JPWO2019116974A1 - Porous microparticles, chromatographic fillers and chromatographic columns - Google Patents

Abstract

An object of the present invention is to provide porous fine particles having high separability and capable of suppressing tailing. Another object of the present invention is to provide a chromatographic filler and a chromatographic column containing the same. The porous fine particles of the present invention are porous fine particles containing a carrier whose surface is modified by a chemical modifier, and the chemical modifier has an aromatic heterocycle.

Description

The present invention relates to porous microparticles, chromatographic fillers and chromatographic columns. More specifically, the present invention relates to porous fine particles having excellent separability, a packing material for chromatography containing the same, and a column for chromatography.

Recrystallization, filtration, distillation, sublimation, chromatography and the like are known as methods for separating a mixture of chemical substances. Recrystallization, filtration, distillation, sublimation, etc. are excellent in terms of cost and are practically used for industrial scale purification. Such an operation is not always suitable for separating the mixture, but the state on the sample side is set to a state in which impurities are less mixed from the beginning, or only those that are very easy to separate are mixed. Purification can be achieved by leaving it in a state where it does not exist. However, in the purification of organic electronics materials and drug substances, the purity required for the materials is very strict, so that the required purity is not satisfied in recrystallization, filtration, distillation, sublimation and the like.

On the other hand, the chromatography method can separate samples with high purity without exposing them to high temperature conditions, and is widely used in the analysis and purification of a wide range of organic compounds such as pharmaceutical, food and electronic device materials. ing. In the chromatography method, adsorption and desorption are repeated due to the interaction between the filler and the compound packed in the column, and the number of theoretical stages is higher than that of recrystallization, filtration, distillation, sublimation, etc., so high-purity separation is possible. Become. Therefore, the ability of the compound to be separated by the chromatography method is greatly influenced by the performance of the filler. Therefore, improving the performance of the filler contributes to the analysis and purification of organic compounds in general.

Chromatographic column fillers have been developed in various ways. For the interaction between the filler and the compound packed in the column, there are examples of separation using hydrophilic interaction, hydrogen bond, ionic bond, dipole-dipole interaction, hydrophobic interaction, etc. Are known.

On the other hand, in order to separate polycyclic aromatic compounds which are chemical substances, π-π and CH-π interactions are often used as interactions with modifying groups of fillers.

The π-π interaction is an intermolecular force acting between aromatic rings of organic compound molecules, and the presence of abundant delocalized electrons on the aromatic ring causes a London dispersion force, that is, an intermolecular force. The CH-π interaction is an intermolecular force acting between the π electron of the aromatic ring and another hydrogen atom, and is polarized with the π electron on the abundant delocalized aromatic ring to be relatively electron deficient. Hydrogen atoms attract each other and intermolecular force works.

By the way, a polycyclic aromatic compound has a structure in which a plurality of aromatic rings are fused and has many π electrons. It is known that polycyclic aromatic compounds are easily aggregated, which is caused by π-π interaction between π electrons on the aromatic ring and between molecules due to CH-π interaction between π electrons and hydrogen atoms. The cause is that force is working. Therefore, in order to peel off this intermolecular interaction, it is necessary to have a stronger interaction than the intermolecular interaction between polycyclic aromatic compounds as a function of the packing material.

Patent Document 1 is an example in which the separability is enhanced by using a polycyclic aromatic compound as a filler in a chromatography method. Polychlorinated biphenyls or fullerenes are separated by using a polycyclic aromatic functional group having 5 to 10 fused rings as a modifying group. In the present invention, increasing the fused ring of the polycyclic aromatic functional group of the modifying group increases the number of π electrons, and therefore the π-π interaction with various aromatic compounds becomes stronger and the holding power becomes stronger. Shown.

In addition, it is used for a stationary phase for liquid chromatography (see Patent Document 2) in which various compounds are separated by utilizing the cohesiveness of the dye or dye by binding a dye or dye to the stationary phase, and for optical division. (See Patent Document 3) and the like are known.

Japanese Unexamined Patent Publication No. 9-432222 Japanese Unexamined Patent Publication No. 6-148159 Japanese Unexamined Patent Publication No. 2005-344040

The present invention has been made in view of the above problems and situations, and a problem to be solved thereof is to provide porous fine particles having high separability and capable of suppressing tailing. Another object of the present invention is to provide a chromatographic filler and a chromatographic column containing the same.

As a result of investigating the causes of the above problems in order to solve the above problems, the present inventors have determined that the compound to be separated and the modifying group of the filler are particularly in the method of separating the polycyclic aromatic compound by the chromatography method. We have found that the separability is improved by using a compound having a specific structure capable of strengthening the π-π interaction and the CH-π interaction, and have reached the present invention.

That is, the above problem according to the present invention is solved by the following means.

1. 1. Porous fine particles containing a carrier whose surface is modified by a chemical modifier, wherein the chemical modifier has an aromatic heterocycle.

2. 2. The porous fine particles according to item 1, wherein the chemical modifier has a plurality of aromatic heterocycles.

3. 3. The porous fine particles according to item 1 or 2, wherein the chemical modifier has a condensed aromatic heterocycle.

4. The porous fine particles according to any one of items 1 to 3, wherein the chemical modifier has a plurality of condensed aromatic heterocycles.

5. The porous fine particles according to any one of items 1 to 4, wherein the chemical modification agent is a fluorescent compound or a phosphorescent compound.

6. The porous fine particles according to any one of items 1 to 5, wherein the carrier is a carrier that has been surface-modified with a chemical modifier having a chemical structure different from that of the chemical modifier. ..

7. The porous fine particles according to any one of claims 1 to 6, wherein the chemical modification agent has any of the structures represented by the following general formulas a-1 to a-16. ..

(In the general formulas a-1 to a-16, X independently represents a carbon atom or a hetero atom, and at least one represents a hetero atom. Each X independently has a substituent. It may form a ring with each other, or may form a ring with each other of the substituents of X. M represents a metal atom. N represents an integer of 1 to 3).
8. The porous fine particles according to any one of items 1 to 7, wherein the chemical modification agent is a metal complex.

9. Item 8. The porous fine particles according to Item 8, wherein the metal complex is an iridium complex or a platinum complex.

10. The porous fine particles according to any one of items 1 to 9, wherein the porous fine particles contain a metal oxide.

