JP7744667B2 - Compound usable as a RAFT agent and method for producing polymer using the same - Google Patents

Description

This disclosure relates to compounds that can be used as RAFT agents and methods for producing polymers using the same.

Living radical polymerization (also known as "controlled radical polymerization") is a known method for obtaining polymers and copolymers with controlled molecular weights. One example of living radical polymerization is reversible addition/fragmentation chain transfer (RAFT) polymerization. RAFT polymerization utilizes a reversible chain transfer reaction mediated by a chain transfer agent (also known as a "RAFT agent") to control the propagation reaction during polymerization. This allows for the production of polymers and block copolymers with narrow molecular weight distributions. RAFT polymerization can be applied to many radically polymerizable monomers, and because it has high tolerance for functional groups in monomers and solvents, it can synthesize a variety of polymers and block copolymers in water or protic solvents. Furthermore, RAFT polymerization produces polymers with RAFT agent fragments attached to the ends of the polymer chains, allowing the functional groups of the RAFT agent to impart functionality to the polymer.

Patent Document 1 (WO 2011/093401) describes a compound represented by the following general formula (1) as a RAFT agent having both surface activity and polymerization controllability, in which R ¹ is an organic group having a hydrophobic-hydrophilic balance (HLB) value of 3 or more as determined by the Griffin method:

Non-Patent Document 1 (Macromolecules 2001, 34, 7269-7275) describes the RAFT polymerization of styrene using benzyl (diethoxyphosphoryl) dithioformate and benzyl (diethoxythiophosphoryl) dithioformate as RAFT agents.

Non-Patent Document 2 (Polymer 48 (2007) 5850-5858) describes the formation of a TiO ₂ /polyacrylic acid (PAA) nanocomposite by RAFT polymerization. 2-(((butylsulfanyl)carbonothioyl)sulfanyl)propanoic acid and 2-(ethoxythiocarbonyl)-2-methylmalonate were used as RAFT agents.

Non-Patent Document 3 (Polymer 51 (2010) 5345-5351) describes the formation of an n-TiO ₂ /polymethyl methacrylate (PMMA) nanocomposite by RAFT polymerization of methyl methacrylate using 4-cyano-4-(dodecylsulfanylthiocarbonylsulfanyl)pentanoic acid coordinated to the surface of nanotitania (n-TiO ₂ ) as a RAFT agent.

Non-Patent Document 4 (J. Mater. Chem. C, 2013, 1, 484-492) describes the formation of a rutile TiO ₂ -polystyrene composite by RAFT polymerization of styrene using 2-(((dodecylthio)carbonothioyl)thio)-2-methylpropanoic acid coordinated to rutile TiO ₂ nanoparticles as a RAFT agent.

International Publication No. 2011/093401

Macromolecules 2001, 34, 7269-7275 Polymer 48 (2007) 5850-5858 Polymer 51 (2010) 5345-5351 J. Mater. Chem. C, 2013, 1, 484-492

The present disclosure aims to provide novel compounds that can be used as RAFT agents for RAFT polymerization in highly polar solvents such as water, and that can be applied to the surface modification of a variety of substrates, such as metal oxides.

The inventors have discovered that thiocarbonylthio group-containing compounds with specific phosphorus-containing groups effectively promote RAFT polymerization in highly polar solvents such as water, and that the surfaces of substrates such as metal oxides can be modified with the compounds via the phosphorus-containing groups, or with polymers obtained by RAFT polymerization using the compounds.

The present invention includes the following aspects:

[Aspect 1]
Formula (1)
(In formula (1),
^R1 is selected from the group consisting of substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, and substituted or unsubstituted heteroaryl groups;
^R2 is a monovalent organic group containing a phosphorus-containing group selected from the group consisting of a phosphate group, a phosphonate group, a phosphate ester group, and a phosphonate ester group;
X is selected from the group consisting of a single bond, S, O, and ^NR3 ;
^R3 is selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group, and may combine with ^R1 to form a heterocyclic structure.
A compound represented by the formula:
[Aspect 2]
The compound according to embodiment 1, wherein X in formula (1) is a single bond or S.
[Aspect 3]
In formula (1), R ² is a group represented by formula (2):
(In formula (2),
R ⁴ is selected from the group consisting of a hydrogen atom, a cyano group, a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, a carboxy group, a substituted or unsubstituted alkoxycarbonyl group having 2 to 20 carbon atoms, and a substituted or unsubstituted aryloxycarbonyl group having 7 to 20 carbon atoms;
^R5 is selected from the group consisting of a hydrogen atom and a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms;
^R6 is a divalent organic group having 1 to 30 carbon atoms;
^R7 is selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, and a substituted or unsubstituted aryl group having 6 to 20 carbon atoms;
Y is selected from the group consisting of a single bond and O;
* indicates the bonding site with the sulfur atom.)
3. The compound according to any one of aspects 1 or 2, represented by:
[Aspect 4]
A compound according to embodiment 3, wherein in formula (2), Y is O and R ⁷ is a hydrogen atom.
[Aspect 5]
A compound according to any one of Aspects 3 and 4, wherein in formula (2), R ⁶ contains an amide bond or an ether bond.
[Aspect 6]
The compound is represented by formula (3)
The compound according to embodiment 1, represented by:
[Aspect 7]
A method for producing a polymer, comprising carrying out RAFT polymerization using a compound according to any one of aspects 1 to 6.
[Aspect 8]
8. The method of producing a polymer according to claim 7, wherein the RAFT polymerization is carried out in an aqueous solvent.
[Aspect 9]
Formula (4)
(In formula (4),
^R1 is selected from the group consisting of substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, and substituted or unsubstituted heteroaryl groups;
^R2 is a monovalent organic group containing a phosphorus-containing group selected from the group consisting of a phosphate group, a phosphonate group, a phosphate ester group, and a phosphonate ester group;
X is selected from the group consisting of a single bond, S, O, and ^NR3 ;
^R3 is selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group, and may combine with ^R1 to form a heterocyclic structure;
Poly represents a polymer chain.
A polymer represented by the formula:
[Aspect 10]
A polymer according to aspect 9, wherein in formula (4), Poly contains at least one structural unit having a zwitterionic structure.
[Aspect 11]
11. A composite material comprising an inorganic substrate selected from the group consisting of titanium oxide, zirconium oxide, and hydroxyapatite, and the polymer according to either of Aspects 9 or 10, wherein a surface of the inorganic substrate is modified with the polymer via the phosphorus-containing group of the polymer.
[Aspect 12]
A method for producing a composite material whose surface is modified with a polymer, the method comprising contacting an inorganic substrate selected from the group consisting of titanium oxide, zirconium oxide, and hydroxyapatite with the polymer according to either of Aspects 9 or 10 in an aqueous solvent having a pH of 7 or higher.
[Aspect 13]
A solid-phase RAFT agent comprising an inorganic substrate selected from the group consisting of titanium oxide, zirconium oxide, and hydroxyapatite, and the compound according to any one of Aspects 1 to 6, wherein the surface of the inorganic substrate is modified with the compound via the phosphorus-containing group of the compound.
[Aspect 14]
14. A method for producing a polymer, comprising carrying out RAFT polymerization using the solid-phase RAFT agent of aspect 13.
[Aspect 15]
15. The method for producing a polymer according to claim 14, wherein the RAFT polymerization is carried out in an aqueous solvent.

