JP7283004B2 - Functional group-containing organic molecule detection sensor, detection method, organic molecule detection array, and organic molecule screening method - Google Patents

Description

Article 30, Paragraph 2 of the Patent Act applies Published on February 25, 2019 in the Proceedings of the 66th Spring Meeting of the Japan Society of Applied Physics, published by the Japan Society of Applied Physics, page 14-021

Article 30, Paragraph 2 of the Patent Act applies Published at the 66th JSAP Spring Meeting held on March 10, 2019

TECHNICAL FIELD The present invention relates to a functional group-containing organic molecule detection sensor, a detection method, an organic molecule detection array, and an organic molecule screening method.

Organic molecules tend to have properties that depend on the functional groups contained in their molecular structure. For example, many organic molecules with thiol or amine groups are known to have an odor. Also, for example, organic molecules having an aldehyde group such as formaldehyde are known to cause sick house syndrome. Therefore, there is a demand for a technique for detecting functional groups in organic molecules contained in specimens.

Analytical techniques using nuclear magnetic resonance (NMR), infrared spectroscopy (FT-IR), and the like are known as conventional techniques for detecting functional groups in organic molecules. However, these analytical techniques require large and expensive analytical equipment, require advanced knowledge to analyze which functional groups are actually contained, and require a large amount of data to measure. They tended to require specimens.

On the other hand, an organic molecule detection sensor comprising two electrodes and a semiconductor member is easy to miniaturize, does not require advanced knowledge because the presence or absence of detection of organic molecules can be read from an electrical signal, and can be arrayed. It has the advantage of being relatively easy to use, and is being developed (see Patent Documents 1 to 4, for example).

Japanese Patent Publication No. 2017-508965 JP 2013-505439 A WO2017/042851 WO2017/002854

However, considering the statistical scrutiny of properties according to the functional groups contained in organic molecules, more diverse functional groups (e.g., thiol groups, amine groups, hydroxy groups, carboxy groups, aldehyde groups, nitro groups) etc.) are required to be individually detectable.

In view of the above circumstances, the present invention provides a functional group-containing organic molecule detection sensor, a detection method, an organic molecule detection array, and an organic molecule screening method capable of detecting functional group-containing organic molecules containing a desired functional group. is the subject.

Specific means for solving the above problems include the following aspects.

[1] two electrodes;
Reactive organic molecules that react with functional group-containing organic molecules containing one or more functional groups selected from the group consisting of thiol groups, amine groups, hydroxyl groups, carboxy groups, aldehyde groups and nitro groups are adsorbed. a semiconductor member;
comprising
A functional group-containing organic molecule detection sensor for detecting the functional group-containing organic molecule contained in a specimen.
[2] The functional group-containing organic molecule detection sensor according to [1], wherein the reactive organic molecule undergoes a nucleophilic addition reaction or a nucleophilic substitution reaction with the functional group-containing organic molecule.
[3] the functional group-containing organic molecule contains a thiol group;
wherein the reactive organic molecule comprises one or more selected from maleimide, bromobimane, a compound containing a skeleton derived from maleimide, and a compound containing a skeleton derived from bromobimane;
The functional group-containing organic molecule detection sensor according to [1] or [2].
[4] the functional group-containing organic molecule contains an amine group;
wherein the reactive organic molecule comprises one or more selected from aromatic halides, aliphatic halides and ester compounds;
The functional group-containing organic molecule detection sensor according to any one of [1] to [3].
[5] The semiconductor member is graphene,
The functional group-containing organic molecule detection sensor according to any one of [1] to [4].
[6] Using the functional group-containing organic molecule detection sensor according to any one of [1] to [5],
A detection method for detecting a functional group-containing organic molecule containing one or more functional groups selected from the group consisting of a thiol group, an amine group, a hydroxy group, a carboxy group, an aldehyde group and a nitro group.
[7] The detection method according to [6], wherein the functional group-containing organic molecule is detected based on a change in potential before and after reaction between the functional group-containing organic molecule and the reactive organic molecule.
[8] An organic molecule detection array comprising the functional group-containing organic molecule detection sensor according to any one of [1] to [5].
[9] Using the organic molecule detection array according to [8],
An organic molecule screening method for screening organic molecules.

According to the present disclosure, functional group-containing organic molecule detection sensors, detection methods, organic molecule detection arrays, and organic molecule screening methods capable of detecting functional group-containing organic molecules containing target functional groups are provided.

(A) Schematic cross-sectional view showing a state before detecting a functional group-containing organic molecule containing a functional group in the functional group-containing organic molecule detection sensor 100 according to the present disclosure, (B) Reactive organic molecule according to the present disclosure 14 and a functional group-containing organic molecule 15 containing a functional group, a schematic diagram showing an example of a reaction to obtain a reaction product 16; is a schematic cross-sectional view showing a state when a functional group-containing organic molecule containing is detected. 4 is a graph showing the relationship between the current of the drain electrode and the voltage of the gate electrode before and after exposure to a specimen in Example 1. FIG. 4 is a graph showing the relationship between voltage change amount ΔV _BA and detection time in Examples 1 to 3. FIG. 10 is a graph showing the relationship between the current of the drain electrode and the voltage of the gate electrode before and after exposure to a specimen in Example 4 and Comparative Example 1. FIG.

In the present disclosure, both multi-layer graphene and single-layer graphene are collectively referred to simply as "graphene."

≪Functional group-containing organic molecule detection sensor≫
The functional group-containing organic molecule detection sensor according to the present disclosure contains two electrodes and one or more functional groups selected from the group consisting of thiol groups, amine groups, hydroxyl groups, carboxy groups, aldehyde groups, and nitro groups. A functional group-containing organic molecule detection sensor for detecting the functional group-containing organic molecule contained in a sample, comprising: a semiconductor member to which a reactive organic molecule that reacts with the functional group-containing organic molecule is adsorbed. The functional group-containing organic molecule detection sensor may contain other members such as a substrate, if necessary.

The sensor for detecting a functional group-containing organic molecule according to the present disclosure has the above configuration, so that at least one functional group selected from the group consisting of a thiol group, an amine group, a hydroxy group, a carboxy group, an aldehyde group, and a nitro group can be detected. Although this mechanism is not necessarily clear, it can be estimated as follows.