11. The porous fine particles according to any one of items 1 to 10, wherein the porous fine particles are porous fine particles containing silicon dioxide.

12. A packing material for chromatography, which comprises the porous fine particles according to any one of items 1 to 11.

13. A column for chromatography, which comprises the porous fine particles according to any one of items 1 to 11.

By the above means of the present invention, it is possible to provide porous fine particles having high separability and capable of suppressing tailing. In addition, a chromatographic filler and a chromatographic column containing the same can be provided.

Although the mechanism of expression or the mechanism of action of the effect of the present invention has not been clarified, it is inferred as follows.

By using porous fine particles modified with a chemical modifier having an aromatic heterocycle, the π-π interaction and CH-π interaction between the compound to be separated and the chemical modifier can be strengthened, which is slight. It is presumed that a filler having high separability can be obtained by increasing the difference in interaction.

Schematic diagram showing the time it takes for a compound to pass through a column Conceptual diagram showing how the transferred compound is adsorbed on the filler (stationary phase) Schematic diagram showing the symmetry coefficient

The porous fine particles of the present invention are porous fine particles containing a carrier whose surface is modified by a chemical modifier, and the chemical modifier has an aromatic heterocycle. This feature is a technical feature common to or corresponding to each of the following embodiments (forms).

In an embodiment of the present invention, from the viewpoint of exhibiting the effect of the present invention, the chemical modification agent preferably has a plurality of the aromatic heterocycles, preferably has a condensed aromatic heterocycle, and further. It is preferable to have a plurality of fused aromatic heterocycles.

Further, since the chemical modifier is a fluorescent compound or a phosphorescent compound, which exhibits luminescence characteristics, it is a compound having a π-conjugated system, and has a π-π interaction and a CH-π interaction. It is preferable because the effect can be obtained.

Further, in the present invention, it is preferable that the carrier is a carrier whose surface is preliminarily modified with a chemical modifier having a chemical structure different from that of the chemical modifier. As a result, by keeping the sample material away from the residual silanol groups of silica gel, it is possible to obtain the effect of suppressing the interaction with the silanol groups that the sample material does not anticipate and promoting the interaction with the modifying group.

In an embodiment of the present invention, it is preferable that the chemical modification agent has a structure represented by the general formulas a-1 to a-16.

Further, when the chemical modifier is a metal complex, the π-π interaction and CH, which are electron-rich or electron-deficient than the hydrocarbon aromatic compound, due to the coordination of the organic molecule having π-conjugation to the metal. It is preferable because the effect of −π interaction can be obtained. Further, the metal complex is preferably an iridium complex or a platinum complex.

Further, in the present invention, it is preferable that the porous fine particles contain a metal oxide. As a result, the effect can be obtained. Further, it is preferable that the porous fine particles are porous fine particles containing silicon dioxide.

The porous fine particles of the present invention can be provided in a chromatographic filler and a chromatography column.

Hereinafter, the present invention, its constituent elements, and modes and modes for carrying out the present invention will be described in detail. In the present application, "~" is used to mean that the numerical values described before and after the value are included as the lower limit value and the upper limit value.

<< Overview of porous fine particles >>
The porous fine particles of the present invention are porous fine particles containing a carrier whose surface is modified by a chemical modifier, and the chemical modifier has an aromatic heterocycle. "Chemical modification" as used in the present invention means adsorbing a compound on the surface of a carrier.

Here, the adsorption may be chemical adsorption (adsorption accompanied by a chemical bond) or physical adsorption (adsorption by physical interaction), or a combination thereof. In the case of chemical adsorption, the chemical bond includes a hydrogen bond, a covalent bond, a coordination bond, an ionic bond, and the like, and further, any combination of two or more of these can be used. In the case of physical adsorption, the physical interaction includes ion-ion interaction, bipolar interaction, Van der Waals, etc., and a combination of two or more of these. May be good.

A polycyclic aromatic compound used as a material for an electronic device or the like needs to have a function of transporting electrons or holes, and therefore has a structure in which an electron-rich or electron-deficient aromatic ring is bonded, and is the same. Since the π-π interaction and CH-π interaction between molecules are strong, they easily aggregate. Various methods for separating such a polycyclic aromatic compound by a chromatography method can be considered as a modifying group of a filler. Among them, when an aromatic is used as a modifying group, the π between the compound to be separated and the modifying group The −π interaction and CH−π interaction were not sufficient, and separation was difficult.

Π-π interaction and CH-π interaction between polycyclic aromatic compounds in order to peel off the π-π interaction and CH-π interaction and adsorb them to the modifying group of the packing material used for chromatography. It is necessary to introduce a strong modifying group.

Therefore, in the present invention, by introducing a heteroatom into the aromatic ring as a chemical modifier of the filler to form an electron-rich or electron-deficient aromatic heterocycle, π-π interaction with the material to be separated, CH-π It has been found that by strengthening the interaction and increasing the slight difference in interaction, a filler having higher separability can be obtained. This effect can be enhanced by having the chemically modifying agent having a condensed aromatic heterocycle, and further by having a plurality of condensed aromatic heterocycles.

《Chemical modifier》
[Aromatic heterocycle]
The chemical modifier according to the present invention has an aromatic heterocycle. Hereinafter, it will be described that the aromatic heterocycle according to the present invention has different behavior of π electrons from the aromatic hydrocarbon ring. As an example of expressing this π property, there is an index called NICS (nucleus-independent chemical shift) value.

This NICS value is an index used for quantifying aromaticity due to magnetic properties. If the ring is aromatic, the center of the ring is strongly shielded by the ring current effect, and conversely if it is antiaromatic. It is anti-shielded (see J. Am. Chem. Soc. 1996, 118, 6317). From the magnitude of the NICS value, the strength of the ring current, that is, the contribution of π electrons to the aromaticity of the ring can be determined. Specifically, it represents the chemical shift (calculated value) of the virtual lithium ion placed directly in the center of the inner ring, and the larger this value is, the stronger the π property is, and the more the electron is in excess.

Several reports have been made on measured NICS values. For example, the Journal of Chemistry. , 2004, 82, 50-69 (Reference A) and The Journal of Organic Chemistry. , 2000, 67, 1333-1338 (Reference B).