The compounds of the present invention can be used as RAFT agents for RAFT polymerization in highly polar solvents such as water, and can also be applied to the surface modification of a variety of substrates, such as metal oxides.

The above description should not be considered as a disclosure of all embodiments of the present invention or all advantages associated with the present invention.

1 is a ¹ H-NMR (400 MHz, D ₂ O) chart of the RAFT agent of Example 1. 1 is a UV-Vis spectrum of the RAFT agent of Example 1. This is a UV-Vis spectrum of RAFT-NHS used as a raw material. 1 is a ¹ H-NMR (400 MHz, D ₂ O) chart of poly(2-methacryloyloxyethyl phosphorylcholine) of Example 2.

The present invention will be described in more detail below for the purpose of illustrating representative embodiments, but the present invention is not limited to these embodiments.

In this disclosure, "(meth)acrylic" means acrylic or methacrylic, and "(meth)acrylate" means acrylate or methacrylate.

[Compound]
In one embodiment, the compound has the formula (1)
It is expressed as:

In formula (1), ^R1 is selected from the group consisting of a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; ^R2 is a monovalent organic group containing a phosphorus-containing group selected from the group consisting of a phosphate group, a phosphonate group, a phosphate ester group, and a phosphonate ester group; X is selected from the group consisting of a single bond, S, O, and ^NR3 ; ^R3 is selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group, and may combine with ^R1 to form a heterocyclic structure.

The compound of this embodiment has a specific phosphorus-containing group, making it highly soluble in highly polar solvents such as water, and it functions as a RAFT agent due to the thiocarbonylthio group (-(C=S)-S-). Therefore, RAFT polymerization can be advantageously carried out using this compound in an aqueous solvent. Furthermore, via the phosphorus-containing group of this compound, the surface of a substrate such as a metal oxide can be modified with this compound or with a polymer obtained by RAFT polymerization using this compound.

R ¹ is selected from the group consisting of substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, and substituted or unsubstituted heteroaryl groups.

The unsubstituted alkyl group for ^R1 is preferably an alkyl group having 1 to 20 carbon atoms, more preferably an alkyl group having 1 to 16 carbon atoms. Examples of alkyl groups having 1 to 20 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group, an n-octyl group, a 2-ethylhexyl group, an n-decyl group, an n-dodecyl group, an n-tetradecyl group, and an n-hexadecyl group.

The unsubstituted aryl group for ^R1 is preferably an aryl group having 6 to 20 carbon atoms, more preferably an aryl group having 6 to 14 carbon atoms. Examples of the aryl group having 6 to 20 carbon atoms include a phenyl group, a naphthyl group, a fluorenyl group, an anthryl group, and a phenanthrenyl group.

The unsubstituted heteroaryl group for ^R1 is preferably a heteroaryl group having 3 to 20 carbon atoms, more preferably a heteroaryl group having 4 to 14 carbon atoms. Examples of heteroaryl groups having 3 to 20 carbon atoms include a furanyl group, a pyridyl group, a thienyl group, a quinolinyl group, a pyrazinyl group, a triazinyl group, a benzofuranyl group, a benzothienyl group, and an indolyl group.

The substituted alkyl group, substituted aryl group, and substituted heteroaryl group for ^R1 are the unsubstituted alkyl group, unsubstituted aryl group, and unsubstituted heteroaryl group, respectively, in which one or more hydrogen atoms have been substituted with a substituent. Examples of the substituent include an alkyl group (excluding substituted alkyl groups), a hydroxyl group, an alkoxy group, an aryloxy group, a hydroxyalkyl group (excluding substituted alkyl groups), an alkoxyalkyl group (excluding substituted alkyl groups), a halogen group, a cyano group, a nitro group, an isocyanato group, an acyl group, a carboxy group, an alkoxycarbonyl group, an epoxy group, and a silyl group. The total number of carbon atoms in the substituent is preferably 1 to 30, and more preferably 1 to 18.

