BI-FUNCTIONAL NANOHYBRIDS

Abstract

Bi-functional nanohybrids including a nanoparticle to the surface of which are covalently coupled chemical functions, one of which being biorthogonal, and their use as support for catalysts.

Claims

1. A bi-functional nanohybrid comprising a nanoparticle to the surface of which are covalently coupled one or more, identical or different, groups selected from: either a group of formula (1) or (1′) ##STR00060## where Ra represents a bioorthogonal function selected from: 1,2,4-triazines of formula (al) ##STR00061## wherein R.sub.3 is a hydrogen atom and is in position 5 of the said 1,2,4-triazine R.sub.1 is selected from ##STR00062## R.sub.2 is selected from: a hydrogen atom a bromine atom, a fluorine atom a —CF.sub.3 group, a —CN group a phenyl group optionally mono- or poly- substituted by a fluorine atom, —OCH.sub.3 group, —CF.sub.3 group, —NO.sub.2 group R.sub.1 and R.sub.2 being independently either in position 3 or 6 of said 1,2,4-triazine; 1,2,4,5-tetrazines of formula (b1) ##STR00063## wherein R.sub.5 is selected from: an oxygen atom, a sulphur atom a —NRp— group with Rp being a hydrogen atom or a (C.sub.1-C.sub.4)alkyl group one of the following groups ##STR00064## R.sub.6 is selected from: a hydrogen atom, a chlorine atom, a methyl group, a —OR or —SR group with R being a (C.sub.1-C.sub.4)alkyl group, —N(CH.sub.3).sub.2 and a phenyl group optionally mono- or poly- substituted with a fluorine atom, —OCH.sub.3 group, —CF.sub.3 group, —NO.sub.2 group, Rb represents an halogen atom, a —ORc or —SRc group with Rc being a hydrogen atom, a —COORc group with Rc being a hydrogen atom, a —NRnRz with Rn and Rz being independently from each other a hydrogen atom, a (C.sub.1-C.sub.4)alkyl group, a phenyl group or a pyridinyl group an azide group, a maleimidyl group, a (C.sub.1-C.sub.4)alkynyl group, an imidazolyl group, a pyridinyl group, a 1,2,4-triazine of formula (a2), when Ra is a 1,2,4,5-tetrazine of formula (bi) ##STR00065## with R.sub.8 being either in position 3 or 6 of said 1,2,4-triazine of formula (a2) is selected from ##STR00066## a 1,2,4,5-tetrazine of formula (b2), when Ra is a 1,2,4-triazine of formula (a1) ##STR00067## with R.sub.9 selected from: an oxygen atom, a sulphur atom and a —NH— group and with R.sub.10 selected from: a chlorine atom —OCH.sub.3 and —SCH.sub.3 and —N(CH.sub.3).sub.2 X1, X2 and X3, same or different, may be absent or when present when present represent a spacer selected from (C.sub.1-C.sub.6)alkyl groups; said groups may comprise one or more oxygen atoms and/or one or more groups ##STR00068## with s, t and u, same or different being integers between 0 and 10, Z represents an C6-aryl group or a 5-6-membered N-heteroaryl group that is at least tri-substituted by substituents allowing the attachment to X1, X2, and X3 respectively, either a group of formula (2) ##STR00069## where Rai represents a bioorthogonal function selected from: 1,2,4-triazine of formula (el) ##STR00070## wherein R.sub.1 is selected from ##STR00071## and R.sub.3 is a hydrogen atom and is in position 5 of the said 1,2,4-triazine R.sub.4 is selected from ##STR00072## R.sub.1and R.sub.4 being independently either in position 3 or 6 of said 1,2,4-triazine R.sub.1 and R.sub.4 being the same or different; 1,2,4,5-tetrazine of formula (f1) ##STR00073## wherein R.sub.5 is selected from: an oxygen atom, a sulphur atom a —NRp— group with Rp being a hydrogen atom or a (C.sub.1-C.sub.4)alkyl group one of the following groups ##STR00074## R.sub.7 may be absent or when present is selected from: an oxygen atom, a sulphur atom a —NRp— group with Rp being a hydrogen atom or a (C.sub.1-C4)alkyl group one of the following groups ##STR00075## R.sub.5 and R7 being the same or different; Rb, X1 and X2 are as defined above with the proviso that Ra and Rb are mutually compatible and that the ratio between Ra and Rb or between Ra1 and Rb is equal to 1/1.

