary with minimal loss, and the delivery capillary can be stably held in position.

[0042] Also preferred are embodiments in which the double-walled hose sections used for guiding the temperature-regulating fluid around the inlet and outlet of the delivery capillary are constructed as a modular system. This modular system is adaptable to different user requirements, NMR spectrometers, and environments, and the double-walled hose sections exist as respective independent, and particularly replaceable, units within this modular system. This modular construction of the double-walled hose sections offers wide applicability and high flexibility for various situations. It eliminates the need for time-intensive modifications to the device guiding the temperature-regulating fluid. Because the double-walled hose sections are constructed as independent units, they can be easily replaced, for example, in case of damage or leakage. These independent units save costs and avoid time-intensive maintenance.

[0043] Furthermore, an extension of this type of implementation is preferred, wherein the double-walled hose sections are implemented as self-contained units with predetermined lengths, particularly having a length of 2m.

[0044] The double-walled hose section can be standardized and mass-produced in this way. Therefore, replacing the double-walled hose section is greatly simplified. The device used to guide the temperature-regulating fluid also remains almost unchanged after replacement.

[0045] Also particularly preferred are the following embodiments of the monitoring device according to the invention, wherein the means for guiding the temperature-regulating fluid around the inlet and outlet delivery capillary includes end components for connecting a double-walled hose section to a fluid pump.

[0046] This is easily achieved in practice: the end component, and therefore the double-walled hose section, can be easily connected to a pump unit, via which temperature-regulating fluid can be supplied for the double-walled hose section. Furthermore, the end component improves the stability of the device used to guide the temperature-regulating fluid.

[0047] In preferred embodiments of these implementations, at least a portion of the end components are configured as multiple variations for simultaneously receiving multiple inlet or outlet delivery capillaries of different reaction liquids.

[0048] Therefore, these end components are configured such that multiple reaction liquids can be simultaneously guided through a device for guiding temperature-controlled fluids via either entry or exit from the delivery capillary. The multiple reaction liquids can then be guided, for example simultaneously or sequentially for short periods, into a hollow NMR sample probe for measurement. This saves time and cost. Furthermore, new and structurally different experimental setups can be designed in a simple manner.

[0049] Preferred developments of these improved solutions are characterized in that the multivariable end component is configured to receive multiple, preferably three, inlet or outlet capillaries, but can only receive one double-walled hose section. All received capillaries can be simultaneously temperature-regulated by the hose section through the temperature-regulating channel of the multivariable end component via a zigzag extension.

[0050] By enabling the acceptance of multiple inlet or outlet capillaries within the multivariable end component, different temperature-controlled reaction liquids can be simultaneously introduced into and extracted from a hollow NMR sample probe. Uniform temperature control of all accepted capillaries can be achieved using only a single double-walled flexible tube section. This double-walled flexible tube section is designed to seamlessly accept or exit multiple inlet or outlet capillaries.

[0051] Preferably, in these extended embodiments, the multivariable end component is provided with two opposing end sections configured to receive two different capillaries and to connect one double-walled flexible tube section; at least two correspondingly opposite intermediate sections are provided, in which only one capillary can be inserted respectively; and the end sections are connected to the intermediate sections such that the double-walled flexible tube sections connected to the respective end sections are connected to the intermediate sections arranged directly adjacent to the end sections.

[0052] This structure has proven particularly successful in practice. It reduces the space requirements of the two opposite end sections and optimizes the use of existing space because it includes not only receiving portions for the two different capillaries but also connectors for a corresponding double-walled hose section. Space is also optimally utilized in the at least two correspondingly opposite intermediate sections, and double-walled hose sections connected to the respective end sections can be guided through.

[0053] Furthermore, preferably, in these extended embodiments, intermediate sections are arranged between each end segment and intermediate segment on one side of the multivariable end component and each end segment and intermediate segment on the opposite side of the multivariable end component. A single capillary is guided through each of these intermediate sections, and the capillary is surrounded by the temperature-regulating channel of the multivariable end component. The intermediate sections protect the individual capillaries from damage and environmental influences. Furthermore, the device for guiding the temperature-regulating fluid is further stabilized by the intermediate sections.

