Patent Description:
Catalysis in industry is widely used for the synthesis of chemicals in large quantities (about <NUM>% of chemical processes are catalysed).

In general, it seems that supported catalysts are mainly used in the fine chemical industry where the added value of the product to be synthesized is high. In addition, the supported catalysis is in line with a concern for compliance with environmental standards (simplicity of filtration, less solvent and recycling of metal facilitated which is in line with the principles of green chemistry).

Catalysts may be mono- or multi-functional, in particular bi-functional. A monofunctional catalyst contains only one type of catalytic site, i.e. every catalytic site or surface exhibits the same qualitative catalytic property as to what reaction or reaction its can catalyse. On the contrary in a multi-functional catalyst, each site catalyses different reactions and reaction steps. Many bifunctional catalysts possess either Lewis or Brønsted basic functionality and a hydrogen-bond donor group suitably positioned over a chiral scaffold. Compared to monofunctional group catalysts, the cooperative effect of the two complementary functional groups can lead to new reactivity and new stereocontrol in reactions.

A substantial effort and cost in organic synthesis are often necessary to design catalysts of the monofunctional type usable in homogeneous phase. This is particularly true in the case of monometallic catalyst as soon as one wishes that the sphere of coordination of the metal is complete, which is a guarantee of performance and efficiency for a catalyst. This same synthetic effort is generally necessary to develop bifunctional catalysts, a fortiori if one wants the coordination sphere of each metal to be complete.

Thus mono- and bi-functional systems have been developed in the literature as.

Furthermore, if such catalysts are to be immobilized, then an additional immobilization step is required, which adds to the synthesis effort. Finally, the number of steps to consider is often too large and prohibitive for researchers who do not wish to engage in a substantial or even large-scale organic synthesis program.

Previous studies have described metalloporphyrins immobilized by coordination binding on electrode or nanoparticle bearing a ligand (<NPL> ;<NPL>). This coordination bond is potentially labile, and remains dependent in particular on the degree of oxidation of the catalyst and the pH of the medium; thus the catalyst can come off from the particle/surface and then be definitively washed once it is released.

Finally, there are already studies describing metalloporphyrins bearing both a coordination ligand and a chemical function allowing the immobilization on surfaces. However, such synthetic strategies are much longer, tedious and more expensive than that of the present invention that is much more straightforward.

Other previous studies describe bi-nuclear models synthesized by simple immobilization of mononuclear complexes on gold electrodes covered with a self-assembled monolayer coating (<NPL>). The models facing each other thus recreate bi-nuclearity, which is achieved only through the controlled number of binding functions at the surface of an electrode. By addressing the nature of the bioorthogonal function and chemical function of the coating, the invention may allow the modular recreation of other sophisticated bi-nuclear systems, whether the metals are identical, model Cu/Cu, or Fe/Fe, or Mn/Mn or Ru/Ru (R. Haak cited above) or different as Fe/Cu (Collman, J. Haak cited above) or whether the ligands of these metals are identical (two tris-pyridyl ligands for example) or different (a porphyrin ligand and a tris-pyridine ligand for example). This same approach can be considered for the design of trinuclear species, in particular tri-metallic catalysts for which the synthesis of ligands to obtain a catalyst in homogeneous phase would become a real challenge.

Finally, if the prior art concerning surfaces (particles, electrodes) functionalized by a bioorthogonal function is vast, there are fewer studies for tetrazines and no studies have been made with triazines and mono- and bi-nuclear catalysts.

Thus there is a need for new catalytic processes that would be less expensive, more green and simpler to achieve. Hence, there is a need for catalysts that would be cheap, easy to synthesize and easy to use as immobilized catalysts.

Consequently, the present invention will partly remedy such efforts and such costs by proposing the immobilization on specific bi-functional nanohybrids of inexpensive catalysts that eventually may not be totally functional catalysts because of an incomplete coordination sphere. The structure of the nanohybrids according to the invention offers such an environment, which:.