Specifically, the pyrazole ring (-14.87) and the thiophene ring (-14.09) are more than the aromatic hydrocarbon rings such as the benzene ring (-7.98) and the naphthalene ring (-8.11). Furan ring (-12.42), pyrazole ring (-13.82), imidazole ring (-13.28), triazole ring (-13.18), oxaziazole ring (-12.44) or thiazole ring (-12.44) The 5-membered aromatic heterocycle such as -12.82) has a larger NICS value, indicating that the aromatic compound has an electron excess. It is expected that the π-π interaction and the CH-π interaction can be strengthened by using a chemical modifier having such an aromatic heterocycle.

Further, it is preferable that the aromatic heterocycle according to the present invention is a condensed aromatic heterocycle because the π-π interaction can be strengthened. Further, it is preferable that the chemical modifier has a plurality of condensed aromatic heterocycles. Further, the chemical modifier may have a plurality of aromatic heterocycles.

Furthermore, since the chemical modifier is a fluorescent compound or a phosphorescent compound, which exhibits luminescence characteristics, it is a compound having a π-conjugated system, and the effects of π-π interaction and CH-π interaction. Is preferable because

[Structure of chemical modifier]
Such a chemical modifier having an aromatic heterocycle preferably has any of the structures represented by the following general formulas a-1 to a-16.

(In the general formulas a-1 to a-16, X independently represents a carbon atom or a hetero atom, and at least one represents a hetero atom. M represents a metal atom. N is an integer of 1 to 3. Represents.)
In the general formulas a-1 to a-16, an oxygen atom, a nitrogen atom, and a sulfur atom are preferably used as the hetero atom represented by X. M represents a metal atom, and iridium or platinum is preferably used. n represents an integer of 1 to 3. Each X may have a substituent independently, may form a ring with each other, or may form a ring between the substituents of X.

Further, the chemical modifier used in the present invention preferably has a structure represented by the following general formulas b-1 to b-24.

(In the general formulas b-1 to b-24, Y independently represents a carbon atom or a nitrogen atom, W independently represents a hetero atom, M represents a metal atom, and R represents a substitution. Represents a group. N represents an integer of 1-3. In general formula b-24, at least one of Y represents a hetero atom.)
In the general formulas b-1 to b-24, the hetero atom represented by W is preferably a nitrogen atom, a sulfur atom or an oxygen atom. The metal atom represented by M is preferably iridium or platinum. n represents an integer of 1 to 3.

Further, each Y may have a substituent independently, may form a ring with each other, or may form a ring between the substituents of Y. R represents a substituent, and the substituents may form a ring with each other.