2. A method for synthesizing a bi-functional nanohybrid according to claim 1, comprising the step of attachment on a nanoparticle bearing at its surface a substituent Xa at least one compound of formula (I) ##STR00076## or of formula (I′) ##STR00077## or of formula (II)
Y-X1-Ra1-X2-Rb wherein Ra, Ra1, Rb, X1, X2, X3 and Z are as defined in claim 1 and Y represents a functional group, which allows the covalent attachment to the surface of said nanoparticle via Xa and is either a chlorine, a bromine or an iodine atom either a -NRpRq group with Rp and Rq being each independently from the other a hydrogen atom, a (C.sub.1-C.sub.4)alkyl group either a carboxylic acid group, either a maleimidyl group, either a thiol group, either a hydroxyl group, either a tosylate group, either a triflate group, either a mesylate group, either an acid halide group, either an acid anhydride group, either an isocyanate group, either an isothiocyanate group, either an azide group, either an alkynyl group, or a N-heteroaryl group selected from pyridinyl and imidazolyl groups

3. A compound of formulas (Ia), (Ib), (Ic), (Id) or (Ie) ##STR00078## wherein Ra represents a 1,2,4-triazine of formula (a1) ##STR00079## or a 1,2,4,5-tetrazine of formula (b1), ##STR00080## Rb represents an halogen atom, a —ORc or —SRc group with Rc being a hydrogen atom, a —COORc group with Rc being a hydrogen atom, a —NRnRz with Rn and Rz being independently from each other a hydrogen atom, a (C.sub.1-C.sub.4)alkyl group, a a phenyl group or a pyridyl group, an azide group, a maleimidyl group, a (C.sub.1-C.sub.4)alkynyl group, an imidazolyl group, a pyridinyl group, a 1,2,4-triazine of formula (a2), when Ra is a 1,2,4,5-tetrazine of formula (b1) ##STR00081## with R.sub.8 being either in position 3 or 6 of said 1,2,4-triazine of formula (a2) is selected from ##STR00082## a 1,2,4,5-tetrazine of formula (b2), when Ra is a 1,2,4-triazine of formula (a1) ##STR00083## with R.sub.9 selected from: an oxygen atom, a sulphur atom and a —NH— group and with R.sub.10 selected from: a chlorine atom —OCH.sub.3 and —SCH.sub.3 and —N(CH.sub.3).sub.2, s.sub.1, t.sub.1, u.sub.1, s2, t2 and u2 same or different are integers between 0 and 10,

4. A compound of formula (II)
Y-X1-Ra1-X2-Rb wherein Ra1 is a 1,2,4-triazine corresponds to formula (e1) ##STR00084## and corresponding to formula (IIa) ##STR00085## wherein Y represents either a chlorine, bromine, iodine atoms either a —COOH group, either a maleimidyl group, either a —OH, —SH or —NH2 group R.sub.1 is selected from ##STR00086## R.sub.3 is a hydrogen atom and is in position 5 of the said 1,2,4-triazine R.sub.4 is selected from ##STR00087## R.sub.1 and R.sub.4 being independently either in position 3 or 6 of said 1,2,4-triazine R.sub.1 and R.sub.4 being the same or different Rb represents an halogen atom, a —ORc or —SRc group with Rm being a hydrogen atom, a —COORc group with Rm being a hydrogen atom, a —NRnRz with Rn and Roz being independently from each other a hydrogen atom, a (C.sub.1-C4)alkyl group, a phenyl group or a pyridinyl group an azide group, a maleimidyl group, a (C.sub.1-C.sub.4)alkynyl group, an imidazolyl group, a pyridinyl group, a 1,2,4-triazine of formula (a2), when Ra is a 1,2,4,5-tetrazine of formula (b1) ##STR00088## with R.sub.8 being either in position 3 or 6 of said 1,2,4-triazine of formula (a2) is selected from ##STR00089## a 1,2,4,5-tetrazine of formula (b2), when Ra is a 1,2,4-triazine of formula (al) ##STR00090## with R.sub.9 selected from: an oxygen atom, a sulphur atom and a —NH— group and with R.sub.10 selected from: a chlorine atom —OCH.sub.3 and —SCH.sub.3 and —N(CH.sub.3).sub.2, and s.sub.1, t.sub.1, u.sub.1, s.sub.2, t.sub.2 and u.sub.2 same or different are integers between 0 and 10.