In the sensor for detecting functional group-containing organic molecules according to the present disclosure, reactive organic molecules that react with functional group-containing organic molecules are adsorbed on a semiconductor member. Therefore, when the sample contains functional group-containing organic molecules, the reactive organic molecules adsorbed to the semiconductor member react with the functional group-containing organic molecules. As a result, the state of the organic molecules adsorbed on the semiconductor member changes. Along with this, the output also fluctuates. Based on this fluctuating output, functional group-containing organic molecules contained in the sample can be detected. Here, output can be potential energy, voltage, current, resistance, transconductance, or the like.

Furthermore, the functional group-containing organic molecule detection sensor according to the present disclosure can detect functional group-containing organic molecules with high sensitivity and high selectivity by having the above configuration. Although this mechanism is not necessarily clear, it can be estimated as follows.

Compared to metal complexes, polymers, etc., reactive organic molecules adsorbed on semiconductor materials show a change in output per molecule before and after reaction with organic molecules containing functional groups (especially when potential energy is used as output). change) tends to be large. Therefore, there is a tendency that the change in output can be obtained as a signal even at a low concentration that is difficult to detect when a metal complex, a polymer, or the like is adsorbed to the semiconductor member. As a result, it is believed that the sensor for detecting functional group-containing organic molecules according to the present disclosure can detect functional group-containing organic molecules with high sensitivity (ppt: parts per trillion, 1/10 ¹² ).
In addition, reactive organic molecules tend to have higher reaction selectivity with respect to functional group-containing organic molecules than metal complexes, polymers, and the like. Therefore, it is thought that there are few erroneous detections (false positives) such as detection of functional group-containing organic molecules having functional groups that do not react with reactive organic molecules.

[Example of Configuration of Sensor for Detecting Functional Group-Containing Organic Molecules]
An example of the configuration of the functional group-containing organic molecule detection sensor according to the present disclosure will be described below with reference to the drawings.
FIG. 1A is a schematic cross-sectional view showing an example of a functional group-containing organic molecule detection sensor 100 according to the present disclosure. That is, it shows an example of a state before detection of a functional group-containing organic molecule containing a functional group.
The functional group-containing organic molecule detection sensor 100 shown in FIG. 1A includes a gate electrode 10, an insulator layer 11, a source electrode 12S, a drain electrode 12D, a semiconductor member 13, a reactive organic molecule 14, Prepare. The gate electrode 10, the source electrode 12S and the drain electrode 12D may be electrically connected to a power supply. The gate electrode 10, source electrode 12S and drain electrode 12D may be electrically connected to a voltmeter.

In the functional group-containing organic molecule detection sensor 100, an insulator layer 11, a semiconductor member 13, and two electrodes 12S and 12D are laminated in this order on a gate electrode 10 in the thickness direction. Reactive organic molecules 14 are physically adsorbed on the surface of the semiconductor member 13 .

Here, FIG. 1B shows an example of a reaction for obtaining a reaction product 16 from a reactive organic molecule 14 and a functional group-containing organic molecule 15 according to the present disclosure. When a solution containing functional group-containing organic molecules 15 containing functional groups is added to the surface of the semiconductor member 13 to which the reactive organic molecules 14 are adsorbed, as shown in FIG. 1(B), the reactive organic molecules 14 are , while being physically adsorbed to the surface of the semiconductor member 13 , react with the functional group-containing organic molecules 15 containing functional groups to form a reaction product 16 .
FIG. 1(C) is a schematic cross-sectional view showing an example of a functional group-containing organic molecule detection sensor 100A according to the present disclosure. That is, it shows an example of the state when detecting a functional group-containing organic molecule containing a functional group. As shown in FIG. 1(C), the obtained reaction product 16 is physically adsorbed on the surface of the semiconductor member 13 in the same manner as the reactive organic molecules 14 .

[Example of detection flow using functional group-containing organic molecule detection sensor]
An example of the flow of detection of organic molecules using the functional group-containing organic molecule detection sensor according to the present disclosure will be described below with reference to FIGS. 1(A) to 1(C).

The organic molecule detection sensor 100 changes the electric current flowing between the two electrodes, that is, the current transfer characteristics, depending on the state of the molecules adsorbed to the semiconductor member 13, such as the charge, molecular weight, and physical size of the molecules. Therefore, in the case where the substance adsorbed to the semiconductor member 13 is the reactive organic molecule 14 shown in FIG. changes. That is, the observed current shifts as the reactive organic molecule 14 changes to the reaction product 16 .

In the functional group-containing organic molecule detection sensor according to the present disclosure, as shown in FIG. A functional group-containing organic molecule containing a functional group is detected from the resulting change in the current transfer property.

[Use]
The functional group-containing organic molecule detection sensor according to the present disclosure is a functional group-containing organic molecule containing one or more functional groups selected from the group consisting of thiol groups, amine groups, hydroxyl groups, carboxy groups, aldehyde groups, and nitro groups. Molecules can be detected. Therefore, the functional group-containing organic molecule detection sensor according to the present disclosure can be used for drug efficacy evaluation such as angina pectoris, biological protein evaluation, safety evaluation, medical use, environmental measurement, putrid gas measurement, and samples in scientific research. It is particularly excellent as a detection device for applications such as functional group analysis of

[Specimen]
The specimen may be a specimen for which it is desired to examine whether or not it contains functional group-containing organic molecules. When a sample is measured using the functional group-containing organic molecule detection sensor according to the present disclosure, the presence or absence of the functional group-containing organic molecule in the sample can be determined using the functional group as an index.

The analyte may be gas, liquid or solid.
The gaseous specimen may be used as it is by exposing it to the region where the reactive organic molecules are adsorbed on the semiconductor member, or by blowing the gaseous specimen into the solution medium to disperse or dissolve the specimen. may be used as The solution medium is not particularly limited as long as it is capable of suspending, dispersing or dissolving the gaseous specimen, and solution media such as organic solvents, water and buffers in which functional group-containing organic molecules are easily dissolved can be used.
A liquid specimen may be used as a liquid specimen as it is, or may be used as a diluent obtained by suspending, dispersing or dissolving an undiluted specimen in a solution medium. The solution medium is not particularly limited as long as it is capable of suspending, dispersing or dissolving the specimen in the solution, and organic solvents, water, buffers, etc., in which functional group-containing organic molecules are easily dissolved can be used.
When the specimen is solid, for example, it is preferable to use a solution obtained by suspending, dispersing, dissolving, or diluting a solid specimen in a medium. The medium is not particularly limited, and a solution medium such as an organic solvent, water, or buffer in which the functional group-containing organic molecule is easily dissolved can be used.
Among the above, the specimen is preferably gas or liquid.

