Host molecule and method for producing same, host molecule-target molecule complex and method for producing same, crystal structure analysis sample and method for producing same, and crystal structure analysis sample preparation kit

Abstract

The present invention pertains to: a host molecule which has one or more openings, one or more walls, and an internal space surrounded by the walls, and in which the walls contain metal ions and a multidentate ligands having a π-conjugated system, and the volume of the internal space is 500×10-30m3 or more; a method for producing said host molecule; a host molecule-target molecule complex; a method for producing said host molecule-target molecule complex; a crystal structure analysis sample; a method for producing said crystal structure analysis sample; and a crystal structure analysis sample preparation kit.

Description

Host molecule and method for producing the same, host molecule-target molecule complex and method for producing the same, sample for crystal structure analysis and method for producing the same, and kit for producing sample for crystal structure analysis

[0001] The present invention relates to a host molecule, a method for producing a host molecule, a host molecule-target molecule complex, a method for producing a host molecule-target molecule complex, a sample for crystal structure analysis, a method for producing a sample for crystal structure analysis, and a kit for producing a sample for crystal structure analysis.

[0002] Single crystal structure analysis, such as single crystal X-ray diffraction, has been known as one of the highly reliable methods for determining molecular structure. However, since single crystal structure analysis requires the use of high-quality single crystals as measurement samples, it can take a lot of time and effort to prepare measurement samples when analyzing the crystal structure of unknown compounds or compounds that are difficult to crystallize.

[0003] A method for solving this problem, which utilizes a single crystal of a porous polymer compound, is known. For example, Patent Document 1 describes a method in which molecules of a compound to be analyzed are regularly arranged in the pores of a single crystal of a polymer complex, and the resulting guest molecule inclusion complex is used as a measurement sample to perform crystal structure analysis (the so-called "method for determining molecular structure by the crystalline sponge method").

[0004] International Publication No. 2014 / 038220

[0005] By using the crystalline sponge method, crystal structure analysis can be performed even when the amount of the target compound is extremely small or when the target compound is a liquid or gas at room temperature.

[0006] However, many of the conventional crystalline sponges (porous polymer compounds) have the problem that they do not have pores or cavities of sufficient size, and therefore can only encapsulate relatively small molecules.

[0007] The present invention solves this problem, and aims to provide a host molecule having large pores, a method for producing this host molecule, the host molecule-target molecule complex, a method for producing the host molecule-target molecule complex, a sample for crystal structure analysis, a method for producing a sample for crystal structure analysis, and a kit for producing a sample for crystal structure analysis.

[0008] In order to solve the above problems, the present inventors have conducted extensive research into molecules having clathration ability, and as a result, have found that when a reaction between a metal ion and a multidentate ligand is carried out in the early stage of the production process of a host molecule in the absence of solvent molecules and in the presence of a large template, a host molecule tends to be produced that has larger voids than usual, which led to the completion of the present invention.

[0009] Thus, according to the present invention, there are provided the following host molecules (1) to (3), methods for producing host molecules (4) to (5), host molecule-target molecule complexes (6), methods for producing host molecule-target molecule complexes (7) to (8), samples for crystal structure analysis (9), methods for producing samples for crystal structure analysis (10) to (11), and kits for producing samples for crystal structure analysis (12).

[0010] [1] A host molecule having one or more openings, one or more wall portions, and an internal space surrounded by the wall portions, wherein the wall portions contain metal ions and multidentate ligands having a π-conjugated system, and the volume of the internal space is 500 × 10 －３０ m ３ [2] The host molecule according to [1], wherein the metal ion is an ion of an element selected from the group consisting of Ti, Fe, Co, Ni, Cu, Zn, Ru, Rh, Pd, Cd, Os, Ir, and Pt. [3] The host molecule according to [1], wherein the multidentate ligand having a π-conjugated system is represented by the following formula (1):

[0011]

[0012] (A is an m-valent group having aromaticity. X is a divalent organic group or a single bond directly connecting A and Y. Y is a coordinating atom or a monovalent group containing a coordinating atom. m is an integer of 2 to 6. Multiple Xs may be different from each other, and multiple Ys may be different from each other.) The host molecule according to [1] or [2], [4] A method for producing a host molecule according to any one of [1] to [3], comprising: (a-1) a step of mixing, in a solid phase, a mononuclear complex containing a metal ion for forming the host molecule, a multidentate ligand having a π-conjugated system for forming the host molecule, and a guest molecule having 50 or more atoms other than hydrogen atoms, which functions as a template when a polynuclear metal complex containing the metal ion and the multidentate ligand is produced; (a-2) a step of preparing a mixed solution by dissolving the mixture obtained in step (a-1) in a solvent; (a-3) a step of precipitating a host molecule-guest molecule complex from the mixed solution obtained in step (a-2); and (a-4) a step of removing the guest molecule from the host molecule-guest molecule complex obtained in step (a-3). [5] A method for producing a host molecule according to [4], further comprising, when the host molecule obtained in step (a-4) contains an uncoordinated coordination atom, (a-5) preparing a mixed solution in which the host molecule obtained in step (a-4) and a mononuclear complex containing a metal ion for forming the host molecule are dissolved, and (a-6) precipitating a host molecule not containing an uncoordinated coordination atom from the mixed solution obtained in step (a-5). [6] A host molecule-target molecule complex comprising the host molecule according to any one of [1] to [3] and a target molecule accommodated in the internal space thereof. [7] A method for producing a host molecule-target molecule complex according to [6], further comprising (b-1) causing the host molecule according to any one of [1] to [3] and the target molecule to coexist in the same system in the presence or absence of a solvent, thereby accommodating the target molecule in the internal space of the host molecule.[8] A method for producing a host molecule-target molecule complex according to [6], comprising: (c-1) a step of mixing, in a solid phase, a mononuclear complex containing a metal ion for forming the host molecule, a multidentate ligand having a π-conjugated system for forming the host molecule, and a target molecule having 50 or more atoms other than hydrogen atoms, which functions as a template when a polynuclear metal complex containing the metal ion and the multidentate ligand is produced; (c-2) a step of dissolving the mixture obtained in step (c-1) in a solvent to prepare a mixed solution; and (c-3) a step of precipitating a host molecule-target molecule complex from the mixed solution obtained in step (c-2). [9] A sample for crystal structure analysis comprising a plurality of host molecules and a plurality of target molecules, wherein the host molecules are the host molecules according to any one of [1] to [3], the plurality of host molecules contained in the sample for crystal structure analysis are three-dimensionally regularly assembled, all or some of the plurality of host molecules contained in the sample for crystal structure analysis accommodate a target molecule in their respective internal spaces, and the plurality of target molecules contained in the sample for crystal structure analysis are three-dimensionally regularly arranged.

[10] A method for producing a sample for crystal structure analysis according to [9], comprising: (d-1) a step of causing the host molecule according to any one of [1] to [3] above and a target molecule to coexist in the same system in the presence or absence of a solvent, thereby accommodating the target molecule in the internal space of the host molecule; and (d-2) a step of (a) precipitating a single crystal comprising the host molecule accommodating the target molecule from a solution obtained by carrying out step (d-1) in the presence of a solvent, or (b) dissolving the host molecule accommodating the target molecule produced by carrying out step (d-1) in the absence of a solvent in a solvent to prepare a solution, and then precipitating a single crystal comprising the host molecule accommodating the target molecule from the solution.

[11] A method for producing a sample for crystal structure analysis according to [9], comprising: (e-1) a step of mixing, in a solid phase, a mononuclear complex containing a metal ion for forming the host molecule, a multidentate ligand having a π-conjugated system for forming the host molecule, and a target molecule having 50 or more atoms other than hydrogen atoms, the target molecule functioning as a template when a polynuclear metal complex containing the metal ion and the multidentate ligand is produced, (e-2) a step of dissolving the mixture obtained in step (e-1) in a solvent to prepare a mixed solution, and (e-3) a step of precipitating a single crystal containing the host molecule accommodating the target molecule from the mixed solution obtained in step (e-2).

[12] A host molecule according to any of [1] to [3], having one or more openings, one or more wall portions, and an internal space surrounded by the wall portions, wherein the wall portions contain a metal ion and a multidentate ligand having a π-conjugated system, and the volume of the internal space is 500×10. －３０ m ３ and a host molecule having a molecular weight of less than 1000; and a kit for preparing a sample for crystal structure analysis.

