WO2007059350A2 - Preparation d'alkoxyamines - Google Patents

Preparation d'alkoxyamines Download PDF

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Publication number
WO2007059350A2
WO2007059350A2 PCT/US2006/044931 US2006044931W WO2007059350A2 WO 2007059350 A2 WO2007059350 A2 WO 2007059350A2 US 2006044931 W US2006044931 W US 2006044931W WO 2007059350 A2 WO2007059350 A2 WO 2007059350A2
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transition metal
reducing agent
reaction
reaction medium
atrp initiator
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PCT/US2006/044931
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English (en)
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WO2007059350A3 (fr
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Krzysztof Matyjaszewski
James Spanswick
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Carnegie Mellon University
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Publication of WO2007059350A3 publication Critical patent/WO2007059350A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C07C239/20—Hydroxylamino compounds or their ethers or esters having oxygen atoms of hydroxylamino groups etherified

Definitions

  • the invention relates to an improved method for the preparation of alkoxyamines and improved methods of conducting atom transfer radical addition or atom transfer radical coupling reactions.
  • the alkoxyamines may be prepared from nitroxides or nitroxide precursors by conducting an atom transfer radical addition reaction between an ATRP initiator and a stable free radical in the presence of a catalytic amount of a transition metal complex and a reducing agent.
  • an N- hydroxy precursor of a nitroxide can be the reducing agent.
  • a stoichiometric amount of a transition metal complex in a lower oxidation state (Cu 1 YZL n ) is used in the reaction to transfer a radically transferable atom or group from a molecule initially comprising the radically transferable atom (R-X) thereby forming a radical (R*).
  • TEMPO is an archetypal nitroxide and is used herein to exemplify reactions in which any nitroxide can participate, (see Figure 1C).
  • This ATRC reaction is quantitative and has been employed to study the rate of activation of a series of initiators by various transition metal complexes suitable for an atom transfer radical polymerization ("ATRP").
  • ATRP atom transfer radical polymerization
  • the final reaction medium still contained a stoichiometric concentration of the transition metal, that is more than 0.5 mole CuX 2 per mole of nitroxide.
  • the transition metal may be removed from the reaction product. Thereby adding a significant cost for purification.
  • a variation on these processes was disclosed in United States Patent No. 6,495,720 wherein a specific type of nitroxide was converted to an alkoxyamines.
  • the reaction employs a transition metal complex comprising ligands, additionally disclosed in United States Patent Nos. 6,512,060 and 6,541,580 and International Patent Application Publication WO 98/40415, to provide more active ATRP catalyst complexes for the coupling reaction.
  • ATRP controlled/'living radical processes
  • ATRP has also been discussed in numerous publications with Matyjaszewski as co-author and reviewed in several book chapters. [ACS Symp. Ser., 1998, 685; ACS Symp. Ser., 2000; 768; Chem. Rev. 2001, 101, 2921-2990; ACS Symp. Ser., 2003; 854.].
  • Similar polymerization processes comprising the similar of reagents may be referred to by different names, such as transition metal mediated polymerization or atom transfer polymerization, but the processes are considered to be identical and are referred to herein as "ATRP".
  • US Patent 6,569,967 (WO 00/49027) concerns formation of alkoxyamines derived from ⁇ -phosphorous nitroxides wherein the preferred process used to prepare the compounds is the method involves the ATRA or ATRC reaction disclosed in WO 98/07758.
  • a transition metal catalyst comprising bipyridine (bpy) was employed in WO 98/07758 for the formation of alkoxyamines from nitroxides, such as TEMPO, and alkyl halides.
  • a reaction is described with molecules comprising multiple halides thereby providing multi-functional ⁇ -substituted nitroxide initiators for nitroxide mediated polymerization.
  • Such multifunction ⁇ -substituted nitroxide initiators may be used in a nitroxide mediated polymerization that would result in star and/or graft copolymers.
  • Reducing agents have been employed to reduce the concentration of the deactivator, or persistent radical, in an ATRP process thereby increasing the rate of reaction. Without a reducing agent, an ATRP process may slow down as the concentration of activator decreases and the deactivator increases due to termination reactions. The ATRP process will stop if all activator is converted to deactivator. Reducing agents were added to the reaction medium at low concentrations compared to the mole fraction of R-X initiators. Sugars have been known as reducing agents for cupric salts, [Cramer, W. Proc. Chem. Soc. 1914, 30, 293]; and various reducing monosaccharides have an effect on the rate of an ATRP of butyl methacrylate.