When the specimen is liquid or solid, from the viewpoint of improving the measurement accuracy, it is possible to perform solid-liquid separation treatment by filtration or the like in advance, and then perform measurement using the functional group-containing organic molecule detection sensor according to the present disclosure. preferable.

Specimens include, for example, environmental specimens, biological specimens, chemical substances, pharmaceuticals, and the like.
Environmental specimens include, for example, food, water, soil, atmospheric air, and the like. Foods include fresh foods, processed foods, and the like. Examples of water include drinking water, groundwater, river water, seawater, domestic wastewater, and industrial wastewater.
Specimens derived from living organisms include, for example, urine, blood, hair, saliva, sweat, nails, exhaled breath, and the like. A biological specimen refers to a specimen derived from humans, non-human animals (mammals other than humans, amphibian reptiles, fish and shellfish, insects, etc.), plants, and the like.

[Functional Group-Containing Organic Molecules]
A functional group-containing organic molecule refers to an organic molecule containing one or more functional groups selected from the group consisting of a thiol group, an amine group, a hydroxy group, a carboxy group, an aldehyde group and a nitro group.

The functional group-containing organic molecule may contain two or less functional groups selected from the group consisting of a thiol group, an amine group, a hydroxy group, a carboxy group, an aldehyde group and a nitro group in a single molecular structure. It preferably contains one functional group selected from the above group, and more preferably contains a thiol group or an amine group.

Functional group-containing organic molecules containing a thiol group include, for example, aromatic thiol compounds and aliphatic thiol compounds. Among the above, the functional group-containing organic molecule containing a thiol group is preferably an aliphatic thiol compound, more preferably an aliphatic thiol compound having 1 to 10 carbon atoms, and further preferably methanethiol. preferable.

Functional group-containing organic molecules containing an amine group include, for example, cyclic amines, chain tertiary amines, secondary amines, and primary amines. Among the above, the functional group-containing organic molecule containing an amine group is preferably a tertiary amine, more preferably a tertiary amine having 3 to 15 carbon atoms, and even more preferably trimethylamine.

When the functional group-containing organic molecule has a plurality of functional groups in one molecular structure, the positional relationship of the plurality of functional groups is not limited to each other. The functional group-containing organic molecules may be used singly or in combination of two or more.

[Semiconductor material]
A functional group-containing organic molecule detection sensor according to the present disclosure includes a semiconductor member on which reactive organic molecules that react with functional group-containing organic molecules are adsorbed.

The material of the semiconductor member is not particularly limited, and known semiconductor members can be applied. Examples of semiconductor members include carbon nanotubes, multilayer graphene, single-layer graphene, gallium, silicon, silicon dioxide, gallium arsenide, silicon carbide, gallium nitride, diamond, gallium oxide, and transition metal dichalcogenide.

Among the above, the semiconductor member is preferably one selected from the group consisting of carbon nanotubes, multi-layer graphene, and single-layer graphene, more preferably multi-layer graphene or single-layer graphene, and single-layer graphene. It is even more preferable to have Hereinafter, both multi-layer graphene and single-layer graphene are collectively referred to simply as “graphene”.

When the semiconductor member is graphene, graphene has a high carrier mobility due to its band structure, so that the change in voltage based on the current transfer characteristic is likely to be observed more clearly. Therefore, when the semiconductor member is graphene, it tends to be possible to detect functional group-containing organic molecules with higher sensitivity. Moreover, when the semiconductor member is graphene, there is no concern about corrosion or the like compared with other inorganic semiconductor members such as silicon, and stable detection is possible even in a solution system, which is preferable.
In particular, when the graphene is single-layer graphene, it tends to be more excellent in high carrier mobility and the like.

The thickness of the semiconductor member is not particularly limited, and known conditions can be applied according to the material used. For example, when the semiconductor member is graphene or carbon nanotubes, the thickness may be determined according to the method for producing the graphene or carbon nanotubes.
For example, when the semiconductor member is a material other than graphene and carbon nanotubes, the thickness of the channel portion of the semiconductor member is preferably 5 nm or more and 100 μm or less, more preferably 5 nm or more and 1 μm or less, and 5 nm or more and 100 nm or less. is more preferable.

[Reactive organic molecules]
A functional group-containing organic molecule detection sensor according to the present disclosure has a reactive organic molecule.
A reactive organic molecule is adsorbed to the semiconductor member.

A reactive organic molecule is an organic molecule that reacts with a functional group-containing organic molecule containing one or more functional groups selected from the group consisting of a thiol group, an amine group, a hydroxyl group, a carboxyl group, an aldehyde group and a nitro group. That's what I mean.

From the viewpoint of efficiently reacting with the functional group-containing organic molecule, the reactive organic molecule is preferably adsorbed on the surface of the semiconductor member.

For example, when the functional group-containing organic molecule detection sensor according to the present disclosure further includes a substrate, a gate electrode, and the like, the reactive organic molecule is provided with the substrate, the gate electrode, and the like in the stacking direction of the functional group-containing organic molecule detection sensor. It is preferably adsorbed to the surface of the semiconductor member on the non-bonded side.

The type of adsorption may be physical adsorption that is adsorbed by van der Waals forces, or chemisorption that is adsorbed by covalent bonds (so-called grafting). The type of adsorption is preferably physical adsorption, for example, from the viewpoint of easily producing a functional group-containing organic molecule detection sensor.

The surface coverage of the reactive organic molecules on the semiconductor member (=number of adsorbed reactive organic molecules/maximum number of reactive organic molecules that can be adsorbed) is preferably 90% or more, more preferably 95% or more. more preferred. That is, the surface coverage is preferably close to 100%. The surface coverage means the surface coverage of the reactive organic molecules on the surface of the semiconductor member that functions as the detection portion.
The surface coverage is measured by cyclic voltammetry using a BAS potentiostat.
The method for setting the surface coverage within the above range is not particularly limited. A method of dropping a solution onto a detection portion of a semiconductor member; a method of spin coating; and the like.