^R1 is preferably an alkyl group of 1 to 16 carbon atoms which may have a substituent, an aryl group of 6 to 14 carbon atoms which may have a substituent, or a heteroaryl group of 4 to 14 carbon atoms which may have a substituent, and more preferably an alkyl group of 1 to 16 carbon atoms which may have a substituent, or an aryl group of 6 to 14 carbon atoms which may have a substituent.

In embodiments in which R ¹ has a substituent, the substituent is preferably an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a cyano group, or a silyl group.

^R2 is a monovalent organic group containing a phosphorus-containing group selected from the group consisting of a phosphoric acid group, a phosphonic acid group, a phosphoric ester group, and a phosphonic acid ester group. When the compound represented by formula (1) is used as a RAFT agent for RAFT polymerization or after RAFT polymerization, the phosphorus-containing group, that is, the phosphoric ester group or the phosphonic acid ester group, may be hydrolyzed to convert it to a phosphoric acid group or a phosphonic acid group.

The phosphorus-containing group of ^R2 is preferably a phosphate group or a phosphonate group, more preferably a phosphate group. The phosphate group and the phosphonate group can further increase the solubility of the compound represented by formula (1) in highly polar solvents such as water.

The number of carbon atoms in ^R2 is preferably 1 to 60, more preferably 1 to 40, and even more preferably 1 to 30. By making the number of carbon atoms in ^R2 1 to 60, the solubility of the compound represented by formula (1) in highly polar solvents such as water can be increased.

In one embodiment, ^R2 is a group of formula (2):
It is expressed as:

In formula (2), ^R4 is selected from the group consisting of a hydrogen atom, a cyano group, a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, a carboxy group, a substituted or unsubstituted alkoxycarbonyl group having 2 to 20 carbon atoms, and a substituted or unsubstituted aryloxycarbonyl group having 7 to 20 carbon atoms; ^R5 is selected from the group consisting of a hydrogen atom and a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms; ^R6 is a divalent organic group having 1 to 30 carbon atoms; ^R7 is selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, and a substituted or unsubstituted aryl group having 6 to 20 carbon atoms; Y is selected from the group consisting of a single bond and O; and * represents a bonding site with the sulfur atom.

^R4 is selected from the group consisting of a hydrogen atom, a cyano group, a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, a carboxy group, a substituted or unsubstituted alkoxycarbonyl group having 2 to 20 carbon atoms, and a substituted or unsubstituted aryloxycarbonyl group having 7 to 20 carbon atoms.

The unsubstituted alkyl group having 1 to 20 carbon atoms for R ⁴ and the unsubstituted aryl group having 6 to 20 carbon atoms for R ⁴ are the same as those described for R ¹ .

Examples of the unsubstituted alkoxycarbonyl group having 2 to 20 carbon atoms for ^R4 include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, and a tert-butoxycarbonyl group. The number of carbon atoms in the unsubstituted alkoxycarbonyl group is preferably 2 to 13.

Examples of the unsubstituted aryloxycarbonyl group having 7 to 20 carbon atoms for R ⁴ include a phenyloxycarbonyl group, a naphthyloxycarbonyl group, an anthryloxycarbonyl group, and a fluorenyloxycarbonyl group.

The substituted alkyl group, substituted aryl group, substituted alkoxycarbonyl group, and substituted aryloxycarbonyl group of ^R4 are, respectively, unsubstituted alkyl groups, unsubstituted aryl groups, unsubstituted alkoxycarbonyl groups, and unsubstituted aryloxycarbonyl groups in which one or more hydrogen atoms have been substituted with a substituent. Examples of the substituent include alkyl groups (excluding substituted alkyl groups and substituted alkoxycarbonyl groups), hydroxyl groups, alkoxy groups, aryloxy groups, hydroxyalkyl groups (excluding substituted alkyl groups and substituted alkoxycarbonyl groups), alkoxyalkyl groups (excluding substituted alkyl groups and substituted alkoxycarbonyl groups), halogen groups, cyano groups, nitro groups, isocyanato groups, acyl groups, carboxy groups, alkoxycarbonyl groups, epoxy groups, and silyl groups. The total number of carbon atoms in the substituents is preferably 1 to 30, more preferably 1 to 18.

^R5 is selected from the group consisting of a hydrogen atom and a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms. The substituted or unsubstituted alkyl group having 1 to 20 carbon atoms of ^R5 is the same as that described for ^R4 .

The bond (S-R ² ) between R ² and the sulfur atom (S) constituting the thiocarbonylthio group is homolytically cleaved during RAFT polymerization, and R ² ·, which is eliminated as a free radical, becomes a polymerization initiation species and restarts the polymerization. Therefore, in formula (2), R ⁴ and R ⁵ , which are substituents on the bonded carbon atom of the sulfur atom (S) constituting the thiocarbonylthio group, are appropriately selected depending on the type of monomer to be polymerized, specifically, the polymerization activity of the monomer.

For example, in the RAFT polymerization of highly active monomers such as methyl (meth)acrylate, (meth)acrylic acid, (meth)acrylamide, acrylonitrile, and styrene, ^R4 is preferably a cyano group, a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, a carboxy group, a substituted or unsubstituted alkoxycarbonyl group having 2 to 20 carbon atoms, or a substituted or unsubstituted aryloxycarbonyl group having 7 to 20 carbon atoms, and more preferably a cyano group or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms. In this embodiment, ^R5 is preferably a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms.

On the other hand, in the RAFT polymerization of low activity monomers such as vinyl acetate, N-vinylpyrrolidone, and N-vinylcarbazole, it is preferred that at least one of ^R4 and ^R5 is a hydrogen atom, or that ^R4 and ^R5 are a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms.