  • the polymer displayed a bimodal molecular weight distribution and it was concluded there may have been side reactions resulting in the formation of a low molecular weight peak. No mechanism was proposed for the results, and it is possible that the low molecular weight peak is due to polymerization from phenoxy radicals in the system.
  • the phenols were added to the ATRP in sub-stoichiometric amounts.
  • octanethiol a free-radical chain transfer agent
  • the octanethiol may have caused a reduction in the concentration of Cu m as a result of the oxidation of the thiol to a disulfide. See Heuts, J. P. A. et al. Macromol. Chem. Phys. 1999, 200, 1380-1385, hereby incorporated by reference in its entirety.
  • the thiols were added to the ATRP in sub-stoichiometric amounts.
  • Lewis acids include aluminium complex compounds, metal halides, e. g. zinc halides, lithium halides, iron trichloride, boron trifiuoride.
  • a preferred aluminium compound is methyl aluminium bis(2,6-di-tert-butyl-4-methyl) phenoxide.
  • the alkoxyamines produced by such processes are suitable for the preparation of macromolecules with controlled topology, composition and functionality by nitroxide mediated polymerization processes, (NMP).
  • the invention relates to an improved method for conducting an atom transfer radical addition (“ATRA”) reaction or an atom transfer radical coupling (“ATRC”) reaction.
  • ATRA atom transfer radical addition
  • ATRC atom transfer radical coupling
  • a radical is formed and, typically, reacted with a vinyl compound to form a product.
  • One embodiment of this invention is directed to a process for the preparation of alkoxyamines, the process comprises reacting an ATRP initiator and a nitroxide in the presence of a reaction medium comprising a reducing agent and at least one transition metal catalyst. Any compound that may act as an ATRP initiator is capable of being used in this coupling reaction.
  • the transition metal catalyst homolytically cleaves the radically transferable atom or group from the ATRP initiator to form a radical.
  • the addition of the radically transferable atom or group to the transition metal catalyst results in an increase in its oxidation state.
  • the transition metal in the higher oxidation state would not be able to initiate formation of an additional radical, that is it is a stoichiometric reaction. Therefore, an equal molar ratio of transition metal to ATRP initiator is typically required. The molar ratio may be decreased if the a substantial portion of the transition metal is in its zero oxidation state and may participate in a redox reaction with an initiator compound twice, in the first reaction forming Cu® and in the second Cu ( ⁇ ) .
  • the reducing agent in the reaction medium allows significantly lower concentrations of transition metal to be present and significantly lower ratios of transition metal to ATRP initiator to be present in the reaction medium and still drive the reaction to completion.
  • the molar ratio of the transition metal to the ATRP initiator may be less than 0.5, or less than 0.1, or even less than 0.05.
  • the transition metal catalyst may be in an oxidized state and the process of the invention may comprise reacting the reducing agent with at least one of the transition metal catalyst in an oxidized state and an ATRP initiator. Reduction of the transition metal catalyst in the higher oxidation state will result in formation of the activator form of the catalyst.
  • the invention is directed to a process comprising coupling an ATRP initiator and a stable free radical in the presence a reaction medium comprising at least one transition metal catalyst and a reducing agent.
  • the molar ratio of the transition metal to the ATRP initiator may be less than 0.5, or less than 0.25, or in certain embodiments less than 0.01.
  • Embodiments of the invention are further directed to an atom transfer radical addition or coupling reaction process comprising an organic reducing agent
  • the preparation of alkoxyamines from nitroxides comprises conducting an atom transfer addition reaction or an atom transfer coupling reaction, wherein an ATRP initiator is activated by a catalytic amount of a transition metal complex in its lower oxidation state.
  • the ATRP initiator interacts with the transition metal complex to form an active radical species that may react with a stable free radical molecule.
  • the stable free radical may be added or generated in the reaction system.
  • the reaction may be driven to completion by a second reaction wherein the transition metal complex in lhe higher oxidation state is reduced to its activator state by reaction with a reducing agent.
  • the stable free radical may be formed in a redox reaction with the transition metal catalyst complex in the higher oxidation state. Such a reaction forms the stable free radical and the transition metal complex in the lower oxidation state.
  • This reaction scheme allows the active transition metal complex to be regenerated and, therefore, to be present in s ⁇ b-stoichiometric concentrations compared to the concentration of radically transferable atoms or groups, or nitroxide precursors in the reaction medium.
