JP7414749B2 - Molecular sensors, molecular detection devices, and molecular detection methods - Google Patents

Description

Embodiments of the present invention relate to a molecular sensor, a molecular detection device, and a molecular detection method.

Sensing technology using odor (gas) sensors can quantify odors in the air. This technology is widely used for odor determination, measurement of volatile organic compounds (VOC) in the atmosphere, performance confirmation of air purifiers, trouble detection with equipment, etc. In recent years, there has been growing interest in applications such as detecting explosives, narcotics, and stimulants, which previously relied on dogs' sense of smell, and diagnosing specific diseases using exhaled breath. Therefore, it is desired to improve the performance of odor (gas) sensors.

Conventional gas sensing devices include Flame Ionization Detector (FID), Photo-lonization Detector (PID), and Infrared Gas Analyzer (Non-Dispersive Infrastructure-Red: NDIR). ) etc. can be mentioned. These devices need to be improved in terms of portability (smaller size and lighter weight), safety, light source lifespan, price, and material recognition. Development is progressing because it is advantageous for use.

Semiconductor gas sensors, which are representative of small sensors, measure gas concentration by utilizing changes in electrical properties such as electrical resistance that occur when oxygen adsorbed on metal oxides is consumed by reducing substances. In recent years, many types of metal oxides such as SnO ₂ , ZnO ₂ , In ₂ O ₃ , WO ₃ and V ₂ O ₃ have come to be used. Further, studies have been conducted to improve sensitivity and selectivity by doping these with Pd, Pt, Au, Ag, etc. However, sensitivity and selectivity are still not sufficient.

On the other hand, from the perspective of further improving the sensitivity, selectivity, simplicity, speed, reliability, stability, etc. of odor (gas) sensors, quartz crystal microbalance (QCM), surface acoustic wave ( Mass detection sensors using surface acoustic waves (SAW), micro cantilevers (MCL), and the like have also attracted attention in recent years. For example, in the case of QCM, a sensor has been proposed in which a sensitive film, such as an organic polymer, that adsorbs target molecules is formed on the device surface. When target molecules are adsorbed to the sensitive membrane, the mass of the membrane increases and the resonant frequency of the crystal oscillator changes. Since the amount of frequency change is proportional to the mass of the adsorbed analyte molecules, the concentration of the analyte molecules can be measured.

Japanese Patent Application Publication No. 2019-124700

Honghan Fei and Seth M. Cohen. , Chem. Commun. ,2014,50,4810-4812 Yongwu Peng et al, Chem. Mater. ,2016,28,14,5095-5101

The problem to be solved by the present invention is to provide a molecular sensor, a molecular detection device, and a molecular detection method that have improved sensitivity and selectivity and are easily reusable.

According to the embodiment, a molecular sensor is provided that includes a sensitive membrane in which a porous member and an ionic liquid coexist. Furthermore, a molecular sensor is provided that includes a sensitive membrane including a porous member and an ionic liquid held in the porous member. Molecular sensors can detect target molecules by measuring changes in physical quantities due to attachment of target molecules to a sensitive membrane.

FIG. 1 is a diagram showing an example of the molecular sensor of the first embodiment. FIG. 2 is a flowchart showing an example of the molecule detection method of the first embodiment. FIG. 3 is a diagram showing an example of the multi-molecule sensor of the first embodiment. FIG. 4 is a diagram showing an example of a radar chart obtained by the multi-molecule sensor of the first embodiment. FIG. 5 is a diagram showing an example of a molecular sensor according to the second embodiment. FIG. 6 is a block diagram showing an example of a molecule detection device according to the third embodiment. FIG. 7 is a block diagram showing an example of a molecule detection device according to the third embodiment. FIG. 8 is a flowchart showing an example of the molecule detection method of the third embodiment. FIG. 9 is a graph showing the amount of change in vibrational frequency detected by the molecule detection device of the third embodiment. FIG. 10 is a graph showing the results of the borneol detection experiments of Example 1, Comparative Example 1, and Comparative Example 2. FIG. 11 is a graph showing the results of the 2-methylisoborneol detection experiments of Example 2, Example 3, and Comparative Example 3. FIG. 12 is a graph showing the results of the ethanol detection experiments of Example 4, Comparative Example 4, and Comparative Example 5. FIG. 13 is a graph showing the results of the ethyl acetate detection experiments of Example 4, Comparative Example 4, and Comparative Example 5. FIG. 14 is a graph showing the results of the ethanol detection experiment of Example 5. FIG. 15 is a graph showing the results of the ethyl acetate detection experiment of Example 5. FIG. 16 is a graph showing the results of a toluene detection experiment in Example 5.

Embodiments will be described below with reference to the accompanying drawings. In addition, in each embodiment, the same code|symbol may be attached|subjected to the substantially same component part, and some descriptions may be abbreviate|omitted. The drawings are schematic, and the relationship between the thickness of each part and the planar dimension, the ratio of the thickness of each part, etc. may differ from the actual one.

According to embodiments, a molecular sensor for detecting target molecules that may be contained in a sample is provided. The molecular sensor according to the embodiment includes a sensitive membrane in which a porous member and an ionic liquid coexist. When target molecules adhere to the sensitive membrane, the physical quantities of the sensitive membrane change. The molecular sensor may further include a detection unit that measures a change in the physical quantity of the sensitive membrane.

Here, the target molecule will be explained. In this specification, "target molecule" refers to a molecule that can be detected by the molecular sensor according to the first embodiment. "Target molecule" does not necessarily refer to one type of molecule, but may refer to an aggregate of multiple types of molecules. The aggregate of multiple types of molecules may be, for example, a group of molecules that collectively constitute one type of odor. Molecular sensors can detect or distinguish between aggregates of multiple types of molecules.

(First embodiment)
The molecular sensor of the first embodiment has a measurement mechanism using a quartz crystal microbalance (QCM) as a detection section.

FIG. 1 shows an example of a molecular sensor 1 according to the first embodiment. FIG. 1(a) shows a plan view of the molecular sensor. FIG. 1(b) is a cross-sectional view taken along line B-B' in FIG. 1(a). FIG. 1(c) is an enlarged view of enclosure C in FIG. 1(a).

The molecular sensor 1 includes a QCM detection section 2 and a sensitive film 3 provided on the surface of the QCM detection section 2. The QCM detection unit 2 includes a disk-shaped crystal substrate 4 and two thin plate-shaped electrodes arranged with the crystal substrate 4 in between, that is, an upper electrode 5 and a lower electrode 6. As shown in FIG. 1A, for example, the upper electrode 5 includes an upper excitation part 5a that is concentric with the crystal substrate 4 and has a diameter smaller than that of the crystal substrate 4, and a part of the periphery of the upper excitation part 5a that connects the crystal. The upper drawer portion 5b extends to the periphery of the substrate 4. The sensitive film 3 is provided, for example, on the surface (upper surface) of the upper excitation section 5a opposite to the crystal substrate 4. The lower electrode 6 includes a lower excitation part 6a that is concentric with the crystal substrate 4 and has a smaller diameter than the crystal substrate 4, and a lower lead-out part 6b that extends from a part of the periphery of the lower excitation part 6a to the periphery of the crystal substrate 4. Be prepared. According to a further embodiment, the sensitive film 3 may also be provided on the surface (lower surface) of the lower excitation part 6a opposite to the crystal substrate 4.

The sensitive membrane 3 includes a porous member 7 and an ionic liquid 8 held in the porous member 7, as shown in the enlarged view ((c) of FIG. 1).

The porous member 7 is made of a porous material formed into a membrane, and has a large number of holes 7a. The size of the pores 7a is preferably about 50 nm or less in diameter. For example, the porous material is preferably a microporous material having micropores (about 2 nm or less in diameter) or a mesoporous material having mesopores (about 2 nm to about 50 nm in diameter).

The material of the porous member 7 is preferably a metal organic framework (MOF), a covalent organic framework (COF), an artificial zeolite, or the like. By using these materials, it is possible to easily grow and form an integral film.

It is preferable that the MOF has high heat resistance and high water resistance. In particular, it is preferable to use a MOF having a structure (described below) in which 12 dicarboxylic acids are coordinated to ₄ six-nuclear Zr ₆ O ₄ (OH) clusters.

上記構造中、○（白丸）は、Ｚｒ_６Ｏ_４（ＯＨ）_４クラスターを示し、実線は、ジカルボン酸配位子を示す。

In the above structure, the circle (white circle) indicates a Zr ₆ O ₄ (OH) ₄ cluster, and the solid line indicates a dicarboxylic acid ligand.

As the MOF having such a structure, it is preferable to use, for example, at least one of UIO-66, UIO-67, UIO-68, and derivatives thereof. In UIO-66, UIO-67, and UIO-68, the dicarboxylic acid ligands are 1,4-benzenedicarboxylic acid, 4,4'-biphenyldicarboxylic acid, and 4,4''-terphenyldicarboxylic acid, respectively. A derivative is one in which a new functional group is introduced to the benzene ring of the ligand contained in these derivatives.The functional group is, for example, an alkyl group, an amino group, a hydroxyl group, an alkoxy group, These include carbonyl groups such as amide groups, aldehyde groups, acyl groups, ester groups, and carboxyl groups.In addition, the derivatives are those in which the benzene ring of the ligand is substituted with a heteroaromatic ring such as a pyridine ring or an imidazole ring. Regarding UIO-67, instead of 4,4'-biphenyldicarboxylic acid, 9-fluorenone-2,7-dicarboxylic acid, fluorene-2,7-dicarboxylic acid, carbazole-2, It also includes those substituted with a heterocyclic compound such as 7-dicarboxylic acid.