[0013] According to the present invention, there are provided a host molecule, a method for producing a host molecule, a host molecule-target molecule complex, a method for producing a host molecule-target molecule complex, a sample for crystal structure analysis, a method for producing a sample for crystal structure analysis, and a kit for producing a sample for crystal structure analysis.

[0014] Pt ６ L ４ FIG. 1 is a diagram showing a model used to calculate the volume of the internal space of the host molecule. ８ L ６ FIG. 1 is a diagram showing the molecular structure of a host molecule (2). ８ L ６ FIG. 1 is a diagram showing a model used to calculate the volume of the internal space of the host molecule (2). ９ L ６ FIG. 1 is a diagram showing the molecular structure of a host molecule (1). ９ L ６ FIG. 1 is a diagram showing a model used to calculate the volume of the internal space of a host molecule (1).

[0015] The present invention will be described in detail below, divided into the following sections: 1) host molecule and method for producing a host molecule, 2) host molecule-target molecule complex and method for producing a host molecule-target molecule complex, 3) sample for crystal structure analysis and method for producing a sample for crystal structure analysis, and 4) kit for producing a sample for crystal structure analysis.

[0016] 1) Host molecule and method for producing host molecule [Host molecule] The host molecule of the present invention has one or more openings, one or more wall portions, and an internal space surrounded by the wall portions. The wall portions contain metal ions and multidentate ligands having a π-conjugated system. The volume of the internal space is 500×10 －３０ m ３ That's all.

[0017] In this specification, the term "molecule" includes not only electrically neutral substances composed of two or more atoms, but also charged substances (ions) composed of two or more atoms. A "host molecule" refers to a molecule that has an opening, a wall, and an internal space and is capable of accommodating a guest molecule in the internal space. A "guest molecule" refers to a molecule accommodated in the internal space of a host molecule. Among guest molecules, molecules that are accommodated in the internal space of a host molecule for a specific purpose, such as molecules of a compound to be analyzed, are referred to as "target molecules." In addition to molecules accommodated in the internal space, molecules before being accommodated or molecules removed from the internal space may also be referred to as "guest molecules" or "target molecules."

[0018] The openings in the host molecule function as entrances for guest molecules to enter the internal space. The shape and size of the openings are not particularly limited as long as the guest molecules can pass through. Assuming the largest circle inscribed in the opening, its diameter is, for example, 0.1 to 5 nm, preferably 0.3 to 3 nm. The number of openings contained in the host molecule is usually 1 to 10, preferably 1 to 5.

[0019] The wall portion of the host molecule is a portion that functions as a wall separating the inside and outside of the host molecule. The number of wall portions contained in the host molecule is usually 1 to 10, preferably 1 to 5. The wall portion contains a metal ion and a multidentate ligand having a π-conjugated system (hereinafter, sometimes referred to as "ligand (α)"). Therefore, the host molecule of the present invention is a polynuclear metal complex.

[0020] The metal ion is not particularly limited as long as it can constitute a polynuclear metal complex. As the metal ion, ions of elements selected from the group consisting of Ti, Fe, Co, Ni, Cu, Zn, Ru, Rh, Pd, Cd, Os, Ir, and Pt are preferred, and ions of elements in Groups 8, 9, or 10 of the periodic table are more preferred. The valence of the metal ion is not particularly limited, and is usually 1 to 4, preferably 1 to 3, and more preferably 2.

[0021] Because the ligand (α) has a π-conjugated system, as will be described later, the guest molecule can easily function as a template when a polynuclear metal complex is formed, making it easier to obtain a host molecule with large voids. Furthermore, when a crystallization-promoting molecule is added when precipitating a host molecule or a host molecule-guest molecule complex from a solution, the π-conjugated system of the ligand (α) facilitates the generation of an affinity interaction between the host molecule and the crystallization-promoting molecule. The ligand (α) is preferably a multidentate ligand containing an aromatic group as its central skeleton. Multidentate ligands containing an aromatic group as their central skeleton are relatively rigid and have excellent planarity, making it easier to maintain the structure of the host molecule. Examples of the ligand (α) include those represented by the following formula (1):

[0022]

[0023] In formula (1), A is an m-valent group having aromaticity. X is a divalent organic group or a single bond directly connecting A and Y. Y is a coordinating atom or a monovalent group containing a coordinating atom. m represents an integer of 2 to 6. Multiple Xs may be different from each other, and multiple Ys may be different from each other.

[0024] The number of atoms (excluding hydrogen atoms) in the group represented by A is usually 6 to 100, preferably 6 to 60, and more preferably 6 to 30. Examples of the group represented by A include a six-membered aromatic group, a group in which a plurality of six-membered aromatic groups are linked by single bonds, and a group having a porphyrin skeleton.

[0025] Examples of the six-membered aromatic group include groups having an aromatic ring such as a benzene ring, a triazine ring, a pyridine ring, and a pyrazine ring. The six-membered aromatic group may have a substituent other than -(-X-Y). Examples of the substituent include an alkyl group having 1 to 10 carbon atoms; and a halogen atom such as a fluorine atom, a bromine atom, or a chlorine atom.

[0026] Examples of the group represented by A include, but are not limited to, the following: In addition, "*" represents a bond (position of bonding to X).

[0027]

[0028]

[0029] In the above formula, M represents a metal ion. Examples of the metal ion include the same ions as those exemplified as metal ions constituting the polynuclear metal complex. Among these, zinc ions are preferred.

[0030] The number of atoms (excluding hydrogen atoms) in the group represented by X is usually 1 to 30, preferably 2 to 20, and more preferably 2 to 10. Examples of the group represented by X include the divalent group represented by A above; hydrocarbon groups such as a methylene group, an ethylene group, a 1,2-ethenediyl group, a 1,2-ethynediyl group (acetylene group), a p-phenylene group, and an m-phenylene group; an amide group (-C(=O)-NH-); an ester group (-C(=O)-O-); an oxymethylene group (-O-CH ２ -); oxyethylene group (-O-CH ２ CH ２ -), etc., but are not limited to these. The group represented by X may also be a group formed by bonding two or more of these groups. Examples of such groups include, but are not limited to, the following:

[0031]

[0032] Examples of the coordinating atom represented by Y include an oxygen atom, a sulfur atom, a nitrogen atom, and a phosphorus atom. The number of atoms (excluding hydrogen atoms) in the monovalent group represented by Y is usually 1 to 20, preferably 1 to 15, and more preferably 1 to 10. Examples of the monovalent group represented by Y include a pyridyl group, an amino group, a hydroxyl group, a deprotonated amide group, a carboxylate group, a sulfonate group, a phosphonate group, a dithiocarboxylate group, a cyano group, and groups containing these groups as a substituent. Examples of the monovalent group represented by Y include the following:

[0033]

[0034] Examples of the ligand (α) include, but are not limited to, the following:

[0035]

[0036]

[0037]

[0038] As the ligand (α), a ligand other than that represented by formula (1) can also be used. Examples of such a ligand include the following.

[0039]

[0040] The host molecule may contain a ligand other than the ligand (α) (hereinafter, sometimes referred to as a "ligand (β)") The ligand (β) plays a role in adjusting the charge of the polynuclear metal complex and occupying vacant coordination sites of the metal ion, thereby suppressing the polynuclear metal complex from polymerizing.

[0041] The ligand (β) is preferably a ligand with a relatively low molecular weight. A low molecular weight ligand is less likely to have adverse effects, such as steric hindrance, on the coordination of the ligand (α). Examples of the ligand (β) include a monodentate ligand and a chelating ligand.

[0042] The monodentate ligand used as the ligand (β) is an oxide ion (O２－ divalent anions such as hydroxide ions (OH － ), chloride ions (Cl － ), bromide ion (Br － ), iodide ion (I － ), thiocyanate ion (SCN － ), nitrate ions (NO ３ － ) and the like; electrically neutral coordinating compounds such as water, ammonia, monoalkylamines, dialkylamines, and trialkylamines; and the like.

[0043] Examples of chelating ligands used as the ligand (β) include bidentate chelating ligands such as ethylenediamine, N,N'-dimethylethylenediamine, N,N,N',N'-tetramethylethylenediamine, 2,2'-bipyridyl, and 1,2-cyclohexanediamine, but are not limited to these.