  • the transition metal complex and reducing agent thereby act as a catalyst for the coupling reaction by continuously forming the radical that reacts with the stable free radical.
  • Figures IA- 1C illustrate reaction schemes of embodiments of the invention for the production of an alkoxyamine
  • Figure IA illustrates a reaction scheme of an embodiment comprising a stable free radical nitroxide added to the reaction medium
  • Figure IB illustrates a reaction scheme of an embodiment comprising a nitroxide prepared from an nitroxide precursor
  • Figure 1C illustrates a reaction scheme of an embodiment of a process for the preparation of an alkoxyamine from R-X, a dormant initiator species, and TEMPO, an stable free radical nitroxide
  • Figure 2 illustrates the reaction scheme of an embodiment of a process comprising activating a dormant initiator by a transition metal complex in the lower oxidation state to form a radical that couples with a nitroxide to form an alkoxyamine with continuous regeneration of the transition metal in the lower oxidation state by reaction with a reducing agent;
  • Figure 3 illustrates the reaction scheme for reduction of Cu ⁇ to CdP by tin ⁇ 2-ethlhexanoate
  • Figures 5A-5C are graphs of the GPC traces from click chemistry reactions of diazido polystyrene with propargyl ether using CuBr/Me 6 TREN as catalyst in reduced concentrations under limited air with hydrazine (Figure 5A), without hydrazine ( Figure 5B), and with a large excess of hydrazine (Figure 5C) after 0.5 hour, 1 hour, 3 hours, 6 hours, 24 hours, and 48 hours.
  • the invention relates to an improved method for conducting an atom transfer radical addition (“ATRA”) reaction or an atom transfer radical coupling (“ATRA”) reaction.
  • ATRA atom transfer radical addition
  • ATRA atom transfer radical coupling
  • a radical is formed and, typically, reacted with a vinyl compound to form a product.
  • One embodiment of this invention is directed to a process for the preparation of alkoxyamines, the process comprises reacting an ATRP initiator and a nitroxide in the presence of a reaction medium comprising a reducing agent and at least one transition metal catalyst. Any compound that may act as an ATRP initiator is capable of being used in this coupling reaction. The inventors believe that the transition metal catalyst homolytically cleaves the radically transferable atom or group from the ATRP initiator to form a radical.
  • the addition of the radically transferable atom or group to the transition metal catalyst results in an increase in its oxidation state.
  • the transition metal in the higher oxidation state would not be able to initiate formation of an additional radical by further reaction with an ATRP initiator. Therefore, an equal molar ratio of transition metal to ATRP initiator is typically required. The molar ratio may be decreased if a substantial portion of the transition metal is in its zero oxidation state and may react with an ATRP initiator compound twice, initially forming Cu w then Cu (D) .
  • the presence of the reducing agent in the reaction medium allows significantly lower concentrations of transition metal catalyst and significantly lower ratios of transition metal catalyst to ATRP initiator to be present in the reaction medium and still drive the reaction to completion.
  • the molar ratio of the transition metal to the ATRP initiator may be less than 0.5, or less than 0.1 , or even 0.05 or most preferably less than 0.01.
  • Embodiments of processes of the invention may comprise a concentration of transition metal catalyst in the reaction medium of less than 1000 ppm, or even less than 100 ppm, and in certain embodiments, the concentration of transition metal catalyst in the reaction medium may be less than 50 ppm.
  • the addition of a base, or excess ligand, to the reaction medium may assist in the coupling reaction and/or reduction reaction.
  • the transition metal catalyst may be in an oxidized state and the process of the invention may comprise reacting the reducing agent with at least one of the transition metal catalyst in an oxidized state and an ATRP initiator. Reduction of the transition metal catalyst in the higher oxidation state will result in formation of the activator form of the catalyst.
  • Embodiments of the present invention include methods of preparing alkoxyamines. In certain embodiments, the processes of the invention may be considered to comprise an ATRC or an ATRA reaction to convert a nitroxide to an alkoxyamine.
  • the process comprises a transition metal complex in a lower oxidation state (M + YfL n ).
  • An ATRP initiator (R-X n ) homolytically transfers at least one radically transferable atom or group (X) in a redox reaction to form the transition metal complex in the higher oxidation state (X-Mt +4 YZL n ) and a radical species (R ).
  • the transition metal complex in the higher oxidation state may comprise the radically transferable atom or group (X) as a ligand or counterion.