[0054] Also preferred is an improved embodiment of the monitoring device according to the present invention, wherein the outer sub-tube and inner sub-tube of the double-walled flexible tube section are inserted into the end component at different distances, and preferably the inner sub-tube is inserted into the end component for a longer length than the outer sub-tube.

[0055] In this way, the corresponding capillary inserted into the inner sub-tube can be sealed particularly easily relative to the outer sub-tube and the temperature-regulating fluid passing between the outer and inner sub-tubes. Furthermore, the temperature-regulating fluid can be guided effortlessly into the intermediate space between the inner and outer sub-tubes.

[0056] In another particularly preferred embodiment of the monitoring device according to the invention, the delivery capillary tubes have uniform external dimensions. This allows for a unified design of the structure of the device for guiding the temperature-regulating fluid and facilitates the use of the monitoring device according to the invention.

[0057] Also preferred is the embodiment in which the delivery capillary is made of a chemically inert plastic, preferably PTFE. This ensures that the delivery capillary is not damaged or contaminated by the reaction liquids generated in the reaction vessel, and that unusable components in the measurements do not escape from the delivery capillary.

[0058] Further advantages of the invention become apparent from the specification and drawings. The illustrated and described embodiments should not be construed as exhaustive, but rather as having exemplary features for describing the invention. Attached Figure Description

[0059] The invention is illustrated in the accompanying drawings and explained in detail with reference to embodiments.

[0060] In the attached diagram:

[0061] Figure 1a A perspective view from an oblique top is shown of a first embodiment of a device for guiding temperature-regulating fluid according to a monitoring device of the present invention, which has end parts configured to receive multiple variations of the device entering or exiting the delivery capillary.

[0062] Figure 1b A perspective view of a second embodiment of a device for guiding temperature-regulating fluid in a monitoring device according to the present invention is shown, having an end member configured to receive only one single variant entering or exiting the delivery capillary.

[0063] Figure 2 Show Figure 1a A portion of a schematic longitudinal sectional view of the device for guiding temperature-regulating fluid is shown therein in plane A;

[0064] Figure 3 Show Figure 1a A portion of a schematic longitudinal sectional view of the device for guiding the temperature-regulating fluid, shown therein in plane B, perpendicular to plane A; and

[0065] Figure 4 A schematic measurement structure is shown for performing NMR measurements using an NMR spectrometer when using the monitoring equipment according to the invention. Detailed Implementation

[0066] exist Figure 1a The diagram shows a perspective view of a first embodiment of a device 10 for guiding temperature-regulating fluid around an inlet and outlet delivery capillary according to a monitoring device of the present invention. In the embodiment shown here, the device 10 includes two end members 11a, 11b, with three intermediate members 12a, 12b, 12c arranged between the two end members. Furthermore, two mutually perpendicular cross-sections A and B are plotted.

[0067] Here, end component 11a has a fluid connector 13a, and end component 11b has a fluid connector 13b. The device 10 for guiding the temperature-regulating fluid is connected to a fluid pump via fluid connectors 13a and 13b, through which the temperature-regulating fluid can be introduced into and withdrawn from the device 10 (see [reference needed]). Figure 4 In the embodiment shown here, a temperature regulating channel and a double-walled hose section extend within the device 10. The temperature regulating channel extends in a zigzag pattern within the end members 11a, 11b, and the double-walled hose section extends within the intermediate members 12a, 12b, 12c between the end members 11a, 11b (see for details). Figure 2 ).

[0068] Temperature-regulating fluid is guided through the device 10 via a temperature-regulating channel and a double-walled hose section. Here, the temperature-regulating fluid is introduced at the fluid connector 13a and guided via the intermediate member 12a to the end member 11b. From there, the temperature-regulating fluid is guided back to the end member 11a via the intermediate member 12b. The temperature-regulating fluid is then guided from the end member 11a to the fluid connector 13b via the intermediate member 12c and exited from the device 10. This achieves uniform temperature regulation throughout the device 10.