[0044] The internal space of the host molecule is a space surrounded by walls. The guest molecule is accommodated in the internal space of the host molecule. The "state in which the guest molecule is accommodated in the internal space" includes a state in which the entire guest molecule is completely accommodated in the internal space, as well as a state in which a part of the guest molecule is accommodated in the internal space and the remaining part of the guest molecule protrudes from the opening. The "internal space" is not limited in shape as long as it can accommodate the guest molecule, and may be elongated, for example, like a "pore." The volume of the internal space is 500 x 10 －３０ m ３ or more, preferably 700×10 －３０ m ３ More preferably, 1000×10 －３０ m ３ The volume of the internal space is 500 x 10 －３０ m ３As a result, large molecules (e.g., molecules with a molecular weight of 500 or more) that have been difficult to include in the past can be easily included. Host molecules with such large internal spaces can be efficiently obtained by utilizing a solid-phase reaction using a template, as described below. The volume of the internal space of the host molecule can be calculated according to the method described in the Examples.

[0045] The size of the host molecule is not particularly limited. When the smallest rectangular parallelepiped capable of accommodating the host molecule is imagined, the length of the longest side of the rectangular parallelepiped is, for example, 0.3 to 15 nm, preferably 1 to 10 nm, and the length of the shortest side is, for example, 0.3 to 15 nm, preferably 0.5 to 10 nm.

[0046] The host molecule of the present invention is, for example, (β1-Pt) ８ L ６ Complex, (β1-Pt) ９ L ６ Complex, (β1-Pd) ８ L ６ Complex, (β1-Pd) ９ L ６ In this specification, for example, (β1-Pt) ８ L ６ The complex is called "Pt ８ L ６ It may be abbreviated as ".

[0047] [Method for Producing Host Molecule] The host molecule of the present invention (hereinafter sometimes referred to as "host molecule (I)") can be produced by, for example, the following production method (A1) or production method (A2).

[0048] [Production Method (A1)] The production method (A1) comprises: (a-1) a step of mixing, in a solid phase, a mononuclear complex containing a metal ion for forming the host molecule, a ligand (α), and a guest molecule having 50 or more atoms other than hydrogen atoms, which functions as a template when a polynuclear metal complex containing the metal ion and the ligand (α) is produced; (a-2) a step of preparing a mixed solution by dissolving the mixture obtained in step (a-1) in a solvent; (a-3) a step of precipitating a host molecule (I)-guest molecule complex from the mixed solution obtained in step (a-2); and (a-4) a step of removing the guest molecule from the host molecule (I)-guest molecule complex obtained in step (a-3).

[0049] Step (a-1) is a step of mixing, in a solid phase, a mononuclear complex containing a metal ion for forming the host molecule, a ligand (α), and a guest molecule having 50 or more atoms other than hydrogen atoms, which serves as a template when a polynuclear metal complex containing the metal ion and the ligand (α) is produced.

[0050] The mononuclear complex containing a metal ion is a source of metal ions for the wall portion of the host molecule (I). The mononuclear complex containing a metal ion preferably contains two or more monodentate ligands and a chelating ligand. By using a mononuclear complex containing a metal ion that contains two or more monodentate ligands and a chelating ligand, it is possible to efficiently suppress the formation of macromolecules from the polynuclear metal complex.

[0051] Examples of the monodentate ligand and chelating ligand include those exemplified as the ligand (β).

[0052] Examples of mononuclear complexes containing metal ions include cis-dinitrato(N,N,N',N'-tetramethylethylenediamine)platinum(II) complex and cis-dinitrato(N,N,N',N'-tetramethylethylenediamine)palladium(II) complex.

[0053] The guest molecule is a molecule that functions as a template when a polynuclear metal complex containing a metal ion and a ligand (α) is produced. The guest molecule's function as a template makes it easier to obtain a host molecule with large voids. For the guest molecule to function as a template, it is preferable for the guest molecule to have an affinity interaction with the ligand (α). Therefore, a guest molecule having an aromatic ring with increased electron density due to an electron-donating substituent is preferably used. Since the ligand (α) coordinates to the metal ion, the electron density of the π-conjugated system decreases. Therefore, a guest molecule having an aromatic ring with increased electron density due to an electron-donating substituent can have an affinity interaction with the ligand (α).

[0054] The guest molecule is a molecule having 50 or more atoms other than hydrogen atoms. By using a molecule having 50 or more atoms other than hydrogen atoms as a guest molecule, a host molecule having large voids can be easily obtained. That is, when a metal ion is reacted with a ligand (α), a host molecule having energetically stable voids of appropriate size is usually produced. However, by having a large guest molecule that prevents the production of such a host molecule present in the reaction system, a host molecule having large voids can be easily obtained.

[0055] Examples of guest molecules include dimethoxypillar[5]arene (number of atoms other than hydrogen atoms: 55), cryptophane E-chloroform inclusion complex (number of atoms other than hydrogen atoms: 73), and calix[8]arene (number of atoms other than hydrogen atoms: 64). Although cyclotriveratrylene has 33 atoms other than hydrogen atoms, two cyclotriveratrylene molecules may be accommodated in one internal space. In the present invention, such a case is treated as a guest molecule having 66 atoms other than hydrogen atoms.

[0056] The reaction in step (a-1) is a solid-phase reaction. As described above, when a polynuclear metal complex is produced, an affinity interaction occurs between a large guest molecule and the ligand (α), making it easier to obtain a host molecule with large pores. However, in a solution, solvent molecules reduce this affinity interaction, so in step (a-1), the mononuclear complex, the ligand (α), and the guest molecule are mixed in the solid phase. There are no particular limitations on the method for mixing the mononuclear complex, the ligand (α), and the guest molecule in the solid phase. For example, a mortar or a ball mill can be used. The mixing time is usually 5 minutes to 12 hours, preferably 1 to 5 hours.

[0057] Step (a-2) is a step of preparing a mixed solution by dissolving the mixture obtained in step (a-1) in a solvent.

[0058] Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, 1,2-dichlorobenzene, and nitrobenzene; aliphatic hydrocarbons such as n-pentane, n-hexane, and n-heptane; alicyclic hydrocarbons such as cyclopentane, cyclohexane, and cycloheptane; nitriles such as acetonitrile and benzonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); amides such as N,N-dimethylformamide and n-methylpyrrolidone; ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane; alcohols such as methanol, ethanol, and isopropyl alcohol; ketones such as acetone, methyl ethyl ketone, and cyclohexanone; cellosolves such as ethyl cellosolve; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; esters such as methyl acetate, ethyl acetate, ethyl lactate, and ethyl propionate; and water. These solvents may be used alone or in combination of two or more.

[0059] In step (a-1), a polynuclear metal complex containing a metal ion and a ligand (α) is thought to be produced. However, this polynuclear metal complex may not be the host molecule (I) but may be its precursor. Therefore, in the method for producing a host molecule of the present invention, step (a-2) is carried out to ensure the production of the host molecule (I) [host molecule (I)-guest molecule complex].

[0060] Step (a-3) is a step of precipitating a host molecule (I)-guest molecule complex from the mixed solution obtained in step (a-2).

[0061] The method for precipitating the host molecule (I)-guest molecule complex is not particularly limited, and examples thereof include concentrating the solution, cooling the solution, and adding a poor solvent.

[0062] In order to precipitate the host molecule (I)-guest molecule complex, a crystallization-promoting molecule may be added to the solution. The crystallization-promoting molecule is a molecule having a structure that allows for an affinity interaction with the wall portion of the host molecule (I). Because the crystallization-promoting molecule has such a structure, by adding the crystallization-promoting molecule to a solution in which the host molecule (I)-guest molecule complex is dissolved, crystals containing the host molecule (I)-guest molecule complex and the crystallization-promoting molecule can be efficiently precipitated.

[0063] Examples of the affinity interaction between the crystallization-promoting molecule and the wall portion of the host molecule include hydrophobic interaction, π-π interaction, CH-π interaction, etc. Among these, π-π interaction is preferred as the affinity interaction between the crystallization-promoting molecule and the wall portion of the host molecule (I) because it is a larger interaction.

[0064] The crystallization-promoting molecule is preferably a molecule having a π-conjugated system, which is likely to form π-π interactions or CH-π interactions with the wall of the host molecule (I).

[0065] The crystallization-promoting molecule is preferably a molecule having an aromatic ring. Molecules having an aromatic ring tend to have excellent planarity, and are therefore suitable for being interposed between the walls of two host molecules (I).

[0066] The crystallization-promoting molecule is preferably a molecule having an anionic group. When the host molecule (I) is a polynuclear metal complex, the host molecule (I) tends to have a positive charge as a whole. In this case, the crystallization-promoting molecule having an anionic group and having a negative charge as a whole molecule can function as a counter ion.