Examples of the substituent represented by R include a hydrogen atom and an alkyl group (for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a (t) butyl group, a pentyl group, a hexyl group, an octyl group, a dodecyl group and a tridecyl group. , Tetradecyl group, pentadecyl group, etc.), cycloalkyl group (eg, cyclopentyl group, cyclohexyl group, etc.), alkenyl group (eg, vinyl group, allyl group, etc.), alkynyl group (eg, propargyl group, etc.), aromatic hydrocarbon Ring group (also referred to as aryl group, for example, phenyl group, p-chlorophenyl group, mesityl group, tolyl group, xsilyl group, naphthyl group, anthryl group, azulenyl group, acenaphthenyl group, fluorenyl group, phenanthryl group, indenyl group, pyrenyl group , Biphenylyl group, etc.), heterocyclic groups (eg, epoxy ring, aziridine ring, thiirane ring, oxetane ring, azetidine ring, thietan ring, tetrahydrofuran ring, dioxolan ring, pyrrolidine ring, pyrazolidine ring, imidazolidine ring, oxazolidin ring, tetrahydro Thiophen ring, sulfolan ring, thiazolidine ring, ε-caprolactone ring, ε-caprolactam ring, piperidine ring, hexahydropyridazine ring, hexahydropyrimidine ring, piperazine ring, morpholin ring, tetrahydropyran ring, 1,3-dioxane ring, 1 , 4-dioxane ring, trioxane ring, tetrahydrothiopyran ring, thiomorpholin ring, thiomorpholin-1,1-dioxide ring, pyranose ring, diazabicyclo [2,2,2] -octane ring, etc.), aromatic heterocyclic group (Pyridyl group, pyrimidinyl group, furyl group, pyrrolyl group, imidazolyl group, benzoimidazolyl group, pyrazolyl group, pyrazinyl group, triazolyl group (for example, 1,2,4-triazol-1-yl group, 1,2,3-triazole group) -1-yl group, etc.), oxazolyl group, benzoxazolyl group, thiazolyl group, isooxazolyl group, isothiazolyl group, frazayl group, thienyl group, quinolyl group, benzofuryl group, dibenzofuryl group, benzothienyl group, dibenzothienyl group, Indolyl group, indolindolyl group, carbazolyl group, carbolinyl group, diazacarbazolyl group (indicating one of the carbon atoms constituting the carbolin ring of the carbolinyl group replaced with a nitrogen atom), quinoxalinyl group, pyridadinyl group. , Triazinyl group, quinazolinyl group, phthalazinyl group, etc.), halogen atom (eg, chlorine atom, bromine atom, etc.) , Iodine atom, fluorine atom, etc.), alkoxyl group (eg, methoxy group, ethoxy group, propyloxy group, pentyloxy group, hexyloxy group, octyloxy group, dodecyloxy group, etc.), cycloalkenyl group (eg, cyclopentyloxy) Group, cyclohexyloxy group, etc.), aryloxy group (eg, phenoxy group, naphthyloxy group, etc.), alkylthio group (eg, methylthio group, ethylthio group, propylthio group, pentylthio group, hexylthio group, octylthio group, dodecylthio group, etc.) , Cycloalkylthio group (eg, cyclopentylthio group, cyclohexylthio group, etc.), arylthio group (eg, phenylthio group, naphthylthio group, etc.), alkoxycarbonyl group (eg, methyloxycarbonyl group, ethyloxycarbonyl group, butyloxycarbonyl group, etc.) , Octyloxycarbonyl group, dodecyloxycarbonyl group, etc.), aryloxycarbonyl group (eg, phenyloxycarbonyl group, naphthyloxycarbonyl group, etc.), sulfamoyl group (eg, aminosulfonyl group, methylaminosulfonyl group, dimethylaminosulfonyl group, etc.) , Butylaminosulfonyl group, hexylaminosulfonyl group, cyclohexylaminosulfonyl group, octylaminosulfonyl group, dodecylaminosulfonyl group, phenylaminosulfonyl group, naphthylaminosulfonyl group, 2-pyridylaminosulfonyl group, etc.), ureido group (eg, methyl Ureid group, ethyl ureido group, pentyl ureido group, cyclohexyl ureido group, octyl ureido group, dodecyl ureido group, phenyl ureido group, naphthyl ureido group, 2-pyridyl amino ureido group, etc.), acyl group (for example, acetyl group, ethyl carbonyl group) , Apropylcarbonyl group, pentylcarbonyl group, cyclohexylcarbonyl group, octylcarbonyl group, 2-ethylhexylcarbonyl group, dodecylcarbonyl group, phenylcarbonyl group, naphthylcarbonyl group, pyridylcarbonyl group, etc.), acyloxy group (eg, acetyloxy group, Ethylcarbonyloxy group, butylcarbonyloxy group, octylcarbonyloxy group, dodecylcarbonyloxy group, phenylcarbonyloxy group, etc.), amide group (for example, methylcarbonylamino group, ethylcarbonylamino group, dimethylcarbonylamino group, propylcarbonylamino) Group, Pentyl Carbonyl Luamino group, cyclohexylcarbonylamino group, 2-ethylhexylcarbonylamino group, octylcarbonylamino group, dodecylcarbonylamino group, phenylcarbonylamino group, naphthylcarbonylamino group, etc.), carbamoyl group (for example, aminocarbonyl group, methylaminocarbonyl group) , Dimethylaminocarbonyl group, propylaminocarbonyl group, pentylaminocarbonyl group, cyclohexylaminocarbonyl group, octylaminocarbonyl group, 2-ethylhexylaminocarbonyl group, dodecylaminocarbonyl group, phenylaminocarbonyl group, naphthylaminocarbonyl group, 2- Pyridylaminocarbonyl group, etc.), sulfinyl group (eg, methylsulfinyl group, ethylsulfinyl group, butylsulfinyl group, cyclohexylsulfinyl group, 2-ethylhexylsulfinyl group, dodecylsulfinyl group, phenylsulfinyl group, naphthylsulfinyl group, 2-pyridylsulfinyl group Etc.), alkylsulfonyl group or arylsulfonyl group (eg, methylsulfonyl group, ethylsulfonyl group, butylsulfonyl group, cyclohexylsulfonyl group, 2-ethylhexylsulfonyl group, dodecylsulfonyl group, phenylsulfonyl group, naphthylsulfonyl group, 2-pyridyl (Sulfonyl group, etc.), amino group (eg, amino group, ethylamino group, dimethylamino group, butylamino group, cyclopentylamino group, 2-ethylhexylamino group, dodecylamino group), anilino group, diarylamino group (eg, diphenyl) Amino group, dinaphthylamino group, phenylnaphthylamino group, etc.), naphthylamino group, 2-pyridylamino group, etc.), nitro group, cyano group, hydroxyl group, mercapto group, alkylsilyl group or arylsilyl group (for example, trimethylsilyl group) , Triethylsilyl group, (t) butyldimethylsilyl group, triisopropylsilyl group, (t) butyldiphenylsilyl group, triphenylsilyl group, trinaphthylsilyl group, 2-pyridylsilyl group, etc.), alkylphosphino group or aryl Phosphino group (dimethylphosphino group, diethylphosphino group, dicyclohexylphosphino group, methylphenylphosphino group, diphenylphosphino group, dinaphthylphosphino group, di (2-pyridyl) phosphosphino group), alkylphosphoryl group or Arylphosphoryl group (dimethylphosphoryl group , Diethylphosphoryl group, dicyclohexylphosphoryl group, methylphenylphosphoryl group, diphenylphosphoryl group, dinaphthylphosphoryl group, di (2-pyridyl) phosphoryl group), alkylthiophosphoryl group or arylthiophosphoryl group (dimethylthiophosphoryl group, diethylthiophosphoryl group) Represents any group selected from (group, dicyclohexylthiophosphoryl group, methylphenylthiophosphoryl group, diphenylthiophosphoryl group, dinaphthylthiophosphoryl group, di (2-pyridyl) thiophosphoryl group). In addition, these substituents may be further substituted by the above-mentioned substituents, or they may be condensed with each other to further form a ring.

Further, an alkyl group, an aromatic hydrocarbon ring group, an aromatic heterocyclic group, a heterocyclic group, and a cycloalkyl group are preferable.

[Modifying group]
In the present invention, the chemical modifier can be used as a compound by physically adsorbing it on the carrier, but the above-mentioned chemical modifier having an aromatic heterocycle chemically bonds with the carrier as a modifying group having an aromatic heterocycle. Can be done. Further, the chemical modifier having an aromatic heterocycle is chemically bonded to a carrier surface-modified with a chemical modifier having a chemical structure different from that of the chemical modifier as a modifying group having an aromatic heterocycle. Specific structures of such modifying groups according to the present invention (hereinafter, also simply referred to as “modifying groups”) are exemplified in the following general formulas c-1 to c-115, but the present invention is limited thereto. It is not something that is done. In the general formulas c-1 to c-115, * refers to a bonding portion with a carrier or a carrier whose surface has been modified in advance.

これらの化学修飾剤又は修飾基は公知の方法で合成することができる。

These chemically modifying agents or modifying groups can be synthesized by known methods.

[Carrier]
The porous fine particles of the present invention contain a carrier whose surface is modified with a chemical modifier. The carrier according to the present invention may be any substance that can be chemically modified, whereby a modifying group having an aromatic heterocycle according to the present invention can be easily introduced.

The carrier is preferably porous fine particles and can be used as a carrier for chromatography.

The porous fine particles are not particularly limited as long as they are porous fine particles containing a substance that functions as a carrier, but the substance that functions as a carrier is preferably a metal oxide, and as an example, silicon dioxide (silica gel). Examples thereof include inorganic metal oxides typified by alumina and zeolite. Further, a polymer material may be used, or a composite material thereof may be used as a carrier. Of these, silicon dioxide (silica gel) is preferable.

The porous fine particles according to the present invention may be surface-modified with another type of chemical modifier in advance. That is, it may be chemically modified in two steps.