This is only possible thanks to the specific design of the nanohybrid according to the invention: the design of this bi-functional nanohybrid is only possible by the very specific design of an organic coating on the nanoparticle surface.

The rationale objective of the invention is to bring a key partner to a catalyst in order to turn on a specific type of activity. Hence, such a partner combined to a given catalyst will allow:.

The inventors have synthetized bi-functional nanohybrids comprising a nanoparticle to the surface of which are covalently coupled one or more, identical or different, groups selected from:.

In all the above compounds a control of a <NUM>/<NUM> ratio between Ra and Rb or between Ra1 and Rb is made possible.

All the following definitions are applicable to compounds of formulas (<NUM>), (<NUM>'), (<NUM>), (a) , (b), (e) and to all compounds according to the instant invention.

A (C<NUM>-C<NUM>)alkyl group includes, for example, straight-chain or branched lower alkyl groups having <NUM> to <NUM> carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

A (C<NUM>-C<NUM>)alkyl group includes, for example, straight-chain or branched alkyl groups having <NUM> to <NUM> carbon atoms, or <NUM> to <NUM> carbon atoms or <NUM> to <NUM> carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, heptyl, octanyl, nonyl, capryl, lauryl, stearyl, eicosyl, hexacosyl, Said group may be substituted.

A (C<NUM>-C<NUM>)cycloalkyl group includes, for example, cycloalkyl groups having <NUM> to <NUM> carbon atoms such as cyclopropyl, cyclobutyl and the like. Said group may be substituted.

An alkylenyl group includes, for example, straight or branched alkyl groups having <NUM> to <NUM> or <NUM> to <NUM> or <NUM> to <NUM> carbon atoms and comprising at least one double bond. Exemplary alkylenyl groups include ethylenyl, propylenyl, iso-propylenyl, butylenyl, iso-butylenyl, pentylenyl, <NUM>-methylbutylenyl, <NUM>-ethylpropylenyl, <NUM>-methylpentylenyl, and the like, wherein the divalent bonds may be at any of the carbon atoms of the alkylenyl group, or as specifically indicated. As used herein, "alkylenyl" also includes cycloalkylenyl when three or more carbon atoms are referenced.

A (C<NUM>-C<NUM>)alkynyl group includes monoradicals of an unsaturated hydrocarbon, having at least <NUM> triple bond. Preferred alkynyl groups include ethynyl, (-C≡CH), propargyl (or propynyl, -C≡CCH3), and the like. Said group may be substituted.

In the present invention, a bioorthogonal function is a chemical function that is not encountered in biomolecules in natural systems, (amine, carboxylic acid, ester, thiols, alcohols, phosphates, etc.. ) and that does not react with these functions. In the present invention, bioorthogonal functions are designed by Ra and Ra1.

Halogen atoms include chlorine, bromine, iodine and fluorine atoms.

An aryl group includes aromatic hydrocarbons having <NUM> to <NUM> carbon atoms.

Preferred groups are C<NUM>-aryl groups. Exemplary aryl groups include phenyl, tolyl, mesityl, naphthyl and anthracenyl. The radicals may also be fused to other saturated, (partially) unsaturated or aromatic ring systems. It is possible for the linkage to particles to take place via any possible ring member of the aryl radical. Said group may be substituted.

An heteroaryl group includes <NUM>-, <NUM>- or <NUM>-membered cyclic aromatic radical, which comprises at least <NUM>, where appropriate also <NUM>, <NUM>, <NUM> or <NUM>, heteroatoms, the heteroatoms being identical or different. It is possible for the linkage to the particles and to A to take place via any possible ring member of the heteroaryl radical. The heterocycle may also be part of a bi- or polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulphur. It is preferred for the heteroaryl radical to be selected from the group comprising pyrrolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, phthalazinyl, indolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl, acridinyl. Said group may be substituted. Preferred are <NUM>-<NUM>-membered cyclic aromatic radical like imidazolyl and pyridinyl.