[0067] Examples of the anionic group include a carboxylate ion group, a sulfonate ion group, and a phosphate ion group, with the carboxylate ion group and the sulfonate ion group being preferred.

[0068] Examples of the crystallization-promoting molecule include a molecule having a pyrene skeleton, a molecule having a naphthalene skeleton, a molecule having a benzene skeleton, and a molecule having a biphenyl skeleton.

[0069] Examples of the crystallization-promoting molecule include 1,3,5-benzenetrimethanesulfonate ion, 1,3,5-benzenetrisulfonate ion, and 1,3,5-benzenetricarboxylate ion.

[0070] Step (a-4) is a step of removing the guest molecule from the host molecule (I)-guest molecule complex obtained in step (a-3). The guest molecule can be removed, for example, by immersing the host molecule (I)-guest molecule complex in a solvent in which the host molecule is not soluble, or by contacting a solution in which the host molecule (I)-guest molecule complex is dissolved with a solvent immiscible with this solution, thereby extracting the host molecule (I) or the guest molecule.

[0071] [Production Method (A2)] Production method (A2) involves performing steps (a-1) to (a-4) to convert a host molecule (I) containing an uncoordinated coordination atom obtained into a host molecule (I) not containing an uncoordinated coordination atom. That is, in addition to steps (a-1) to (a-4), production method (A2) further includes: (a-5) a step of preparing a mixed solution in which the host molecule (I) obtained in step (a-4) and a mononuclear complex containing a metal ion for forming the host molecule are dissolved; and (a-6) a step of precipitating the host molecule (I) not containing an uncoordinated coordination atom from the mixed solution obtained in step (a-5).

[0072] Step (a-5) is a step of preparing a mixed solution in which the host molecule (I) obtained in step (a-4) and a mononuclear complex containing a metal ion for forming the host molecule are dissolved. If the host molecule (I) is dissolved in a solution after step (a-4), a mixed solution can be obtained by dissolving the mononuclear complex in the solution. Furthermore, if the host molecule (I) obtained after step (a-4) is solid, a mixed solution can be obtained by dissolving the host molecule (I) and the mononuclear complex in a solvent.

[0073] Examples of the mononuclear complex used in step (a-5) include the same as those described as the mononuclear complex in step (a-1). Examples of the solvent used in step (a-5) include the same as those described as the solvent in step (a-2).

[0074] In the mixed solution obtained in step (a-5), the uncoordinated coordinating atoms are coordinated to the newly added metal ions, and a host molecule (I) that does not contain uncoordinated coordinating atoms is produced.

[0075] In step (a-6), the generated host molecule (I) that does not contain an uncoordinated coordinating atom is precipitated from the mixed solution. Examples of a method for precipitating the host molecule (I) that does not contain an uncoordinated coordinating atom from the mixed solution include the same method as the precipitating method of the host molecule (I)-guest molecule complex in step (a-3).

[0076] As described above, it is believed that the internal space of a known polynuclear metal complex containing a ligand (α) and having an internal space can be expanded by using the above-mentioned production method (A1) or production method (A2). An example of such a known polynuclear metal complex is shown below together with the ligand (α) that constitutes the polynuclear metal complex. When expressing the quantitative ratio of the metal ion and the ligand (α) that constitute the polynuclear metal complex, the metal ion is represented as "M", the ligand (α) is represented as "L", and, if necessary, the second ligand (α) is represented as "X".

[0077] [Rule 26, amended 29.10.2025]

[0078] In the above formula, Pd represents a palladium ion coordinated with a bidentate chelating ligand (e.g., ethylenediamine). The main component ratio of this polynuclear metal complex is [M ６ L ４ ].

[0079]

[0080] In the above formula, Pd represents a palladium ion coordinated with a bidentate chelating ligand (e.g., ethylenediamine). The main component ratio of this polynuclear metal complex is [M ６ L ４ ].

[0081] [Rule 26, amended 29.10.2025]

[0082] In the above formula, Pd represents a palladium ion coordinated with a bidentate chelating ligand (e.g., ethylenediamine). The main component ratio of this polynuclear metal complex is [M ６ L ３ In the ligand represented by L, M represents a metal ion such as a Zn ion.

[0083]

[0084] In the above formula, Pd represents a palladium ion coordinated with a bidentate chelating ligand (e.g., ethylenediamine). The main component ratio of this polynuclear metal complex is [M ６ L ２ X ３ ].

[0085]

[0086] In the above formula, Pd represents a palladium ion coordinated with a bidentate chelating ligand (e.g., ethylenediamine). The main component ratio of this polynuclear metal complex is [M ６ L １ ].

[0087]

[0088] In the above formula, Pd represents a palladium ion coordinated with a bidentate chelating ligand (e.g., ethylenediamine). The main component ratio of this polynuclear metal complex is [M １２ L２ ].

[0089] [Rule 26, amended 29.10.2025]

[0090] In the above formula, Pd represents a palladium ion coordinated with a bidentate chelating ligand (e.g., ethylenediamine). The main component ratio of this polynuclear metal complex is [M １２ L ４ ].

[0091]

[0092] In the above formula, Pd represents a palladium ion coordinated with a bidentate chelating ligand (e.g., ethylenediamine). The main component ratio of the polynuclear metal complex on the left is [M １０ L ４ ], and the main component ratio of the polynuclear metal complex on the right is [M ８ L ４ ].

[0093]

[0094] In the above formula, Pd represents a palladium ion coordinated with a bidentate chelating ligand (e.g., ethylenediamine). The main component ratio of the polynuclear metal complex on the left is [M ８ L ４ ], and the main component ratio of the polynuclear metal complex on the right is [M ６ L ４ ].

[0095]

[0096] In the above formula, Pt represents a platinum ion coordinated with a bidentate chelating ligand (e.g., ethylenediamine). The main component ratio of this polynuclear metal complex is [M ４ L ４ ].

[0097]

[0098] In the above schematic diagram, the sphere represents a palladium ion coordinated with a bidentate chelating ligand (e.g., ethylenediamine). The main component ratio of this polynuclear metal complex is [M ６ L ２ ].

[0099]

[0100] In the above schematic diagram, the sphere represents a palladium ion coordinated with a bidentate chelating ligand (e.g., ethylenediamine). The main component ratio of this polynuclear metal complex is [M １２ L ４ ].

[0101] Details of the synthesis methods of these polynuclear metal complexes are described in WO 2018 / 159692.

[0102] 2) Host Molecule-Target Molecule Complex and Method for Producing the Host Molecule-Target Molecule Complex [Host Molecule-Target Molecule Complex] The host molecule (I)-target molecule complex comprises a host molecule (I) and a target molecule accommodated in the internal space thereof.

[0103] The target molecule is a molecule accommodated in the internal space of the host molecule for a specific purpose, and examples of the target molecule include a molecule whose structure needs to be clarified by crystal structure analysis, a molecule to be isolated from a mixture, a molecule that needs to be stabilized, a drug molecule in drug delivery, and a molecule for adjusting the internal space for forming the host molecule (II) described below.

[0104] The form of the target molecule is not particularly limited, and it may be in a solid, liquid, or gaseous state at room temperature (20° C.).

[0105] The molecular weight of the target molecule is usually 4,000 or less, preferably 3,000 or less. There is no particular lower limit to the molecular weight of the target molecule, but it is usually 50 or more.

[0106] The host molecule (I) may accommodate one or more target molecules in its internal space.

[0107] Since the host molecule (I) has large pores, the host molecule (I)-target molecule complex may further accommodate a target molecule. That is, the host molecule (I) and the target molecule may function together as a host molecule (hereinafter, sometimes referred to as "host molecule (II)") that encapsulates another target molecule (hereinafter, the target molecule that constitutes the host molecule (II) may be referred to as "molecule for adjusting the internal space").

[0108] If the target molecule is too small compared to the internal space of the host molecule (I), the target molecule may not be stably accommodated. In such a case, by forming the host molecule (II) using an internal space-controlling molecule, the small target molecule can be stably encapsulated.

[0109] Examples of molecules for adjusting the internal space include cyclotriveratrylene and calix[8]arene.

[0110] [Method for Producing a Host Molecule-Target Molecule Complex] The host molecule (I)-target molecule complex can be produced, for example, by the following production method (B) or production method (C).

[0111] [Production Method (B)] The production method (B) includes the step of: (b-1) causing a host molecule (I) and a target molecule to coexist in the same system in the presence or absence of a solvent, thereby accommodating the target molecule in the internal space of the host molecule (I).