In one embodiment, R ⁴ is a cyano group and R ⁵ is an unsubstituted alkyl group having 1 to 20 carbon atoms.

^R6 is a divalent organic group having 1 to 30 carbon atoms.

Examples of ^R6 include linear alkanediyl groups having 1 to 20 carbon atoms, such as methylene, ethylene, propane-1,3-diyl, butane-1,4-diyl, hexane-1,6-diyl, octane-1,8-diyl, decane-1,10-diyl, and dodecane-1,12-diyl; saturated cyclic hydrocarbon groups having 5 to 20 carbon atoms, such as cyclopentanediyl, cyclohexanediyl, norbornanediyl, and adamantanediyl; and unsaturated cyclic hydrocarbon groups having 6 to 30 carbon atoms, such as phenylene and naphthylene. Some or all of the hydrogen atoms in these groups may be substituted with alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl, or with groups containing heteroatoms, such as oxygen, sulfur, nitrogen, and halogen atoms. A heteroatom such as an oxygen atom, a nitrogen atom or a sulfur atom may be present between the carbon atoms constituting ^R6 .

^R6 preferably contains an amide bond or an ether bond, more preferably an amide bond. The amide bond and the ether bond can increase the solubility of the compound represented by formula (1) in highly polar solvents such as water. Examples of ^R6 containing an ether bond include groups containing a polyalkylene oxide moiety such as polyethylene oxide (PEO) and polypropylene oxide (PPO).

^R7 is selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, and a substituted or unsubstituted aryl group having 6 to 20 carbon atoms. The substituted or unsubstituted alkyl group having 1 to 20 carbon atoms and the substituted or unsubstituted aryl group having 6 to 20 carbon atoms of ^R7 are the same as those described for ^R4 .

^R7 is preferably a hydrogen atom, an alkyl group having 1 to 16 carbon atoms which may have a substituent, or an aryl group having 6 to 14 carbon atoms which may have a substituent, and more preferably a hydrogen atom.

Y is selected from the group consisting of a single bond and O. When Y is a single bond, the phosphorus-containing group is a phosphonic acid group or a phosphonic acid ester group. When Y is O, the phosphorus-containing group is a phosphate group or a phosphate ester group.

In one embodiment, Y is O and R ⁷ is a hydrogen atom.

X is selected from the group consisting of a single bond, S, O, and ^NR3 . X together with ^R1 influences the rate of addition-fragmentation reactions during RAFT polymerization.

For example, in the RAFT polymerization of highly active monomers such as methyl (meth)acrylate, (meth)acrylic acid, (meth)acrylamide, acrylonitrile, and styrene, X is preferably a single bond or S. In embodiments where X is a single bond, ^R1 is preferably an optionally substituted aryl group having 6 to 14 carbon atoms. In embodiments where X is S, ^R1 is preferably an optionally substituted alkyl group having 1 to 16 carbon atoms.

On the other hand, in RAFT polymerization of low activity monomers such as vinyl acetate, N-vinylpyrrolidone, and N-vinylcarbazole, X is preferably O or ^NR3 . In an embodiment where X is O, ^R1 is preferably an alkyl group having 1 to 16 carbon atoms which may have a substituent. In an embodiment where X is ^NR3 , ^R1 is preferably an alkyl group having 1 to 16 carbon atoms which may have a substituent.

^R3 is selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group. The substituted or unsubstituted alkyl group, substituted or unsubstituted aryl group, and substituted or unsubstituted heteroaryl group of ^R3 are the same as those described for ^R1 .

^R3 is preferably an alkyl group having 1 to 16 carbon atoms which may have a substituent, or an aryl group having 6 to 14 carbon atoms which may have a substituent.

^R3 may bond with ^R1 to form a heterocyclic structure. Examples of heterocyclic structures include saturated heterocyclic rings such as a pyrrolidine ring, an imidazolidine ring, a pyrazolidine ring, and a piperidine ring, and unsaturated heterocyclic rings such as a pyrrole ring, an imidazole ring, a pyrazole ring, and a pyridine ring. Some or all of the hydrogen atoms on the carbon atoms or heteroatoms constituting the heterocyclic structure may be substituted with an alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group; or a halogen atom such as fluorine, chlorine, bromine, or iodine.

In one embodiment, X is a single bond or S.

In one embodiment, the compound has formula (3):
It is expressed as:

[Method of producing the compound]
The compound represented by formula (1) can be synthesized by a known method, for example, by forming an ester bond or an amide bond between a compound having a thiocarbonylthio group and a carboxy group or a derivative thereof and a compound having a phosphorus-containing group and a hydroxyl group or an amino group.

For the formation of ester or amide bonds, carboxy groups can be activated using known activating reagents, such as N-hydroxysuccinimide (NHS), thionyl chloride (SOCl ₂ ), and phosphorus tribromide (PBr ₃ ). N-hydroxysuccinimide forms an N-succinimidyl ester as an activated intermediate. Thionyl chloride and phosphorus tribromide form an acid halide as an activated intermediate.

As an example, the compound represented by formula (3) can be obtained as follows. 4-cyano-4-(phenylcarbonothioylthio)pentanoic acid, a compound having a thiocarbonylthio group and a carboxy group, is reacted with N-hydroxysuccinimide to synthesize the activated ester N-succinimidyl 4-cyano-4-(phenylcarbonothioylthio)pentanoate (RAFT-NHS). Next, RAFT-NHS is reacted with O-phosphorylethanolamine to form an amide bond, synthesizing the compound represented by formula (3).

