Structural and Spectroscopic Characterization of Metastable Thiolate-Ligated Manganese(III)–Alkylperoxo Species

Metastable Mn–peroxo species are proposed to form as key intermediates in biological oxidation reactions involving O2 and C–H bond activation. The majority of these have yet to be spectroscopically characterized, and their inherent instability, in most cases, precludes structural characterization. Cysteinate-ligated metal–peroxos have been shown to form as reactive intermediates in both heme and nonheme iron enzymes. Herein we report the only examples of isolable Mn(III)–alkylperoxo species, and the first two examples of structurally characterized synthetic thiolate-ligated metal–peroxos. Spectroscopic data, including electronic absorption and IR spectra, and ESI mass spectra for 16O vs 18O-labeled metastable Mn(III)–OOR (R = tBu, Cm) are discussed, as well as preliminary reactivity

Structural and Spectroscopic Characterization of Metastable Thiolate-Ligated Manganese(III)–Alkylperoxo Species

Metastable Mn–peroxo species are proposed to form as key intermediates in biological oxidation reactions involving O2 and C–H bond activation. The majority of these have yet to be spectroscopically characterized, and their inherent instability, in most cases, precludes structural characterization. Cysteinate-ligated metal–peroxos have been shown to form as reactive intermediates in both heme and nonheme iron enzymes. Herein we report the only examples of isolable Mn(III)–alkylperoxo species, and the first two examples of structurally characterized synthetic thiolate-ligated metal–peroxos. Spectroscopic data, including electronic absorption and IR spectra, and ESI mass spectra for 16O vs 18O-labeled metastable Mn(III)–OOR (R = tBu, Cm) are discussed, as well as preliminary reactivity

Structural and Spectroscopic Characterization of Metastable Thiolate-Ligated Manganese(III)–Alkylperoxo Species

Metastable Mn–peroxo species are proposed to form as key intermediates in biological oxidation reactions involving O2 and C–H bond activation. The majority of these have yet to be spectroscopically characterized, and their inherent instability, in most cases, precludes structural characterization. Cysteinate-ligated metal–peroxos have been shown to form as reactive intermediates in both heme and nonheme iron enzymes. Herein we report the only examples of isolable Mn(III)–alkylperoxo species, and the first two examples of structurally characterized synthetic thiolate-ligated metal–peroxos. Spectroscopic data, including electronic absorption and IR spectra, and ESI mass spectra for 16O vs 18O-labeled metastable Mn(III)–OOR (R = tBu, Cm) are discussed, as well as preliminary reactivity

Synthesis and Structural Characterization of a Series of Mn^IIIOR Complexes, Including a Water-Soluble Mn^IIIOH That Promotes Aerobic Hydrogen-Atom Transfer

Hydrogen-atom-transfer (HAT) reactions are a class of proton-coupled electron-transfer (PCET) reactions used in biology to promote substrate oxidation. The driving force for such reactions depends on both the oxidation potential of the catalyst and the p<i>K</i>_a value of the proton-acceptor site. Both high-valent transition-metal oxo M^IVO (M = Fe, Mn) and lower-valent transition-metal hydroxo compounds M^IIIOH (M = Fe, Mn) have been shown to promote these reactions. Herein we describe the synthesis, structure, and reactivity properties of a series of Mn^IIIOR compounds [R = ^<i>p</i>NO₂Ph (<b>5</b>), Ph (<b>6</b>), Me (<b>7</b>), H (<b>8</b>)], some of which abstract H atoms. The Mn^IIIOH complex <b>8</b> is water-soluble and represents a rare example of a stable mononuclear Mn^IIIOH. In water, the redox potential of <b>8</b> was found to be pH-dependent and the Pourbaix (<i>E</i>_p,c vs pH) diagram has a slope (52 mV pH^–1) that is indicative of the transfer a single proton with each electron (i.e., PCET). The two compounds with the lowest oxidation potential, hydroxide- and methoxide-bound <b>7</b> and <b>8</b>, are found to oxidize 2,2′,6,6′-tetramethylpiperidin-1-ol (TEMPOH), whereas the compounds with the highest oxidation potential, phenol-ligated <b>5</b> and <b>6</b>, are shown to be unreactive. Hydroxide-bound <b>8</b> reacts with TEMPOH an order of magnitude faster than methoxide-bound <b>7</b>. Kinetic data [<i>k</i>_H/<i>k</i>_D = 3.1 (<b>8</b>); <i>k</i>_H/<i>k</i>_D = 2.1 (<b>7</b>)] are consistent with concerted H-atom abstraction. The reactive species <b>8</b> can be aerobically regenerated in H₂O, and at least 10 turnovers can be achieved without significant degradation of the “catalyst”. The linear correlation between the redox potential and pH, obtained from the Pourbaix diagram, was used to calculate the bond dissociation free energy (BDFE) = 74.0 ± 0.5 kcal mol^–1 for Mn^IIOH₂ in water, and in MeCN, its BDFE was estimated to be 70.1 kcal mol^–1. The reduced protonated derivative of <b>8</b>, [Mn^II(S^Me2N₄(tren))­(H₂O)]⁺ (<b>9</b>), was estimated to have a p<i>K</i>_a of 21.2 in MeCN. The ability (<b>7</b>) and inability (<b>5</b> and <b>6</b>) of the other members of the series to abstract a H atom from TEMPOH was used to estimate either an upper or lower limit to the Mn^IIO­(H)­R p<i>K</i>_a based on their experimentally determined redox potentials. The trend in p<i>K</i>_a [21.2 (R = H) > 16.2 (R = Me) > 13.5 (R = Ph) > 12.2 (R = ^<i>p</i>NO₂Ph)] is shown to oppose that of the oxidation potential <i>E</i>_p,c [−220 (R = ^<i>p</i>NO₂Ph) > −300 (R = Ph) > −410 (R = Me) > −600 (R = H) mV vs Fc^+/0] for this particular series