The surface density of the reactive organic molecules in the semiconductor member (that is, the number of reactive organic molecules adsorbed on the semiconductor member) is preferably 10 ¹¹ molecules/cm ² or more, and is 10 ¹² molecules/cm ² or more. more preferably 10 ¹³ molecules/cm ² or more. The surface density means the surface density of the reactive organic molecules on the surface of the semiconductor member that functions as the detection portion.
The surface density is measured by cyclic voltammetry using a BAS potentiostat.
The method for setting the surface density within the above range is not particularly limited. can be dropped onto the detection portion of the semiconductor member; a method of spin coating; and the like.

The reactive organic molecule is not particularly limited as long as it is an organic molecule that reacts with the functional group-containing organic molecule. Examples of reactive organic molecules include functional group-containing organic molecules, elimination reactions, electrophilic addition reactions, nucleophilic addition reactions, electrophilic substitution reactions, nucleophilic substitution reactions, addition-elimination reactions, and combinations of these reactions. Examples include organic molecules that are capable of such reactions as

Among the above, the reactive organic molecule is preferably an organic molecule capable of reacting with a functional group-containing organic molecule at room temperature (25° C.) without the addition of a catalyst, an oxidizing agent, etc., and a nucleophilic addition reaction. , a nucleophilic substitution reaction, an addition-elimination reaction, and a combination of these reactions. More preferably, it is an organic molecule capable of

The positions at which the reactive organic molecule and the functional group-containing organic molecule react are not limited, and the reaction may occur at any desired position.
Even if one reactive organic molecule reacts with one functional group-containing organic molecule, two or more functional group-containing organic molecules react with each other. It may be in a mode of reacting.

The type of the reaction is not limited to the above examples, and may be a known organic reaction or a novel organic reaction.

The reactive organic molecule preferably undergoes a nucleophilic addition reaction or a nucleophilic substitution reaction with the functional group-containing organic molecule. When a reactive organic molecule undergoes a nucleophilic addition reaction or a nucleophilic substitution reaction with a functional group-containing organic molecule, the resulting reaction product tends to have electronic properties significantly different from those of the reactive organic molecule. Therefore, the transfer characteristics tend to be significantly different between the semiconductor member on which the reaction product is adsorbed and the semiconductor member on which the reactive organic molecule is adsorbed. In other words, it is considered that the detection sensitivity for detecting functional group-containing organic molecules is likely to increase.

The reactive organic molecules may be used singly or in combination of two or more.
Reactive organic molecules may be synthetic or commercially available.

A reactive organic molecule is a group that has a skeleton derived from an aromatic group or a heterocyclic compound in addition to the skeleton of the organic molecule that reacts with the functional group-containing organic molecule, as long as the reaction with the functional group-containing organic molecule is not inhibited. and one or more substituents selected from the group consisting of aliphatic groups.

When the reactive organic molecule further has the above-described substituents in addition to the organic molecule skeleton that reacts with the functional group-containing organic molecule, the reactive organic molecule is more adsorbed to the semiconductor member (especially graphene and carbon nanotube). tend to In particular, when the reactive organic molecule has an aromatic group, there is a tendency that the reactive organic molecule is more likely to be adsorbed on the semiconductor member due to π-electron interaction or the like.

Examples of aromatic groups include, but are not limited to, groups obtained by removing one hydrogen atom at an arbitrary position from aromatic compounds such as naphthalene, anthracene, and pyrene. Among the above, the aromatic group preferably includes a group obtained by removing one hydrogen atom at an arbitrary position from pyrene.

The group having a skeleton derived from a heterocyclic compound is not particularly limited, and examples thereof include groups obtained by removing one hydrogen atom at an arbitrary position from a heterocyclic compound such as porphyrin, thiophene, and pyridine. Among the above, the group having a skeleton derived from a heterocyclic compound preferably includes a group obtained by removing one hydrogen atom at an arbitrary position from porphyrin.

Examples of the aliphatic group include, but are not limited to, aliphatic groups having 1 to 15 carbon atoms. Among the above, the aliphatic group preferably contains an aliphatic group having 1 to 10 carbon atoms, more preferably an aliphatic group having 1 to 5 carbon atoms.

The reactive organic molecule may have, in one molecule, one or more substituents selected from the group consisting of an aromatic group, a group having a heterocyclic compound-derived skeleton, and an aliphatic group. .

In the reactive organic molecule, a plurality of "organic molecule skeletons that react with functional group-containing organic molecules" are selected from the group consisting of "an aromatic group, a group having a skeleton derived from a heterocyclic compound, and an aliphatic group. It may be a molecule having such that it is linked via "one or more substituents".

Examples of applicable reactive organic molecules are described below for each functional group of the functional group-containing organic molecule. The term "compound having a skeleton derived from (each exemplary compound)" described below refers to a derivative of each exemplary compound having a reactive site that reacts with a functional group in each exemplary compound.

(Reactive organic molecules that react with thiol groups)
Reactive organic molecules that react with a thiol group include reactive organic molecules that are capable of at least one of a nucleophilic addition reaction and a nucleophilic substitution reaction with a thiol group.
Examples of reactive organic molecules capable of undergoing a nucleophilic addition reaction with a thiol group include carbonyl compounds.
Examples of reactive organic molecules capable of undergoing a nucleophilic substitution reaction with a thiol group include aromatic halides, aliphatic halides, and cyclic amine compounds.
Examples of carbonyl compounds include maleimide; o-phthalaldehyde, m-phthalaldehyde, p-phthalaldehyde, pyrenemaleimide, naphthalenemaleimide, N-(9-acridinyl)maleimide, and other compounds containing a maleimide-derived skeleton; mentioned.
Examples of aromatic halides include halogenated benzoxadiazole; compounds containing a skeleton derived from halogenated benzoxadiazole such as 4-fluoro-2,1,3-benzoxadiazole; and the like.
Examples of aliphatic halides include bromobimane; compounds containing a skeleton derived from the aforementioned bromobimane, such as chlorobimane; and the like.
Cyclic amine compounds include aziridine; compounds containing a skeleton derived from aziridine such as methyl aziridine-2-carboxylate; and the like.