The formation of ester or amide bonds can also be promoted using known condensing agents. Examples of condensing agents include carbodiimide-based condensing agents such as N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; imidazole-based condensing agents such as N,N'-carbonyldiimidazole; and triazine-based condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM).

In another embodiment, the compound represented by formula (1) can be synthesized by phosphorylating the hydroxyl group of a compound having a thiocarbonylthio group and a hydroxyl group using a phosphating agent such as morpholinophosphorodichloridate. The compound having a thiocarbonylthio group and a hydroxyl group may contain a polyalkylene oxide moiety such as polyethylene oxide (PEO) or polypropylene oxide (PPO). The compound having a thiocarbonylthio group and a hydroxyl group can also be obtained by forming an amide bond between a compound having a thiocarbonylthio group and a carboxyl group and an alkanolamine such as ethanolamine. The activating reagent or condensing agent described above can also be used to form this amide bond.

[Method for producing polymers by RAFT polymerization]
The compound of formula (1) can be used to produce a polymer by RAFT polymerization. The RAFT polymerization can be solution polymerization, emulsion polymerization, suspension polymerization, or bulk polymerization. The RAFT polymerization can be batch or continuous.

<monomer>
The monomer to be applied to the RAFT polymerization using the compound represented by formula (1) is not particularly limited as long as it is capable of RAFT polymerization, and examples thereof include vinyl compounds such as styrene, vinyltoluene, α-methylstyrene, chlorostyrene, p-methoxystyrene, p-butoxystyrene, styrenesulfonic acid and its salts, vinyl acetate, vinyl chloride, N-vinylpyrrolidone, and N-vinylcarbazole; alkyl(meth)acrylates such as methyl(meth)acrylate, ethyl(meth)acrylate, n-butyl(meth)acrylate, isobutyl(meth)acrylate, n-hexyl(meth)acrylate, n-octyl(meth)acrylate, isooctyl(meth)acrylate, 2-ethylhexyl(meth)acrylate, cyclohexyl(meth)acrylate, and isobornyl(meth)acrylate; acrylates; (meth)acrylamides such as (meth)acrylamide, N,N-dimethyl(meth)acrylamide, and N-isopropyl(meth)acrylamide; (meth)acrylic acid; unsaturated nitriles such as acrylonitrile and methacrylonitrile; silicon-containing unsaturated monomers such as vinyltrimethoxysilane and vinyltriethoxysilane; unsaturated carboxylic acids and acid anhydrides and esters thereof such as maleic acid, maleic anhydride, maleic acid esters, fumaric acid, and fumaric acid esters; and maleimides such as maleimide, N-methylmaleimide, N-ethylmaleimide, N-propylmaleimide, N-butylmaleimide, N-hexylmaleimide, N-octylmaleimide, N-dodecylmaleimide, N-stearylmaleimide, N-phenylmaleimide, and N-cyclohexylmaleimide. These monomers may be substituted with a halogen atom such as fluorine, chlorine, bromine, or iodine. These monomers may further have functional groups such as hydroxyl groups, carboxyl groups, epoxy groups, amino groups, phosphate groups, phosphonic acid groups, phosphate ester groups, phosphonate ester groups, sulfonyl groups, sulfo groups, ammonium groups, etc. The monomers may have zwitterionic structures containing both acidic and basic groups.

Multifunctional monomers can also be used as monomers. Examples of multifunctional monomers include bifunctional (meth)acrylates such as allyl (meth)acrylate, 1,4-butanediol di(meth)acrylate, 1,6-hexanediol di(meth)acrylate, ethylene glycol di(meth)acrylate, cyclohexanedimethanol di(meth)acrylate, diethylene glycol di(meth)acrylate, dipropylene glycol di(meth)acrylate, and polyethylene glycol di(meth)acrylate; trifunctional (meth)acrylates such as glycerol tri(meth)acrylate, trimethylolpropane tri(meth)acrylate, and pentaerythritol tri(meth)acrylate; and (meth)acrylates with four or more functional groups such as ditrimethylolpropane tetra(meth)acrylate, dipentaerythritol penta(meth)acrylate, and pentaerythritol tetra(meth)acrylate.

The above monomers may be used alone or in combination of two or more.

The amount of monomer used can be determined so that the product of the molar ratio of the monomer to the compound represented by formula (1) used as the RAFT agent (number of moles of monomer/number of moles of compound represented by formula (1)) and the molecular weight of the monomer equals the target molecular weight of the polymer.

<Radical Polymerization Initiator>
RAFT polymerization can be carried out using a known radical polymerization initiator in the presence of the compound represented by formula (1).

Examples of radical polymerization initiators include organic peroxides such as benzoyl peroxide, cumene peroxide, and di-t-butyl peroxide; azo compounds such as 1,1'-azobis(cyclohexanecarbononitrile), 2,2'-azobis(2-methylpropionamidine) dihydrochloride, 4,4'-azobis(4-cyanovaleric acid), 2,2'-azobisisobutyronitrile, 2,2'-azobis(2,4-dimethylvaleronitrile), and 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile); and redox initiators. Radical polymerization initiators may be used alone or in combination of two or more.

The amount of radical polymerization initiator used is determined so that the molar ratio of the compound represented by formula (1) used as the RAFT agent to the radical initiator (number of moles of the compound represented by formula (1) / number of moles of the radical polymerization initiator) is generally 1 or more, or 10 or more, and 10,000 or less, or 5,000 or less.

<solvent>
As the solvent for RAFT polymerization, an organic solvent or an aqueous solvent can be used.