  • the radical species may then react with a nitroxide (R 1 R 2 N-O * ) to form an alkoxyamine (R 1 R 2 N-O-R).
  • transition metal complex in the higher oxidation state will, in most cases, be unable to further activate another compound (R-X n ) comprising a radically transferable atom or group.
  • the transition metal complex in the higher oxidation state, (X- Mt +4 YZL n ) may then be reduced to the lower oxidation state, (M + YZL n ), by a reaction with a reducing agent in a reduction reaction, in certain embodiments, such a reaction does not form a radical species.
  • An embodiment of such a reduction reaction is shown in Figure 3.
  • a copper based catalyst complex interacts with a mono-functional macroinitiator comprising a halide as the radically transferable atom.
  • Figure IA illustrates a reaction scheme of an embodiment comprising reacting an ATRP initiator (RX) and a nitroxide (0-NR 1 R 2 ) in the presence of a reaction medium comprising a reducing agent and at least one transition metal catalyst (M t + ) in a lower oxidation state.
  • the transition metal complex is involved in a redox reaction with the compound (RX) to form a radical that reacts with the stable free radical nitroxide ( 11 ONR 1 R 2 ) to form an alkoxyamine (RONR 1 R 2 ) and a transition metal complex in the higher oxidation state (M t 4+ X).
  • FIG. 1B illustrates another embodiment of the process of the invention comprising an additional reaction converts a nitroxide precursor, such as HONR 1 R 2 to a nitroxide (*ONRiR 2 ).
  • the nitroxide prepared from the nitroxide precursor may then react to with the radical to form the alkoxyamine.
  • Figure 1C illustrates a reaction scheme of a more specific embodiment of a process for the preparation of an alkoxyamine from R-X, a dormant initiator species, and TEMPO, a stable free radical nitroxide.
  • the invention is also exemplified by the reaction scheme shown in Figure IB by the oxidation/reduction reaction of l-hydroxy-2,2,6,6-tetramethyl-piperidine/TEMPO with copper complexes can be used in a catalytic cycle to form alkoxyamines.
  • l-hydroxy-2,2,6,6-tetramethyl-piperidine is oxidized to TEMPO by a Cu(II) complex forming a Cu(I) complex.
  • the Cu(I) complex may then remove a radically transferable atom or group from an ATRP initiator in a reduction reaction forming a radical that can couple with the nitroxide, TEMPO.
  • the Cu(II) complex can oxidize a further molecule of l-hydroxy-2,2,6,6-tetramethyl-piperidine to TEMPO continuing the reaction in a forward direction.
  • This reaction is applicable to any nitroxide precursor in the presence of a suitable catalyst complex.
  • Figure 2 illustrates a reaction scheme of an embodiment of a process comprising activating an ATRP initiator that is a polymeric initiator or a initiator attached to a particle or a substrate (Pn-X) by a transition metal complex in the lower oxidation state to form a radical that couples with a nitroxide to form an alkoxyamine.
  • the reaction scheme of Figure 2 also illustrates the continuous regeneration of the transition metal in the lower oxidation state by reaction with a reducing agent.
  • Embodiments of the process of the invention may comprise a reducing agent that can reduce the transition metal complex in an oxidized state to an lower oxidized state and convert the reducing agent to an oxidized agent.
  • the reducing agent should not form an oxidized agent that can itself or form another species that can either interact with the catalyst complex or interact with the stable free radical nitroxide.
  • Reducing agents that conduct the reduction reaction, essentially without formation of radicals capable of interacting with any reagent present in the reaction medium are preferred.
  • Stanous 2-ethylhexanoate, (Sn(2EH) 2 ) is one of many possible reducing agents that may be used in embodiments of the present invention.
  • Sn(2EH) 2 can reduce Cu r ⁇ to CxP (See Figure 3) in a non-radical forming reduction reaction.
  • embodiments may comprise reducing agents that are more environmentally benign than the transition metals. None of the previous reactions wherein reducing agents are added to an ATRP to increase the rate suggest that the reducing agents may be used to reduce the molar ratio of the transition metal catalyst to the atom transfer radical polymerization initiator nor that the reducing agents be suitable for other reactions involving atom transfer from an ATRP initiator.
  • the reducing power of different transition metal complexes are known [Lingane, J, J., Chem. Rev.; 29 1 1941: Vlcek, A. A., Coord. Chem. Rev.
  • transition metal complex selected as the catalyst for the ATRC reaction, preferably, without further significant participation in the reaction process.