Among the above, the reactive organic molecule that reacts with a thiol group is maleimide, bromobimane, a compound containing a skeleton derived from maleimide, and a compound derived from bromobimane, from the viewpoint of efficiently reacting with a thiol group at room temperature (25 ° C.). It preferably comprises a skeleton-containing compound, more preferably maleimide or bromobimane, even more preferably bromobimane.
A compound having a skeleton derived from bromobimane means a reaction point that reacts with a thiol group in bromobimane (specifically, a CH ₂ Br site substituted with a pyrazolo[1,2-a]pyrazole-1,7-dione skeleton). It refers to a bromobimane derivative that has

(Reactive organic molecules that react with amine groups)
Reactive organic molecules that react with amine groups include reactive organic molecules that are capable of nucleophilic substitution reactions with amine groups.
Examples of reactive organic molecules capable of undergoing a nucleophilic substitution reaction with an amine group include aromatic halides, aliphatic halides, ester compounds, sulfanyl halide compounds, isothiocyanate compounds, fluorescamine, and fluorescamine-derived A compound having a skeleton can be mentioned.

Aromatic halides include bromoethylnaphthalene, bromomethylnaphthalene, bromoethylpyrene, and the like.
Aliphatic halides include bromopentane, chloropentane, bromohexane, chlorohexane and the like.
Examples of ester compounds include succinimide ester compounds, tetrafluoroester compounds, aminobimane, and the like.
Halogenated sulfanyl compounds include benzenesulfonyl chloride, 2-naphthalenesulfonyl chloride and the like.
Examples of isothiocyanate compounds include benzyl isothiocyanate and naphthalene isothiocyanate.

Among the above, the reactive organic molecule that reacts with the amine group is one selected from aromatic halides, aliphatic halides and ester compounds from the viewpoint of efficiently reacting with the amine group at room temperature (25 ° C.). It preferably includes the above.

(Reactive organic molecules that react with hydroxy groups)
Examples of reactive organic molecules that react with hydroxyl groups include reactive organic molecules capable of addition-elimination reactions (such as esterification reactions) with hydroxyl groups.
Examples of reactive organic molecules capable of undergoing an addition-elimination reaction with a hydroxy group include aromatic halides, aliphatic halides, carboxylic acid compounds (acyl halide compounds), isocyanate compounds, and the like.

Aromatic halides include DMEQ-COCl, benzo[b]thiophene-2-carbonyl chloride and the like.
Aliphatic halides include 1-adamantanecarbonyl chloride and the like.
Carboxylic acid compounds include 9-anthroyl cyanide, 1,5-diisocyanatonaphthalene, phenethyl isocyanate and the like.
Examples of isocyanate compounds include methyl isocyanate and coumarin 2-isocyanate.

Among the above, the reactive organic molecule that reacts with the hydroxy group preferably contains at least one of an aromatic halide and an aliphatic halide from the viewpoint of efficiently reacting with the hydroxy group at room temperature (25°C).

(Reactive organic molecules that react with carboxy groups)
Examples of reactive organic molecules that react with a carboxy group include reactive organic molecules capable of addition-elimination reactions (such as esterification reactions) and nucleophilic substitution reactions with a carboxy group.
Examples of reactive organic molecules capable of undergoing an addition-elimination reaction with a carboxyl group include alcohol compounds, halogenated acetyl compounds, cyclic secondary amine compounds, amidine compounds, and thiol compounds.
Examples of reactive organic molecules capable of undergoing a nucleophilic substitution reaction with a carboxy group include halogenated alkyl compounds.

Examples of alcohol compounds include naphthylethanol and pyrenylethanol.
Halogenated acetyl compounds include compounds having a halogenated acetyl group (*--C(=O)--CH ₂ --X, where X represents a halogen atom) such as 4-bromophenacyl bromide.
Cyclic secondary amine compounds include compounds having a piperazino group and compounds having a pyrrolidino group.
Examples of amidine compounds include compounds having a urea skeleton such as N,N'-diisopropyl-O-(4-nitrobenzyl)isourea; 1-(4-nitrobenzyl)-3-p-tolyltriazene, 4-( compounds having a triazene skeleton such as N-hydrazinocarbonylmethyl-N-methylamino)-7-nitro-2,1,3-benzoxadiazole;
Thiol compounds include 4-acetamido-7-mercapto-2,1,3-benzoxadiazole and the like.
Halogenated alkyl compounds include compounds having a halogenated alkyl group such as 9-chloromethylanthracene.

Among the above, the reactive organic molecules that react with carboxy groups are naphthylethanol and 4-(N-hydrazinocarbonylmethyl-N-methylamino) from the viewpoint of efficient reaction with carboxy groups at room temperature (25°C). -7-nitro-2,1,3-benzoxadiazole is preferred.

(reactive organic molecules that react with aldehyde groups)
Examples of reactive organic molecules that react with aldehyde groups include reactive organic molecules capable of undergoing nucleophilic addition reactions, addition-elimination reactions (such as aldol reactions), and the like with aldehyde groups.
Examples of reactive organic molecules capable of undergoing a nucleophilic addition reaction with an aldehyde group include carbonyl compounds and nitro compounds.
Examples of reactive organic molecules capable of addition-elimination reaction with aldehyde groups include amine compounds and alcohol compounds.

Examples of carbonyl compounds include benzaldehyde and naphthalenealdehyde.
Nitro compounds include nitrobenzyl bromide and the like.
Amine compounds include primary amine compounds such as alkoxyamine, 1,2-diamino-4,5-methylenedioxybenzene, 2-amino-4,5-dimethoxythiophenol; 4-(N,N-dimethylaminosulfonyl )-7-hydrazino-2,1,3-benzoxadiazole and other compounds having a hydrazino group.
Examples of alcohol compounds include naphthylethanol and benzyl alcohol.

Among the above, the reactive organic molecule that reacts with the aldehyde group preferably contains an amine compound from the viewpoint of efficiently reacting with the aldehyde group at room temperature (25 ° C.), a compound having a hydrazino group or a primary amine compound more preferably.

(reactive organic molecules that react with nitro groups)
Reactive organic molecules that react with a nitro group include reactive organic molecules that can undergo nucleophilic addition reactions, nucleophilic substitution reactions, and the like with nitro groups.
Examples of reactive organic molecules capable of undergoing a nucleophilic addition reaction with a nitro group include carbonyl compounds.

Examples of carbonyl compounds include naphthalenealdehyde and benzaldehyde.

Examples of reactive organic molecules capable of undergoing a nucleophilic substitution reaction with a nitro group include compounds represented by general formula (NTR1).