Horse Heart Myoglobin Catalyzes the H₂O₂-Dependent Oxidative Dehalogenation of Chlorophenols to DNA-Binding Radicals and Quinones^†

The heme-containing respiratory protein, myoglobin (Mb), best known for oxygen storage, can exhibit peroxidase-like activity under conditions of oxidative stress. Under such circumstances, the initially formed ferric state can react with H2O2 (or other peroxides) to generate a long-lived ferryl [Fe(IV)O] Compound II (Cpd II) heme intermediate that is capable of oxidizing a variety of biomolecules. In this study, the ability of Mb Cpd II to catalyze the oxidation of carcinogenic halophenols is demonstrated. Specifically, 2,4,6-trichlorophenol (TCP) is converted to 2,6-dichloro-1,4-benzoquinone in a H2O2-dependent process. The fact that Mb Cpd II is an active oxidant in halophenol dehalogenation is consistent with a traditional peroxidase order of addition of H2O2 followed by TCP. With 4-chlorophenol, a dimerized product is formed, consistent with a mechanism involving generation of a reactive phenoxy radical intermediate by an electron transfer process. The radical nature of this process may be physiologically relevant since recent studies have revealed that phenoxy radicals and electrophilic quinones, specifically of the type described herein, covalently bind to DNA [Dai, J., Sloat, A. L., Wright, M. W., and Manderville, R. A. (2005) Chem. Res. Toxicol. 18, 771−779]. Thus, the stability of Mb Cpd II and its ability to oxidize TCP may explain why such compounds are carcinogenic. Furthermore, the initial rate of dehalogenation catalyzed by Mb Cpd II is nearly comparable to that of the same reaction carried out by turnover of the ferric state, demonstrating the potential physiological danger of this long-lived, high-valent intermediate

Synthesis and Structural Characterization of a Series of Mn^IIIOR Complexes, Including a Water-Soluble Mn^IIIOH That Promotes Aerobic Hydrogen-Atom Transfer