  • Different transition metal complexes may be reduced to a different degree by the same reagent.
  • the reducing agent may undergo a dehydrohalogenation reaction after oxidation.
  • the addition of a base or excess ligand may accelerate some reduction reactions particularly when the reduction reaction involves direct or indirect formation of an acid species.
  • the base may be in the form of additional N- containing ligand, for example.
  • the activity of the reducing agent can however be controlled by selecting a reducing agent that is only slightly soluble in the reaction medium.
  • the slow dissolution of the agent in the reaction medium maintains a low concentration of the reducing agent in the reaction that controllably drives the reaction forward while reducing the tendency of unwanted radical-First radical coupling reactions.
  • Paleos [Paleos, C. M.; Dais, P. Journal of the Chemical Society, Chemical Communications 1977, 345-346] discussed the ready reduction of some nitroxide free radicals with ascorbic acid, but use of a solvent in which ascorbic acid or one of its derivatives has poor solubility allows slow controlled abstraction of the haJide generating a radical for capture rather than reduction of the nitroxide.
  • the low concentration of reducing agent in solution with the reactants minimizes the interaction of the stable free radical and the reducing agent. In some embodiments, the reaction will not proceed forward if the concentration of reducing agent is too high.
  • the concentration of the reducing agent may be controlled by continuously or intermittently adding a small amount of reducing agent or by utilizing a reducing agent with a low solubility in the other components of the reaction medium.
  • the low solubility of the reducing agent limits the concentration of the reducing agent in the phase that comprises the stable free radical or the nitroxide. It is believed that the low concentration of a strong reducing agent limits any interaction between the reducing agent and the stable free radical or nitroxide that would inhibit or prevent the coupling reaction from occurring.
  • the solubility of the reducing agent should be such that the concentration of the reducing agent in the phase of the reaction medium that comprises the stable free radical or the nitroxide is less than 5 wt.% or less than lwt.%for a reducing agent with a high reducing activity, less than 1000 ppm or less than 500 ppm, or even less than 100 ppm for even more active reducing agents.
  • concentrations of less than 100 ppm or even 50 ppm is sufficient to reduce the transition metal complex from an oxidized state to an activator state in anisole solvent. At this concentration, ascorbic acid doesn't interact with the stable free radical but still performs the required reduction of the of the transition metal catalyst.
  • the ascorbic acid may remain as a solid in the reaction medium and then be solubilized as the soluble ascorbic acid is converted to dehydroascorbic acid.
  • the phase of the reaction that comprises the stable free radical or the nitroxide is the phase that comprises a substantial portion of the stable free radical or nitroxide.
  • the phase need not, but may, comprise all of the stable free radical or nitroxide.
  • the mechanism of inhibition of the reaction is not known in the presence of an active reducing agent, it is speculated that if too much of an active reducing agent is present in the reaction medium, the stable free radical or nitroxide maybe reduced to a non-reactive form. For instance, the nitroxide may be reduced by loss of oxygen to a more stable form. Conversely, a second mechanism in which title reducing agent donates hydrogen to the nitroxide may result in a non-reactive species.
  • the concentration of the reducing agent in the phase of the reaction medium that comprises the stable free radical of the nitroxide should be balanced with the activity of the reducing agent, specifically the activity of the reducing agent to interact with the other reactants to inhibit the reaction.
  • the concentration of the reducing agent in the phase of the reaction medium that comprises the stable free radical of the nitroxide may also be controlled by the addition rate of the reducing agent to the reaction medium.
  • a more soluble reducing agent may be added in such a manner to maintain the desired concentrations of reducing agent as described above.
  • the reducing agent may be soluble in the reaction medium or in at least one phase of the reaction medium, such as the suspending phase or the organic phase for reaction processes having at least two phases.
  • the reaction medium may include water.
  • reducing agent will be at least partially soluble in the desired phase of the reaction medium, have a reducing rate to substantially maintain the desired ratio of transition metal in the lower oxidation state to the higher oxidation state.
  • the addition of a base or excess ligand to any phase of the reaction medium may assist in increasing the concentration of the transition metal catalyst allowing extraction of the radically transferable atom or group from the ATRP initiator.
  • the reducing agent may be added to a higher oxidation state catalyst complex forming an active catalyst complex, possibly by an outer sphere electron transfer reaction or by formation of the activator through a lower energy transition state complex that does not result in full separation ' of intermediate species which could result in formation of independent activating species.