[0069] Figure 1a The end components 11a and 11b are configured as multiple variants (“multi-variant end components”) 14a and 14b, through which multiple inlet or outlet delivery capillaries can be received. In the embodiment shown here, no delivery capillaries are inserted into the multiple-variant end components 14a and 14b. However, in other embodiments not shown, one, two, or three delivery capillaries may be inserted into the multiple-variant end components 14a and 14b. For example, two inlet delivery capillaries with different reaction liquids and one outlet delivery capillary for discharging the reaction liquid may be inserted into the multiple-variant end components 14a and 14b.

[0070] Furthermore, in the embodiment shown here, the end components 11a, 11b have three capillary receiving portions 15a, 15b, 15c. The capillary receiving portions 15a, 15b, 15c are connected to a guide passage portion that guides the end components 11a, 11b and intermediate components 12a, 12b, 12c (not shown in detail).

[0071] Here, the multi-variant end component 14a has two opposite end sections 16a' and 16c' and an intermediate section 17b', and the multi-variant end component 14b has two opposite end sections 16a' and 16c' and an intermediate section 17b'. End sections 16a' and 16a' include a fluid connector 13a, a capillary receiving portion 15a, and an intermediate member 12a. End sections 16c' and 16c' include a fluid connector 13b, a capillary receiving portion 15c, and an intermediate member 12c. Intermediate sections 17b' and 17b' include a capillary receiving portion 15b and an intermediate member 12b. End section 16a' is connected to intermediate section 17b', and end section 16c' is connected to intermediate section 17b'.

[0072] The two end components 11a and 11b, as shown in the embodiment, each have two square structural elements. The three intermediate components 12a, 12b, and 12c have columnar structural elements.

[0073] exist Figure 1bThe image shows a perspective view of a second embodiment of a device 10 for guiding temperature-regulating fluids into and out of a delivery capillary tube according to a monitoring device of the present invention. In the embodiment shown here, the device 10 includes two end parts 11a, 11b, with an intermediate member 12 arranged between the two end parts.

[0074] Here, end component 11a has a fluid connector 13a, and end component 11b has a fluid connector 13b. The device 10 for guiding the temperature-regulating fluid is connected to a fluid pump via fluid connectors 13a and 13b, through which the temperature-regulating fluid can be introduced into and withdrawn from the device 10 (see [reference needed]). Figure 4 The temperature control channel extends within the end components 11a and 11b, and the double-walled flexible hose section extends within the intermediate component 12b between the end components 11a and 11b (see for details). Figure 2 ).

[0075] Temperature-regulating fluid is guided through the device 10 via a temperature-regulating channel and a double-walled hose section. The temperature-regulating fluid is introduced at the fluid connector 13a on the end member 11a and guided via the intermediate member 12 to the fluid connector 13b on the end member 11b. This enables uniform temperature regulation within the device 10.

[0076] Here, the end components 11a and 11b are configured as single variants (“single variant end components”) 18a and 18b, which can receive a single entry into or exit from the delivery capillary. However, in the embodiment shown here, no delivery capillary is inserted into the single variant end components 18a and 18b.

[0077] In addition, Figure 1b In the illustrated embodiment, end members 11a and 11b have capillary receiving portions 15. The capillary receiving portions 15 are connected to a guiding passage portion that guides the end members 11a and 11b and the intermediate member 12 (not shown in detail).

[0078] The two end components 11a and 11b in the embodiment shown here are each constructed as a square structural element, and the intermediate component 12 is constructed as a columnar structural element.

[0079] Figure 2 Show Figure 1a The device 10 is shown in a schematic longitudinal sectional view in plane A. The longitudinal sectional view shows a portion of the end member 11a and a portion of the intermediate member 12a.

[0080] In the embodiment shown here, an outer sub-hose 19 is arranged centrally in the intermediate member 12a, the outer sub-hose extending slightly into the end member 11a and communicating with the outer sealing sleeve 20. Furthermore, an inner sub-hose 21 extends centrally in the intermediate member 12a within the outer sub-hose 19. The inner sub-hose 21 extends axially more than halfway into the end member 11a and communicates with the inner sealing sleeve 22. Here, in the intermediate member 12a, the inner sub-hose 21 is nested within the outer sub-hose 19. Here, the inner sub-hose 21 extends axially significantly beyond the outer sub-hose 19.