5. A compound of formula (II)
Y-X1-Ra1-X2-Rb wherein Ra1 is a 1,2,4,5-tetrazine corresponds to formula (f1) ##STR00091## and corresponding to formula (IIb) ##STR00092## wherein Y represents either a chlorine, bromine, iodine atoms either a —COOH group, either a maleimidyl group, either a —OH, —SH or —NH2 group R.sub.5 is selected from: an oxygen atom, a sulphur atom a —NRp- group with Rp being a hydrogen atom or a (C.sub.1-C.sub.4)alkyl group one of the following groups ##STR00093## R.sub.7 may be absent or when present is selected from: an oxygen atom, a sulphur atom a —NRp- group with Rp being a hydrogen atom or a (C.sub.1-C.sub.4)alkyl group one of the following groups ##STR00094## R.sub.5 and R.sub.7 being the same or different Rb represents an halogen atom, a —ORc or —SRc group with Rc being a hydrogen atom, a —COORc group with Rc being a hydrogen atom, a —NRnRz with Rn and Rz being independently from each other a hydrogen atom, a (C.sub.1-C.sub.4)alkyl group, a (C.sub.3-C.sub.6)cycloalkyl group, a phenyl group or a pyridyl group, an azide group, a maleimidyl group, a (C.sub.1-C4)alkynyl group, an imidazolyl group, a pyridinyl group, a 1,2,4-triazine of formula (a2), when Ra is a 1,2,4,5-tetrazine of formula (b1) ##STR00095## with R.sub.8 being either in position 3 or 6 of said 1,2,4-triazine of formula (a2) is selected from ##STR00096## a 1,2,4,5-tetrazine of formula (b2), when Ra is a 1,2,4-triazine of formula (a1) ##STR00097## with R.sub.9 selected from: an oxygen atom, a sulphur atom and a —NH— group and with R.sub.10 selected from: a chlorine atom —OCH.sub.3 and —SCH.sub.3 and —N(CH.sub.3)2, and s.sub.1, t.sub.1, u.sub.1, s.sub.2, t.sub.2 and u.sub.2 same or different being integers between 0 and 10.

6. A method for turning on a specific type of activity by bringing a key partner selected from the group comprising a ligand, a chiral moiety or another metal complex to a catalyst, said method comprising a step of contacting said key partner with a bi-functional nanohybrid according to claim 1.

7. A use of a bi-functional nanohybrid according to claim 1 as support for at least one catalyst.

8. A method for catalysing a chemical reaction comprising adding a bi-functional nanohybrid according to claim 1 supporting at least one catalyst in the reaction medium.

Description

[0360] The invention will be illustrated by the examples I and II below and by FIGS. 1 to 4.

[0361] FIG. 1 illustrates the synthesis of compound 2 of formula (IIb) according to example 1.1. DIPEA: N,N-diisopropylethylamine; ACN: acetonitrile

[0362] FIG. 2 illustrates the synthesis of a modified manganese porphyrin 3 according to example 1.2.

[0363] FIG. 3 illustrates the synthesis of a bi-functional nanohybrid 4 according to example 1.3.

[0364] FIG. 4 illustrates the immobilization of the modified manganese porphyrin 3 on the bi-functional nanohybrid 4 according to example 1.4.