As an example of preferable porous fine particles, the silica gel generally used as a packing material for chromatography is illustrated. The preferable specific surface area is about 1 to 1500 m ² / g, and the particle size is in the range of 1 to 1000 μm. The range of preferably 2 to 50 μm, the pore diameter is in the range of 1 to 100 nm, the depth is in the range of 20 to 1000 nm, the more preferable range of depth is 50 to 500 nm, and the most preferable range of depth is. It is 50 to 150 nm. Further, when the pitch of the pores is defined as the distance between the centers of the pores, the preferable pitch is in the range of 2 to 500 nm, the more preferable pitch range is 2 to 100 nm, and the most preferable pitch range is 2 to 50 nm. Is.

[Surface modification of carrier]
The carrier is preferably a surface-modified carrier in advance. Specifically, it is preferable that the above-mentioned modifying group having an aromatic heterocycle according to the present invention is chemically bonded to the carrier surface-modified by the surface modifying group. It is also possible to use a carrier in which porous fine particles chemically modified with a surface modifying group are further subjected to an end capping treatment. Further, it is also a preferable embodiment that the modifying group having the aromatic heterocycle according to the present invention and the surface-modified carrier are bonded via a divalent linking group.

As such a group that surface-modifies the carrier binds to the modifying group having an aromatic heterocycle according to the present invention via a divalent linking group, the following general formula d-1 or general formula e-1 It is preferable to have a structure represented by.

(In the general formula d-1, L ₁ and L ₂ each independently represent a single bond or a divalent linking group. M and o each represent an integer of 0 to 5. * Is the present invention. Represents a link with a modifying group having such an aromatic heterocycle. R ₁ represents an element that independently links with a carrier.)
The divalent linking groups represented by L ₁ and L ₂ include a substituted or unsubstituted alkylene group, an arylene group or a heteroarylene group, −O−, −S−, −S (= O) _2- , −. Examples thereof include N (R)-, carboxy group, carbonyl group, sulfonicyl group, carbamoyl group, sulfamoyl group and amide group.
R ₁ represents an element that independently links to the carrier, and a carbon atom, an oxygen atom, or a nitrogen atom is particularly preferable.

(In the general formula e-1, L ₁ represents a single bond or a divalent linking group, m and o represent an integer of 0 to 5, respectively. Ar is a divalent linking group which is an aromatic hydrocarbon. * Represents a linking portion with a modifying group having an aromatic heterocycle according to the present invention. R ₁ represents an element that independently links to a carrier.)
In the formula e-1, _{L 1} and _{R 1} has the same meaning as _{L 1} and _{R 1} in the general formula d-1.

Examples of the divalent linking group which is an aromatic hydrocarbon represented by Ar include ortho, para or metaphenylene, naphthylene, biphenylene, anthraceneylene, terphenylene and the like.

Specific structures of a pre-surface-modified carrier having a divalent linking group preferably used in the present invention are exemplified below in f-1 to f-15, but the present invention is not limited thereto.

In the following general formulas f-1 to f-15, * represents a connecting portion with the above-mentioned modifying group having an aromatic heterocycle according to the present invention, and a wavy line represents a connecting portion with a carrier.

The specific structure of the porous fine particles containing the carrier modified by the chemical modifier of the present invention is the modifying group having the aromatic heterocycle according to the present invention shown in c-1 to c-115 and f-1. It is preferable to have a structure in which the carrier which has been surface-modified in advance as shown in ~ f-15 is bonded. Specifically, it is preferable to have the structures illustrated in 1-1 to 1-25 below. The wavy line represents the connection with the carrier.

<< Column chromatography method >>
The porous fine particles of the present invention are used in a column chromatography method (hereinafter, also referred to as a chromatographic method) and can be used as a filler having excellent separability.

Here, the column chromatography method will be described.
In column chromatography, the adsorption of the filler (stationary phase) on the compound is called retention. In column chromatography, the compound moves toward the outlet of the column while repeating adsorption to the packing material (stationary phase) and elution to the solvent (mobile phase). While adsorbed on the packing material (stationary phase), the compound does not advance inside the column, but proceeds to the tip of the column when it elutes into the solvent (mobile phase). Therefore, a compound having a strong interaction, that is, a compound that has been adsorbed on the packing material (stationary phase) for a long time, takes longer to pass through the column.

In FIG. 1, the time t ₁ until the compound passes through the column is called the hold time, and the time until the compound that does not interact with the filler (stationary phase) passes through the column is called the hold-up time. At this time, t ₁ ′, which is obtained by subtracting the hold-up time from the holding time, is called the space-corrected holding time, and this compound was adsorbed by the packing material (stationary phase) of the column and did not proceed in the column. It will be a net time. Further, the ratio k of the space-corrected holding time and the hold-up time is called a holding coefficient, and is an index showing how easily the compound is held in the filler (stationary phase).

Further, the meaning of the retention coefficient k will be described. Regarding the retention of the compound by the stationary phase, it can be expressed as shown in FIG. 2 when the single compound is A and the retention site of the filler (stationary phase) is B. This is exactly the chemical equilibrium, and the equilibrium constant K of this equilibrium can be expressed as [A + B] / [A] + [B]. Considering in correspondence with FIG. 1, t ₀ represents the time during which the compound and the filler (stationary phase) exist in the relationship of [A] + [B], and t ₁ ′ (that is, in FIG. 1, t ₁ '= represents t _{1 −} t ₀ ) represents the time that exists in the relationship of [A + B]. Therefore, it can be replaced with k = t ₁ '/ t ₀ = [A + B] / [A] + [B], which is the same as the equilibrium constant K. That is, in high performance liquid chromatography (HPLC), the retention coefficient k gives the strength (affinity) of the interaction between the filler (stationary phase) and the compound in the form of an equilibrium constant.

In the actual measurement system, both the compound amount [A] and the retention site amount [B] of the packing material (stationary phase) are finite, and both can be settled at the ratio of the equilibrium constant for correct separation. It is necessary to have a large amount. For example, in the case of a compound having an equilibrium constant of 10000 and a filler (stationary phase), the equilibrium relationship can be correctly realized if there are 10001 and 10001 holding sites of the compound. However, when 100,000 compounds are present for the retention site 10001, 10,000 retention sites are bound to the compound, and 90,000 surplus compounds try to be adsorbed on the remaining one retention site. It occurs and the equilibrium is not established. As a result, the balance of suction and desorption is lost, leading to reading, tailing, and broadening of the peak width, and as a result, it is presumed that separation is hindered.