Nanoparticle means a natural material, accidentally formed or manufactured containing free particles, in the form of an aggregate or an agglomerate, of which at least <NUM>% of the particles, in the size distribution, have one or more external dimensions between <NUM> and <NUM>. In the disclosure the focus is made on metal oxide-, metal-, and carbon-based nanoparticles.

According to the invention an integer between <NUM> and <NUM> means <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>.

According to the invention "covalently coupled" or "covalently bound" are equivalent.

According to the disclosure, "Ra and Rb are mutually compatible" means that they do not react together and the one skilled in the art will be able to choose them in view of his general knowledge.

In an embodiment not according to the invention, Ra in formula (<NUM>) and (<NUM>') is a <NUM>,<NUM>,<NUM>-triazine of formula (a1)
<CHM>
wherein.

R<NUM> and R<NUM> being independently either in position <NUM> or <NUM> of said <NUM>,<NUM>,<NUM>-triazine.

In another embodiment Ra in formula (<NUM>) and (<NUM>') is a <NUM>,<NUM>,<NUM>,<NUM>-tetrazine of formula (b1)
<CHM>
wherein.

Z represents a C<NUM>-aryl group or a <NUM>-<NUM>-membered N-heteroaryl group that is at least tri-substituted by substituents allowing the attachment to X1, X2, and X3 respectively.

In another embodiment not according to the invention, Ra1 in formula (<NUM>) corresponds to a <NUM>,<NUM>,<NUM>-triazine of formula (e1)
<CHM>
wherein.

R<NUM> and R<NUM> being independently either in position <NUM> or <NUM> of said <NUM>,<NUM>,<NUM>-triazine R<NUM> and R<NUM> being the same or different.

In a specific embodiment according to the invention, Ra1 of formula (<NUM>) corresponds to a <NUM>,<NUM>,<NUM>,<NUM>-tetrazine of formula (f1)
<CHM>
wherein.

In all the embodiments according to the invention, X1, X2, and Rb are as defined in the appended claims. Ra and Rb are mutually compatible and the ratio between Ra and Rb or Ra1 et Rb is equal to <NUM>/<NUM>.

In another embodiment not according to the invention, X1 and X3 same or different, represent a spacer -(CH<NUM>)n- with n = <NUM> to <NUM> and X2 represents a spacer with the formula
<CHM>
with s and t, same or different being integers between <NUM> and <NUM>.

Further disclosed is a method for synthesizing a bi-functional nanohybrid comprising the step of attachment on a nanoparticle bearing at its surface a substituent Xa at least one compound of formula (I)
<CHM>
or of formula (I')
<CHM>
or of formula (II)
<CHM>
wherein.

A triflate group is equivalent to a trifluoromethane sulfonyl group.

A mesylate group is an ester of methanesulfonic acid.

As acid halide group may be cited acyl chloride functional group, such as acetyl chloride functional group.

As acid anhydride group may be cited carboxylic anhydride functional group.

The choice of Xa will be conditioned by the nature of Y and the choice of Y will be conditioned by the nature of Xa, each of them being chosen in order to have the possibility to create between them a covalent bond. The one skilled in the art will be able to make the choice on the basis of his general knowledge.

The covalent bond may be any one of a by classical chemical reactions non-degradable bond. Here, examples of the non-degradable bond may include amine, ammonium, ether, thioether, ester and amide and the like, but the present invention is not necessarily limited thereto. All these bonds are well known from the one skilled in the art.

The step of attachment is realised by known methods in the art as for example the one according to Chem. <NUM>, <NUM>-<NUM>.

Further disclosed, but not according to the invention is a compound of formulas (Ia), (Ib), (Ic), (Id) or
<CHM>
<CHM>
<CHM>
wherein.