[0112] The phrase "host molecule (I) and target molecule coexist in the same system" means that these components are placed in a state where they can come into contact with each other. Therefore, the "same system" does not necessarily have to be a single-phase system as a whole.

[0113] Examples of a state in which the host molecule (I) and the target molecule coexist in the same system in the presence of a solvent include a state in which the host molecule (I) is dissolved or suspended in a solution or suspension obtained by dissolving at least a part of the target molecule in a solvent.

[0114] Examples of a state in which the host molecule (I) and the target molecule coexist in the same system in the absence of a solvent include a state in which the host molecule (I) is placed in a container in which the gaseous target molecule is present, and a state in which the host molecule (I) is dissolved or suspended in the liquid target molecule.

[0115] The amount of the target molecule that is allowed to coexist with the host molecule (I) is usually 0.1 equivalent or more, preferably 1 equivalent or more, relative to the amount of the host molecule (I).

[0116] The conditions for accommodating the target molecule in the internal space of the host molecule (I) are not particularly limited. The temperature for accommodating the target molecule in the internal space of the host molecule (I) is usually 0 to 100° C., preferably 20 to 100° C. The time for accommodating the target molecule in the internal space of the host molecule (I) is usually 30 seconds to 72 hours, preferably 0.5 to 24 hours.

[0117] In step (b-1), it can be confirmed that the target molecule has been accommodated in the internal space of the host molecule (I) by observing a color change or measuring an NMR spectrum.

[0118] In production method (B), a purification treatment or the like may be performed after step (b-1) as needed. For example, if a solution in which the host molecule (I)-target molecule complex is dissolved is obtained in step (b-1), a highly pure host molecule (I)-target molecule complex can be obtained by precipitating crystals. Furthermore, if a solid-state host molecule (I)-target molecule complex is obtained in step (b-1), a highly pure host molecule (I)-target molecule complex can be obtained by recrystallization. In these crystallization treatments, the same method as that described as the precipitating method for the host molecule (I)-guest molecule complex in step (a-3) of production method (A1) can be used.

[0119] [Production Method (C)] The production method (C) comprises: (c-1) a step of mixing, in a solid phase, a mononuclear complex containing a metal ion for forming the host molecule, a ligand (α), and a target molecule having 50 or more atoms other than hydrogen atoms, which functions as a template when a polynuclear metal complex containing the metal ion and the ligand (α) is produced; (c-2) a step of preparing a mixed solution by dissolving the mixture obtained in step (c-1) in a solvent; and (c-3) a step of precipitating a host molecule (I)-target molecule complex from the mixed solution obtained in step (c-2).

[0120] The production method (C) is the same as steps (a-1) to (a-3) of the production method (A1) except that the guest molecule is the target molecule.

[0121] 3) Sample for crystal structure analysis and method for producing sample for crystal structure analysis [Sample for crystal structure analysis] The sample for crystal structure analysis of the present invention comprises a plurality of host molecules and a plurality of target molecules. The host molecules are host molecules (I), and the plurality of host molecules (I) are three-dimensionally regularly assembled. All or some of the plurality of host molecules (I) accommodate a target molecule in their internal space, and the plurality of target molecules are three-dimensionally regularly arranged.

[0122] The expressions "a plurality of host molecules are three-dimensionally regularly assembled" and "a plurality of target molecules are three-dimensionally regularly arranged" respectively refer to a state in which the molecular structure of the host molecule or the molecular structure of the target molecule can be determined by crystal structure analysis. Therefore, by performing crystal structure analysis using the sample for crystal structure analysis of the present invention, the molecular structure of the target molecule can be clarified. In this way, the sample for crystal structure analysis of the present invention has single crystallinity among the host molecule (I)-target molecule complexes in the solid state.

[0123] The size of the sample for crystal structure analysis is not particularly limited. When clarifying the molecular structure of a target molecule, it is preferable to use a sample for crystal structure analysis of a size suitable for the crystal structure analyzer to be used. For example, when performing crystal structure analysis using a commercially available X-ray crystal structure analyzer, when the smallest rectangular parallelepiped capable of accommodating the sample for crystal structure analysis is imagined, the length of its long side is usually 10 to 500 μm, preferably 50 to 500 μm, and the length of its short side is usually 10 to 500 μm, preferably 10 to 200 μm.

[0124] When a plurality of samples for crystal structure analysis are irradiated with synchrotron X-rays and the molecular structure of a target compound is determined based on the collected diffraction intensity data, the minimum rectangular parallelepiped that can accommodate the samples for crystal structure analysis is imagined to have a long side length of usually 0.1 to 100 μm, preferably 1 to 100 μm, and a short side length of usually 0.1 to 100 μm, preferably 1 to 10 μm.

[0125] When crystal structure analysis is performed by microelectron diffraction, when the smallest rectangular parallelepiped capable of accommodating a sample for crystal structure analysis is imagined, the length of its long side is usually 0.1 to 1000 nm, preferably 1 to 1000 nm, and the length of its short side is usually 0.1 to 100 nm, preferably 0.1 to 10 nm.

[0126] [Method for Producing a Sample for Crystal Structure Analysis] The sample for crystal structure analysis of the present invention can be produced, for example, by the following production method (D) or production method (E).

[0127] [Production Method (D)] Production method (D) comprises: (d-1) a step of causing a host molecule (I) and a target molecule to coexist in the same system in the presence or absence of a solvent, thereby accommodating the target molecule in the internal space of the host molecule (I); and (d-2) a step of (a) precipitating a single crystal comprising the host molecule (I) accommodating the target molecule from a solution obtained by carrying out step (d-1) in the presence of a solvent, or (b) dissolving the host molecule (I) accommodating the target molecule, which has been produced by carrying out step (d-1) in the absence of a solvent, in a solvent to prepare a solution, and then precipitating a single crystal comprising the host molecule (I) accommodating the target molecule from this solution.

[0128] Step (d-1) is the same as step (b-1) in production method (B).

[0129] When step (d-1) is carried out in the presence of a solvent, a sample for crystal structure analysis of the present invention can be obtained by carrying out step (d-2)(a). In step (d-2)(a), a single crystal containing a host molecule (I) accommodating a target molecule is precipitated from the solution obtained in step (d-1).

[0130] When step (d-1) is performed in the absence of a solvent, a sample for crystal structure analysis of the present invention can be obtained by performing step (d-2)(b). In step (d-2)(b), the host molecule (I) accommodating the target molecule produced by performing step (d-1) is dissolved in a solvent to prepare a solution, and a single crystal containing the host molecule (I) accommodating the target molecule is precipitated from this solution.

[0131] The concentration of the host molecule (I) containing the target molecule in the solution for precipitating the single crystal is usually 0.1 to 50 mM, preferably 1 to 20 mM. The temperature of the solution for precipitating the single crystal is usually 0 to 80° C., preferably 4 to 50° C. The standing time for precipitating the single crystal is usually 1 to 240 hours, preferably 1 to 24 hours.

[0132] Examples of the method for precipitating the single crystal include the same methods as those described for precipitating the host molecule (I)-guest molecule complex in step (a-3) of production method (A1). When the crystallization-promoting molecule is added, the amount thereof is usually 0.1 to 10 equivalents, preferably 0.1 to 1 equivalent, relative to the host molecule (I).

[0133] [Production Method (E)] Production method (E) comprises: (e-1) a step of mixing, in a solid phase, a mononuclear complex containing a metal ion for forming the host molecule, a ligand (α), and a target molecule having 50 or more atoms other than hydrogen atoms, which functions as a template when a polynuclear metal complex containing the metal ion and the ligand (α) is produced; (e-2) a step of preparing a mixed solution by dissolving the mixture obtained in step (e-1) in a solvent; and (e-3) a step of precipitating, from the mixed solution obtained in step (e-2), a single crystal containing the host molecule (I) accommodating the target molecule.

[0134] Production method (E) is the same as production method (C) except that the host molecule (I)-target molecule complex is precipitated as a single crystal. Examples of the method for precipitating the host molecule (I)-target molecule complex as a single crystal include the same methods as those described in step (d-2) of production method (D).

[0135] 4) Crystal structure analysis sample preparation kit The crystal structure analysis sample preparation kit of the present invention comprises a host molecule (I) and a host molecule having one or more openings, one or more wall portions, and an internal space surrounded by the wall portions, wherein the wall portions contain a metal ion and a multidentate ligand having a π-conjugated system, and the volume of the internal space is 500 × 10 －３０ m ３ and a host molecule (hereinafter, sometimes referred to as "host molecule (III)") having a molecular weight of less than 1.