Therefore, it is considered that the shape loss such as peak tailing, reading, or broadening due to overload can be solved by preparing more adsorption sites on the filler (stationary phase).

<< Chromatographic filler >>
The chromatographic filler of the present invention is characterized by containing the porous fine particles of the present invention. Regarding the packing material for chromatography of the present invention, residual active groups that have not been completely reacted even with the present invention may be used by end-capping with different modified structures. Further, the operation of replacing the fine particles with a dry gas may be performed at the time of end capping. The structure of the endcapping may be any one that can react with the residual active group on the particles, and for example, an alkylsilyl group, an acyl group, an alkoxyl group, an alkylamino group and the like having a small exclusion volume are particularly preferable. It is not limited.

Further, for the purpose of the present invention, it is particularly convenient that the above-mentioned chemical modifier is a so-called end capping agent.

The filler obtained by the present invention is preferably used as a filler for column chromatography, particularly as a filler for high performance liquid chromatography or a filler for supercritical fluid chromatography, but is not limited thereto. For example, it may be used as a carrier or an adsorbent for thin layer chromatography, or may be used in the form of a filtration aid or a filter.

<< Column for chromatography >>
The column for chromatography of the present invention is characterized by containing the porous fine particles of the present invention, and is subjected to column chromatography.

The column of the present invention has the effect of reducing so-called reading, tailing, and peak width broadening.

Usually, with respect to reading and tailing, a symmetry coefficient can be mentioned as an index showing the performance of a column in chromatography. The symmetry factor (tailing coefficient) is an index showing the degree of peak symmetry, and is represented by the following formula in FIG.

(Symmetry coefficient: S)
S = W (0.05h) / 2f
W (0.05h): Peak width at 1/20 of the peak height h from the peak baseline)
f: The peak width of W (0.05h) is divided into two by a perpendicular line extending from the peak apex to the horizontal axis. .. When S> 1, the peak has a shape bulging to the right, that is, a tailing shape. When S <1, the peak has a shape bulging to the left, that is, a leading shape. Therefore, the closer S is to 1, the better the performance as a column. The symmetry coefficient of the column of the present invention is preferably 0.70 <S <1.30, more preferably 0.80 <S <1.20, and 0.85 <S <1.15. It is more preferable to have.

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto. In the examples, the indication of "parts" or "%" is used, but unless otherwise specified, it indicates "parts by mass" or "% by mass".

[Example 1]
In the following examples, the porous fine particles of the present invention having the structure exemplified by 1-1 to 1-25 in which the modifying group having the aromatic heterocycle according to the present invention and the carrier surface-modified in advance are bonded are used. As the comparative fine particles, fine particles having the following structure were used.

The numbers of the porous fine particles used in the following examples and the numbers indicating the structure were made to correspond with each other.

<Preparation of porous fine particles 1-1>
A specific surface area of 350 m ² / g with a pore diameter of 100 Å and an average particle diameter of about 5 μm, a surface coverage of aminopropyl groups of 4.1 μmol / m ² , and 2.00 g of spherical silica gel LiChrospher (registered trademark manufactured by Merck) were vacuum dried for 16 hours. The silica gel was placed in a reaction vessel substituted with a 2-dibenzofurancarboxylic acid (2.88 g, 10 mmol) as a modifying group under a nitrogen atmosphere. 30 mL of dehydrated tetrahydrofuran was placed in the reaction vessel, and EDC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide) (3.10 g, 20 mmol) was added as a condensing agent. The reaction vessel was placed in an ultrasonic generator and subjected to ultrasonic waves to react at 40 ° C. for 4 hours.

The obtained silica gel was collected by filtration using a glass filter (G-4), 300 mL of tetrahydrofuran, 300 mL of methanol and 300 mL of acetone were sequentially washed and collected, vacuum dried, and porous, which is a chemically modified packing material for chromatography. Fine particles 1-1 were obtained.

<Preparation of porous fine particles 1-2 to 1-4, 1-6 to 1-8, 1-10, 1-11, 1-14 and 1-17 to 1-20>
The procedure was the same as for the preparation of the porous fine particles 1-1, except that the 2-dibenzofurancarboxylic acid was changed to various carboxylic acids corresponding to the illustrated structures as the modifying groups, and the chemical-modified chromatographic filling was performed. Porous fine particles 1-2 to 1-4, 1-6 to 1-8, 1-10, 1-11, 1-14 and 1-17 to 1-20 as agents were obtained.

<Preparation of porous fine particles 1-5>
A specific surface area of 450 m ² / g with a pore diameter of 100 Å and an average particle diameter of about 5 μm, and 2.00 g of spherical Daiso gel SP-100-5-P (manufactured by Daiso) were vacuum dried for 16 hours and placed in a reaction vessel together with 30 mL of dehydrated toluene. , 2.25 mL of pyridine was added with stirring, and the inside of the system was replaced with nitrogen. To this, 5.50 g of 5- (7- (chlorodimethylsilyl) heptyl) benzo [lmn] phenanthridine was added, and the mixture was stirred at room temperature for 24 hours. The obtained silica gel was collected by filtration using a glass filter (G-4), 300 mL of tetrahydrofuran, 300 mL of methanol and 300 mL of acetone were sequentially washed and collected, vacuum dried, and porous, which is a chemically modified packing material for chromatography. Fine particles 1-5 were obtained.

<Preparation of porous fine particles 1-9, 1-12, 1-13, 1-15 and 1-22 to 1-25>
The procedure was the same as for the production of the porous fine particles 1-5, except that 5- (7- (chlorodimethylsilyl) heptyl) benzo [lmn] phenanthridine was changed to a chlorodimethylsilylated product as a modifying group. Porous fine particles 1-9, 1-12, 1-13, 1-15 and 1-22 to 1-25, which are chemically modified chromatographic fillers, were obtained.