These MOFs not only have high heat resistance and water resistance, but also have a wide choice of film forming methods, from microcrystals to thin films, and are easy to apply to the sensitive film 3. It is also excellent in that it is unlikely to dissolve or decompose even if it comes into contact with the ionic liquid 8. The six-nuclear Zr ₆ O ₄ (OH) ₄ cluster may be partially or completely dehydrated by heating under reduced pressure or the like, and may change into Zr ₆ O ₅ (OH) ₂ , Zr ₆ O ₆ , or the like. However, even if it has such a structure, it can be used without any problems, and if necessary, it can be adjusted to the state before dehydration.

Other MOFs such as MIL-53, MIL-101, MOF-74, ZIF-8, NU-1000, or CAU-24 can also be used.

The COF may have at least one of an imine bond, an azine bond, an enamine bond, a hydrazone bond, or an imide bond obtained by a condensation reaction between a ligand having an amino group and a ligand having an aldehyde group or a carbonyl group. preferable. For example, COFs include COF-LZU1, COF-300, TAPB-PDA-COF, COF-TpPa-1, DAAQ-TFP-COF, N ₃ -COF, ACOF-1, COF-42, COF-43, PI-COF. It is preferable to use at least one of PI-COF-1, PI-COF-2, PI-COF-3, PI-COF-4, PI-COF-5, and the like.

The chemical structures of the COFs listed above are shown below.

式中、ＣＯＦ－ＬＺＵ１、ＣＯＦ－３００及びＴＡＰＢ－ＰＤＡ－ＣＯＦの矢印はイミン結合（Ｒ_２Ｃ＝Ｎ－Ｒ）の位置を示し、ＣＯＦ－ＴｐＰａ－１、ＤＡＡＱ－ＴＦＰ－ＣＯＦの矢印はエナミン結合（Ｒ_２Ｃ＝ＣＲ－ＮＲ_２）を示し、Ｎ_３－ＣＯＦ及びＡＣＯＦ－１の矢印はアジン結合（Ｒ_２Ｃ＝Ｎ－Ｎ＝ＣＲ_２）を示し、ＣＯＦ－４２及びＣＯＦ－４３の矢印はヒドラゾン結合（Ｒ_２Ｃ＝Ｎ－ＮＲ_２）を示し、ＰＩ－ＣＯＦ－１～５の矢印はイミド結合（ＲＣＯ－ＮＲ－ＣＯＲ）を示す。式中、「Ｒ」は、水素、炭化水素基又は官能基を有する炭化水素基であり、式中に複数Ｒがある場合、各Ｒは同じ基であっても異なる基であってもよい。 The imine bond, azine bond, enamine bond, hydrazone bond, or imide bond contained in the COF listed above is shown below.

In the formula, the arrows of COF-LZU1, COF-300, and TAPB-PDA-COF indicate the positions of imine bonds (R ₂ C=NR), and the arrows of COF-TpPa-1, DAAQ-TFP-COF indicate the positions of enamine bonds. The arrows in N ₃ -COF and ACOF-1 indicate the azine bond (R ₂ C=N-N=CR ₂ ), and the arrows in COF-42 and COF-43 indicate the bond (R ₂ C=CR-NR ₂ ). Arrows indicate hydrazone bonds (R ₂ C=N-NR ₂ ), and arrows for PI-COF-1 to 5 indicate imide bonds (RCO-NR-COR). In the formula, "R" is hydrogen, a hydrocarbon group, or a hydrocarbon group having a functional group, and when there is a plurality of R in the formula, each R may be the same group or a different group.

These materials are easy to synthesize, have excellent heat resistance and water resistance, and are also excellent in that they are unlikely to dissolve or decompose even when they come into contact with the ionic liquid 8.

The porous member 7 is not limited to the above-mentioned materials, and activated carbon, mesoporous silica, etc. can also be used.

The porous member 7 may be, for example, formed from a porous material as a continuous, integral membrane. Further, in the case of a crystalline material, it may be a single continuous crystal. When such a porous member 7 is used, the risk of the sensitive membrane 3 collapsing due to physical stimulation such as vibration is reduced. As a result, more stable detection is possible.

Alternatively, the porous member 7 may be formed by gathering particulate or powdered porous materials and/or fragments of porous materials into a film shape, or the problem may be solved even if the porous member 7 is not in a film shape. do not have. The size of the particles, powder, and fragments is preferably sufficiently large compared to the diameter of the pores 7a of the porous member 7, for example, preferably 10 times or more the diameter. Such a porous member 7 has a large specific surface area. Therefore, more target molecules can be adsorbed, and detection sensitivity can be further improved.

The ionic liquid 8 is a salt consisting of an anion and a cation and having a melting point of 150° C. or lower. The type of ionic liquid 8 is not limited, but examples of anions include hydroxide ion, halogen anion, trifluoromethanesulfonyl, bis(trifluoromethanesulfonyl)imide, bis(fluorosulfonyl)imide, and tetrafluoroborate. , hexafluorophosphate, acetate, dicyanamide, p-toluenesulfonate, tetrachloroferrate, tetrachloroaluminate, tetrafluoroaluminate, hexafluoroantimonate, methanesulfonate, trifluoro(trifluoromethyl)borate, thiocyanate , diethyl phosphate, ethyl sulfate and the like. Examples of cations include organic ammonium, imidazolium, morpholium, phosphonium, piperidinium, pyridinium, pyrrolidinium, sulfonium, and the like.

Examples of the ionic liquid 8 include 1-butyl-3-methylimidazolium hexafluorophosphate (BMIM-PF ₆ ), 1-butyl-4-methylpyridinium hexafluorophosphate (BMPy-PF ₆ ), and 1-ethyl- 3-methylpyridinium ethyl sulfate (EMPy-ES), 1-ethyl-3-hydroxymethylpyridinium ethyl sulfate (EHMPy-ES), etc. can be used.

In this specification, the ionic liquid 8 coexisting with the porous member 7 refers to a state in which the ionic liquid 8 and the porous member 7 are provided in the sensitive membrane; 7 is at least partially in contact with. Being in contact means, for example, that the ionic liquid 8 is encapsulated inside the pores 7a of at least some of the porous members 7, and that the ionic liquid 8 is on the surface of the porous member 7 or in the vicinity of the porous member. Including the case where it exists outside of 7. When the porous member 7 is used as a molecular sensor, the detection sensitivity of target molecules is considered to vary depending on the shape and size of the pores 7a. Therefore, by making the ionic liquid 8 exist inside the pores 7a, the size of the space inside the pores 7a and the size of the interaction can be adjusted, so that the selectivity of target molecules adhering to the sensitive membrane 3, Specificity and also stability of detection may be improved. On the other hand, even when the ionic liquid 8 is present on or near the surface of the porous member 7, the target substance is adsorbed in two stages via the ionic liquid 8 and into the porous member 7, thereby increasing the selectivity of the target molecule. Specificity and stability of detection may also be improved. Moreover, when the surface shape of the porous member 7 has macroscopic irregularities, the surface area of the ionic liquid 8 can be substantially increased. Therefore, there is also the effect of increasing the probability of contact between the ionic liquid 8 and the target molecules.

To identify the state in which the ionic liquid 8 and the porous member 7 coexist, the sensitive membrane 3 is washed with a solvent such as methanol or ethanol that dissolves the ionic liquid 8 but does not dissolve the porous member 7. Then, only the ionic liquid is extracted and subjected to infrared spectroscopy such as IR (infrared spectroscopy), FTIR (Fourier transform infrared spectroscopy), NMR (nuclear magnetic resonance), GC-MS (gas chromatograph mass spectrometry), etc. It is possible to identify the On the other hand, the porous member 7 after cleaning can be analyzed by crystal structure analysis using XRD (X-ray diffraction method), surface and cross-sectional shape observation using SEM (Scanning Electron Microscope), and TEM (Transmission Electron Microscope), and EDX (Energy Dispersive X-ray Substances can be identified by comprehensively using elemental analysis (analysis), XPS (X-ray photoelectron spectroscopy), NMR (nuclear magnetic resonance), TGA (thermogravimetric analysis), BET method (specific surface area measurement), etc. .

When the ionic liquid 8 enters the pores 7a of the porous member 7, the pores 7a of the porous member 7 function as spaces having specific properties (for example, size, shape, and/or polarity). The characteristics of such a space can limit the type and amount of target molecules that enter the space. As a result, the type or amount of attached target molecules can be reflected in the amount of change in the physical quantity of the sensitive film 3, such as the mass, electrical resistance, or electrical conductivity. This may be one factor in which the molecular sensor 1 exhibits selectivity.