[0136] The kit for preparing a sample for crystal structure analysis of the present invention may contain one type of host molecule (I) or two or more types of host molecules (I).

[0137] The meanings of the terms "opening," "wall," "internal space," "metal ion," and "multidentate ligand having a π-conjugated system" in the host molecule (III) constituting the crystal structure analysis sample preparation kit of the present invention are the same as those in the host molecule (I). Therefore, the only difference between the host molecule (III) and the host molecule (I) is the volume of the internal space.

[0138] Examples of the host molecule (III) include known polynuclear metal complexes that contain a ligand (α) and have inclusion ability, which are exemplified above as polynuclear metal complexes that can expand the internal space. The crystal structure analysis sample preparation kit of the present invention may contain one type of host molecule (III) or two or more types.

[0139] The crystal structure analysis sample preparation kit of the present invention may include the crystallization-promoting molecule.The crystal structure analysis sample preparation kit of the present invention may include the internal space control molecule.

[0140] When using the crystal structure analysis sample preparation kit of the present invention, by appropriately selecting either the host molecule (I) or the host molecule (III) or by using both, samples for crystal structure analysis can be efficiently produced regardless of the size or properties of the target molecule.

[0141] The present invention will be described in more detail below with reference to examples, although the present invention is not limited to the following examples in any way.

[0142] In the following examples: １ H NMR spectrum and １３ The C NMR spectrum was measured using an ECZ-600 [UltraCOOL probe ( １ H: 600 MHz; １３ C: 151 MHz)] or JEOL ECZ-500 [Royal Probe ( １ A Shimadzu UV-1900 was used to measure absorption spectra. A Waters Xevo G2-XS QTof was used to measure LC-MS (ESI-MS) spectra. A Rigaku XtaLAB Synergy-S, Rigaku XtaLAB P200, or Rigaku XtaLAB Synergy-Custom was used for single-crystal X-ray crystal structure analysis [X-ray source: CuKα (λ=1.5418 Å)].

[0143] [Calculation of the volume of the internal space of the host molecule] The volume of the internal space of the host molecule was calculated using MoloVol [J. Appl. Cryst., 55, 1033-1044 (2022)] under the following conditions: probe mode: two probes small probe radius: 2.0 Å large probe radius: 3.5 Å grid resolution: 0.2 Å optimization depth: 4

[0144] [Reference Example 1] Using the above program, Pt ６ L ４ The volume of the internal space of the host molecule (the molecule with the regular octahedral structure shown below) was calculated to be 474 × 10 －３０ m ３ In this calculation, a dummy carbon atom was placed at the center of a triangle with the three Pt atoms constituting the opening as vertices to distinguish the inside and outside of the host molecule (Figure 1).

[0145]

[0146] [Example 1] Pt ８ L ６ Synthesis of Host Molecule-Guest Molecule Complex: cis-dinitrato(N,N,N',N'-tetramethylethylenediamine)platinum(II) (Pt in the scheme below) (433 mg, 1 mmol), 2,4,6-tris(4-pyridyl)-1,3,5-triazine (L in the scheme below) (235 mg, 0.75 mmol), and dimethoxypillar[5]arene (H1 in the scheme below) (94 mg, 0.13 mmol) were ground using a ball mill at 400 rpm for 3 hours. The resulting orange powder was dissolved in 12 mL of distilled water, and the resulting solution was heated at 100°C for 7 days. After filtering the solution, the solvent in the filtrate was removed under vacuum. The resulting crude crystals were recrystallized from methanol to obtain a red crystalline powder (2·H1 in the scheme below) (199 mg, 32.5 μmol). The red crystalline powder (2·H1) was １The compound was identified by H NMR, ESI-ToF-MS, and single-crystal X-ray crystallography. Single crystals were prepared by adding acetone to an aqueous solution of the red crystalline powder (2·H1) using the vapor diffusion method.

[0147]

[0148] [Example 2] Pt ８ L ６ Isolation of host molecule: After preparing an aqueous solution (10 mM, 1 mL) of the red crystalline powder (2·H1) obtained in Example 1, Pt was extracted from the aqueous phase by repeating the extraction (washing) process 15 times using 1 mL of dichloromethane. ８ L ６ The host molecule (2 in the above scheme) was obtained quantitatively. ８ L ６ The host molecule (2) is １ H NMR, １３ The compound was identified by C NMR, IR, and single crystal X-ray crystal structure analysis. The molecular structure is shown in Figure 2. The single crystal was prepared by the following method.

[0149] (Single crystal production method) Pt ８ L ６ CuI and pyridine were added to an aqueous solution of the host molecule (2), and the mixture was stirred at 25°C and then filtered. 1,3,5-benzenetrimethanesulfonic acid sodium salt was then added to the filtrate, which was then allowed to stand at 10°C for several days. Acetone was added to the solution by vapor diffusion to precipitate single crystals.

[0150] (Calculation of the volume of the internal space) Using the above program, ８ L ６ The volume of the internal space of the host molecule (2) was calculated to be 924 × 10 －３０ m ３ In this calculation, in order to distinguish the inside and outside of each opening of the host molecule, dummy carbon atoms were placed at the center of a triangle with vertices corresponding to the three Pt atoms that make up the opening, and at the center of a square with vertices corresponding to the four Pt atoms that make up the opening, and another dummy carbon atom was placed at the center of the host molecule (Figure 3).

[0151] [Example 3] Pt ９ L６ Synthesis of host molecule: Pt obtained in Example 2 ８ L ６ To an aqueous solution (2.1 mM, 15 mL) of the host molecule (2 in the scheme below), cis-dinitrato(N,N,N',N'-tetramethylethylenediamine)platinum(II) (Pt in the scheme below) (139 mg, 0.32 mmol) was added, and the mixture was stirred at 60°C for 22 hours. The solvent was removed from the solution under vacuum, and the resulting crude crystals were recrystallized from methanol and washed with acetone to give off-white powdery Pt ９ L ６ An acetone solvate (117 mg, 20.2 μmol) of the host molecule (1 in the following scheme) was obtained. ９ L ６ The host molecule (1) is １ H NMR, １３ The compound was identified by C NMR, ESI-ToF-MS, IR, and single crystal X-ray crystal structure analysis. The molecular structure is shown in Figure 4. The single crystal was prepared by the following method.

[0152] (Single crystal production method) Pt ９ L ６ An aqueous solution of the host molecule (1) (3 mM, 100 μL) was placed in a glass tube, and acetone was added by the vapor diffusion method to precipitate a single crystal.

[0153]

[0154] (Calculation of the volume of the internal space) Using the above program, ９ L ６ The volume of the internal space of the host molecule (1) was calculated to be 1639 × 10 －３０ m ３ In this calculation, in order to distinguish the inside and outside of each opening of the host molecule, dummy carbon atoms were placed at the center of a triangle with vertices corresponding to the three Pt atoms that make up the opening, and at the center of a square with vertices corresponding to the four Pt atoms that make up the opening, and another dummy carbon atom was placed at the center of the host molecule (Figure 5).

[0155] [Example 4] Pt ９ L ６Inclusion of target molecule in host molecule (1) ９ L ６ Cyclotriveratrylene (H2 in the following scheme) (4.1 mg, 9 μmol) was suspended in a heavy water solution (0.3 mL) of the host molecule (1 in the following scheme) (17.2 mg, 3 μmol), and the suspension was heated at 60° C. for 10 minutes. The resulting mixture was filtered, and the inclusion complex (1·(H2) in the following scheme) was obtained as an orange solution. ２ ) was quantitatively obtained. ２ )teeth, １ H NMR, １３ The single crystal was prepared by the following method.

[0156] (Single crystal preparation method) Inclusion complex (1·(H2) ２ Five equivalents of 1,3,5-benzenetrimethanesulfonic acid sodium salt were added to an aqueous solution (10 mM) of 1,3,5-benzenetrimethanesulfonic acid sodium salt, and the mixture was filtered. The solvent in the filtrate was slowly evaporated at 15°C over a week to precipitate single crystals.

[0157]

[0158] [Example 5] Inclusion complex (1·(H2) ２ ) Inclusion of the target molecule of the inclusion complex (1·(H2) obtained in Example 4) ２ Adamantane (G1 in the following scheme) (4.1 mg, 30 μmol) was added to a heavy water solution (5 mM, 600 μL, 3 μmol) of 1H2. The mixture was heated at 60° C. for 10 minutes. The mixture was then filtered to quantitatively obtain the inclusion complex (1·(H2·G1·H2) in the following scheme) as an orange solution. The inclusion complex [1·(H2·G1·H2)] was １ H NMR, １３ The single crystal was prepared by the following method.