Hydrogen-atom-transfer (HAT) reactions are a class of proton-coupled electron-transfer (PCET) reactions used in biology to promote substrate oxidation. The driving force for such reactions depends on both the oxidation potential of the catalyst and the p<i>K</i>_a value of the proton-acceptor site. Both high-valent transition-metal oxo M^IVO (M = Fe, Mn) and lower-valent transition-metal hydroxo compounds M^IIIOH (M = Fe, Mn) have been shown to promote these reactions. Herein we describe the synthesis, structure, and reactivity properties of a series of Mn^IIIOR compounds [R = ^<i>p</i>NO₂Ph (<b>5</b>), Ph (<b>6</b>), Me (<b>7</b>), H (<b>8</b>)], some of which abstract H atoms. The Mn^IIIOH complex <b>8</b> is water-soluble and represents a rare example of a stable mononuclear Mn^IIIOH. In water, the redox potential of <b>8</b> was found to be pH-dependent and the Pourbaix (<i>E</i>_p,c vs pH) diagram has a slope (52 mV pH^–1) that is indicative of the transfer a single proton with each electron (i.e., PCET). The two compounds with the lowest oxidation potential, hydroxide- and methoxide-bound <b>7</b> and <b>8</b>, are found to oxidize 2,2′,6,6′-tetramethylpiperidin-1-ol (TEMPOH), whereas the compounds with the highest oxidation potential, phenol-ligated <b>5</b> and <b>6</b>, are shown to be unreactive. Hydroxide-bound <b>8</b> reacts with TEMPOH an order of magnitude faster than methoxide-bound <b>7</b>. Kinetic data [<i>k</i>_H/<i>k</i>_D = 3.1 (<b>8</b>); <i>k</i>_H/<i>k</i>_D = 2.1 (<b>7</b>)] are consistent with concerted H-atom abstraction. The reactive species <b>8</b> can be aerobically regenerated in H₂O, and at least 10 turnovers can be achieved without significant degradation of the “catalyst”. The linear correlation between the redox potential and pH, obtained from the Pourbaix diagram, was used to calculate the bond dissociation free energy (BDFE) = 74.0 ± 0.5 kcal mol^–1 for Mn^IIOH₂ in water, and in MeCN, its BDFE was estimated to be 70.1 kcal mol^–1. The reduced protonated derivative of <b>8</b>, [Mn^II(S^Me2N₄(tren))­(H₂O)]⁺ (<b>9</b>), was estimated to have a p<i>K</i>_a of 21.2 in MeCN. The ability (<b>7</b>) and inability (<b>5</b> and <b>6</b>) of the other members of the series to abstract a H atom from TEMPOH was used to estimate either an upper or lower limit to the Mn^IIO­(H)­R p<i>K</i>_a based on their experimentally determined redox potentials. The trend in p<i>K</i>_a [21.2 (R = H) > 16.2 (R = Me) > 13.5 (R = Ph) > 12.2 (R = ^<i>p</i>NO₂Ph)] is shown to oppose that of the oxidation potential <i>E</i>_p,c [−220 (R = ^<i>p</i>NO₂Ph) > −300 (R = Ph) > −410 (R = Me) > −600 (R = H) mV vs Fc^+/0] for this particular series

Synthesis and Structural Characterization of a Series of Mn^IIIOR Complexes, Including a Water-Soluble Mn^IIIOH That Promotes Aerobic Hydrogen-Atom Transfer

Hydrogen-atom-transfer (HAT) reactions are a class of proton-coupled electron-transfer (PCET) reactions used in biology to promote substrate oxidation. The driving force for such reactions depends on both the oxidation potential of the catalyst and the p<i>K</i>_a value of the proton-acceptor site. Both high-valent transition-metal oxo M^IVO (M = Fe, Mn) and lower-valent transition-metal hydroxo compounds M^IIIOH (M = Fe, Mn) have been shown to promote these reactions. Herein we describe the synthesis, structure, and reactivity properties of a series of Mn^IIIOR compounds [R = ^<i>p</i>NO₂Ph (<b>5</b>), Ph (<b>6</b>), Me (<b>7</b>), H (<b>8</b>)], some of which abstract H atoms. The Mn^IIIOH complex <b>8</b> is water-soluble and represents a rare example of a stable mononuclear Mn^IIIOH. In water, the redox potential of <b>8</b> was found to be pH-dependent and the Pourbaix (<i>E</i>_p,c vs pH) diagram has a slope (52 mV pH^–1) that is indicative of the transfer a single proton with each electron (i.e., PCET). The two compounds with the lowest oxidation potential, hydroxide- and methoxide-bound <b>7</b> and <b>8</b>, are found to oxidize 2,2′,6,6′-tetramethylpiperidin-1-ol (TEMPOH), whereas the compounds with the highest oxidation potential, phenol-ligated <b>5</b> and <b>6</b>, are shown to be unreactive. Hydroxide-bound <b>8</b> reacts with TEMPOH an order of magnitude faster than methoxide-bound <b>7</b>. Kinetic data [<i>k</i>_H/<i>k</i>_D = 3.1 (<b>8</b>); <i>k</i>_H/<i>k</i>_D = 2.1 (<b>7</b>)] are consistent with concerted H-atom abstraction. The reactive species <b>8</b> can be aerobically regenerated in H₂O, and at least 10 turnovers can be achieved without significant degradation of the “catalyst”. The linear correlation between the redox potential and pH, obtained from the Pourbaix diagram, was used to calculate the bond dissociation free energy (BDFE) = 74.0 ± 0.5 kcal mol^–1 for Mn^IIOH₂ in water, and in MeCN, its BDFE was estimated to be 70.1 kcal mol^–1. The reduced protonated derivative of <b>8</b>, [Mn^II(S^Me2N₄(tren))­(H₂O)]⁺ (<b>9</b>), was estimated to have a p<i>K</i>_a of 21.2 in MeCN. The ability (<b>7</b>) and inability (<b>5</b> and <b>6</b>) of the other members of the series to abstract a H atom from TEMPOH was used to estimate either an upper or lower limit to the Mn^IIO­(H)­R p<i>K</i>_a based on their experimentally determined redox potentials. The trend in p<i>K</i>_a [21.2 (R = H) > 16.2 (R = Me) > 13.5 (R = Ph) > 12.2 (R = ^<i>p</i>NO₂Ph)] is shown to oppose that of the oxidation potential <i>E</i>_p,c [−220 (R = ^<i>p</i>NO₂Ph) > −300 (R = Ph) > −410 (R = Me) > −600 (R = H) mV vs Fc^+/0] for this particular series