Here, a method for specifying that an ionic liquid is held in a porous member will be explained.
When the ionic liquid 8 is held inside the porous member 7, when a spectrum is obtained by infrared spectroscopy such as IR or FTIR, Raman spectroscopy, etc., due to the interaction between the ionic liquid 8 and the porous member 7, A shift may be observed in the spectrum of a specific wavelength (wavenumber). Further, a specific bond energy shift may be observed by XPS (X-ray photoelectron spectroscopy). Furthermore, compared to the porous member 7 alone, the pore volume and specific surface area may be reduced by the BET method or the like. Furthermore, when the ionic liquid 8 is completely encapsulated inside the porous member 7, analysis by DSC (differential scanning calorimetry) shows exothermic peaks and endothermic peaks due to crystallization and melting that can be seen in the ionic liquid 8 alone. may disappear due to the confinement effect. For example, by integrating these analyses, it can be determined that the ionic liquid 8 is held in the porous member 7. It is also possible to analyze the presence distribution of the ionic liquid 8 in the porous member 7 using TOF-SIMS (time-of-flight secondary ion mass spectrometry) or the like.
The characteristics of the space can be easily changed by adjusting the combination of types and/or quantity ratios of the porous member 7 and the ionic liquid 8. Since there are many types of porous members 7 and ionic liquids 8, there are a huge number of combinations, and a wide variety of sensitive membranes 3 can be manufactured. Therefore, the sensitive membrane 3 corresponding to various target molecules can be manufactured and can be applied to various fields.

The ratio of ionic liquid 8 to porous material 7 is, for example, 5×10 ⁻⁵ to 3 by weight. If the weight ratio is less than 5 × 10 ^-5 , the coexistence effect will be reduced or the effect will become unstable, and if the weight ratio is more than 3, the characteristics of the ionic liquid 8 will be the main one, so the porous The performance of material 7 is difficult to exhibit. A more preferred ratio of ionic liquid 8 to porous material 7 is in the range of 5×10 ⁻⁴ to 1.5 by weight.

The sensitive membrane 3 can be formed, for example, by dropping a dispersion containing the material of the porous member 7 and the ionic liquid 8 onto a desired member (for example, the upper electrode 5). Alternatively, after forming the porous member 7 into a film first, the ionic liquid 8 may be dropped onto the porous member 7. A diluent such as methanol may be added to the dispersion liquid or ionic liquid 8, and the diluted liquid may be removed by drying after film formation. Furthermore, when the porous member 7 is synthesized from raw materials, the ionic liquid 8 can be mixed in advance with the raw materials before synthesis and film formation.

It is preferable to heat the sensitive film 3 after film formation. Heating is desirably 100° C. or higher for the purpose of removing moisture and 200° C. or lower for avoiding decomposition. For example, heating is preferably carried out at about 120° C. for 2 hours, followed by cooling to room temperature. Further, in order to promote the diffusion of the ionic liquid 8 into the holes 7a, the heating may be performed under reduced pressure as appropriate.

For example, when manufacturing a plurality of sensitive films 3, after forming a plurality of porous members 7 in an array, different types of ionic liquids 8 are dropped onto each porous member 7 using an inkjet printer or a microdispenser. can be easily manufactured. Alternatively, the amount of the same type of ionic liquid 8 may be varied for each porous member 7 and dropped.

The upper electrode 5 and the lower electrode 6 are preferably made of, for example, Pt, Au, Ag, Cu, Mo, Ni, Ti, W, Al, ITO, AZO, or the like. Typically, a film in which a 200 nm Au layer is laminated on a 10 nm Ti layer is used. The upper electrode 5 and the lower electrode 6 do not need to have the shape shown in FIG. 1A as long as they can excite the crystal substrate 4.

The crystal substrate 4 is preferably AT-cut, for example. The crystal substrate 4 does not have to have a disc-like shape as shown in FIG. 1(a), but may have a polygonal shape or the like.

The dimensions of the QCM detection section 2 are not limited, and may be similar to those of a general QCM element. For example, the diameter of the crystal substrate 4 is preferably about 2 mm to 10 mm. Regarding the dimensions of the sensitive film 3, it is preferable that the sensitive film 3 is formed, for example, into a disk shape that is concentric with the upper excitation part 5a and has a smaller diameter when viewed from above. Although not limited to this, the diameter of the sensitive film 3 is preferably set to be, for example, 20% to 90% of the area of the crystal substrate 4. The thickness of the sensitive film 3 is preferably about 10 nm to 5 μm, for example.

The molecular sensor 1 also includes an AC power source (not shown) that applies voltage between the upper electrode 5 and the lower electrode 6 through lead wires, etc., and a frequency measuring device (not shown) that detects the frequency of the crystal substrate 4. It may further include.

-Molecular detection method Next, a method for detecting target molecules in a sample will be explained. Here, detecting may mean, for example, detecting the type and/or amount of the target molecule.

The sample is, for example, a solid or liquid that can generate molecules of interest. The solid or liquid sample may be one in which target molecules are generated at room temperature and atmospheric pressure. Alternatively, the sample may generate target molecules when exposed to air, when flowing a carrier gas such as N ₂ or argon, when heated, or the like. The types of samples are not limited, but include drugs, food and drink, drinking water, living things, fragrances, cargo or baggage, household goods, electrical appliances, and the like. Alternatively, the sample may be a gas. The gas sample is, for example, air, exhaled breath, exhaust gas, or gaseous fuel.

The target molecule is, for example, a chemical substance in a gaseous state. For example, target molecules include, but are not limited to, volatile organic compounds (VOC), oxygen, hydrogen, carbon dioxide, carbon monoxide, nitrogen, noble gases, hydrogen sulfide, ammonia, and nitrogen oxides. , acetylene, ethylene, methane, ethane, propane, etc. The target molecule may be, for example, a narcotic/stimulant, gunpowder, explosive, chemical weapon, fresh food, or a chemical substance generated from or contained in a specific animal, plant, or the like. Alternatively, 2-methylisoborneol, geosmin, etc., which are causative substances of mold odor, may be used.

As described above, the target molecule is not necessarily one type of molecule, but may include multiple types of molecules. The plurality of types of molecules may be, for example, a group of molecules constituting one odor.

The detection method according to the embodiment includes, for example, the following steps, as shown in FIG.
(S1) a contact step of bringing the target molecule into contact with the sensitive membrane 3;
(S2) a measurement step of measuring changes in the physical quantities of the sensitive film 3 due to attachment of the target molecule; and (S3) a determining step of determining the type or amount of the target molecule from the measurement results.

An example of the procedure of the detection method will be described below.

First, a molecular sensor 1 is prepared. Next, the target molecules are brought into contact with the sensitive membrane 3 by, for example, placing the molecular sensor 1 in an environment where the sample exists, bringing the sample close to the molecular sensor 1, or blowing or suctioning the sample. Contact step S1).

The target molecules can adhere to the sensitive film 3 through the contact step S1. If the target molecule is a molecule that easily adheres to the sensitive membrane 3, the target molecule can enter from the surface of the sensitive membrane 3 and penetrate into the inner pores 7a.

Next, physical quantities of the sensitive film 3 are measured using the QCM detection unit 2 (measurement step S2). For example, the measurement may be carried out over time before the contact step S1, and measurement data may be used when the amount of change in the measured value is maximum or a constant value (saturation value). Alternatively, a rate of change in measured values over a certain period of time may be used. Alternatively, the measurement need not be performed over time; in that case, the measurement may be performed at least two times, before and after the contact step S1.

According to a further embodiment, no measurement need be carried out before the contacting step S1. At that time, the physical quantity measurement value obtained in the past when the target molecule is not attached to the sensitive film 3 may be used as the measurement value before the contact step S1. Alternatively, as the measurement value before the contact step S1, a measurement value of a gas that does not contain the target molecule in a detectable amount, such as the atmosphere, may be used.

In the QCM detection unit 2, the mass of the sensitive film 3 can be measured by converting the vibration frequency of the crystal substrate 4 into an electrical signal and detecting it. After the contact step S1, the vibration frequency of the crystal substrate 4 changes due to the energy loss corresponding to the mass of the target molecules attached to the sensitive film 3, and thereby a changed electrical signal measurement value is obtained.

Next, the type or amount of the target molecule is determined using the measurement results obtained in the measurement step S2 (determination step S3). First, the amount of change in the measured value before and after the contact step S1 is calculated. For example, the amount of change is calculated by subtracting the measured value after the contacting step S1 from the measured value before the contacting step S1. The amount of change may be used in the next step as it is in the electrical signal, or may be converted into the amount of change in a physical quantity. Next, the type or amount of the target molecule is determined from the amount of change.

For example, before performing this detection method, by measuring in advance changes in physical quantities for multiple types of known standard target molecules for multiple types of sensitive membranes 3, target molecules that can be detected for each type of sensitive membrane 3 types can be associated with each other.

Therefore, if there is a change in the physical quantity of a sample using a specific sensitive membrane 3, by comparing it with the above correspondence, it can be determined that the target molecule contained in the sample is one of the standard target molecules that can be detected by the sensitive membrane 3. It can be determined that there is. Furthermore, if no change in the physical quantity is observed in the sample, the detection is repeated using other sensitive membranes 3, and by finding the sensitive membrane 3 in which the physical quantity has changed, the type of target molecule can be narrowed down. Can be done. This can be done at once by using a multi-molecule sensor including a plurality of molecular sensors, which will be described later.