Examples of organic solvents include ketones such as acetone and methyl ethyl ketone (MEK); alcohols such as methanol, ethanol, and isopropanol (IPA); ethers such as diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, and propylene glycol monomethyl ether; esters such as ethyl acetate, butyl acetate, propylene glycol monomethyl ether acetate, and 2-ethoxyethyl acetate; aromatic hydrocarbons such as toluene and xylene; sulfoxides such as dimethyl sulfoxide; and amides such as dimethylformamide and dimethylacetamide. These organic solvents may be used alone or in combination.

Examples of aqueous solvents include water and mixtures of water and water-soluble organic solvents. Examples of water-soluble organic solvents include alcohols such as methanol, ethanol, and isopropanol (IPA); ethers such as diethyl ether and tetrahydrofuran; sulfoxides such as dimethyl sulfoxide; and amides such as dimethylformamide and dimethylacetamide. Water-soluble organic solvents may be used alone or in combination. The water content in the aqueous solvent may be 1% by mass or more, 2% by mass or more, or 5% by mass or more, and 100% by mass or less, 90% by mass or less, or 80% by mass or less.

In one embodiment, the RAFT polymerization is carried out in an aqueous solvent.

<Polymerization temperature>
The polymerization temperature is generally −20 to 200° C., and preferably 40 to 160° C. The polymerization time can be appropriately determined depending on the polymerization activity of the monomer and the type of the compound represented by formula (1) used as the RAFT agent, and can be, for example, 10 minutes to 120 hours.

<Copolymer>
The compound represented by formula (1) can also be used to synthesize a block copolymer, which is one of the characteristics of RAFT polymerization. For example, a diblock copolymer can be synthesized by polymerizing a first monomer followed by adding and polymerizing a second monomer. A multiblock copolymer can then be synthesized by sequentially polymerizing a third monomer, a fourth monomer, and so on. In another embodiment, the copolymer is a gradient copolymer, a random copolymer, or a statistical copolymer. For example, a gradient copolymer, a random copolymer, or a statistical copolymer can be synthesized by adding each monomer to the reaction solution in a predetermined ratio, or by adding the monomers to the reaction solution in a ratio that changes as the polymerization progresses, or by both.

[polymer]
In one embodiment the polymer is
Formula (4)
It is expressed as:

In formula (4), ^R1 is selected from the group consisting of a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; ^R2 is a monovalent organic group containing a phosphorus-containing group selected from the group consisting of a phosphate group, a phosphonate group, a phosphate ester group, and a phosphonate ester group; X is selected from the group consisting of a single bond, S, O, and ^NR3 ; ^R3 is selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group, and may bond with ^R1 to form a heterocyclic structure; and Poly represents a polymer chain.

R ¹ , R ² , and X in formula (4) are the same as those described for the compound represented by formula (1). That is, the polymer represented by formula (4) is a polymer in which the fragments generated by cleavage of the S-R ² bond in the compound represented by formula (1) are added to the ends of the polymer chain.

Poly in formula (4) is a polymer chain derived from the above-mentioned monomer. Examples of such polymer chains include homopolymers such as polystyrene, polyvinyl acetate, polyvinyl chloride, poly(N-vinylpyrrolidone), poly(meth)acrylate, poly(meth)acrylic acid, polyacrylonitrile, and polymaleimide, as well as block copolymers thereof.

In one embodiment, in formula (4), Poly contains at least one structural unit having a zwitterionic structure. Examples of monomers that form structural units having a zwitterionic structure include phosphorylcholines having a radically polymerizable group, such as 2-methacryloyloxyethyl phosphorylcholine.

The number average molecular weight (Mn) and weight average molecular weight (Mw) of the polymer can be controlled by the molar ratio of the monomer to the compound represented by formula (1) used as the RAFT agent (number of moles of monomer/number of moles of compound represented by formula (1)). The polydispersity index (Mw/Mn) of the polymer is generally 1 or more, 1.5 or less, 1.3 or less, or 1.1 or less. In this disclosure, "number average molecular weight" and "weight average molecular weight" respectively refer to the molecular weight measured by gel permeation chromatography (GPC) using a standard substance commonly used for the polymer being measured.

[Composite material]
In one embodiment, the composite material comprises an inorganic substrate selected from the group consisting of titanium oxide, zirconium oxide, and hydroxyapatite, and the above-described polymer, and the surface of the inorganic substrate is modified with the polymer via the phosphorus-containing group of the polymer.

In one embodiment, the inorganic substrate comprises titanium oxide.

The shape and size of the inorganic substrate are not particularly limited. Examples of inorganic substrates include particles, plates, discs, spheres, rods, and other irregular shapes.

The inorganic substrate may be nanoparticles. The average primary particle diameter of the nanoparticles is generally 1 to 150 nm. The average primary particle diameter of the nanoparticles is determined by the following procedure: 100 nanoparticles are randomly selected from an electron micrograph obtained by photographing nanoparticles using a transmission electron microscope (TEM) or a scanning electron microscope (SEM). The maximum cross-sectional length of each nanoparticle is defined as the diameter of the nanoparticle. The volume of this diameter converted into a sphere is calculated, and the 50% diameter (median diameter, D ₅₀ ) in the cumulative volume distribution of the 100 nanoparticles is defined as the average primary particle diameter of the nanoparticles. In one embodiment, the nanoparticles are titanium oxide nanoparticles.

[Method of manufacturing composite material]
In one embodiment, a method for producing a composite material includes contacting an inorganic substrate selected from the group consisting of titanium oxide, zirconium oxide, and hydroxyapatite with the polymer in an aqueous solvent having a pH of 7 or higher. The surface of the composite material is modified with the polymer via the phosphorus-containing groups of the polymer.

Aqueous solvents include those described above as solvents used in RAFT polymerization.