<Preparation of porous fine particles 1-16>
2.00 g of spherical Daiso gel SP-100-5-P (manufactured by Daiso) having a pore size of 100 Å and an average particle size of about 5 μm and a specific surface area of 450 m ² / g was vacuum dried for 16 hours and placed in a reaction vessel together with 20 mL of toluene. While stirring, 500 mg of 3-glusidexipropyltrimethoxysilane was added, and the mixture was heated at 110 ° C. for 6 hours. After cooling, the slurry was suction filtered, the silica gel was washed with an organic solvent, and then dried at 80 ° C. for 12 hours to obtain 2.3 g of desired epoxy group-linked silica gel.

To a 200 mL beaker, add 2.35 g of 8- (dibenzo [d, b] furan-2-yl) -5H-pyrido [4,3-b] indol and 80 mL of tetrahydrofuran, and add 2.30 g of the above epoxy group-modified silica gel. It was. After stirring at room temperature for 1 hour, the mixture was allowed to stand for 16 hours. An appropriate amount of 1 mol / L hydrochloric acid was added with stirring again to adjust the pH to 4.0. The obtained silica gel was collected by filtration using a glass filter (G-4), 300 mL of tetrahydrofuran, 300 mL of methanol and 300 mL of acetone were sequentially washed and collected, vacuum dried, and porous, which is a chemically modified packing material for chromatography. Fine particles 1-16 were obtained.

<Preparation of porous fine particles 1-21>
3- (Dibenzo [d, b] furan-2-yl) -5H-pyrido [4,3-b] indole as a modifying group 3,11-diphenyl-11,12-dihydroindro [2,3- a] Except for the change to carbazole, the same operation as in the preparation of the porous fine particles 1-16 was carried out to obtain the porous fine particles 1-21, which is a chemically modified packing material for chromatography.

<Preparation of porous fine particles 1-26 and 1-27>
Except for changing 2-dibenzofurancarboxylic acid to various carboxylic acids as modifying groups, the same procedure as for the production of porous fine particles 1-1 was carried out, and the porous fine particles 1-, which is a chemically modified packing material for chromatography, were prepared. 26 and 1-27 were obtained.

[Modification amount]
The amount of modification of the prepared porous fine particles 1-1 to 1-27 was determined from the mass difference before and after the reaction. Specifically, for the porous fine particles 1-1 to 1-27, the modification amount (mmol / g) per mass of silica gel was determined and shown in Table I as an index of the modification amount.
(Pollous Fine Particles 1-1): Assuming that the mass increased after the modification is the amount of increase in the reaction of the modifying group to the amino group due to dehydration condensation, the amount of substance to increase the modifying group was obtained and increased by 180 mg. Since the increased molar mass was 195 g / mol, it increased by 0.92 mmol. Since 2.00 g of silica gel was used, the modification amount per mass of silica gel was 0.46 mmol / g.

(Pollous fine particles 1-2-1-4, 1-6 to 1-8, 1-10, 1-11, 1-14, 1-17 to 1-20 and 1-26 to 1-27): These Table I shows the amount of modification per silica gel mass obtained in the same manner.
(Pollous fine particles 1-5): Assuming that the mass increased after modification from silica gel is the reaction increase due to the modifying group, the amount of substance to increase the modifying group was obtained and increased by 340 mg, so that the increased molar mass of the modifying group was Since it was 361 g / mol, it increased by 0.94 mmol. Since 2.00 g of silica gel was used, the modification amount per mass of silica gel was 0.47 mmol / g.

(Pollous fine particles 1-9, 1-12, 1-13, 1-15 and 1-22 to 1-25): Table I shows the modification amounts per silica gel mass obtained in the same manner. ing.
(Pollous fine particles 1-16): Assuming that the mass increased after modification from glycidyloxypropyl silica gel is the amount of increase in the reaction due to modification, the amount of substance for increasing the modifying group was obtained, and the amount increased by 376 mg, so that the number of modifying groups increased. Since the molar mass was 334 g / mol, it increased by 1.1 mmol. Since 2.3 g of silica gel was used, the modification amount per mass of silica gel was 0.48 mmol / g.

(Pollous fine particles 1-21): Table I shows the modification amount per silica gel weight obtained in the same manner.

From Table I, it is shown that there is no significant difference in the amount of modification of the modifying group per mass of silica gel, and that the difference in separability between the present invention and the comparative example can be simply regarded as the difference in the modifying group. ..

[Example 2]
<Verification of electronic effect>
The porous fine particles prepared in Example 1 were filled into stainless steel columns having an inner diameter of 4.6 mm and a length of 15 cm by a slurry filling method using isopropyl alcohol. Then, the separability of the packing material was evaluated from the chromatograms obtained by performing liquid chromatography and supercritical chromatography on various sample samples using the obtained columns.

(Liquid chromatography method)
More specifically, the liquid chromatography device performed analytical experiments on each column under the following conditions.

Equipment: LC-2000Plus (manufactured by JASCO Corporation)
Mobile phase: Hexane / Ethyl acetate = 60/40
Mobile phase flow rate: 1.0 mL / min
Pressure: 14 MPa
Temperature: 50 ° C
Detection: PDA (254 nm)
Sample: Dichloromethane, concentration 200 μg / mL, 1 to 5 μL according to detection sensitivity
The retention time of each sample with each filler was examined, and the retention coefficient and the separation coefficient of octafluoronaphthalene, 1-methylnaphthalene, and 1-methoxynaphthalene with respect to naphthalene were calculated based on the retention time.

The retention coefficient and separation coefficient α were calculated by the following equations.

Retention coefficient k: Calculated by applying the following formula, where the solvent shock is the hold-up time t ₀ and the retention time of the component is t.

k = (t−t ₀ ) / t ₀
Separation coefficient α: For component A and reference component B, when the retention coefficients are k _A and k _B , respectively, the calculation is applied to the following formula.

α = k _A / k _B

As is clear from Table II, the chromatography using the porous fine particles of the present invention as a filler tends to retain them for a longer period of time. Regarding the porous fine particles 1-2 using the iridium complex as a modifying group, the electron-deficient octafluoronaphthalene has a small separation coefficient, and the electron-rich 1-methoxynaphthalene has a large separation coefficient. On the other hand, with respect to the porous fine particles 1-1, 1-3 and 1-4 in which π electrons are considered to be excessive, the electron-deficient octafluoronaphthalene has a large separation coefficient, and the electron-rich 1-methoxynaphthalene has a separation coefficient. small. From these facts, it was found that it is possible to control the retention time of the aromatic compound by deficient or excessive electrons in the aromatic ring of the filler.