It is also possible to determine the amount and concentration of target molecules using the molecular sensor 1. For example, using the sensitive membrane 3 associated with a specific standard target molecule, a calibration curve of the amount of change in the physical quantity of the sensitive membrane 3 is created using a plurality of concentrations of the standard target molecule. By comparing the amount of change in the sample with this calibration curve, it is possible to determine the concentration of the target molecule.

In a further embodiment, the molecule detection method may further include a heating removal step of removing target molecules attached to the sensitive film 3 by heating the sensitive film 3 after the measurement step S2. For example, heating is preferably performed at 80° C. to 200° C. for about 10 seconds to 600 seconds. By performing heating under these conditions, target molecules that have entered the sensitive film 3 can be easily released. Since the porous member 7 and the ionic liquid 8 have excellent heat resistance of, for example, 200° C. or higher, almost all of the target molecules can be removed without denaturing the structure of the sensitive membrane 3 even under such heating conditions. can. As a result, a decrease in sensitivity due to the remaining target molecules is prevented, and detection can be performed with high sensitivity again. For this reason, the molecular sensor 1 of the embodiment can be reused by a simple operation of heating, which is economical.

The molecular sensor 1 may include a temperature control device that heats the sensitive membrane 3.

According to the molecular sensor 1 of the embodiment, by changing the type and quantity ratio of the porous member 7 and the ionic liquid 8 as described above, the size, shape, polarity, etc. of the space to which target molecules adhere can be easily adjusted. Can be adjusted. Therefore, it is possible to provide a variety of sensitive membranes 3 for selectively and specifically detecting a variety of target molecules.

Further, the porous member 7 has a large number of pores 7a and has a large specific surface area. For example, the specific surface area is about ten m ² /g to several thousand m ² /g. By using such a porous member 7, a large number of spaces are formed into which the target molecules as described above can enter, and a larger number of target molecules can be adsorbed. Therefore, it is possible to perform detection with higher sensitivity.

In addition, since the molecular structure of the pores 7a of the porous member 7 has continuous chemical bonds in two or three dimensions, it is difficult to deform and is maintained almost uniformly throughout the porous member 7. . Therefore, there is little variation in the size, shape, and/or polarity of the space into which the target molecules enter as described above, and stable detection can be performed.

-Multi-molecule sensor According to a further embodiment, a multi-molecule sensor including a plurality of molecular sensors of different types is provided. Moreover, here, "the types are different from each other" means that the combinations of types and/or quantity ratios of the porous member 7 and the ionic liquid 8 used in the sensitive membrane 3 are different from each other. "Different from each other" does not necessarily mean that all molecular sensors are different, and includes some of them being the same.

FIG. 3 shows a multi-molecule sensor 10. The multi-molecule sensor 10 includes four types of molecular sensors 1a to 1d arranged in an array on a substrate 11. The molecular sensors 1a to 1d each have the same configuration as the molecular sensor 1 described above, and each includes a different type of sensitive film 3a to 3d. The other configurations may be the same.

In the multi-molecule sensor 10, changes in the physical quantities of the sensitive films 3a to 3d can be measured individually. For example, each of the molecular sensors 1a to 1d may be individually equipped with a frequency measuring device (not shown), or one frequency measuring device may sequentially measure each of the molecular sensors 1a to 1d one by one.

In the detection method using the multi-molecule sensor 10, for example, measurement is performed by bringing one type of sample into contact with the molecular sensors 1a to 1d at a time. As a result, four amounts of change (data a to d) corresponding to the molecular sensors 1a to 1d are obtained. When a plurality of data a to d are combined and recognized as one pattern, the pattern may differ depending on the type of target molecule. For example, by recording variation patterns for multiple types of standard target molecules in advance and comparing the patterns in the sample with those, if there are standard target molecules with similar patterns, it is determined that the same type of target molecules exist in the sample. can do.

The pattern can be, for example, a ratio of four amounts of change. Alternatively, for example, by representing the data a to d in a radar chart as shown in FIG. 4, the pattern can be obtained as a polygon with a specific shape. Since this shape may differ depending on the type of target molecule, the type of target molecule can be easily identified by performing the above comparison based on the shape.

It is also possible to determine the amount of target molecules based on the size of the entire pattern. For example, if the shape of a polygon on a radar chart is similar to a certain standard target molecule, but the size of the polygon is larger, the target molecule contained in the sample is the same type as the standard target molecule, but it is different from the standard target molecule. It can be seen that the amount is larger than that of

The number of molecular sensors included in the multi-molecule sensor is not limited to four, and two, three, or four or more may be arranged. Preferably, three or more molecular sensors are arranged. The more molecular sensors there are, the more accurately target molecules with similar chemical structures can be detected. It is also possible to reproduce the sense of smell of living things by arranging the same number of olfactory receptors as the living things. Further, the plurality of molecular sensors do not necessarily have to be arranged in an array, and may be arranged in a straight line, in a circle, at random positions, or the like.

According to a further embodiment, it is also possible to apply pattern recognition as described above and perform analysis using machine learning or the like to identify or differentiate the types of samples containing a plurality of types of target molecules. For example, a pattern can be obtained for each odor made of multiple chemical substances, such as the odor of roses and the odor of wine, using a multi-molecule sensor. By comparing the patterns of a plurality of known standard samples, it is possible to detect the type and amount of the sample from the pattern obtained from the sample. Furthermore, it is also possible to identify or distinguish between compounds that have slight compositional differences, such as different brands, even if they smell like the same wine.

The sensitive membrane of the multi-molecule sensor can be easily manufactured by forming a plurality of porous members 7 in an array and then dropping different ionic liquids 8 onto each porous member 7 using an inkjet printer or a microdispenser. Alternatively, the same type of ionic liquid 8 may be dropped in different amounts.

(Second embodiment)
According to the second embodiment, a molecular sensor having a measurement mechanism using a micro cantilever (MCL) as a detection section is provided.

FIG. 5 shows a molecular sensor 20 including an MCL detection section 21. 5(a) is a plan view of the molecular sensor 20, and FIG. 5(b) is a cross-sectional view of the molecular sensor 20 taken along the line B-B'.

The molecular sensor 20 in this example includes an MCL detection section 21 and a sensitive film 3 provided on the surface thereof.

The MCL detection unit 21 has an elongated rectangular shape when viewed from above, and has a fixed end 21a fixed to the support body 22 and a free end 21b that is not fixed. That is, it has a cantilever shape. The MCL detection unit 21 has a layered structure and includes a substrate 23 at the bottom layer. A lower electrode 24 is laminated on the substrate 23 . A piezoelectric body 25 is laminated on the lower electrode 24 . An elongated first upper electrode 26a and a second upper electrode 26b are laminated along two long sides of the piezoelectric body 25. Furthermore, a detection electrode 27 is stacked on the piezoelectric body 25 located on the fixed end 21a side between the first upper electrode 26a and the second upper electrode 26b.

The sensitive film 3 is preferably fixed to a portion of the uppermost surface of the MCL detection section 21 near the free end 21b. For example, the sensitive film 3 is fixed on the piezoelectric body 25 between the first upper electrode 26a and the second upper electrode 26b. Between the piezoelectric body 25 and the sensitive film 3, there is a conductive film such as an Au thin film (not shown), an insulating film such as SiO ₂ , a metal oxide film such as Al ₂ O ₃ or TiO ₂ , a silane coupling agent, and a self-organizing film. A monomolecular film or the like may be present.

The first upper electrode 26a, the second upper electrode 26b, and the lower electrode 24 are connected to an AC power source or the like, and apply an AC voltage to the piezoelectric body 25. Since the piezoelectric body 25 is deformed by voltage application, it expands and contracts with the alternating current voltage and vibrates at a predetermined resonant frequency. The detection electrode 27 detects the frequency of the piezoelectric body 25.

The substrate 23 is formed using silicon, glass, resin, etc., for example.

The upper electrode 26, the lower electrode 24, and the detection electrode 27 are formed using a metal material such as Pt, Au, Mo, W, or Al.

The piezoelectric body 25 is made of, for example, lead zirconate titanate (PZT), lead zinc niobate-lead titanate solid solution (PZN-PT), lead manganate niobate-lead zirconate titanate solid solution (PMnN-PZT), or aluminum nitride. (AlN), zinc oxide (ZnO), potassium sodium niobate (KNN), lithium niobate (LiNbO ₃ ), and the like.

The dimensions of the MCL detection section 21 are not limited, and may be similar to those of a general MCL element. For example, the dimensions of the sensitive film 3 when viewed in plan may be set to be 20% to 90% of the area of the MCL 21. The thickness of the cross section is preferably about 10 nm to 5 μm.

Such a molecular sensor 20 can also be used in the same detection method as in the first embodiment. In the molecular sensor 20, when a target molecule adheres to the sensitive film 3, an energy loss corresponding to the mass of the target molecule occurs, so that the resonant frequency of the piezoelectric body 25 changes. By measuring it with the detection electrode 27, the target molecule can be detected.