The pH of the aqueous solvent can be adjusted using alkaline compounds such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkaline earth metal hydroxides such as calcium hydroxide. The pH of the aqueous solvent may also be adjusted using a buffering agent. The pH of the aqueous solvent may be 8 or higher, or 9 or higher, and is generally 11 or lower, or 10 or lower.

The contact temperature is preferably 0 to 60°C, and more preferably 10 to 40°C.

Solid-phase RAFT agents
In one embodiment, the solid-phase RAFT agent comprises an inorganic substrate selected from the group consisting of titanium oxide, zirconium oxide, and hydroxyapatite, and a compound represented by formula (1), and the surface of the inorganic substrate is modified with the compound via a phosphorus-containing group of the compound.

The inorganic substrate of the solid-phase RAFT agent is the same as that described for the composite material.

The solid-phase RAFT agent can be produced by contacting an inorganic substrate selected from the group consisting of titanium oxide, zirconium oxide, and hydroxyapatite with a compound represented by formula (1) in an aqueous solvent having a pH of 7 or higher. The aqueous medium, its pH, and the contact temperature are the same as those described for the method for producing a composite material.

[Method for producing polymers by RAFT polymerization using solid-phase RAFT agents]
A polymer can be produced by RAFT polymerization using the solid-phase RAFT agent. This polymer may be in the form of a composite material in which fragments of the solid-phase RAFT agent are bound to the ends of the polymer chain. The monomers, radical polymerization initiator, solvent, and polymerization temperature used in the RAFT polymerization of this embodiment are the same as those described for the method for producing a polymer by RAFT polymerization using the compound represented by formula (1).

In one embodiment, RAFT polymerization using a solid-phase RAFT agent is carried out in an aqueous solvent.

The compounds, polymers, composite materials, and solid-phase RAFT agents disclosed herein can be suitably used in the production of functional materials that can be used in aqueous systems, such as ultrasound sensitizers, photocatalysts, functional cell sheets, drug transport carriers, mechanochemical materials, temperature sensors, separation membranes, and water retention agents.

The present invention will be explained in more detail below based on examples, but the present invention is not limited to these examples.

Example 1: Synthesis of RAFT Agent O-phosphorylethanolamine (O-PEA, 0.388 g, 2.7 mmol) was dissolved in sodium carbonate buffer (pH 9, 25 mL). N-succinimidyl 4-cyano-4-(phenylcarbonothioylthio)pentanoate (RAFT-NHS, 0.94 g, 2.5 mmol) was dissolved in 50 mL of DMSO. The two resulting solutions were mixed in a recovery flask and reacted overnight at room temperature while being protected from light. After the reaction, the reaction solution was purified using reverse-phase chromatography. Specifically, DMSO, salts, and unreacted O-PEA were first removed using 100% water. Then, the product and unreacted RAFT-NHS were separated and recovered using a 1:1 (volume ratio) mixed solvent of methanol and water. Methanol was removed under reduced pressure from the recovered product using an evaporator, and the remaining water was removed by freeze-drying to obtain the RAFT agent of Example 1 in a yield of 61%. The reaction scheme is shown below.

^{The 1} H-NMR (400 MHz, D ₂ O) chart of the RAFT agent of Example 1 is shown in FIG.
¹ H-NMR (400 MHz, D ₂ O): δ = 7.90 (d, 2H, benzene), 7.66 (t, 1H, benzene), 7.47 (t, 2H, benzene), 3.92 (d, 2H, -C H ₂ -O-), 3.42 (t, 2H, -NH-C H ₂ -), 2.62-2.50 (m, 4H, -C H _{2 -C} H ₂ -C(=O)-), 1.92 (s, 3H, C H ₃ ).

Figure 2A shows the UV-Vis spectrum of the RAFT agent of Example 1. Figure 2B shows the UV-Vis spectrum of RAFT-NHS used as the starting material. These UV-Vis spectra were measured using a DMSO solution with a sample concentration of 10 mmol/L. In the RAFT agent of Example 1, the maximum absorption wavelength (λmax = 514 nm) derived from the dithiobenzoate group hardly shifts from the maximum absorption wavelength (λmax = 513 nm) derived from the dithiobenzoate group of RAFT-NHS used as the starting material, and the molar extinction coefficients are also equivalent, indicating that the RAFT structure is maintained in the RAFT agent of Example 1.

Example 2 RAFT Polymerization The RAFT agent of Example 1 (4.06 mg, 10 μmol), 2-methacryloyloxyethyl phosphorylcholine (MPC) (0.3 g, 1.0 mmol, molar ratio of MPC to RAFT agent (MPC/RAFT agent) = 100), and water-soluble azo polymerization initiator V-501 (4,4'-azobis(4-cyanovaleric acid), 0.56 mg, 2.0 μmol) were weighed and dissolved in 3 mL of water. The resulting solution was placed in a Schlenk flask, and after purging the Schlenk flask with a nitrogen atmosphere, a RAFT polymerization reaction was carried out in an oil bath at 70°C for 15 hours while shielded from light, yielding poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) with the following structure. The polymerization rate was determined by ¹ H-NMR (400 MHz, D ₂ O) from the change in the integral ratio of the double bond between DMSO used as an internal standard and MPC, and was found to be 99%.

^{The 1} H-NMR (400 MHz, D ₂ O) chart of PMPC of Example 2 is shown in FIG.
^1H -NMR (400MHz, D ₂ O): δ = 8.00 (d, 2H, benzene), 7.73 (t, 1H, benzene), 7.57 (t, 2H, benzene), 4.33-4.13 (br, 594H, -O-C H ₂ -C H ₂ -O-P (=O) (-O ^- ) -O-C H ₂ -), 3.72 (t, 891H, -N ⁺ (C H ₃ ) ₃ ), 1.95 (br, 198H, -C H ₂ -C (CH ₃ )-C(=O)-), 1.13-0.96 (br, 277H, -CH ₂ -C(C H ₃ )-C(=O)-).