Synthesis and Structural Characterization of a Series of Mn^IIIOR Complexes, Including a Water-Soluble Mn^IIIOH That Promotes Aerobic Hydrogen-Atom Transfer

Hydrogen-atom-transfer (HAT) reactions are a class of proton-coupled electron-transfer (PCET) reactions used in biology to promote substrate oxidation. The driving force for such reactions depends on both the oxidation potential of the catalyst and the p<i>K</i>_a value of the proton-acceptor site. Both high-valent transition-metal oxo M^IVO (M = Fe, Mn) and lower-valent transition-metal hydroxo compounds M^IIIOH (M = Fe, Mn) have been shown to promote these reactions. Herein we describe the synthesis, structure, and reactivity properties of a series of Mn^IIIOR compounds [R = ^<i>p</i>NO₂Ph (<b>5</b>), Ph (<b>6</b>), Me (<b>7</b>), H (<b>8</b>)], some of which abstract H atoms. The Mn^IIIOH complex <b>8</b> is water-soluble and represents a rare example of a stable mononuclear Mn^IIIOH. In water, the redox potential of <b>8</b> was found to be pH-dependent and the Pourbaix (<i>E</i>_p,c vs pH) diagram has a slope (52 mV pH^–1) that is indicative of the transfer a single proton with each electron (i.e., PCET). The two compounds with the lowest oxidation potential, hydroxide- and methoxide-bound <b>7</b> and <b>8</b>, are found to oxidize 2,2′,6,6′-tetramethylpiperidin-1-ol (TEMPOH), whereas the compounds with the highest oxidation potential, phenol-ligated <b>5</b> and <b>6</b>, are shown to be unreactive. Hydroxide-bound <b>8</b> reacts with TEMPOH an order of magnitude faster than methoxide-bound <b>7</b>. Kinetic data [<i>k</i>_H/<i>k</i>_D = 3.1 (<b>8</b>); <i>k</i>_H/<i>k</i>_D = 2.1 (<b>7</b>)] are consistent with concerted H-atom abstraction. The reactive species <b>8</b> can be aerobically regenerated in H₂O, and at least 10 turnovers can be achieved without significant degradation of the “catalyst”. The linear correlation between the redox potential and pH, obtained from the Pourbaix diagram, was used to calculate the bond dissociation free energy (BDFE) = 74.0 ± 0.5 kcal mol^–1 for Mn^IIOH₂ in water, and in MeCN, its BDFE was estimated to be 70.1 kcal mol^–1. The reduced protonated derivative of <b>8</b>, [Mn^II(S^Me2N₄(tren))­(H₂O)]⁺ (<b>9</b>), was estimated to have a p<i>K</i>_a of 21.2 in MeCN. The ability (<b>7</b>) and inability (<b>5</b> and <b>6</b>) of the other members of the series to abstract a H atom from TEMPOH was used to estimate either an upper or lower limit to the Mn^IIO­(H)­R p<i>K</i>_a based on their experimentally determined redox potentials. The trend in p<i>K</i>_a [21.2 (R = H) > 16.2 (R = Me) > 13.5 (R = Ph) > 12.2 (R = ^<i>p</i>NO₂Ph)] is shown to oppose that of the oxidation potential <i>E</i>_p,c [−220 (R = ^<i>p</i>NO₂Ph) > −300 (R = Ph) > −410 (R = Me) > −600 (R = H) mV vs Fc^+/0] for this particular series