Furthermore, the molecular sensor 20 can also be a multi-molecule sensor. For example, a plurality of types of molecular sensors 20 having different configurations of the sensitive membranes 3 may be fixed to one support 22. Furthermore, a plurality of types of molecular sensors 20 having different configurations of the sensitive membranes 3 may be fixed to different supports.

Although an example using the QCM detection section 2 and the MCL detection section 21 has been described above, the detection section is not limited to these, and other measurement mechanisms may be used. It is preferable that the detection unit is a mechanism that can measure changes in the mass of the sensitive film 3, for example.

According to a further embodiment, a detection unit using surface acoustic waves (SAW) or the like is provided. The SAW detection unit includes, for example, two sets of interdigitated electrodes (IDE) arranged on the surface of the piezoelectric substrate at a desired interval. The sensitive membrane 3 can be arranged, for example, between two sets of electrodes on a piezoelectric substrate. When a target molecule adheres to the sensitive film 3, a change occurs in the propagation speed and amplitude of the surface acoustic wave propagating on the surface of the piezoelectric substrate, and by detecting this with two electrodes, the target molecule can be detected.

Alternatively, a detection section equipped with a mechanism capable of measuring changes in electrical resistance, impedance, electrical conductivity, etc. of the sensitive film 3 may be used. Such a detection unit uses, for example, a field effect transistor (FET), an interdigitated electrode (IDE), or the like.

For example, when using a FET, the sensitive film 3 can be arranged as a channel connecting, for example, a source electrode and a drain electrode. When using an IDE type sensor, the sensitive film 3 can be provided, for example, between or on the electrodes of the IDE.

(Third embodiment)
-Molecular Detection Device According to the third embodiment, a molecule detection device including any of the molecular sensors described above is provided. As shown in FIG. 6, the molecular detection device 100 includes a detection unit 101 including the molecular sensor 1 and a processing device 102.

The detection unit 101 includes an intake hole 30, a gas generator 31, a detection chamber 32, and an exhaust hole 33. Each of these members is connected, for example, by a flow path. The arrows in the figure represent the direction of gas flow.

A filter (not shown) may be provided between the intake hole 30 and the pump 35. The intake hole 30 and the gas generator 31 are connected, for example, by a flow path 34a. For example, a pump 35, a pressure regulator 36, and a mass flow controller 37 are installed in the flow path 34a in this order from the intake hole 30 side toward the gas generator 31.

The gas generator 31 includes, for example, a container 31a for accommodating a sample 38, a gas introduction pipe 31b for introducing atmospheric air taken in from the intake hole 30 into the container 31a, and a gas outlet for introducing gas from inside the container 31a. It includes a tube 31c and a sample inlet (not shown). The gas introduction pipe 31b is arranged, for example, to face the sample 38 housed at the bottom of the container 31a. The gas outlet pipe 31c is connected to the detection chamber 32 through a flow path 34c in which a three-way valve 39b is interposed.

A three-way valve 39a is interposed between the mass flow controller 37 and the gas introduction pipe 31b of the gas generator 31. One valve of the three-way valve 39a is connected to the gas introduction pipe 31b, and the other valve is connected to a flow path 34c connecting the gas outlet pipe 31c and the three-way valve 39b via a flow path 34b. A valve for preventing backflow to the gas generator 31 may be separately provided immediately before the flow path 34b is connected to the flow path 34c.

A flow path 34d is connected to the third valve of the three-way valve 39b. The other end of the flow path 34d is directly connected to the exhaust hole 33. The three-way valve 39b is switched to send gas to the detection chamber 32 when measuring, and is switched to send gas to the flow path 34d when not measuring, and discharges the gas from the exhaust hole 33. .

The detection chamber 32 houses the molecular sensor 1. The molecular sensor 1 analyzes target molecules contained in the gas sent from the gas generator 31. The detection chamber 32 may include a temperature adjustment device 32a for heating and cooling the sensitive membrane 3 of the molecular sensor 1. The detection chamber 32 may further include a power source (not shown) that applies voltage to the detection section of the molecular sensor 1.

The detection chamber 32 is connected to the exhaust hole 33 by a flow path 34e, so that the gas that has been analyzed is exhausted through the flow path 34e.

For example, the detection unit 101 further includes a driver 46 (see FIG. 7) that drives a pump 35, a pressure regulator 36, a mass flow controller 37, a three-way valve 39a, a three-way valve 39b, a temperature adjustment device 32a, and a power source according to a command from a CPU 40 (described later). You may prepare.

The detection chamber 32 may be formed into a cassette shape, for example, and may be attached to the detection unit 101 so as to be removable. In that case, the molecular sensor 1 can be replaced depending on the type of target molecule to be detected. Alternatively, there is no problem even if the detection chamber 32 is fixed to the detection unit 101. The molecular sensor 1 disposed in the detection chamber 32 may be the molecular sensor of any of the embodiments described above. Moreover, a plurality of molecular sensors may be set, and a multi-molecule sensor may be used.

The processing device 102 includes, for example, a CPU 40, a storage unit 41, an input device 42, and a display device 43, as shown in FIG. The processing device 102 may further include an interface (I/F) 44 that outputs the measured value from the molecular sensor 1 as an electrical signal to the storage unit 41, and an I/F 45 that outputs a drive signal to the driver 46. .

The CPU 40 controls each part of the detection unit 101 and the processing device 102 and calculates measured values according to a program.

The storage unit 41 stores programs executed by the CPU 40, information on the measured values output from the molecular sensor 1, calculation formulas and calibration curves used to calculate the measured values, and/or measured values or patterns of standard target molecules. Remember. The storage unit 41 includes a nonvolatile memory, such as a flash memory, and a volatile memory, such as a RAM.

The input device 42 includes a keyboard, a mouse, switches, buttons, etc. for inputting various information to the processing device 102.

The display device 43 includes a display that displays calculation results and the like as charts and text. Instead of providing the input device 42 and the display device 43 separately, a touch panel having a display function and an input function may be provided.

Each part within the processing device 102 is connected by, for example, a system bus 47.

The molecule detection device 100 does not need to include the gas generator 31. In that case, measurement can be performed by bringing the intake hole 30 closer to the sample 38, by further blowing or suctioning air, or by placing the molecule detection device 100 in a space where the sample 38 exists.

The molecular sensor 1 can be manufactured as a chip on the order of 1 mm. Further, the molecule detection device 100 can also be a portable device with a size on the order of several tens of centimeters.

A method of operating the molecule detection device 100 will be explained using FIG. 8.

First, carrier gas is vented into the detection chamber 32 (S101). The carrier gas is, for example, the atmosphere, but may be other gases. As the carrier gas, for example, N ₂ or argon gas connected to a cylinder or the like may be used. When using a cylinder, a pump is not used and it is directly connected to the pressure regulator 36.

For example, based on a command from the CPU 40, the three-way valve 39a is switched to the gas generator 31 side, the three-way valve 39b is switched to the detection chamber 32 side, and the pump 35 is driven through the driver 46. By driving the pump 35, the carrier gas is sent into the detection chamber 32 from the intake hole 30 through the flow path 34a, the gas generator 31, and the flow path 34c. Mass flow controller 37 controls the flow rate of carrier gas. By this operation, the gas previously contained in the detection chamber 32 is discharged to the outside from the exhaust hole 33.

Next, measurement is started using the molecular sensor 1 (S102). In the measurement, if the molecular sensor 1 is a sensor using QCM, a voltage is applied between the upper electrode 5 and the lower electrode 6, and the vibration frequency of the crystal substrate 4 is measured with a frequency measuring device. The obtained electrical signal (measured value of the carrier gas) is sent to the storage unit 41 at a constant sampling rate and stored therein.

Next, the sample 38 is placed into the container 31a from the sample inlet (not shown) of the container 31a of the gas generator 31 (S103). The carrier gas is discharged from the gas introduction pipe 31b of the gas generator 31 toward the sample 38 in the container 31a, and is discharged from the gas discharge pipe 31c to the flow path 34c. At this time, target molecules generated from the sample 38 are also mixed and discharged from the gas outlet pipe 31c together with the carrier gas. The carrier gas containing target molecules that has flowed into the flow path 34c is vented into the detection chamber 32 (S104).

In the molecular sensor 1, the vibration frequency of the crystal substrate 4 changes due to the adsorption of target molecules onto the sensitive film 3. Thereafter, the carrier gas containing the target molecules is exhausted from the exhaust hole 33 through the flow path 34e. If the sample 38 does not enter the container 31a, the three-way valve 39a may be switched to allow the carrier gas to flow into the flow path 34b, and the suction hole 30 may be brought close to the sample 38 to perform suction.

Next, the sample 38 is taken out from the gas generator 31 (S105). This allows carrier gas that does not contain target molecules to be vented into the detection chamber 32 . If target molecules remain in the container 31a, the carrier gas can be quickly vented into the detection chamber 32 by switching the three-way valve 39a to the flow path 34b side.