[0159] (Single Crystal Preparation Method) Five equivalents of 1,3,5-benzenetrimethanesulfonic acid sodium salt were added to an aqueous solution (10 mM) of the inclusion complex [1·(H2·G1·H2)], followed by filtration. The solvent in the filtrate was slowly evaporated at 15°C over a period of one week to precipitate single crystals.

[0160]

[0161] [Example 6] Inclusion complex (1·(H2) ２ ) Inclusion of the target molecule of the inclusion complex (1·(H2) obtained in Example 4) ２ Tetramethylsilane (G2) (50 μmol) was added to a heavy water solution (0.5 mM, 600 μL, 0.3 μmol) of 1H2. The mixture was stirred at 25°C for 45 minutes. The mixture was then filtered to quantitatively obtain the inclusion complex (1·(H2·G2·H2)) as a yellow solution. The inclusion complex [1·(H2·G2·H2)] was １ Identification was performed by 1 H NMR.

[0162] [Example 7] Inclusion complex (1·(H2) ２ ) Inclusion of the target molecule of the inclusion complex (1·(H2) obtained in Example 4) ２ Norbornadiene (G3) (10 μmol) was added to a heavy water solution (0.5 mM, 600 μL, 0.3 μmol) of 1H� ... １ Identification was performed by 1 H NMR.

[0163] [Example 8] Inclusion complex (1·(H2) ２ The inclusion complex (1·(H2·G4·H2)) was quantitatively obtained as a deep yellow solution by the same method as in Example 7, except that tetrabromomethane (G4) was used instead of norbornadiene. The inclusion complex (1·(H2·G4·H2)) was １ The single crystal was prepared by the following method.

[0164] (Single Crystal Production Method) 1,3,5-benzenetrimethanesulfonic acid sodium salt was added to an aqueous solution (10 mM) of the inclusion complex [1·(H2·G4·H2)], followed by filtration. The solvent in the filtrate was slowly evaporated at 15°C over a period of one week to precipitate single crystals.

[0165] Example 9: Inclusion complex (1·(H2)２ The inclusion complex (1·(H2·G5·H2)) was quantitatively obtained as a deep orange solution by the same method as in Example 7, except that ferrocene (G5) was used instead of norbornadiene. The inclusion complex (1·(H2·G5·H2)) was １ Identification was performed by 1 H NMR.

[0166] [Example 10] Inclusion complex (1·(H2) ２ The inclusion complex (1·(H2·G6·H2)) was quantitatively obtained as a pale yellow solution by the same method as in Example 7, except that 1,4-dimethylpyridinium iodide (G6) was used instead of norbornadiene. The inclusion complex (1·(H2·G6·H2)) was １ The single crystal was prepared by the following method.

[0167] (Single Crystal Preparation Method) 1,3,5-benzenetrimethanesulfonic acid sodium salt was added to an aqueous solution (10 mM) of the inclusion complex [1·(H2·G6·H2)], followed by filtration. The solvent in the filtrate was slowly evaporated at 15°C over a period of one week to precipitate single crystals.

[0168] [Example 11] Inclusion complex (1·(H2) ２ The inclusion complex (1·(H2·G7·H2)) was quantitatively obtained as a yellow solution by the same method as in Example 7, except that transplatin (G7) was used instead of norbornadiene. The inclusion complex (1·(H2·G7·H2)) was １ Identification was performed by 1 H NMR.

[0169] [Example 12] Inclusion complex (1·(H2) ２ ) Inclusion of the target molecule of the inclusion complex (1·(H2) obtained in Example 4) ２ Iodine (G8) (10 μmol) was added to a heavy water solution (0.5 mM, 600 μL, 0.3 μmol) of 1H� ...１ Identification was performed by 1 H NMR.

[0170] [Example 13] Inclusion complex (1·(H2) ２ The inclusion complex (1·(H2·G9·H2)) was quantitatively obtained as a deep yellow solution by the same method as in Example 7, except that o-carborane (G9) was used instead of norbornadiene. The inclusion complex (1·(H2·G9·H2)) was １ The single crystal was prepared by the following method.

[0171] (Single Crystal Preparation Method) 1,3,5-benzenetrimethanesulfonic acid sodium salt was added to an aqueous solution (10 mM) of the inclusion complex [1·(H2·G9·H2)], followed by filtration. The solvent in the filtrate was slowly evaporated at 15°C over a period of one week to precipitate single crystals.

[0172] Example 14: Inclusion complex (1·(H2) ２ The inclusion complex (1·(H2·G10·H2)) was quantitatively obtained as a deep yellow solution by the same method as in Example 7, except that diamantane (G10) was used instead of norbornadiene. The inclusion complex [1·(H2·G10·H2)] was １ Identification was performed by 1 H NMR.

[0173] Example 15: Inclusion complex (1·(H2) ２ The inclusion complex (1·(H2·G10·H2)) was quantitatively obtained as a deep yellow solution by the same method as in Example 7, except that [2,2]paracyclophane (G11) was used instead of norbornadiene. The inclusion complex [1·(H2·G11·H2)] was １ Identification was performed by 1 H NMR.

[0174] [Example 16] Inclusion of rifampicin ９ L ６Rifampicin (a drug for treating mycobacteriosis, molecular weight 823) (4.1 mg, 9 μmol) was suspended in a heavy water solution (1.0 mL) of the host molecule (17.2 mg, 3 μmol) and heated at 60° C. for 5 minutes. The resulting mixture was filtered to quantitatively obtain the inclusion complex as an orange solution. １ Identification was performed by 1 H NMR.

[0175]

[0176] Example 17: Inclusion complex of cyclosporine An inclusion complex was obtained in the same manner as in Example 16, except that cyclosporine (immunosuppressant, molecular weight 1203) was used instead of rifampicin. １ Identification was performed by 1 H NMR.

[0177]

[0178] Example 18: Inclusion complex of spiramycin An inclusion complex was obtained in the same manner as in Example 16, except that spiramycin (anti-Toxoplasma gondii agent, molecular weight 843) was used instead of rifampicin. １ Identification was performed by 1 H NMR.

[0179]

[0180] Example 19 Inclusion complex of 10-deacetylbaccatin III An inclusion complex was obtained in the same manner as in Example 16, except that 10-deacetylbaccatin III (an anticancer drug synthesis intermediate, molecular weight 545) was used instead of rifampicin. １ Identification was performed by 1 H NMR.

[0181]

[0182] [Example 20] Pd ８ L ６Synthesis of host molecule-guest molecule complex: cis-dinitrato(N,N,N',N'-tetramethylethylenediamine)palladium(II) (13.8 mg, 40 μmol), 2,4,6-tris(4-pyridyl)-1,3,5-triazine (9.4 mg, 30 μmol), and pillar[5]arene (4.4 mg, 0.5 μmol) were ground using a mortar and pestle for 10 minutes. 1 mL of heavy water was added to the resulting powder, and the mixture was heated at 100°C for 5 minutes. Then, the mixture was filtered to obtain empty Pd ６ L ４ The inclusion complex was obtained as a red solution containing the compound in a yield of 34% (NMR). １ Identification was performed by 1 H NMR.

[0183] Example 21: Pd ９ L ６ Synthesis of Host Molecule-Guest Molecule Complex Cryptophan E was synthesized according to J. Chem. Soc., Chem. Commun. 9, 582-584 (1988). Purification by gel permeation chromatography using chloroform as a solvent gave a cryptophane E-chloroform inclusion complex.

[0184] Cis-dinitrato(N,N,N',N'-tetramethylethylenediamine)palladium(II) (Pd in ​​the scheme below) (15.6 mg, 45 μmol), 2,4,6-tris(4-pyridyl)-1,3,5-triazine (L in the scheme below) (9.4 mg, 30 μmol), and cryptophane E-chloroform inclusion complex (H3·CHCl in the scheme below) ３ ) (5.2 mg, 5.0 μmol) was ground in a ball mill at 250 rpm for 1 hour. 1 mL of heavy water was added to the resulting powder, and the mixture was heated at 60°C for 10 minutes. The mixture was then filtered to obtain empty Pd ６ L ４ The yellow solution containing the compound was treated with an inclusion complex (1'·(H3·CHCl ３ )) was obtained in 60% yield (NMR). ３ ))teeth, １ H NMR, １３The single crystal was prepared by the following method.