  • the reducing agent may be considered to be a trap for the radically transferable atoms or groups.
  • a trap for the radically transferable atoms or groups is any compound can trap the radically transferable atom or group to prevent the radically transferable atom or group, exemplified by a halogen, from further participation in the activation process or the deactivation process.
  • the halogen trap may reduce the transition metal compound in a higher oxidation state to a transition metal compound in the lower oxidation state.
  • the reducing agent employed to reduce a transition metal complex in the higher oxidation state is a precursor to the stable free radical.
  • a nitroxide precursor such as 1 - hydroxy-2,2,6,6-tetramethyl-piperidine
  • the transition metal complexes participate in a dual redox reaction forming both reactive molecules.
  • the higher oxidation state transition metal complex participates in a redox reaction with l-hydroxy-2,2,6,6-tetramethyl ⁇ piperidine forming TEMPO and a Cu(I) complex which abstracts a halogen atom from an ATRP initiator forming a radical to couple with the stable free radical and a Cu(II) complex thereby completing one redox cycle for the transition metal complex.
  • All catalyst complexes suitable for ATRP will be suitable in embodiments of the process of the invention.
  • the ligand of the catalyst complex affects the activation rate constants and the solubility of the transition metal complex in the reaction medium.
  • the activity of transition metal complexes comprising specific exemplary ligands for a specific ATRP initiator, ethyl 2-bromoisobutyrate, is shown in Figure 4.
  • a catalyst complex with a suitable ligand may be selected to provide a suitable reaction rate for the targeted coupling reaction.
  • a preferred transition metal complex would result in a process comprising a minimum of R* / R* coupling and, therefore predominantly all R*'s are captured by the stable free radical.
  • Suitable complexes include: CuCl 2 /dNbpy, CuCl 2 /PMDETA, CuBr 2 /PMDETA, CuCl 2 Me 6 TREN or preferentially for formation of alkoxyamines CuX 2 /Cyclam since that particular complex is a very efficient activator but poor deactivator. Unlike an ATRP, where deactivation of the growing radical is important, deactivation is undesirable for an ATRC or ATRA.
  • This procedure has all the benefits of a normal ATRC initiated reaction plus the benefits, or freedom, of adding the catalyst complex to the reaction medium in its more stable higher oxidation state, in the presence of the initiator (R-X), and, optionally, in the presence of dissolved oxygen.
  • the ATRP initiator may be attached to a surface.
  • the rate of the initiation of the coupling reactions can be tuned by the addition rate, amount, or composition of the reducing agent, hi this way, the rate of the ATRC can be constantly controlled throughout the coupling process by adjusting, for example, the Cu (I VCu ( ⁇ ) ratio with the continuous or intermittent addition of the reducing agent.
  • the reducing agent may be poorly soluble in the reaction medium, hi such an embodiment, the rate of slow dissolution of the reducing agent moderates the rate of the reduction reaction. Indeed, if the solubility of the reducing agent is very low, the rate of the reduction reaction may be moderated by the rate of the heterogeneous reaction of the Cu(II) complex with the solid surface of the reducing agent.
  • the amount of reducing agent added should be sufficient to reduce most of the transition metal complex is a higher oxidation state to its lower oxidation state, remove any excess oxygen from the system, and continue to reduce the transition metal in the higher oxidation state formed as a result of the activation reactions, in some cases, at a similar rate to formation of the transition metal in the higher oxidation state.
  • a further aspect of the invention is that oxygen does not have to be removed from the reaction medium prior to adding the reducing agent and initiating the coupling process.
  • the reducing agent can continuously reduce the higher oxidation state transition metal complex so that it additionally interacts with the dissolved oxygen and removes it from the process. In some processes, however, it may be desirable to limit the dissolved oxygen in the reaction medium.
  • Embodiments of the present invention include reducing agents that reduce the transition metal catalyst in the oxidized state, and when the higher oxidation state comprises radically transferable atoms or groups as a ligand or counterion by removal of a radically transferable atom or group, typically a halogen.
  • the reducing agent is such that it prevents the radically transferable atom or group from further participating in activation processes.