Next, the temperature control device 32a is driven by a command from the CPU 40 to heat the sensitive film 3 (S106). As a result, the target molecules are removed from the sensitive membrane 3. Subsequently, the sensitive film 3 is cooled down to the original temperature by the temperature control device 32a. Note that it is also possible to remove the target molecules from the sensitive film 3 only by venting the carrier gas without performing the heating in step S106. Thereafter, the carrier gas containing the target molecules is exhausted from the exhaust hole 33 through the flow path 34e. After that, measurement with the molecular sensor is stopped (S107).

After that, if there are other samples to be measured (S108, Yes), the process may return to step S102 and the measurement may be performed again. If there are no more samples to be measured and the measurement is to be completed (S108, No), the drive of the pump 35 is stopped and the ventilation of the carrier gas is stopped (S109).

On the other hand, after completing the measurement in step S107, the CPU 40 retrieves the stored measured values and arithmetic expressions from the storage unit 41 and calculates the amount of change in the measured values. For example, as shown in FIG. 9, the data to be analyzed can be obtained by subtracting the carrier gas measurement value (baseline) obtained in step S102 from the maximum value or saturation value of the measurement value obtained in step S104. It may also be the amount of change in vibration frequency that can be obtained. This means the total amount of target molecules adsorbed onto the molecular sensor 1. Alternatively, the data to be analyzed may be the slope of the rise of the vibration frequency obtained in step S104. This means the rate of adsorption of target molecules onto the molecular sensor 1. Alternatively, the data to be analyzed may be the slope of the fall of the vibration frequency in step S106. This means the desorption rate of the target molecule from the molecular sensor 1. Alternatively, it may be the vibration frequency change amount that can be obtained by subtracting the measured value (baseline) obtained at the end of step S106 from the maximum value or saturation value obtained in step S104. This means the total amount of target molecules desorbed from the molecular sensor 1. These amounts of change are output from the CPU 40 to the storage section 41 and stored therein. When the detection chamber 32 includes a plurality of molecular sensors, the CPU 40 further calculates a variation pattern for each molecular sensor, and outputs and stores the pattern in the storage unit 41.

Subsequently, the CPU 40 retrieves the amount of change and the calculation formula, if necessary, a calibration curve, a measured value or pattern of a standard target molecule, etc. from the storage unit 41, and determines the type and/or amount of the target molecule. The determination result is output from the CPU 40 to the storage unit 41 and stored therein. The determination result may be output to the display device 43.

When measuring multiple samples, the results are output for each of the multiple samples in order.

The data processing, calculation, and analysis described above do not necessarily need to be performed using the CPU 40 and storage unit 41 within the molecule detection device 100, and may be performed using external hardware. Alternatively, data processing, computation and analysis may be performed using the cloud via a network. In that case, the molecule detection device 100 may include a data transmitter and a data receiver (not shown).

According to the molecule detection device described above, target molecules can be detected with improved sensitivity and selectivity. In addition, it is easily reusable and can be used repeatedly, which is advantageous for field work.

[example]
Hereinafter, an example in which a QCM molecular sensor equipped with the sensitive membrane shown in Table 1 was manufactured and a target molecule was detected using it will be described.

(Manufacture of MOF/ionic liquid molecular sensor 1)
・Synthesis and activation of UIO-67 microparticles UIO-67 was developed by Honghan Fei and Seth M. Cohen. , Chem. Commun. , 2014, 50, 4810-4812. The synthesized crystals were filtered off by suction filtration. At this time, it was washed with dimethylformamide, a synthesis solvent, and then further washed with methanol. Next, it was dried under reduced pressure at 120° C. for 3 hours, and then stored under a purged state with N ₂ .

・Mixing with 1-butyl-3-methylimidazolium hexafluorophosphate (BMIM-PF ₆ ) 0.1 g of BMIM-PF ₆ and 0.2 g of UIO-67 activated above in a 100 ml flask. Then, methanol was added to dilute the total amount to 30 g. Thereafter, the mixture was stirred at room temperature for about 6 hours to obtain a MOF/ionic liquid dispersion.

- Film formation on QCM The MOF/ionic liquid dispersion obtained above was diluted with methanol and adjusted to 0.1 wt%. An appropriate amount of this solution was dropped onto the upper Au electrode (5 mmφ) of a QCM with a resonance frequency of 9 MHz using a micropipette, and then dried at 80° C. for 1 hour. This completely removed methanol and formed a MOF/ionic liquid composite film on the QCM electrode. Thereafter, in order to promote the diffusion of the ionic liquid into the MOF pores, it was heated at 120° C. for 2 hours under reduced pressure and cooled to room temperature to obtain the molecular sensor of Example 1.

Similarly, a MOF single film was formed on a QCM electrode to obtain a molecular sensor of Comparative Example 1. Further, a molecular sensor of Comparative Example 2 was obtained by forming an ionic liquid alone on a QCM electrode.

(Gas detection experiment)
Gas (borneol, the following formula) was detected using the molecular sensors of Example 1, Comparative Example 1, and Comparative Example 2.

These three types of molecular sensors were set in the detection chamber shown in FIG. 6, and an appropriate amount of borneol powder was introduced into the gas generator. A gas containing 0.75 ppm of borneol was then generated by bubbling laboratory atmosphere as a carrier gas at a flow rate of 1000 ml/min. The generated gas was sent onto a molecular sensor, and changes in the vibration frequency of the QCM were measured.

The results are shown in FIG. The graph shown in FIG. 10 shows the amount of change in the frequency of the oscillator (Hz/(ppm·μg)) in each molecular sensor when the value before contact with the sample is set to 0.

The frequency change amount of the molecular sensor of Example 1 was 75 Hz/(ppm·μg). On the other hand, in Comparative Example 1, the amount of change in frequency was approximately 6.6 Hz/(ppm·μg), and in Comparative Example 2, it was 5.3 Hz/(ppm·μg). The amount of change in Example 1 was about 10 times or more compared to Comparative Examples 1 and 2, indicating that the sensitivity was dramatically improved.

The above results showed that by using a porous member and a sensitive membrane containing an ionic liquid, target molecules can be detected with higher sensitivity than when either one of them is used. Furthermore, in the MOF/ionic liquid composite sensitive membrane, the flow and diffusion caused by the ionic liquid being a liquid are prevented by the combination with the MOF, which is thought to contribute to the stability of the sensor characteristics.

(Manufacture of MOF/ionic liquid molecular sensor 2)
- Formation of MOF/ionic liquid composite thin film The UIO-67 thin film was developed by Erika Virmani et al., J. Am. Chem. Soc. The film was formed with reference to 2018, 140, 4812-4819. Specifically, 0.66 mmol (213 mg) of ZrOCl _{2.8H 2} O, 0.66 mmol (159 mg) of biphenyl dicarboxylic acid, 7.8 g of acetic acid, 94 g of dimethylformamide, 1-butyl-3-methylimidazolium hexafluoro Two types of raw material solutions were obtained by weighing and mixing 11.7 mg and 117 mg of a dimethylformamide diluted solution (0.1 wt%) of phosphate (BMIM-PF ₆ ), respectively. A mixed solution of 0.8 ml of acetic acid and 4.2 ml of dimethylformamide was placed in a 100 ml glass container, and a Teflon (registered trademark) block with a side of 1 cm was placed at the bottom of the container. A QCM board was placed on the top of the Teflon block. An appropriate amount of the above raw material solution was dropped onto the QCM substrate using a microsyringe. The glass container was gently placed in an oven and heated at 100° C. for 3 hours. Furthermore, it was taken out from the glass container and heated on a hot plate in the atmosphere at 120°C for 2 hours to remove excess solvent and water. In this way, UIO-67 is formed in a self-organized manner while the raw material solution is dried in a solvent atmosphere, and at the same time, the ionic liquid (BMIM-PF ₆ ) coexists. Since the molecular formula of UIO-67 is represented by Zr ₆ O ₄ (OH) ₄ (C ₁₄ H ₈ O ₄ ) ₆ , the theoretical weight of UIO-67 when 100% of the raw materials are reacted is assumed to be 234 mg. Therefore, the mass ratio of ionic liquid (BMIPF ₆ ) to UIO-67 is 5×10 ⁻⁵ and 5×10 ⁻⁴ , respectively. In this way, molecular sensors of Example 2 with a mass ratio of 5×10 ⁻⁵ and Example 3 with a mass ratio of 5×10 ⁻⁴ were obtained. Further, a UIO-67 single film was formed on the QCM electrode in the same manner as above except that no ionic liquid was included, to obtain a molecular sensor of Comparative Example 3 (mass ratio is 0).

(Gas detection experiment)
Gas (2-methylisoborneol, the following formula) was detected using the molecular sensors of Example 2 and Comparative Example 3.

These three types of molecular sensors were set in the detection chamber shown in FIG. 6, and an appropriate amount of 2-methylisoborneol powder was introduced into the gas generator. A gas containing an average of 54 ppb of 2-methylisoborneol was then generated by bubbling laboratory atmosphere as a carrier gas at a flow rate of 200 ml/min. The generated gas was sent onto a molecular sensor, and changes in the vibration frequency of the QCM were measured. Since the frequency change of QCM was very slow, it was decided to evaluate the rate of frequency change per unit time. The graph shown in FIG. 11 shows the frequency change rate (Hz/(min·μg)) per unit weight of the MOF film in each molecular sensor.