Further, 1-methylnaphthalene having a methyl group has a longer retention time than the porous fine particles 1-1, 1-3 and 1-4 in which π electrons are excessive. This indicates that the CH-π interaction, which is the interaction between the H of the methyl group and the π electron, works and strongly interacts to enhance the cognitive ability.

It was also found that the separation coefficient was increased by introducing a linking group. This is because a linking group is introduced between the carrier and the modifying group to keep the sample material away from the residual silanol group of silica gel, thereby suppressing the interaction with the silanol group that the sample material does not anticipate, and mutual interaction with the modifying group. It is considered that the action is promoted.

In this way, by making the π-electron state of the aromatics that make up the modifying group contained in the stationary phase electron-deficient, the π-π interaction with the electron-rich material is strengthened, and the aromatics that make up the modifying group. By making the π-electron state of π-electrons excessive, the π-π interaction with the electron-deficient material and the CH-π interaction can be strengthened, so that the compound can be separated efficiently. Therefore, by using the filler of the present invention, it is desirable to effectively separate a group of compounds that are difficult to separate when the electron density of π electrons is constant, such as a polycyclic aromatic hydrocarbon group. Compounds can be obtained with high purity.

(Supercritical chromatography method)
Following the liquid chromatography method, supercritical chromatography was also performed. From the obtained chromatograms, the separation performance of the filler was similarly evaluated.

The supercritical chromatography device performed analytical experiments on each column under the following conditions.

(Supercritical chromatography conditions)
Equipment: UPC2 (manufactured by Nippon Waters)
Mobile phase: carbon dioxide / ethyl acetate = 60/40
Mobile phase flow rate: 2.5 mL / min
Pressure: 14 MPa
Temperature: 50 ° C
Detection: PDA (254 nm)
Sample: Dichloromethane, concentration 200 μg / mL, 1 to 5 μL according to detection sensitivity
The retention time of each sample with each filler is examined, and based on the retention time, the retention coefficient and the separation coefficient of octafluoronaphthalene, 1-methylnaphthalene, and 1-methoxynaphthalene with respect to naphthalene are the same as in the liquid chromatography method. Calculated in.

As is clear from Table III, chromatographs using the fillers according to the invention tend to retain longer. Similar to liquid chromatography, compounds such as polycyclic aromatic hydrocarbon groups that are difficult to separate in a filler having a modifying group having a constant π electron electron density can also be used as the filler of the present invention. By using it, it is possible to effectively separate and obtain a desired compound with high purity.

[Example 3]
<Verification of organic electroluminescence material separation>
We also conducted experiments on the separation of organic electroluminescence materials (organic EL materials), which are one of the polycyclic aromatic compounds used as materials for electronic devices. As in the above experiment, the retention time of each sample was examined using HPLC and SFC, and the separation coefficient was calculated based on the retention time. Using 1,3-bis-N carbazolylbenzene (mCP) used as a host of the light emitting layer of the organic EL material and Ir (ppy) ₃ used as a dopant of the light emitting layer as samples, Ir (Ir) for mCP ppy) The separation coefficient of ₃ was calculated. The liquid chromatography apparatus and conditions and the supercritical chromatography apparatus and conditions are the same as described above. The results obtained are shown in Table IV.

As is clear from Table IV, in both liquid chromatography and supercritical chromatography, the separation coefficient of Ir (ppy) _{3 with} respect to mCP of Comparative Example is 1 or more and 1.5 or less, whereas the filling of Examples When the agent was used, the separation coefficient was 2.5 or more or 0.1 or less in each case. It was confirmed that the filler of the present invention has a higher distinguishing property than the conventionally used filler, and it was found that the filler is excellent as a column.

(Desirable value of separation factor),
<Effect of tailing suppression>
Furthermore, using Ir (ppy) ₃ as a sample, the column performance when each column, injection amount and sample concentration were increased was evaluated by the symmetry coefficient and the presence or absence of tailing. The liquid chromatography device and conditions were the same as above, and the sample solution was injected with orthodichlorobenzene (100 mg / mL, 10 μL). The results are shown in Table V.

As is clear from Table V, the examples have an effect of suppressing tailing with respect to the comparative example, and particularly the effect of suppressing tailing with Ir (ppy) ₃ when an aromatic heterocycle is used as a modifying group. It turned out that there is.

The porous fine particles of the present invention have high separability, can suppress tailing, and can be suitably applied to a packing material for chromatography and a column for chromatography.

Claims (13)

Porous fine particles having a surface modified with a carrier modified by a chemical modifier, wherein the chemical modifier has an aromatic heterocycle. The porous fine particles according to claim 1, wherein the chemical modifier has a plurality of aromatic heterocycles. The porous fine particles according to claim 1 or 2, wherein the chemical modifier has a condensed aromatic heterocycle. The porous fine particles according to any one of claims 1 to 3, wherein the chemical modifier has a plurality of condensed aromatic heterocycles. The porous fine particles according to any one of claims 1 to 4, wherein the chemical modifier is a fluorescent compound or a phosphorescent compound. The porous fine particles according to any one of claims 1 to 5, wherein the carrier is a carrier that has been surface-modified with a chemical modifier having a chemical structure different from that of the chemical modifier. .. The porous fine particles according to any one of claims 1 to 6, wherein the chemical modification agent has any of the structures represented by the following general formulas a-1 to a-16. ..

(In the general formulas a-1 to a-16, X independently represents a carbon atom or a hetero atom, and at least one represents a hetero atom. Each X independently has a substituent. It may form a ring with each other, or may form a ring with each other of the substituents of X. M represents a metal atom. N represents an integer of 1 to 3). The porous fine particles according to any one of claims 1 to 7, wherein the chemical modifier is a metal complex. The porous fine particles according to claim 8, wherein the metal complex is an iridium complex or a platinum complex. The porous fine particles according to any one of claims 1 to 9, wherein the porous fine particles contain a metal oxide. The porous fine particles according to any one of claims 1 to 10, wherein the porous fine particles are porous fine particles containing silicon dioxide. A packing material for chromatography, which comprises the porous fine particles according to any one of claims 1 to 11. A column for chromatography, which comprises the porous fine particles according to any one of claims 1 to 11.

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