  • suitable reducing agents for the present invention may be, for example, ascorbic acid, ascorbic acid-6-palmitaite (A6P), stannous compounds, stannous oxalate, sodium sulfite, sulfur compounds of alow oxidation state, sodium hydrogen sulfite, inorganic salts comprising a metal ion, hydrazine hydrate, alkylthiols, mercaptoethanol, carbonyl compounds which can easily be enolized, acetyl acetonate, camphorsulfonic acid, hydroxy-acetone, reducing sugars, monosaccharides, glucose and related sugars, tetrahydrofuran, dihydroanthracene, silanes, 2,3 dimethylbutadiene, amines, polyamines, hydrazine derivatives, formamidinesulflnic acid, silane compounds, borane compounds, aldehydes, and derivatives of such compounds.
  • A6P ascorbic acid
  • Suitable reducing agents may also be antioxidants and the following list of antioxidants provides a further selection of reducing agents.
  • Antioxidants suitable as reducing agents include but are not limited to, alkylated monophenols, for example 2,6-di- tert-butyl-4-methylphenol, 2-butyl-4,6-di-methylphenol, 2,6-di-tert-butyl-4-ethylphenol, 2,6- di-tert-butyl-4-n-butylphenol, 2,6-di-tert-butyl-4-isobutylphenol, 2,6-dicyclopentyl-4- methylphenol, 2-(.alpha.-methylcyclohexyl)-4,6-di-methyl ⁇ henol, 2,6-dioctadecyl-4- methylphenol, 2,4,6-tricyclohexylphenol, 2,6-di-tert-butyl-4-methoxymethylphenol, linear nonylphenols or nonylphenol
  • Embodiments of the coupling process of the present invention may comprise any ATRP initiator thereby providing a great selection of R-groups on the formed nitroxide.
  • An ATRP initiator may be any ATRP initiator, such as a chemical molecule or functionalized particle with a transferable (pseudo)halogen that can form an active radical species. Many different types of halogenated compounds, for example, are potential ATRP initiators. In prior art references, many ATRP initiators are described.
  • the ATRP initiator may have a low molecular weight or a high molecular weight such as a macromolecule and/or comprise a solid particle, or a surface, for example.
  • ATRP initiators may comprise at least two radically transferable atoms or groups or be a polymer or a solid.
  • Embodiments of the method of the present invention may be performed in bulk or in a solvent.
  • the solvent may be a protic media or a non-protic media.
  • a protic media is a media that comprises at least one component that is capable of being a proton donor.
  • the protic media may comprise water and at least one alcohol, for example.
  • the alcohol of the protic media may be, for example, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, heptanol, or mixtures thereof.
  • Embodiments of the present invention also include coupling reactions conducted in non-protic media, wherein the non-protic media comprises an aromatic solvent, such as, but not limited to, anisole, xylene, benzene, a halogenated benzene derivative, or other nonprotic solvents.
  • an aromatic solvent such as, but not limited to, anisole, xylene, benzene, a halogenated benzene derivative, or other nonprotic solvents.
  • inert refers to a substituent or compound means that the substituent or compound will not undergo modification either (1) in the presence of reagents that will likely contact the substituent or compound, or (2) under conditions that the substituent or compound will likely be subjected to (e.g., chemical processing carried out subsequent to attachment an "inert" moiety to a substrate surface).
  • Optional or “optionally” means that the subsequently described circumstance may or may not occur and is not necessary, so that the description includes instances where the circumstance occurs and instances where it does not.
  • the phrase “optionally substituted” means that a non-hydrogen substituent may or may not be present, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present.
  • the ligand(s) which should in certain embodiments at least partially preferentially solubilize both oxidation states of the catalyst into the reaction medium while forming a catalyst complex with appropriate activity.
  • the ligand for the transition metal complex may also facilitate removal of the transition metal from the organic phase after the reaction has been completed.
  • a ligand with some hydrophilic character, particularly when complexed with the higher transition state transition metal, can cause the higher oxidation state of the transition metal complex to migrate from an organic phase to a contacting aqueous phase. Further the transition metal complex can separate from the aqueous phase as a solid, thereby providing a means to recycle the transition metal.
  • the transition metal complex in the higher oxidation state is converted to the lower oxidation state by the reducing agent and migration is minimized.
  • the reaction is complete exposure to air forms the higher oxidation state catalyst and enhances migration to a contacting aqueous phase. Indeed in bulk or solution reactions water may be added at the end of the reaction solely to remove the complex. The catalyst may then separate out as a solid and be readily recycled.
  • the resulting alkoxyamine is essentially colorless.
  • the process of the invention can be conducted in a biphasic system.
  • the lower oxidation state of the transition metal complex may be at least partially soluble in the dispersed phase while the higher oxidation state may be less soluble in the dispersed phase.