Further disclosed is a compound of formulas (Ia1), (Ib1), (Ic1), (Id1) or (Ie1)
<CHM>
<CHM>
<CHM>
wherein.

Further disclosed is a compound of formula (II) wherein Ra1 is a <NUM>,<NUM>,<NUM>-triazine of formula (e1) and corresponding to formula (IIa)
<CHM>
wherein.

Further disclosed is a compound of formula (II) wherein Ra1 is a <NUM>,<NUM>,<NUM>-triazine corresponds to formula (e1)
<CHM>
and corresponding to formula (IIa1)
<CHM>
wherein.

Further disclosed is a compound of formula (II) wherein Ra1 is a <NUM>,<NUM>,<NUM>,<NUM>-tetrazine corresponds to formula (f1) and corresponding to formula (IIb)
<CHM>
wherein.

Further disclosed is a compound of formula (II) wherein Ra1 is a <NUM>,<NUM>,<NUM>,<NUM>-tetrazine corresponds to formula (f1)
<CHM>
and corresponding to formula (IIb1)
<CHM>
wherein.

Another object according to the invention is a method for bringing a key partner for example a ligand, a chiral moiety, another metal complex to a catalyst comprising a step of contacting said key partner with a nanohybrid according to the invention as disclosed in the attached claims in order to turn on a specific type of activity.

A chiral moiety brought closeby to the catalyst will make enantioselective catalysis possible.

A metal complex brought closeby to a catalyst (which is a metal complex by itself) will lead to a bimetallic species, which in some case may undergo bimetallic catalysis. If instead of a metal complex a ligand is brought closeby to a catalyst, subsequent metallation of the resulting catalyst/ligand pair could be versatile, an array of metals could be introduced in the chelate to afford a wide range of bimetallic species.

Thus the method according to the invention permits to create / to complete a mono- / bi-nuclear catalyst coordination sphere.

According to the disclosure, a control of a <NUM>/<NUM> ratio between Ra and Rb or between Ra1 and Rb is made possible.

In a first mode (first mode), a ligand L1 able to coordinate with a metal M is bound to Ra (Scheme 1A) or Ra1 (Scheme 1B) ; Rb remains unmodified and may be for example an imidazole, a thiol or an amine and acts as a ligand. Rb will make it possible to complete the coordination sphere of the metal. <CHM>
<CHM>
<CHM>.

In a second mode (second mode), a ligand L1 able to coordinate with a metal M1 is bound to Ra (Scheme 2A) or Ra1 (Scheme 2B); Rb remains unmodified and may be for example an imidazole, a thiol or an amine and acts as a ligand. Rb will coordinate a second metal (M2) to develop a binuclear catalyst or two catalytic sites (M1 and M2)
<CHM>
<CHM>.

In a third mode (third mode), Ra (Scheme 3A) or Ra1 (Scheme 3B) and Rb are both modified in order to permit the binding of a ligand L1 and a ligand L2 respectively said ligands being able to recreate the complete coordination sphere of a unique metal (M). <CHM>
<CHM>.

In a fourth mode (fourth mode), Ra (Scheme 4A) or Ra1 (Scheme 4B) and Rb are both modified in order to permit the binding of a ligand L1 and a ligand L2 respectively said ligands being able to recreate the coordination sphere of two metals (M1) and (M2) to give a binuclear catalyst or two catalytic sites. <CHM>
<CHM>.

Another object according to the invention is the use of a nanohybrid according to the present invention as defined in the appended claims as support for at least one catalyst.

According to the invention, the catalyst may be any catalyst known from the one in the art in particular it may be chosen in the group comprising:.

Another object according to the invention is a method for catalysing a chemical reaction comprising adding a nanohybrid according to the invention as defined in the appended claims supporting at least one catalyst in the reaction medium.

According to the invention, nanohybrids may be used for example for oxidation, C-C coupling, hydrogenation etc. according to the catalyst supported by said nanohybrid.