[0365] FIG. 5 illustrates the synthesis of a compound of formula (Id1) according to example III. DIPEA: N,N-diisopropylethylamine; ACN: acetonitrile, DMF:dimethylformamide; Cs.sub.2O.sub.3:caesium carbonate; HBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

EXAMPLE I: SYNTHESIS OF AN OXIDATION CATALYST NANOHYBRID 1 FROM A MAGNETIC IRON OXIDE NANOPARTICLE, A 1,2,4,5-TETRAZINE AS BIOORTHOGONAL FUNCTION (Ra1), AN IMIDAZOL AS CHEMICAL FUNCTION (Rb) AND A BICYCLONONYNE-CONTAINING MANGANESE PORPHYRIN

[0366] ##STR00058##

1.1. Synthesis of Compound 2 of Formula (IIb)

[0367] In a first step, 3,6-dichloro-1,2,4,5-tetrazine (100 mg, 0.66 mmol) is reacted with imidazole (45 mg, 0.66 mmol) and N,N-diisopropylethylamine (DIPEA) (120 μL, 0.66 mmol) in acetonitrile (ACN) (6 mL) at room temperature. After 5 minutes, the formation of the product is confirmed by TLC (ethyl acetate/dichloromethane, 2:8) and HPLC-MS. In a second step, glycine (50 mg, 0.66 mmol) solubilized in water (1mL) and DIPEA (120 μL, 0.66 mmol) are added to the reaction mixture. After 10 minutes, the formation of the final product 2 is confirmed by TLC (methanol/dichloromethane, 1:1) and HPLC-MS. Solvents are eliminated under reduced pressure and the crude final product is purified by semi-preparative HPLC to give the final product 2 according to scheme 1 given in FIG. 1.

1.2. Synthesis of a Modified Manganese Porphyrin 3

[0368] The manganese porphyrin has been synthetized according to and adapted from methods described in the literature (Org. Lett. 2004, 6, 1033-1036; J. Phys. Chem. B 2006, 110, 15955 and Synlett 1999 (1) 61-62) and modified by the introduction of a (bicyclo[6.1.0]non-4-yn-9-ylmethanol) moiety according to the following method illustrated in scheme 2 in FIG. 2. This function makes the specific and selective binding of the catalyst to the nanohybrid possible.

1.3. Synthesis of the Bi-Functional Nanohybrid 4

[0369] The synthesis is based on the work of Jeremy PARIS (Iron oxides nanoparticles and titanate nanotubes dedicated to multimodal imaging and anticancer therapy, 2013, Université de Bourgogne)

[0370] In a first step, an —NH.sub.2 function is introduced at the surface of the nanoparticles with (3-aminopropyl)triethoxysilane.

[0371] Bare nanoparticles were subjected to 3-aminopropyltriethoxysilane (APTES) in an equivalent mass ratio into 20 mL of a 1:1 ethanol/water mixture. The mixture was submitted to an ultrasonic treatment. The mixture was then submitted to mechanical stirring (60 rpm) during 48 h. 20 mL of glycerol was then added followed by the evaporation of the ethanol/water mixture. Finally, glycerol was removed by acetone addition to the nanoparticle suspension accompanied by a magnetic decantation. Nanoparticles were finally re-suspended into ultrapure water yielding nanoparticles coating —NH.sub.2 function.

[0372] In a second step the coupling between the nanoparticles of iron oxide and the organic compound 2 is achieved in the presence of NHS and EDC as coupling agents.

[0373] Nanoparticles coating —NH2 groups were subjected to an equivalent mass ratio of compound 2 in the presence of N-(3-dimethylaminopropyl)-N-2-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) at 2.0 and 2.2 molar equivalent respectively according to scheme 3. The mixture was magnetically stirred (500 rpm) in 30 mL of water during 48 h at room temperature followed by magnetic decantation and washing with 4×50 mL water leading to the bi-functional nanohybrid 4 (see scheme 3 in FIG. 3).