The frequency change rate of the molecular sensor of Example 2 was 0.140 Hz/(min·μg). Further, the frequency change rate of the molecular sensor of Example 3 was 0.179 Hz/(min·μg). On the other hand, in Comparative Example 3, the frequency change rate was 0.088 Hz/(min·μg). In this example, the effect of improving sensitivity appeared with a very small amount of 5×10 ⁻⁵ or 5×10 ⁻⁴ in mass ratio to MOF. The reason for this is thought to be that the ionic liquid existed on the surface of the MOF rather than inside the MOF, promoting the initial adsorption of 2-MIB molecules.

(Manufacture of COF/ionic liquid molecular sensor 1)
-Synthesis of COF-LZU1 COF-LZU1 was synthesized as described by Yongwu Peng et al., Chem. Mater. Synthesized with reference to 2016, 28, 14, 5095-5101. The synthesized crystals were filtered off by suction filtration. At this time, it was washed with anhydrous THF, anhydrous acetone, and anhydrous dichloromethane, dried under reduced pressure at 120° C. for 3 hours, and then stored in a state purged with N ₂ .

・Mixing with BMIM-PF ₆ Into a 100ml flask, put 0.1g of BMIM-PF ₆ and 0.2g of COF-LZU1 activated above, and then add methanol to make a total of 30g. Diluted. Thereafter, the mixture was stirred at room temperature for about 6 hours to obtain a COF/ionic liquid dispersion.

- Film formation on QCM The COF/ionic liquid dispersion obtained above was diluted with methanol and adjusted to 0.1 wt%. An appropriate amount of this solution was dropped onto the upper Au electrode (5 mmφ) of a QCM with a resonance frequency of 9 MHz using a micropipette, and then dried at 80° C. for 1 hour. This completely removed methanol and formed a COF/ionic liquid composite film on the QCM electrode. Thereafter, in order to promote diffusion of the ionic liquid into the COF pores, it was heated at 120° C. for 2 hours under reduced pressure and cooled to room temperature to obtain the molecular sensor of Example 4.

Similarly, a MOF single film was formed on the QCM electrode to obtain a molecular sensor of Comparative Example 4. In addition, a molecular sensor of Comparative Example 5 was obtained by forming an ionic liquid alone on a QCM electrode.

(Gas detection experiment)
Gases (ethanol and ethyl acetate) were detected using the molecular sensors of Example 4, Comparative Example 4, and Comparative Example 5. These three types of molecular sensors were set in the detection chamber shown in FIG. 6, and an appropriate amount of ethanol or ethyl acetate was introduced into the gas generator. Gases containing up to 426 ppm of ethanol and up to 192 ppm of ethyl acetate were then generated by bubbling laboratory air as a carrier gas at a flow rate of 200 ml/min. The generated gas was sent onto a molecular sensor, and changes in the vibration frequency of the QCM were measured.

The results for ethanol are shown in FIG. 12, and the results for ethyl acetate are shown in FIG. 13. Each graph shows the amount of change in frequency (Hz/(ppm·μg)) per unit weight of the sensitive membrane of the vibrator when the value before contact with the sample in each molecular sensor is set to 0.

In ethanol, the frequency change amount of the molecular sensor in Example 4 was 0.052 Hz/(ppm μg), in Comparative Example 4 it was 0.019 Hz/(ppm μg), and in Comparative Example 5 it was 0.023 Hz/(ppm μg). )Met. In ethyl acetate, the amount of change in the molecular sensor of Example 4 was 0.085 Hz/(ppm・μg), in Comparative Example 4 it was 0.013Hz/(ppm・μg), and in Comparative Example 5 it was 0.039Hz/(ppm・μg). μg). The amount of change in Example 4 is about 2.7 times and about 2.3 times compared to Comparative Example 4, and about 6.5 times and about 2.2 times compared to Comparative Example 5, and the sensitivity was shown to be increasing.

The above results showed that by using a porous member and a sensitive membrane containing an ionic liquid, target molecules can be detected with higher sensitivity than when either one of them is used. Furthermore, in the COF/ionic liquid composite sensitive membrane, the flow and diffusion caused by the ionic liquid being a liquid are prevented by the combination with the COF, which is thought to contribute to the stability of the sensor characteristics.

(Manufacture of COF/ionic liquid molecular sensor 2)
・Surface treatment of QCM substrate A QCM with a resonance frequency of 9 MHz was ultrasonically cleaned in ethanol for 10 minutes, then in methanol for 10 minutes, and immersed in a methanol solution of 16-mercaptohexadecanoic acid (0.3 g/L) for 3 days. , modified on the Au electrode.

- Formation of COF-LZU1 thin film on QCM 32 mg of 1,3,5-triformylbenzene and 32 mg of p-phenylenediamine were dissolved in 20 g of 1,4-dioxane to prepare a raw material solution. A surface-treated QCM substrate was placed in the center of a glass Petri dish, and an appropriate amount of the raw material solution was dropped onto the QCM's Au electrode using a microsyringe. Thereafter, several drops of 3 mol/L acetic acid were added to the outer periphery of the QCM substrate in the petri dish, and the glass petri dish was covered. Thereafter, it was dried at room temperature under acetic acid vapor, taken out from the petri dish, and further heated and dried on a hot plate at 120°C for 2 hours. Next, the QCM substrate was washed in methanol for 2 minutes to remove unreacted raw materials and large grain size crystals to obtain a COF-LZU1 thin film. Further, it was dried under reduced pressure at 120° C. for 3 hours, and then stored under a purged state with N ₂ .

・Preparation of diluted ionic liquid solution As ionic liquids, 1-butyl-4-methylpyridinium hexafluorophosphate (BMPy-PF ₆ ), 1-ethyl-3-methylpyridinium ethyl sulfate (EMPy-ES), 1-ethyl -3-Hydroxymethylpyridinium ethyl sulfate (EHMPy-ES) was prepared and diluted with a mixed solvent of methanol and acetone (volume ratio 1:1) to prepare a 0.05 wt% solution.

- Addition of ionic liquid to COF-LZU1 thin film on QCM An appropriate amount of the diluted ionic liquid solution prepared above was dropped onto the COF-LZU1 thin film using a microsyringe while monitoring changes in the vibration frequency of the QCM. Thereafter, in order to promote evaporation of the solvent and diffusion of the ionic liquid into the COF pores, it was heated at 120° C. for 2 hours under reduced pressure and cooled to room temperature, to obtain the molecular sensor of Example 5. At this time, the amount of BMPy-PF ₆ to the COF-LZU1 thin film was 0.83 in mass ratio, the amount of EMPy-ES was 0.74 in mass ratio, and the amount of EHMPy-ES was 1.04 in mass ratio. Ta.

(Gas detection experiment)
Gases (ethanol, ethyl acetate, and toluene) were detected using the molecular sensor of Example 5. These three types of molecular sensors were set in the detection chamber shown in FIG. 6, and an appropriate amount of ethanol, ethyl acetate, or toluene was introduced into the gas generator. Gases containing up to 227 ppm of ethanol, up to 151 ppm of ethyl acetate, and up to 73 ppm of toluene were then generated by bubbling laboratory atmosphere as a carrier gas at a flow rate of 200 ml/min. The generated gas was sent onto a molecular sensor, and changes in the vibration frequency of the QCM were measured.

The results for ethanol are shown in FIG. 14, the results for ethyl acetate are shown in FIG. 15, and the results for toluene are shown in FIG. 16. Each graph shows the amount of change in frequency (Hz/(ppm·μg)) per unit weight of the sensitive membrane of the vibrator when the value before contact with the sample in each molecular sensor is set to 0.

In ethanol, the frequency change of the molecular sensor using BMPy-PF ₆ of Example 5 was 0.010 Hz/(ppm μg), and the frequency change of the molecular sensor using EMPy-ES was 0.028 Hz/(ppm・μg), and the frequency change amount of the molecular sensor using EHMPy-ES was 0.021 Hz/(ppm・μg). For ethyl acetate, the frequency change of the molecular sensor using BMPy-PF ₆ of Example 5 is 0.009 Hz/(ppm μg), and the frequency change of the molecular sensor using EMPy-ES is 0.018 Hz/ (ppm·μg), and the frequency change amount of the molecular sensor using EHMPy-ES was 0.013 Hz/(ppm·μg). In toluene, the amount of frequency change of the molecular sensor using BMPy-PF ₆ of Example 5 is 0.022 Hz/(ppm μg), and the amount of frequency change of the molecular sensor using EMPy-ES is 0.025 Hz/( ppm・μg), and the frequency change amount of the molecular sensor using EHMPy-ES was 0.022 Hz/(ppm・μg).

From the above results, it was found that a molecular sensor using a sensitive membrane containing three different ionic liquids exhibits different sensitivity characteristics for each gas: ethanol, ethyl acetate, and toluene. In other words, it was shown that gases can be detected and distinguished by pattern recognition depending on the type and amount of coexisting ionic liquids.