In the general formula (NTR1), X ¹ is a halogen atom or an alkyl ether group (R ^X1 -O-*, * represents a site bonding to a carbon atom, and R ^X1 represents an alkyl group having 1 to 10 carbon atoms ). EWG ¹ represents one selected from the group consisting of a halogen atom, a carboxyl group, a cyano group, an arylsulfonyl group and an aryl group. R ¹ represents one selected from the group consisting of an aromatic group, a group having a skeleton derived from a heterocyclic compound, and an aliphatic group.

In general formula (NTR1), the halogen atom represented by ^X1 includes a fluorine atom, a chlorine atom and an iodine atom.
In general formula (NTR1), an alkyl ether group represented by X ¹ (R ^X1 -O-*, * represents a site bonding to a carbon atom, and R ^X1 represents an alkyl group having 1 to 10 carbon atoms. ) includes an alkyl ether group having 1 to 10 carbon atoms. Examples of alkyl ether groups having 1 to 10 carbon atoms include methyl ether group, ethyl ether group, propyl ether group, pentyl ether group, butyl ether group, hexyl ether group, octyl ether group and nonyl ether group.

In general formula (NTR1), the halogen atom represented by EWG ¹ includes the same halogen atom as the halogen atom represented by X ¹ .
In general formula (NTR1), the arylsulfonyl group represented by EWG ¹ includes an arylsulfonyl group having 6 to 20 carbon atoms. The arylsulfonyl group having 6 to 20 carbon atoms includes, for example, a phenylsulfonyl group, a pyridylsulfonyl group, a naphthylsulfonyl group, a tolylsulfonyl group and the like.
In general formula (NTR1), the aryl group represented by EWG ¹ includes an aryl group having 6 to 20 carbon atoms. Examples of the aryl group having 6 to 20 carbon atoms include phenyl group, pyridyl group, naphthyl group and tolyl group.

In the general formula (NTR1), the aromatic group, the group having a heterocyclic compound-derived skeleton, and the aliphatic group represented by R ¹ are aromatic groups in the aforementioned substituents that the reactive organic molecule may have. groups, groups having skeletons derived from heterocyclic compounds, and groups similar to aliphatic groups.

Among the above, the reactive organic molecule that reacts with the nitro group preferably contains naphthalene aldehyde from the viewpoint of efficiently reacting with the nitro group at room temperature (25° C.).

As one embodiment of the functional group-containing organic molecule detection sensor, a reactive organic molecule may undergo a nucleophilic addition reaction or a nucleophilic substitution reaction with a functional group-containing organic molecule.

As an embodiment of the functional group-containing organic molecule detection sensor, the functional group-containing organic molecule contains a thiol group, and the reactive organic molecule is maleimide, bromobimane, a compound containing a skeleton derived from maleimide, and a skeleton derived from bromobimane. It may be an aspect containing one or more selected from compounds containing.

As one embodiment of the functional group-containing organic molecule detection sensor, the functional group-containing organic molecule has an amine group, and the reactive organic molecule is one or more selected from aromatic halides, aliphatic halides, and ester compounds. It may be a mode including.

(Method for Forming Semiconductor Member Adsorbed with Reactive Organic Molecules)
A method for forming a semiconductor member to which reactive organic molecules are adsorbed includes, for example, a method in which a semiconductor member is appropriately formed by a known method, and then reactive organic molecules are adsorbed on the manufactured semiconductor member.

For example, when the semiconductor member is an inorganic material such as silicon, the method for forming the semiconductor member includes a photolithography method, a vacuum deposition method, a sputtering method, an inkjet method, and the like.
For example, when the semiconductor member is graphene or carbon nanotube, the method for forming the semiconductor member includes a mechanical exfoliation method, a thermal decomposition method of silicon carbide, a chemical vapor deposition method (CVD method), an arc discharge method, and a laser evaporation method. etc. Among the above, when the semiconductor member is graphene or carbon nanotubes, the semiconductor member is preferably formed by the chemical vapor deposition method (CVD method).

The method for adsorbing the reactive organic molecules to the semiconductor member is not particularly limited. For example, (1) a method of impregnating a semiconductor member in a solution containing a reactive organic molecule, (2) a method of dropping a solution containing a reactive organic molecule onto a portion of the semiconductor member to be adsorbed, and (3) spin coating. Reactive organic molecules may be adsorbed on the semiconductor member by a method or the like. The concentration of the reactive organic molecules in the solution containing the reactive organic molecules is preferably 10 μmol/L or higher, more preferably 100 μmol/L or higher.

〔electrode〕
(Two electrodes: source electrode and drain electrode)
A functional group-containing organic molecule detection sensor according to the present disclosure includes two electrodes.
The two electrodes function as so-called source and drain electrodes.
The two electrodes are provided such that at least part of the electrodes are in direct contact with the semiconductor member.

Materials for the electrodes are not particularly limited, and known materials can be applied independently.
Materials for the electrodes include, for example, metals such as Al, Mo, Cr, Ta, Ni, Ti, Au, and Ag; alloys such as Al—Nd and APC; silicon materials; metal oxide conductive films such as tin oxide, zinc oxide, indium oxide, indium tin oxide (ITO), and zinc indium oxide (IZO); organic conductive compounds such as polyaniline, polythiophene, and polypyrrole; A mixture of; Among the above, the electrode material is preferably one or more selected from the group consisting of Ti, Ni and Au from the viewpoint of preventing oxidation and reaction with functional group-containing organic molecules. It is more preferable to include at least one. In particular, when the outermost surface layer of the electrode is Au, it is preferable from the viewpoint of resistance reduction of the electrode, suppression of oxidation of the electrode, and the like.

The electrode may be a single layer or a laminate of two or more layers.
As one aspect of the present disclosure, each of the two electrodes may be, for example, a laminate in which Ti and Au are laminated in this order in the thickness direction so as to be in direct contact with the semiconductor member.

The positional relationship between the two electrodes is not limited to each other, and may be appropriately set based on known conditions according to the desired channel running time, charging time, and the like.

The thickness of the two electrodes is preferably, for example, 5 nm or more and 1 μm or less, more preferably 10 nm or more and 200 nm or less, and even more preferably 10 nm or more and 150 nm or less. When the electrode is a laminate, the thickness of the electrode means the thickness of the laminate.

(gate electrode)
If necessary, the functional group-containing organic molecule detection sensor according to the present disclosure may further include a gate electrode in addition to the source and drain electrodes.

When the functional group-containing organic molecule detection sensor is provided with a gate electrode, a more precise electrical signal can be obtained as a drain current-gate voltage characteristic. In other words, the accuracy of detecting functional group-containing organic molecules tends to improve.