  • a water-soluble reducing agent may be preferred for embodiments of the present ATRC invention since the higher oxidation state transition metal would be reduced in the aqueous phase and driven back to the organic phase.
  • An example of how the reducing agents can be selected to be additionally environmentally benign would be a combination of ascorbic acid or vitamin C and a sugar for a biphasic coupling process may require less than 100 ppm transition metal complex as the catalyst.
  • the amount of reducing agent, or agents, that is required to be added to the reaction can be approximated by consideration of the moles of initiator added to the reaction plus the amount of transition metal added to the reaction and the expected level of impurities in the system.
  • Example 1 The amount of reducing agent, or agents, that is required to be added to the reaction can be approximated by consideration of the moles of initiator added to the reaction plus the amount of transition metal added to the reaction and the expected level of impurities in the system.
  • Ethyl-2-bromoisobutyrate 0.10 mL (0.68 mmol); TEMPO, 0.128 g (0.82 rnrnol); CuBr 2 , 0.0015 g (0.0068 mmol); dNbpy, 0.0056 g (0.0136 mmol) and toluene, 2.0 mL were added sequentially to a 10 mL Schlenk flask. The system was deoxygenated by bubbling nitrogen through the solution for 40 minutes.

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Abstract

Les variantes du processus de préparation d'alkoxyamines de l'invention portent sur une réaction de couplage à l'intérieur d'un milieu de couplage comprenant initialement au moins: un catalyseur de métal de transition, une amorce ATRP, un nitroxyde ou un précurseur de nitroxyde, et éventuellement un agent réducteur. Dans certaines exécutions, l'agent réducteur est le précurseur de nitroxyde. L'agent réducteur peut être ajouté au début ou pendant le processus de couplage de manière continue ou intermittente. Le processus de couplage peut par ailleurs consister à faire réagir l'agent réducteur avec au moins l'un des catalyseurs de métal de transition à l'état oxydé et comporter un atome ou un groupe transférable radicalement pour former un composé ne participant pas significativement à la conduite du processus de couplage. Dans d'autres exécution, on fait réagir un agent réducteur avec au moins un catalyseur à l'état oxydé et une amorce ATRP pour lancer et/ou maintenir l'activité catalytique pendant tout le processus de couplage entre le radical formé et le nitroxyde ajouté.
PCT/US2006/044931 2005-11-17 2006-11-17 Preparation d'alkoxyamines WO2007059350A2 (fr)

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Cited By (14)

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US8404788B2 (en) 2004-03-05 2013-03-26 Carnegie Mellon University Atom transfer radical polymerization process
US7893174B2 (en) 2004-03-05 2011-02-22 Carnegie Mellon University Atom transfer radical polymerization process
US7795355B2 (en) 2004-03-05 2010-09-14 Carnegie Mellon University Preparation of functional polymers
US8273823B2 (en) 2005-08-23 2012-09-25 Carnegie Mellon University Atom transfer radical polymerization in microemulsion and true emulsion polymerization processes
US7893173B2 (en) 2005-08-26 2011-02-22 Carnegie Mellon University Polymerization process with catalyst reactivation
US8367051B2 (en) 2006-10-09 2013-02-05 Carnegie Mellon University Preparation of functional gel particles with a dual crosslink network
US8252880B2 (en) 2007-05-23 2012-08-28 Carnegie Mellon University Atom transfer dispersion polymerization
US8865797B2 (en) 2007-05-23 2014-10-21 Carnegie Mellon University Hybrid particle composite structures with reduced scattering
US9644042B2 (en) 2010-12-17 2017-05-09 Carnegie Mellon University Electrochemically mediated atom transfer radical polymerization
US10072042B2 (en) 2011-08-22 2018-09-11 Carnegie Mellon University Atom transfer radical polymerization under biologically compatible conditions
US9533297B2 (en) 2012-02-23 2017-01-03 Carnegie Mellon University Ligands designed to provide highly active catalyst complexes
JP2016525163A (ja) * 2013-07-09 2016-08-22 ヒルティ アクチエンゲゼルシャフト 反応樹脂組成物及びその使用
US9982070B2 (en) 2015-01-12 2018-05-29 Carnegie Mellon University Aqueous ATRP in the presence of an activator regenerator
US11174325B2 (en) 2017-01-12 2021-11-16 Carnegie Mellon University Surfactant assisted formation of a catalyst complex for emulsion atom transfer radical polymerization processes

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