[0185] (Single crystal preparation method) Inclusion complex (H3·CHCl ３ Five equivalents of 1,3,5-benzenetrimethanesulfonic acid sodium salt were added to an aqueous solution of the above compound, and the mixture was filtered. The solvent in the filtrate was slowly evaporated at 15°C over a period of one week to precipitate single crystals.

[0186]

[0187] Example 22: Pd ９ L ６ Synthesis of host molecule-guest molecule complex: cis-dinitrato(N,N,N',N'-tetramethylethylenediamine)palladium(II) (Pd in ​​the scheme below) (15.6 mg, 45.0 μmol), 2,4,6-tris(4-pyridyl)-1,3,5-triazine (L in the scheme below) (9.4 mg, 30 μmol), and calix[8]arene (H4 in the scheme below) (4.4 mg, 5.0 μmol) were ground in a ball mill at 250 rpm for 1 hour. 1 mL of heavy water was added to the resulting powder, and the mixture was heated at 60°C for 10 minutes. Subsequently, the mixture was filtered to obtain empty Pd ６ L ４ The inclusion complex (1'.H4 in the scheme below) was obtained as a yellow solution containing the compound in a yield of 36% (NMR). After vacuum concentration, the precipitate was recovered and found to have a purity of 80 mol%. １ H NMR, １３ The single crystal was prepared by the following method.

[0188] (Method for Producing Single Crystals) 1,3,5-benzenetrimethanesulfonic acid sodium salt and 1,3-dichlorobenzene were added to an aqueous solution of the inclusion complex (1'·H4), and the solvent in the solution was slowly evaporated at 15°C over a period of one week to precipitate single crystals.

[0189]

[0190] Example 23 Inclusion of guest molecules in inclusion complex (1'·H4) 2,6-di-tert-butyl-1,4-benzoquinone (G12 in the scheme below) (4.0 mg, 18 μmol) was added to a heavy water solution (3 mM, 600 μL, 1.8 μmol) of the inclusion complex (1'·H4) obtained in Example 22, and the mixture was stirred at 60°C for 5 minutes. The mixture was then filtered to quantitatively obtain the inclusion complex (1·(H4·G12) in the scheme below) as an orange solution. The inclusion complex [1·(H4·G12)] was １ H NMR, １３ The single crystal was prepared by the following method.

[0191] (Method for Producing Single Crystals) A heavy water solution of 1,3,5-benzenetrimethanesulfonic acid sodium salt (20 mM, 0.1 mL), 0.1 mL of heavy water, and a saturated aqueous solution of the inclusion complex [1·(H4·G12)] (0.1 mL) were layered in a 4.4 mm diameter microtube from the bottom up, and the mixture was allowed to stand at 30°C for several days to precipitate single crystals.

[0192]

[0193] Example 24 Inclusion of Paclitaxel An inclusion complex was obtained in the same manner as in Example 16, except that paclitaxel (antineoplastic agent, molecular weight 854) was used instead of rifampicin. The inclusion complex was identified by 1H NMR.

[0194]

[0195] Example 25 Inclusion of Fidaxomicin An inclusion complex was obtained in the same manner as in Example 16, except that fidaxomicin (antibiotic, molecular weight 1058) was used instead of rifampicin. The inclusion complex was identified by 1H NMR.

[0196]

[0197] Example 26 Inclusion of Salinomycin An inclusion complex was obtained in the same manner as in Example 16, except that salinomycin (antibiotic, molecular weight 751) was used instead of rifampicin. The inclusion complex was identified by 1H NMR.

[0198]

Claims

A host molecule having one or more openings, one or more wall portions, and an internal space surrounded by the wall portions, the wall portion contains a metal ion and a multidentate ligand having a π-conjugated system, The volume of the internal space is 500 x 10 －３０ m ３ That's it, host molecule.

2. The host molecule of claim 1, wherein the metal ion is an ion of an element selected from the group consisting of Ti, Fe, Co, Ni, Cu, Zn, Ru, Rh, Pd, Cd, Os, Ir, and Pt. 　 The polydentate ligand having a π-conjugated system is represented by the following formula (1): (A is an m-valent group having aromaticity. X is a divalent organic group or a single bond directly connecting A and Y. Y is a coordinating atom or a monovalent group containing a coordinating atom. m is an integer of 2 to 6. Multiple Xs may be different from each other, and multiple Ys may be different from each other.) The host molecule according to claim 1 , which is a ligand represented by the formula: (a-1) a step of mixing, in a solid phase, a mononuclear complex containing a metal ion for forming the host molecule, a polydentate ligand having a π-conjugated system for forming the host molecule, and a guest molecule having 50 or more atoms other than hydrogen atoms, which serves as a template when a polynuclear metal complex containing the metal ion and the polydentate ligand is generated; (a-2) preparing a mixed solution by dissolving the mixture obtained in step (a-1) in a solvent; (a-3) precipitating a host molecule-guest molecule complex from the mixed solution obtained in step (a-2); and (a-4) removing the guest molecule from the host molecule-guest molecule complex obtained in step (a-3); The method for producing the host molecule according to claim 1 , comprising: 　 In the case where the host molecule obtained in the step (a-4) contains an uncoordinated coordinating atom, (a-5) preparing a mixed solution in which the host molecule obtained in step (a-4) and a mononuclear complex containing a metal ion for forming the host molecule are dissolved; and (a-6) precipitating host molecules that do not contain uncoordinated coordinating atoms from the mixed solution obtained in step (a-5); The method for producing a host molecule according to claim 4 , comprising: 　 A host molecule-target molecule complex comprising the host molecule of claim 1 and a target molecule accommodated in the internal space thereof. (b-1) A step of causing the host molecule according to claim 1 and a target molecule to coexist in the same system in the presence or absence of a solvent, thereby accommodating the target molecule in the internal space of the host molecule; The method for producing a host molecule-target molecule complex according to claim 6, comprising: (c-1) mixing, in a solid phase, a mononuclear complex containing a metal ion for forming the host molecule, a polydentate ligand having a π-conjugated system for forming the host molecule, and a target molecule having 50 or more atoms other than hydrogen atoms, which serves as a template when a polynuclear metal complex containing the metal ion and the polydentate ligand is generated; (c-2) preparing a mixed solution by dissolving the mixture obtained in step (c-1) in a solvent; and (c-3) precipitating the host molecule-target molecule complex from the mixed solution obtained in step (c-2); The method for producing a host molecule-target molecule complex according to claim 6, comprising: 　 A sample for crystal structure analysis comprising a plurality of host molecules and a plurality of target molecules, The host molecule is the host molecule of claim 1 , the plurality of host molecules contained in the sample for crystal structure analysis are three-dimensionally regularly assembled, all or some of the plurality of host molecules contained in the sample for crystal structure analysis accommodate a target molecule in their internal spaces; The sample for crystal structure analysis includes a plurality of target molecules that are regularly arranged three-dimensionally. (d-1) A step of accommodating the target molecule in the internal space of the host molecule by causing the host molecule according to claim 1 and the target molecule to coexist in the same system in the presence or absence of a solvent; and (d-2) (a) precipitating a single crystal containing a host molecule accommodating a target molecule from a solution obtained by carrying out step (d-1) in the presence of a solvent, or (b) dissolving the host molecule accommodating the target molecule produced by carrying out step (d-1) in the absence of a solvent in a solvent to prepare a solution, and then precipitating a single crystal containing a host molecule accommodating a target molecule from this solution; The method for producing a sample for crystal structure analysis according to claim 9, comprising: (e-1) a step of mixing, in a solid phase, a mononuclear complex containing a metal ion for forming the host molecule, a polydentate ligand having a π-conjugated system for forming the host molecule, and a target molecule having 50 or more atoms other than hydrogen atoms, which serves as a template when a polynuclear metal complex containing the metal ion and the polydentate ligand is generated; (e-2) preparing a mixed solution by dissolving the mixture obtained in step (e-1) in a solvent; and (e-3) A step of precipitating single crystals containing host molecules accommodating target molecules from the mixed solution obtained in step (e-2); The method for producing a sample for crystal structure analysis according to claim 9, comprising: 　 A host molecule according to claim 1; A host molecule having one or more openings, one or more wall portions, and an internal space surrounded by the wall portions, wherein the wall portions contain metal ions and multidentate ligands having a π-conjugated system, and the volume of the internal space is 500×10 －３０ m ３ a host molecule that is less than A sample preparation kit for crystal structure analysis comprising:

Images