The number-average molecular weight and molecular weight distribution of PMPC were measured by gel permeation chromatography using pH 7 phosphate buffer (0.2 M) as the eluent. The measurement sample was prepared by dissolving 2 mg of PMPC in 1 mL of phosphate buffer. A molecular weight calibration curve was created using polyethylene glycol of known molecular weight. While the theoretical molecular weight of PMPC is 30,000, the number-average molecular weight Mn was 32,600, the weight-average molecular weight Mw was 33,900, and the dispersity Mw/Mn was 1.04.

The compounds, polymers, composite materials, and solid-phase RAFT agents disclosed herein can be suitably used in the production of functional materials that can be used in aqueous systems, such as ultrasound sensitizers, photocatalysts, functional cell sheets, drug transport carriers, mechanochemical materials, temperature sensors, separation membranes, and water retention agents.

Claims (15)

Formula (1)
(In formula (1),
^R1 is selected from the group consisting of substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, and substituted or unsubstituted heteroaryl groups;
^R2 is a monovalent organic group containing a phosphorus-containing group selected from the group consisting of a phosphate group, a phosphonate group, a phosphate ester group, and a phosphonate ester group;
X is selected from the group consisting of a single bond, S, O, and ^NR3 ;
^R3 is selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group, and may combine with ^R1 to form a heterocyclic structure.
A compound represented by the formula:
In formula (1), X is a single bond or S;
In formula (1), R ² is a group represented by formula (2):
(In formula (2),
R4 is selected from the ^group consisting of a cyano group, a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, a carboxy group, a substituted or unsubstituted alkoxycarbonyl group having 2 to 20 carbon atoms, and a substituted or unsubstituted aryloxycarbonyl group having 7 to 20 carbon atoms;
R5 is selected from the group consisting of substituted or unsubstituted alkyl groups having 1 to 20 carbon atoms ^;
R6 is a divalent organic group having 1 to 30 carbon atoms ^;
R7 is selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, and a substituted or unsubstituted aryl group having 6 to 20 carbon atoms ^;
Y is selected from the group consisting of a single bond and O;
* indicates the bonding site with the sulfur atom.)
A compound represented by the formula: In formula (1), X is a single bond, and R ¹ The compound according to claim 1, wherein is an aryl group having 6 to 14 carbon atoms which may have a substituent. In formula (2), R ⁴ is a cyano group, and R ⁵ The compound according to claim 1 or 2, wherein is an unsubstituted alkyl group having 1 to 20 carbon atoms. The compound according to any one of claims 1 to 3, wherein in formula (2), Y is O and R ⁷ is a hydrogen atom. The compound according to any one of claims 1 to 4, wherein in formula (2), R ⁶ contains an amide bond or an ether bond. The compound is represented by formula (3)
The compound according to claim 1, represented by: A method for producing a polymer, comprising performing RAFT polymerization using the compound described in any one of claims 1 to 6. The method for producing a polymer described in claim 7, wherein the RAFT polymerization is carried out in an aqueous solvent. Formula (4)
(In formula (4),
^R1 is selected from the group consisting of substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, and substituted or unsubstituted heteroaryl groups;
^R2 is a monovalent organic group containing a phosphorus-containing group selected from the group consisting of a phosphate group, a phosphonate group, a phosphate ester group, and a phosphonate ester group;
X is selected from the group consisting of a single bond, S, O, and ^NR3 ;
^R3 is selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group, and may combine with ^R1 to form a heterocyclic structure;
Poly represents a polymer chain.
A polymer represented by the formula:
In formula (4), X is a single bond or S;
In formula (4), R ² is a group represented by formula (2)
(In formula (2),
R4 is selected from the ^group consisting of a cyano group, a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, a carboxy group, a substituted or unsubstituted alkoxycarbonyl group having 2 to 20 carbon atoms, and a substituted or unsubstituted aryloxycarbonyl group having 7 to 20 carbon atoms;
R5 is selected from the group consisting of substituted or unsubstituted alkyl groups having 1 to 20 carbon atoms ^;
R6 is a divalent organic group having 1 to 30 carbon atoms ^;
R7 is selected from the group consisting of a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, and a substituted or unsubstituted aryl group having 6 to 20 carbon atoms ^;
Y is selected from the group consisting of a single bond and O;
* indicates the bonding site with the sulfur atom.)
A polymer represented by the formula : The polymer described in claim 9, wherein, in formula (4), Poly contains at least one structural unit having a zwitterionic structure. A composite material comprising an inorganic substrate selected from the group consisting of titanium oxide, zirconium oxide, and hydroxyapatite, and the polymer described in claim 9 or 10, wherein the surface of the inorganic substrate is modified with the polymer via the phosphorus-containing group of the polymer. A method for producing a composite material whose surface is modified with a polymer, comprising contacting an inorganic substrate selected from the group consisting of titanium oxide, zirconium oxide, and hydroxyapatite with the polymer described in claim 9 or 10 in an aqueous solvent having a pH of 7 or higher. A solid-phase RAFT agent comprising an inorganic substrate selected from the group consisting of titanium oxide, zirconium oxide, and hydroxyapatite, and the compound according to any one of claims 1 to 6, wherein the surface of the inorganic substrate is modified with the compound via the phosphorus-containing group of the compound. A method for producing a polymer, comprising conducting RAFT polymerization using the solid-phase RAFT agent described in claim 13. The method for producing a polymer described in claim 14, wherein the RAFT polymerization is carried out in an aqueous solvent.