[0081] The outer sub-hose 19 is radially closed and has a cylindrical shape, as is the inner sub-hose 21. In the embodiment shown here, the inner sub-hose 21 has an inner diameter d that is typically about 0.16 cm. i The internal sub-hose 21 and the external sub-hose 19 are arranged co-centrally.

[0082] In the overlapping area of ​​the outer sub-hose 19 and the inner sub-hose 21, specifically in the intermediate member 12a and, to a lesser extent, in the end member 11a, the outer sub-hose 19 and the inner sub-hose 21 constitute a double-walled hose section 23. The double-walled hose section 23 includes an intermediate region 24 through which the temperature-regulating fluid 25 is guided. The double-walled hose section 23 is connected to the temperature-regulating channel 26.

[0083] In the embodiment shown here, a cylindrical inlet delivery capillary 105 is inserted into an inner sub-tube 21 via a capillary receiving portion 15a on an end member 11a. The inner sub-tube 21 is geometrically adapted to the cylindrical inlet delivery capillary 105. To facilitate easier insertion (and subsequent removal) of the inlet delivery capillary 105, the inner sub-tube 21 is made of a sliding material having a coefficient of friction μ < 0. Alternatively, the inner sub-tube 21 may also be made of an expandable material. In the embodiment shown here, the inlet delivery capillary 105 is made of PTFE. This chemically inert plastic ensures that the reactive liquid guided through the inlet delivery capillary 105 does not corrode the inlet delivery capillary 105 and, for example, does not cause leakage.

[0084] The outer diameter d of the capillary tube 105 enters ae Here it is approximately 0.16 cm. Therefore, the outer diameter d of the capillary tube 105 entering the capillary tube is... ae and the inner diameter d of the internal sub-tube 21 iThe situation is largely the same under these circumstances. Thus, the inlet delivery capillary 105 is flush with the inner sub-tube 21, thereby achieving good temperature regulation when the temperature-regulating fluid 25 flows in the intermediate region 24, and also ensuring a stable arrangement of the inlet delivery capillary 105 within the inner sub-tube 21. In another embodiment, not shown, the inner diameter d of the inner sub-tube 21... i It can be larger than the outer diameter d of the capillary tube 105. a .

[0085] To regulate the temperature of the inserted delivery capillary 105 and the reaction liquid transported therein, a temperature-regulating fluid 25 is introduced into the device 10 via fluid connector 13a. From there, the temperature-regulating fluid is then guided through temperature-regulating channel 26 into the middle region 24 of the double-walled hose section 23. The temperature-regulating fluid 25 is then withdrawn via fluid connector 13b (not shown in detail).

[0086] In the embodiment shown here, the double-walled hose section 23 exists as a separate, replaceable unit and is constructed as a modular component system. Furthermore, the double-walled hose section 23 exists here as a self-contained unit, having a length typically of 2m (only the first 10cm of the double-walled hose section 23 is shown in this figure).

[0087] Figure 3 Show Figure 1a The device 10 is shown in a schematic longitudinal sectional view in plane B, perpendicular to plane A. The longitudinal sectional view shows a portion of the end member 11a, namely the end section 16c' and the intermediate section 17b', as well as a portion of the intermediate members 12b and 12c. Figure 3 The configuration of the double-walled flexible section 23 in the middle is similar to Figure 2 The configuration of the double-walled flexible section 23 is consistent.

[0088] exist Figure 3 In the illustrated embodiment, the cylindrical inlet delivery capillary 105 has been inserted into the inner sub-tube 21' by the capillary receiver 15b on the end member 11a, and the cylindrical outlet delivery capillary 108 has been inserted into the inner sub-tube 21" by the capillary receiver 15c on the end member 11a. The inner sub-tube 21' is geometrically adapted to the cylindrical inlet delivery capillary 105, and the inner sub-tube 21" is geometrically adapted to the cylindrical outlet delivery capillary 108.

[0089] To facilitate easier insertion (and subsequent removal) of the delivery capillaries 105, 108, the inner sub-tubes 21', 21" are made of a sliding material with a coefficient of friction μ < 0.05. In the embodiment shown here, the delivery capillaries 105, 108 are made of PTFE.