Although several embodiments of the invention have been described, these embodiments are presented by way of example and are not intended to limit the scope of the invention. These novel embodiments can be implemented in various other forms, and various omissions, substitutions, and changes can be made without departing from the gist of the invention. These embodiments and their modifications are included within the scope and gist of the invention, as well as within the scope of the invention described in the claims and its equivalents.
Below, the invention described in the original claims of this application will be added.
[1]
A molecular sensor comprising a sensitive membrane in which a porous member and an ionic liquid coexist, and capable of detecting a target molecule by measuring a change in a physical quantity of the sensitive membrane due to attachment of the target molecule.
[2]
The molecular sensor according to [1], wherein the ionic liquid is held in the porous member.
[3]
The molecular sensor according to [1] or [2], wherein the porous member is a metal organic framework (MOF).
[4]
The metal-organic structure has hexanuclear Zr. ₆ O ₄ (OH) ₄ The molecular sensor according to [3], which has a structure in which 12 dicarboxylic acids are coordinated to a cluster.
[5]
The molecular sensor according to [4], wherein the metal-organic framework is at least one of UIO-66, UIO-67, UIO-68, or a derivative thereof.
[6]
The molecular sensor according to [1] or [2], wherein the porous member is a covalent organic framework (COF).
[7]
The covalent organic structure is at least one of an imine bond, an azine bond, an enamine bond, a hydrazone bond, or an imide bond obtained by a condensation reaction between a ligand having an amino group and a ligand having an aldehyde group or a carbonyl group. The molecular sensor according to [6], which has the following.
[8]
The covalent organic frameworks include COF-LZU1, COF-300, TAPB-PDA-COF, COF-TpPa-1, DAAQ-TFP-COF, N ₃ - at least one of COF, ACOF-1, COF-42, COF-43, PI-COF-1, PI-COF-2, PI-COF-3, PI-COF-4, PI-COF-5; The molecular sensor according to [7].
[9]
The molecular sensor according to any one of [1] to [8], further comprising a temperature adjustment device configured to heat the sensitive film.
[10]
The ratio of the ionic liquid to the porous member of the sensitive membrane is 5×10 by weight. ^-5 -3, the molecular sensor according to any one of [1] to [9].
[11]
The target molecule comprises a molecular sensor comprising a sensitive membrane in which a porous member and an ionic liquid coexist, and a detection section configured to measure a change in physical quantity of the sensitive membrane due to attachment of the target molecule. Molecular detection device for detection.
[12]
The device according to [11], wherein the ionic liquid is held in the porous member.
[13]
The detection unit includes any one of a measurement mechanism using a Quartz Crystal Microbalance (QCM), a Surface Acoustic Wave (SAW), or a Micro Cantilever (MCL). The device according to [11] or [12].
[14]
The molecular detection device includes a plurality of the molecular sensors,
The device according to any one of [11] to [13], wherein the plurality of molecular sensors include at least sensors in which the combination and/or quantitative ratio of the porous member of the sensitive membrane and the ionic liquid are different from each other. .
[15]
further equipped with a processing device,
The processing device is configured to determine the type and/or amount of the target molecule by recognizing the amounts of change in the plurality of physical quantities obtained from the plurality of molecular sensors as one pattern. The device according to [14].
[16]
The device according to any one of [11] to [15], further comprising a temperature control device configured to heat the sensitive film.
[17]
a contact step of bringing a target molecule into contact with a sensitive membrane in which a porous member and an ionic liquid coexist; a measuring step of measuring a change in physical quantity of the sensitive membrane due to attachment of the target molecule; A method for detecting a target molecule, including a determination step of determining the type or amount of the molecule.
[18]
The method according to [17], wherein the ionic liquid is retained in the porous member.
[19]
The method according to [17] or [18], wherein the porous member is a metal organic framework (MOF).
[20]
The method according to [17] or [18], wherein the porous member is a covalent organic framework (COF).
[21]
The contacting step and the measuring step are performed using a plurality of sensitive membranes having different combinations and/or quantitative ratios of the porous member and the ionic liquid,
In the determining step, the type and/or amount of the target molecule is determined by recognizing the amount of change in each of the physical quantities of the plurality of sensitive films as one pattern [17] to [20]. ] The method described in any one of the following.
[22]
The method according to any one of [17] to [21], further comprising a heating removal step of removing the target molecule from the sensitive film by heating the sensitive film after the measuring step.

1, 1a, 1b, 1c, 1d, 20...Molecular sensor, 2...QCM detection unit,
3, 3a, 3b, 3c, 3d...sensitive film,
7... Porous member, 7a... Hole, 8... Ionic liquid,
21...MCL detection unit, 32a...temperature adjustment device, 38...sample,
100...Molecular detection device, 102...Processing device.

Claims (20)

A sensitive membrane including a porous member having pores with a diameter of 50 nm or less and an ionic liquid held in the porous member is provided , and the target can be detected by measuring changes in physical quantities of the sensitive membrane due to adhesion of target molecules. A molecular sensor that can detect molecules. The molecular sensor according to claim 1, wherein the porous member is a metal organic framework (MOF) or a covalent organic framework (COF). a porous member that is a metal organic framework (MOF) or a covalent organic framework (COF); and a sensitive membrane containing an ionic liquid held in the porous member; A molecular sensor capable of detecting a target molecule by measuring a change in physical quantity due to the attachment of the target molecule to a sensitive membrane. The molecular sensor according to claim 3, wherein the porous member has pores with a diameter of 50 nm or less. 4. The molecular sensor according to claim 3 , wherein the metal-organic framework has a structure in which 12 dicarboxylic acids are coordinated to ₄ Zr ₆ O ₄ (OH) clusters with 6 nuclei. The molecular sensor according to claim 5 , wherein the metal-organic framework is at least one of UIO-66, UIO-67, UIO-68, or a derivative thereof. The covalent organic structure is at least one of an imine bond, an azine bond, an enamine bond, a hydrazone bond, or an imide bond obtained by a condensation reaction between a ligand having an amino group and a ligand having an aldehyde group or a carbonyl group. The molecular sensor according to claim 6 , comprising: The covalent organic frameworks include COF-LZU1, COF-300, TAPB-PDA-COF, COF-TpPa-1, DAAQ-TFP-COF, N ₃ -COF, ACOF-1, COF-42, COF- 8. The molecular sensor according to claim 7 , which is at least one of 43, PI-COF-1, PI-COF-2, PI-COF-3, PI-COF-4, and PI-COF-5. The molecular sensor according to any one of claims 1 to 8 , further comprising a temperature adjustment device configured to heat the sensitive membrane. The molecular sensor according to any one of claims 1 to 9 , wherein the ratio of the ionic liquid to the porous member of the sensitive membrane is 5×10 ⁻⁵ to 3 by weight. A sensitive membrane including a porous member having pores with a diameter of 50 nm or less and an ionic liquid held in the porous member , and configured to measure changes in physical quantities of the sensitive membrane due to attachment of target molecules. A molecule detection device for detecting the target molecule, comprising a molecule sensor including a detection section. a sensitive membrane comprising a porous member made of a metal organic framework (MOF) or a covalent organic framework (COF); and an ionic liquid held in the porous member; A molecule detection device for detecting the target molecule, comprising a molecular sensor including a detection unit configured to measure a change in physical quantity due to attachment of the target molecule to a sensitive membrane. The detection unit includes any one of a measurement mechanism using a Quartz Crystal Microbalance (QCM), a Surface Acoustic Wave (SAW), or a Micro Cantilever (MCL). The device according to claim 11 or 12 . The molecular detection device includes a plurality of the molecular sensors,
The device according to any one of claims 11 to 13 , wherein the plurality of molecular sensors include at least sensors in which combinations and/or quantitative ratios of the porous member of the sensitive membrane and the ionic liquid are different from each other. further equipped with a processing device,
The processing device is configured to determine the type and/or amount of the target molecule by recognizing the amounts of change in the plurality of physical quantities obtained from the plurality of molecular sensors as one pattern. 15. The apparatus of claim 14 . Apparatus according to any one of claims 11 to 15 , further comprising a temperature regulating device configured to heat the sensitive membrane. A contacting step of bringing a target molecule into contact with a sensitive membrane that includes a porous member having pores with a diameter of 50 nm or less and an ionic liquid held in the porous member , and a change in physical quantity of the sensitive membrane due to attachment of the target molecule. A method for detecting a target molecule, the method comprising: a measuring step of measuring the target molecule; and a determining step of determining the type or amount of the target molecule from the measurement result. Target molecules are added to a sensitive membrane that includes a porous member made of a metal organic framework (MOF) or a covalent organic framework (COF) and an ionic liquid held in the porous member. Detection of a target molecule, comprising a contact step of contacting the sensitive membrane, a measurement step of measuring a change in physical quantity due to attachment of the target molecule to the sensitive membrane, and a determination step of determining the type or amount of the target molecule from the measurement result. Method. The contacting step and the measuring step are performed using a plurality of sensitive membranes having different combinations and/or quantitative ratios of the porous member and the ionic liquid,
According to claim 17 or 18 , in the determining step, the type and/or amount of the target molecule is determined by recognizing the amount of change in each of the physical quantities of the plurality of sensitive films as one pattern. Method described. The method according to any one of claims 17 to 19 , further comprising a heating removal step of removing the target molecule from the sensitive film by heating the sensitive film after the measuring step.

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