When a gate electrode is further provided, the semiconductor member is provided on the gate electrode via an insulator layer, which will be described later, without being in direct contact with the gate electrode.

Materials for the gate electrode include materials similar to those for the source and drain electrodes. Among the above materials, the silicon material doped with the above metals, impurities (boron, phosphorus, etc.) is preferable for the gate electrode. If the gate electrode is made of the silicon material, the silicon material itself can also serve as a substrate, which will be described later, which is preferable from the manufacturing point of view.

The thickness of the gate electrode is, for example, preferably 5 nm or more and 1 mm or less, more preferably 10 nm or more and 700 μm or less, and even more preferably 20 nm or more and 600 μm or less. When the gate electrode is, for example, a silicon material that also serves as the substrate, the thickness of the gate electrode refers to the thickness of the silicon material that also serves as the substrate.

(Method of forming electrodes)
A method for forming the electrodes is not particularly limited, and a known method can be applied as appropriate. Examples of methods for forming the electrodes include chemical vapor deposition (CVD), photolithography, vacuum deposition, sputtering, inkjet, and plating.

[Insulator layer]
The functional group-containing organic molecule detection sensor according to the present disclosure may further include an insulator layer.

When the functional group-containing organic molecule detection sensor according to the present disclosure further includes a gate electrode, it also includes an insulator layer that electrically insulates between the gate electrode and the semiconductor member.

The material of the insulator layer is not particularly limited, and known insulator layer materials in detection sensors, transistors, wiring, and the like can be applied.
Examples of materials for the insulator layer include metal oxides such as silicon dioxide, yttrium oxide, aluminum oxide and hafnium oxide; glass; resins; ceramics;

The thickness of the insulator layer is, for example, preferably 1 nm or more and 1 μm or less, more preferably 2 nm or more and 500 nm or less, and even more preferably 5 nm or more and 300 nm or less.

A method for forming the insulator layer is not particularly limited, and a known method can be applied as appropriate. Examples of methods for forming the insulator layer include chemical vapor deposition, vacuum deposition, sputtering, spin coating, photolithography, inkjet, and thermal oxidation.

〔substrate〕
The functional group-containing organic molecule detection sensor according to the present disclosure may further include a substrate.
The shape of the substrate includes a plate shape, a curved surface shape, a container shape, and the like, and may be designed as appropriate according to the type and application of the specimen. As for the type of the substrate, known substrate materials for detection sensors, transistors, wiring, and the like can be applied. Examples of substrates include silicon materials, glass, resins, ceramics, and composite materials thereof.

A commercially available substrate may be used, or a new substrate may be produced. A method for manufacturing the substrate is not particularly limited, and a known method can be applied as appropriate.

≪Detection method≫
According to the detection method according to the present disclosure, by using the functional group-containing organic molecule detection sensor according to the present disclosure, the Functionalized organic molecules containing one or more functional groups can be detected.

The detection method according to the present disclosure is not particularly limited as long as it is a method for detecting functional group-containing organic molecules using the functional group-containing organic molecule detection sensor according to the present disclosure.

For example, the detection method according to the present disclosure includes:
a contacting step of contacting a sample to be examined for the presence or absence of a functional group-containing organic molecule with a functional group-containing organic molecule detection sensor;
a voltage applying step of applying a voltage to two electrodes in the functional group-containing organic molecule detection sensor;
a detection step of detecting functional group-containing organic molecules contained in the specimen;
may contain

As one aspect of the detection method according to the present disclosure, the detection step is based on a change in potential before and after the reaction between the functional group-containing organic molecule and the reactive organic molecule. It may be a step of detecting contained organic molecules.

≪Organic molecule detection array≫
An organic molecule detection array according to the present disclosure comprises a functional group-containing organic molecule detection sensor according to the present disclosure. An organic molecule detection array according to the present disclosure can detect organic molecules of interest.

The organic molecule detection array may contain at least one functional group-containing organic molecule detection sensor according to the present disclosure, and preferably contains two or more.

The target organic molecule may be a naturally occurring compound, a derivative of a naturally occurring compound, or an organic synthetic compound, as long as it is an organic molecule. The target organic molecule may or may not be a functional group-containing organic molecule.

<<Organic molecule screening method>>
The organic molecule screening method according to the present disclosure screens organic molecules using the organic molecule detection array according to the present disclosure. More specifically, the organic molecule screening method according to the present disclosure uses the organic molecule detection array according to the present disclosure to confirm the presence or absence of specific organic molecules contained in a specimen (hereinafter simply referred to as the “confirmation step”). Also called.). The organic molecule screening method may contain other steps.

By using the organic molecule detection array according to the present disclosure, the organic molecule screening method according to the present disclosure can detect the functional group-containing organic molecules contained in the sample by functional group. Therefore, it is possible to efficiently screen for specific organic molecules contained in the sample.

For the organic molecule screening method, a known configuration and screening method may be applied as they are, except for using the organic molecule detection array according to the present disclosure.

The target organic molecule may be a naturally occurring compound, a derivative of a naturally occurring compound, or an organic synthetic compound, as long as it is an organic molecule. The target organic molecule may or may not be a functional group-containing organic molecule.

[Examples 1 to 4]
<<Fabrication of functional group-containing organic molecule detection sensor>>
A functional group-containing organic detection device having the configuration shown in FIG. 1 was produced. Specifically, first, an insulator layer 11 (material: silicon dioxide) with a thickness of 290 nm is formed on a gate electrode 10 (material: silicon doped with boron or phosphorus) of 1.2 cm×1.2 cm×0.52 mm in thickness. , formed by thermal oxidation. Single-layer graphene as the semiconductor member 13 was formed on the obtained insulator layer 11 by chemical vapor deposition.
Then, Ti was vacuum-deposited on the single-layer graphene, which is the semiconductor member 13, so that at least part of Ti was in contact with the single-layer graphene and the thickness was 10 nm. Subsequently, Au was vacuum-deposited on the vacuum-deposited Ti layer so that at least part of the Au was in contact with the monolayer graphene and the thickness was 70 nm. The obtained laminate of Ti and Au was used as the source electrode 12S. By a similar method, a layered body of Ti and Au was produced on the monolayer graphene, and this was used as the drain electrode 12D. Thus, a field effect transistor including the gate electrode 10, the insulator layer 11, the source electrode 12S, the drain electrode 12D, and the semiconductor member 13 was formed.