[0090] The outer diameter d of the capillary tube 105 enters ae Here it is typically about 0.16 cm, the outer diameter d of the discharge delivery capillary 108. aa It is also approximately 0.16 cm. Therefore, the delivery capillaries 105 and 108 have the same external dimensions. The outer diameter d of the delivery capillaries 105 and 108 aa d ae and the inner diameter d of the internal sub-tubes 21', 21” i’ d i” (They are 0.16 cm each) and are roughly the same size. Thus, the delivery capillaries 105 and 108 are flush against the inner sub-tubes 21' and 21" respectively.

[0091] In order to uniformly and simultaneously regulate the temperature of the inserted delivery capillaries 105, 108 and the reaction liquid delivered therein, portions of the double-walled hose sections 23 are interconnected via temperature regulation channels 26.

[0092] Figure 4 A schematic measurement structure for performing NMR measurements using a monitoring device 100 according to the invention is shown. According to the invention, the monitoring device has a closed temperature-regulating loop for a temperature-regulating fluid 25, the loop being geometrically designed such that the temperature-regulating fluid 25 always flows in only one predetermined direction in each spatial region of the loop and that no reverse flow of the temperature-regulating fluid 25 occurs at the direct adjacency of the spatial regions.

[0093] A reaction liquid 102 is generated in a reaction vessel 101. The reaction liquid 102 is directed toward an NMR spectrometer 103 and into an NMR sample probe 104 therein, so that the chemical reaction can be measured in real time by means of NMR spectroscopy.

[0094] The reaction liquid 102 is delivered to the sample probe 104 via the inlet delivery capillary 105 (shown as a solid line here). For this purpose, the reaction liquid 102 is further guided into the NMR sample probe 104 via the pump device 106. The measured reaction liquid 102 is then guided into the reaction vessel 101 via the outlet delivery capillary 108 (shown as a dashed line here).

[0095] To ensure uniform temperature control of the reaction liquid 101 throughout the entire measuring structure, delivery capillaries 105 and 108 extend correspondingly through devices 10a, 10b, and 10c for guiding the temperature-regulating fluid in three sections 109, 110, and 112. In sections 109 and 110, only the delivery capillary 105 extends through devices 10a and 10b. In section 112, only the delivery capillary 108 extends through device 10c.

[0096] Temperature-regulating fluid is pumped (guided) into devices 10a, 10b, and 10c via fluid pump 113. Fluid pump 113 and devices 10a, 10b, and 10c are interconnected via fluid lines 114 (four fluid lines 114 shown as dashed lines in the example shown here). (For clarity, fluid connectors on devices 10a, 10b, and 10c are not shown). In the example shown here, the temperature-regulating fluid is first guided by fluid pump 113 clockwise through fluid lines 114 into device 10c, then into device 10a, from there into device 10b, and from there back to fluid pump 113. Therefore, a closed temperature-regulating loop is involved, thereby achieving uniform temperature control. In the example shown here, note that reaction vessel 101 and pump device 106 are not connected to fluid pump 113 via fluid lines 114. These fluid lines 114 are guided around reaction vessel 101 and pump device 106 in a manner configured as bypasses 115, respectively.

[0097] List of reference numerals

[0098] 10, 10a to 10c (devices for guiding temperature-regulating fluids)

[0099] Components at ends 11a and 11b

[0100] 12, 12a, 12b, 12c Middleware

[0101] 13a, 13b fluid connectors

[0102] 14a, 14b multiple variants, multiple variant end components

[0103] 15, 15a, 15b, 15c capillary receiving section

[0104] 16a', 16a (at the lower end) end section

[0105] 16c', 16c (at the upper end) end section

[0106] 17b', 17b” intermediate section

[0107] 18a, 18b single variants, single variant end components

[0108] 19 External Sub-Hose

[0109] 20 External sealing sleeve

[0110] 21, 21', 21” internal sub-tube

[0111] 22 Internal sealing sleeve

[0112] 23 (Double-wall type) hose section

[0113] 24 Middle Area

[0114] 25 Temperature-regulating fluid

[0115] 26 temperature control channels

[0116] 100 surveillance equipment

[0117] 101 Reaction Vessel

[0118] 102 reaction liquid

[0119] 103 NMR spectrometer

[0120] 104 NMR sample probe

[0121] 105 enters the delivery capillary

[0122] 106 Pump Unit

[0123] 108 discharge delivery capillary

[0124] Section 109 (between the reaction vessel and the pump unit)