Our technological solution in particular via magnetic iron-oxide-based nanohybrids also makes catalyst recovery easier with a simpler, faster and more efficient process than with catalysts immobilized on nanoparticles of silica (non-magnetic) or on polymers. The process according to the invention does not require changing the process, simply using a magnetic recovery system such as a permanent magnet or a temporary magnet (electromagnet). This minimizes the use of solvents and the number of purification steps and addresses issues relevant to green chemistry.

This magnetic solution allows easy catalyst recovery in a solution where only the supported catalyst is present (no solvents, reagents or products), which allows either to re-engage the catalyst in a new run (easy reuse) or to treat the catalyst at the end of its life (easy recycling).

Finally, the property of being able to covalently, specifically and selectively attach one or two ligands at a single anchor point will allow the pre-organisation of the catalyst site(s) in order to counteract the limits of the supported catalysis (catalyst deactivation, lower catalytic activity and metal release).

The invention will be illustrated by the examples I and II below and by <FIG>.

In a first step, <NUM>,<NUM>-dichloro-<NUM>,<NUM>,<NUM>,<NUM>-tetrazine (<NUM>, <NUM> mmol) is reacted with imidazole (<NUM>, <NUM> mmol) and N,N-diisopropylethylamine (DIPEA) (<NUM>µL, <NUM> mmol) in acetonitrile (ACN) (<NUM>) at room temperature. After <NUM> minutes, the formation of the product is confirmed by TLC (ethyl acetate/dichloromethane, <NUM>:<NUM>) and HPLC-MS. In a second step, glycine (<NUM>, <NUM> mmol) solubilized in water (<NUM>) and DIPEA (<NUM>µL, <NUM> mmol) are added to the reaction mixture. After <NUM> minutes, the formation of the final product <NUM> is confirmed by TLC (methanol/dichloromethane, <NUM>:<NUM>) 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 <NUM> according to scheme <NUM> given in <FIG>.

The manganese porphyrin has been synthetized according to and adapted from methods described in the literature (<NPL>;<NPL>and<NPL>) and modified by the introduction of a (bicyclo[<NUM>. <NUM>]non-<NUM>-yn-<NUM>-ylmethanol) moiety according to the following method illustrated in scheme <NUM> in <FIG>. This function makes the specific and selective binding of the catalyst to the nanohybrid possible.

The synthesis is based on the work of <NPL>)
In a first step, an -NH<NUM> function is introduced at the surface of the nanoparticles with (<NUM>-aminopropyl)triethoxysilane.

Bare nanoparticles were subjected to <NUM>-aminopropyltriethoxysilane (APTES) in an equivalent mass ratio into <NUM> of a <NUM>:<NUM> ethanol/water mixture. The mixture was submitted to an ultrasonic treatment. The mixture was then submitted to mechanical stirring (<NUM> rpm) during <NUM>. <NUM> 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<NUM> function.

In a second step the coupling between the nanoparticles of iron oxide and the organic compound <NUM> is achieved in the presence of NHS and EDC as coupling agents.

Nanoparticles coating -NH<NUM> groups were subjected to an equivalent mass ratio of compound <NUM> in the presence of N-(<NUM>-dimethylaminopropyl)-N-<NUM>-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) at <NUM> and <NUM> molar equivalent respectively according to scheme <NUM>. The mixture was magnetically stirred (<NUM> rpm) in <NUM> of water during <NUM> at room temperature followed by magnetic decantation and washing with 4x50 mL water leading to the bi-functional nanohybrid <NUM> (see scheme <NUM> in <FIG>).