Subsequently, the single-layer graphene field effect transistor was immersed in a dichloromethane solution of the reactive organic molecules 14 shown in Table 1 at room temperature (25° C.) for 60 minutes, so that the reactive organic molecules 14 were deposited on the surface of the single-layer graphene. was physically adsorbed. A field effect transistor including a single-layer graphene to which the reactive organic molecules 14 were adsorbed was used as the functional group-containing organic molecule detection sensor 100 in each example.

≪Detection of functional group-containing organic molecules≫
Voltages were applied to the gate electrode 10, the source electrode 12S and the drain electrode 12D of the functional group-containing organic molecule detection sensor 100 of each example, and the current transfer characteristics of the functional group-containing organic molecule detection sensor 100 of each example were determined.
Next, the functional group-containing organic molecule 15 shown in Table 1 was detected using the functional group-containing organic molecule detection sensor 100 of each example. Specifically, the functional group-containing organic molecules 15 of the types shown in Table 1 are applied as a gaseous specimen to the surface of the semiconductor member to which the reactive organic molecules 14 are adsorbed so that the exposed space has the concentration shown in Table 1. , using a calibrated gas generator and a mass flow controller, at a temperature of 23° C. and a humidity of 0% RH for 20 minutes, followed by exposure. After that, a voltage was applied to each of the gate electrode 10, the source electrode 12S, and the drain electrode 12D, and the current transfer characteristics of the functional group-containing organic molecule detection sensor 100 in each example were obtained. Furthermore, for Examples 1 to 3, current transfer characteristics were determined over time with the functional group-containing organic molecule 15 exposed.

[Comparative Example 1]
In Comparative Example 1, instead of the functional group-containing organic molecule 15 that reacts with the reactive organic molecule 14, the functional group-containing organic molecule that does not react with the reactive organic molecule shown in Table 1 was used as a liquid sample. The functional group-containing organic molecule 15 was detected using the same specifications as in 1.

Table 1 shows the detection conditions and results of the functional group-containing organic molecule detection sensor of each example. FIG. 2 shows a graph representing the relationship between the current of the drain electrode and the voltage of the gate electrode before and after exposure to the specimen in Example 1. As shown in FIG. FIG. 3 shows a graph representing the relationship between the voltage change amount ΔV _BA and the detection time in Examples 1-3. FIG. 4 shows a graph representing the relationship between the current of the drain electrode and the voltage of the gate electrode before and after exposure to the specimen in Example 4 and Comparative Example 1. In FIG.

As shown in FIG. 2, it was found that the voltage peak value of the gate electrode derived from the current transfer characteristics of graphene, which is a semiconductor member, increased from _VB to _VA before and after exposure to the specimen. Therefore, from this voltage change ΔV _BA (=V _B −V _A ), it was found that the functional group-containing organic molecule detection sensor of each example could detect the functional group-containing organic molecule contained in the specimen. Furthermore, as shown in FIG. 3, it was found that the functional group-containing organic molecule detection sensors of Examples 1 to 3 were capable of detecting functional group-containing organic molecules at a concentration of 40 ppt.
As shown in FIG. 4, in the case of Comparative Example 1 in which an organic molecule having a functional group (hydroxy group) that does not react with the reactive organic molecule was used instead of the functional group-containing organic molecule, there was no significant change in the sensorgram. I found out. At this time, in Example 4 using the functional group-containing organic molecule that reacts with the reactive organic molecule under the same conditions as in Comparative Example 1, the voltage peak value clearly shifts.

10 Gate electrode 11 Insulator layer 12S Source electrode 12D Drain electrode 13 Semiconductor member 14 Reactive organic molecule 15 Functional group-containing organic molecule 16 Reaction product 100 Functional group-containing organic molecule detection sensor 100A Functional group-containing organic molecule detection sensor

Claims (8)

two electrodes;
Reactive organic molecules that react with functional group-containing organic molecules containing one or more functional groups selected from the group consisting of thiol groups, amine groups, hydroxyl groups, carboxy groups, aldehyde groups and nitro groups are adsorbed. a semiconductor member;
with
the reactive organic molecule undergoes a nucleophilic addition reaction or a nucleophilic substitution reaction with the functional group-containing organic molecule;
A functional group-containing organic molecule detection sensor for detecting the functional group-containing organic molecule contained in a specimen. two electrodes;
Reactive organic molecules that react with functional group-containing organic molecules containing one or more functional groups selected from the group consisting of thiol groups, amine groups, hydroxyl groups, carboxy groups, aldehyde groups and nitro groups are adsorbed. a semiconductor member;
with
the functional group-containing organic molecule contains a thiol group;
wherein the reactive organic molecule comprises one or more selected from maleimide, bromobimane, a compound containing a skeleton derived from maleimide, and a compound containing a skeleton derived from bromobimane;
A functional group-containing organic molecule detection sensor for detecting the functional group-containing organic molecule contained in a specimen. two electrodes;
Reactive organic molecules that react with functional group-containing organic molecules containing one or more functional groups selected from the group consisting of thiol groups, amine groups, hydroxyl groups, carboxy groups, aldehyde groups and nitro groups are adsorbed. a semiconductor member;
with
the functional group-containing organic molecule contains an amine group;
wherein the reactive organic molecule comprises one or more selected from aromatic halides, aliphatic halides and ester compounds;
A functional group-containing organic molecule detection sensor for detecting the functional group-containing organic molecule contained in a specimen. wherein the semiconductor member is graphene;
The functional group-containing organic molecule detection sensor according to any one of claims 1 to 3 . Using the functional group-containing organic molecule detection sensor according to any one of claims 1 to 4 ,
A detection method for detecting a functional group-containing organic molecule containing one or more functional groups selected from the group consisting of a thiol group, an amine group, a hydroxy group, a carboxy group, an aldehyde group and a nitro group. detecting the functional group-containing organic molecule based on a change in potential between the two electrodes derived from current transfer characteristics of the semiconductor member before and after the reaction between the functional group-containing organic molecule and the reactive organic molecule; The detection method according to claim 5 . An organic molecule detection array comprising the functional group-containing organic molecule detection sensor according to any one of claims 1 to 4 . Using the organic molecule detection array according to claim 7 ,
An organic molecule screening method for screening organic molecules.

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