[0125] Section 110 (between the pump unit and the NMR spectrometer)

[0126] Section 112 (between the NMR spectrometer and the reaction vessel)

[0127] 113 fluid pump

[0128] 114 fluid piping

[0129] 115 Bypass

[0130] d aa (Outer diameter of the discharge capillary)

[0131] d ae (Outer diameter of the capillary tube)

[0132] d i d i’ d i” (Inner diameter of the internal sub-tube)

[0133] Reference List

[0134] Publications considered for assessing patentability:

[0135] [0]FOLEY, David A. et al., “NMR flow tubes for online NMR reaction monitoring”, Analytical Chemistry, Vol. 86, No. 24, 2014, pp. 12008-12013

[0136] [1]DE102015206030B3≈EP3076197B1≈US9,476,848B1

[0137] [2]EP2407796B1≈US8,686,729B2

[0138] [3] InsightMR, Bruker Corporation, Billerica, Massachusetts, USA

Claims

1. A monitoring device (100) for measuring a reaction liquid (102) generated in a reaction vessel (101) in an NMR spectrometer (103), the monitoring device (100) having at least the following components: A hollow NMR sample probe (104) for receiving the reaction liquid (102) to be measured in the NMR spectrometer (103). An inlet delivery capillary (105) is used to receive the reaction liquid (102) from the reaction vessel (101) and to deliver the reaction liquid (102) from the reaction vessel (101) to the sample probe (104) via a pump device (106). Discharge capillary (108) for returning the reaction liquid (102) from the sample probe (104) to the reaction vessel (101). Devices (10, 10a to 10c) for guiding temperature-regulating fluid (25) around the inlet and outlet delivery capillaries (105; 108). The apparatus (10, 10a to 10c) for guiding the temperature-regulating fluid (25) around the inlet and outlet delivery capillaries (105; 108) has a hose section (23) that is double-walled and constructed of two nested, radially closed sub-hose sections (19; 21, 21', 21"), each including an outer sub-hose (19) and an inner sub-hose (21, 21', 21"), through which the temperature-regulating fluid (25) flows, and the inlet delivery capillary (105) or outlet delivery capillary (108) is arranged radially within the inner sub-hose (21, 21', 21"). Its features are, The monitoring device (100) has a closed temperature control loop for the temperature control fluid (25), the temperature control loop being geometrically designed such that the temperature control fluid (25) always flows in only one predetermined direction in each spatial region of the temperature control loop and that no reverse flow of the temperature control fluid (25) occurs at the direct adjacency of the spatial regions.

2. The monitoring equipment according to claim 1, characterized in that, The inner sub-tubes (21, 21', 21") and the outer sub-tube (19) are arranged co-centered.

3. The monitoring equipment according to claim 1, characterized in that, The inner sub-tubes (21, 21', 21") are geometrically configured such that the inlet delivery capillary (105) and the outlet delivery capillary (108) can be inserted into and pulled out of the inner sub-tubes (21, 21', 21").

4. The monitoring device according to claim 3, characterized in that, The inner diameter (d) of the inner sub-tubes (21, 21', 21) i d i’ d i” The outer diameter (d) of the corresponding inlet delivery capillary (105) or the corresponding outlet delivery capillary (108) is designed to be greater than or equal to the outer diameter of the corresponding inlet delivery capillary (105). ae d aa ).

5. The monitoring device according to claim 4, characterized in that, At least the inner sub-tubes (21, 21', 21") are made of a material having a sliding material having a coefficient of friction μ≤1, and / or at least the inner sub-tubes are made of an expandable material.