In a third step, the covalent binding of the porphyrin is achieved via the bioorthogonal function <NUM>,<NUM>,<NUM>,<NUM>-tetrazine of the bi-functional nanohybrid <NUM> and the partner bioorthogonal function (a bicyclo[<NUM>. <NUM>]non-<NUM>-yn-<NUM>-ylmethanol function) of the modified manganese porphyrin <NUM> according to scheme <NUM>. The mixture was stirred at room temperature into <NUM> of a <NUM>:<NUM> tetrahydrofuran/water mixture for <NUM> followed by magnetic decantation and washing with 3x50 mL tetrahydrofuran and 3x50 mL water. The resulting nanohybrid <NUM> was characterized by both UV/Vis (band at <NUM> characteristic of a manganese porphyrin), ICP analysis (with a Mn(Porphyrin - <NUM>%)/Fe(nanoparticle - <NUM>% ; msample = <NUM> ; calculation method see <NPL>) ratio indicating a coverage of <NUM> Mnporphyrin/nm<NUM>).

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.

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

At the end of the reaction, the end product of the reaction, <NUM>-phenyloxyran was formed as shown by both TLC and GC analyses.

In this example, the bi-functional nanohybrid consists of iron oxide nanoparticles (magnetic properties), a <NUM>,<NUM>,<NUM>,<NUM>-tetrazine as bioorthogonal function (Ra1) and an imidazole as chemical function (Rb). The <NUM>,<NUM>,<NUM>,<NUM>-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.

<CHM>
corresponding to a compound of formula (I) wherein Ra is a <NUM>,<NUM>,<NUM>,<NUM>-tetrazine of formula (b1) with R<NUM> is an oxygen atom and R<NUM>=- SCH<NUM>CH<NUM> (i.e. SRm group with Rm being an ethyl group), Y is an hydroxyl group, X1 is absent, X3 is absent, Rb represents an imidazolyl group, X2 is a propyl group, and Z is a C6-aryl group (phenyl-based group).

Claim 1:
Bi-functional nanohybrid comprising a metal oxide-based nanoparticle to the surface of which are covalently coupled one or more, identical or different, groups of formula (<NUM>), wherein said nanoparticle is a natural material, accidentally formed or manufactured containing free particles, in the form of an aggregate or an agglomerate, of which at least <NUM>% of the particles, in the size distribution, have one or more external dimensions between <NUM> and <NUM>, and wherein:
said group of formula (<NUM>) is as follows:
<CHM>
where
• Ra1 represents a bioorthogonal <NUM>,<NUM>,<NUM>,<NUM>-tetrazine function of formula (f1)
<CHM>
wherein
R<NUM> is selected from:
✔ an oxygen atom, a sulphur atom
✔ a -NRp- group with Rp being a hydrogen atom or a (C<NUM>-C<NUM>)alkyl group selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl,
✔ one of the following groups
<CHM>
<CHM>
<CHM>
<CHM>
R<NUM> 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<NUM>-C<NUM>)alkyl group selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl,
✔ one of the following groups
<CHM>
<CHM>
<CHM>
<CHM>
R<NUM> and R<NUM> being the same or different,
• Rb represents
o an halogen atom,
o a -ORc or -SRc group with Rc being a hydrogen atom,
o a -COORc group with Rc being a hydrogen atom,
o a -NRnRz with Rn and Rz being independently from each other a hydrogen atom, a (C<NUM>-C<NUM>)alkyl group selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl, a phenyl group or a pyridinyl group
o an azide group,
o a maleimidyl group,
o a (C<NUM>-C<NUM>)alkynyl group,
o an imidazolyl group,
o a pyridinyl group,
o a <NUM>,<NUM>,<NUM>-triazine of formula (a2), when Ra1 is a <NUM>,<NUM>,<NUM>,<NUM>-tetrazine of formula (f1)
<CHM>
with R<NUM> being either in position <NUM> or <NUM> of said <NUM>,<NUM>,<NUM>-triazine of formula (a2) and selected from
<CHM>
• X1 and X2, same or different, may be absent or when present represent a spacer selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, isopentyl, and hexyl,
with the proviso that the ratio between Ra1 and Rb is equal to <NUM>/<NUM>.