1.4. Immobilization of the Modified Manganese Porphyrin 3 on the Bi-Functionnal Nanohybrid 4

[0374] In a third step, the covalent binding of the porphyrin is achieved via the bioorthogonal function 1,2,4,5-tetrazine of the bi-functional nanohybrid 4 and the partner bioorthogonal function (a bicyclo[6.1.0]non-4-yn-9-ylmethanol function) of the modified manganese porphyrin 3 according to scheme 4. The mixture was stirred at room temperature into 30 mL of a 1:1 tetrahydrofuran/water mixture for 15 h followed by magnetic decantation and washing with 3×50 mL tetrahydrofuran and 3×50 mL water. The resulting nanohybrid 1 was characterized by both UV/Vis (band at 440 nm characteristic of a manganese porphyrin), ICP analysis (with a Mn(Porphyrin—0.17%)/Fe(nanoparticle—45.37%; m.sub.sample=4.19 mg ; calculation method see Chem. Comm. 2013, 7394-7396) ratio indicating a coverage of 0.3 Mnporphyrin/nm.sup.2).

EXAMPLE II: USE OF THE NANOHYBRID ACCORDING TO THE INVENTION AS CATALYST

[0375] The manganese porphyrin immobilised on the bi-functional nanohybrid prepared according to example I has been tested in an epoxydation reaction to examine its catalytic activities.

[0376] The reaction was examined with styrene in the presence of the immobilized manganese porphyrin and iodosylbenzene as an oxydant.

[0377] At the end of the reaction, the end product of the reaction, 2-phenyloxyran was formed as shown by both TLC and GC analyses.

[0378] In this example, the bi-functional nanohybrid consists of iron oxide nanoparticles (magnetic properties), a 1,2,4,5-tetrazine as bioorthogonal function (Ra1) and an imidazole as chemical function (Rb). The 1,2,4,5-tetrazine allows the specific and selective binding of the porphyrin ligand. The imidazole function then plays the role of second ligand by coordinating manganese, thus stabilizing manganese porphyrin and increasing its catalytic activity.

EXAMPLE III: SYNTHESIS OF COMPOUND 7 OF FORMULA (Id1)

[0379] ##STR00059##

[0380] corresponding to a compound of formula (Id1) wherein Ra is a 1,2,4,5-tetrazine of formula (b1) with R.sub.5 absent et R.sub.6=—SCH2CH.sub.3, n=0, Rb represents an imidazolyl group and t=0 et s=3.

[0381] In a first step, 3,6-dichloro-1,2,4,5-tetrazine (100 mg, 0.66 mmol) is reacted with ethanethiol (50 μL, 0.67 mmol) and N,N-diisopropylethylamine (DIPEA) (115 μL, 0.67 mmol) in dimethylformamide (DMF) (6 mL) at room temperature. After 5 minutes, the formation of the intermediate 5 is confirmed by HPLC-MS. In a second step, this reaction mixture is added to a mixture of 3,5-dihydroxybenzoic acid (102 mg, 0.66 mmol) in DMF (6 mL) previously reacted with caesium carbonate (Cs.sub.2CO.sub.3) (431 mg, 1.32 mmol). After 2 hours at room temperature, the formation of the intermediate 6 is confirmed by HPLC-MS. Solvents are eliminated under reduced pressure and the crude is dissolved in a mixture of dichloromethane/water and acidified with hydrochloric acid. Phases are separated, the organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography eluting with dichloromethane/methanol 9:1 to afford the intermediate 6. Finally, this intermediate 6 (60 mg, 0.20 mmol) is reacted with 3-aminopropylimidazole (30 4, 0.25 mmol), HBTU (93 mg, 0.25 mmol) and DIPEA (90 4, 0.51 mmol) in DMF (5 mL) at room temperature. After 23 hours, the formation of the product 7 is confirmed by HPLC-MS. The reaction mixture is concentrated under reduced pressure and the crude is dissolved in a mixture of dichloromethane/water. Phases are separated and the aqueous phase is extracted with DCM. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography eluting with dichloromethane/methanol 95:5 to afford the final product 7 according to scheme 5 given in FIG. 5.