6. The monitoring device according to any one of claims 1 to 5, characterized in that, The double-walled hose section (23) of the device (10, 10a to 10c) for guiding the temperature-regulating fluid (25) around the inlet and outlet delivery capillaries (105; 108) is constructed as a modular system that can be adapted to different user requirements, NMR spectrometers (103) and environments, and the double-walled hose section (23) exists as a corresponding independent unit in the modular system.

7. The monitoring device according to claim 6, characterized in that, The double-walled hose section (23) is implemented as a self-contained unit with a predetermined length.

8. The monitoring device according to any one of claims 1 to 5, characterized in that, The device (10, 10a to 10c) for guiding the temperature-controlled fluid (25) around the inlet and outlet delivery capillaries (105; 108) includes end parts (11a, 11b) for connecting the double-walled hose section (23) to the fluid pump (113).

9. The monitoring device according to claim 8, characterized in that, At least a portion of the end components (11a, 11b) are configured as multiple variants (14a, 14b) for simultaneously receiving multiple inlet delivery capillaries or outlet delivery capillaries (105; 108) for different reaction liquids (102).

10. The monitoring device according to claim 9, characterized in that, The multiple variant end components (14a, 14b) are configured to receive multiple inlet or outlet delivery capillaries (105; 108), but the multiple variant end components can receive only one double-walled hose section (23), and all received capillaries can be simultaneously temperature-controlled through the hose section via a tortuous temperature-controlled channel (26) extending through the multiple variant end components (14a, 14b).

11. The monitoring device according to claim 10, characterized in that, The multiple variant end components (14a, 14b) have two opposite end sections (16a', 16a”, 16c', 16c”) configured to receive two different capillaries and to connect one double-walled flexible tube section (23) to each end section. They are provided with at least two correspondingly opposite intermediate sections (17b', 17b”) in which only one capillary can be inserted, and the end sections (16a”, 16c') are connected to the intermediate sections (17b', 17b”) such that the double-walled flexible tube section (23) connected to the corresponding end section (16a”, 16c') is connected to the intermediate section (17b', 17b”) which is directly adjacent to the end section (16a”, 16c').

12. The monitoring device according to claim 11, characterized in that, Intermediate members (12; 12a, 12b, 12c) are arranged between the end sections (16a', 16a”, 16c', 16c”) and the intermediate section (17b', 17b”) on one side of the multivariable end components (14a, 14b) and the end sections (16a', 16a”, 16c', 16c”) and the intermediate section (17b', 17b”) on the opposite side of the multivariable end components (14a, 14b). A single capillary is guided through these intermediate members, and the capillary is surrounded by the temperature-regulating channel (26) of the multivariable end components (14a, 14b).

13. The monitoring device according to claim 8, characterized in that, The outer sub-tube (19) and inner sub-tubes (21, 21', 21") of the double-walled hose section (23) are inserted into the end members (11a, 11b) at different distances.

14. The monitoring device according to any one of claims 1 to 5, characterized in that, The delivery capillary tubes have the same external dimensions.

15. The monitoring device according to any one of claims 1 to 5, characterized in that, The delivery capillary is made of chemically inert plastic.

16. The monitoring device according to claim 1, characterized in that, The monitoring device (100) is configured to examine chemical reactions using NMR spectroscopy.

17. The monitoring device according to claim 5, characterized in that, The sliding material has a friction coefficient μ≤0.

1.

18. The monitoring device according to claim 5, characterized in that, The sliding material has a friction coefficient μ≤0.

05.

19. The monitoring device according to claim 6, characterized in that, In the combined component system, the double-walled hose section (23) exists as a corresponding independent replaceable unit.

20. The monitoring device according to claim 7, characterized in that, The double-walled flexible hose section (23) is implemented as a self-contained unit with a length of 2m, each with a predetermined length.

21. The monitoring device according to claim 10, characterized in that, The multiple variant end components (14a, 14b) are configured to receive three inlet or outlet delivery capillaries.

22. The monitoring device according to claim 13, characterized in that, The inner sub-tube (21, 21', 21") is inserted into the end component for a longer length than the outer sub-tube (19).

23. The monitoring device according to claim 15, characterized in that, The delivery capillary is made of PTFE.

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