Synthesis and Structural Characterization of a Series of Mn^IIIOR Complexes, Including a Water-Soluble Mn^IIIOH That Promotes Aerobic Hydrogen-Atom Transfer

Hydrogen-atom-transfer (HAT) reactions are a class of proton-coupled electron-transfer (PCET) reactions used in biology to promote substrate oxidation. The driving force for such reactions depends on both the oxidation potential of the catalyst and the p<i>K</i>_a value of the proton-acceptor site. Both high-valent transition-metal oxo M^IVO (M = Fe, Mn) and lower-valent transition-metal hydroxo compounds M^IIIOH (M = Fe, Mn) have been shown to promote these reactions. Herein we describe the synthesis, structure, and reactivity properties of a series of Mn^IIIOR compounds [R = ^<i>p</i>NO₂Ph (<b>5</b>), Ph (<b>6</b>), Me (<b>7</b>), H (<b>8</b>)], some of which abstract H atoms. The Mn^IIIOH complex <b>8</b> is water-soluble and represents a rare example of a stable mononuclear Mn^IIIOH. In water, the redox potential of <b>8</b> was found to be pH-dependent and the Pourbaix (<i>E</i>_p,c vs pH) diagram has a slope (52 mV pH^–1) that is indicative of the transfer a single proton with each electron (i.e., PCET). The two compounds with the lowest oxidation potential, hydroxide- and methoxide-bound <b>7</b> and <b>8</b>, are found to oxidize 2,2′,6,6′-tetramethylpiperidin-1-ol (TEMPOH), whereas the compounds with the highest oxidation potential, phenol-ligated <b>5</b> and <b>6</b>, are shown to be unreactive. Hydroxide-bound <b>8</b> reacts with TEMPOH an order of magnitude faster than methoxide-bound <b>7</b>. Kinetic data [<i>k</i>_H/<i>k</i>_D = 3.1 (<b>8</b>); <i>k</i>_H/<i>k</i>_D = 2.1 (<b>7</b>)] are consistent with concerted H-atom abstraction. The reactive species <b>8</b> can be aerobically regenerated in H₂O, and at least 10 turnovers can be achieved without significant degradation of the “catalyst”. The linear correlation between the redox potential and pH, obtained from the Pourbaix diagram, was used to calculate the bond dissociation free energy (BDFE) = 74.0 ± 0.5 kcal mol^–1 for Mn^IIOH₂ in water, and in MeCN, its BDFE was estimated to be 70.1 kcal mol^–1. The reduced protonated derivative of <b>8</b>, [Mn^II(S^Me2N₄(tren))­(H₂O)]⁺ (<b>9</b>), was estimated to have a p<i>K</i>_a of 21.2 in MeCN. The ability (<b>7</b>) and inability (<b>5</b> and <b>6</b>) of the other members of the series to abstract a H atom from TEMPOH was used to estimate either an upper or lower limit to the Mn^IIO­(H)­R p<i>K</i>_a based on their experimentally determined redox potentials. The trend in p<i>K</i>_a [21.2 (R = H) > 16.2 (R = Me) > 13.5 (R = Ph) > 12.2 (R = ^<i>p</i>NO₂Ph)] is shown to oppose that of the oxidation potential <i>E</i>_p,c [−220 (R = ^<i>p</i>NO₂Ph) > −300 (R = Ph) > −410 (R = Me) > −600 (R = H) mV vs Fc^+/0] for this particular series

Nitrile Hydration by Thiolate- and Alkoxide-Ligated Co-NHase Analogues. Isolation of Co(III)-Amidate and Co(III)-Iminol Intermediates

Nitrile hydratases (NHases) are thiolate-ligated Fe(III)- or Co(III)- containing enzymes, which convert nitriles to the corresponding amide under mild conditions. Proposed NHase mechanisms involve M(III)-NCR, M(III)-OH, M(III)-iminol, and M(III)-amide intermediates. There have been no reported crystallographically characterized examples of these key intermediates. Spectroscopic and kinetic data support the involvement of a M(III)-NCR intermediate. A H-bonding network facilitates this enzymatic reaction. Herein we describe two biomimetic Co(III)−NHase analogues that hydrate MeCN, and four crystallographically characterized NHase intermediate analogues, [CoIII(SMe2N4(tren))(MeCN)]2+ (1), [CoIII(SMe2N4(tren))(OH)]+ (3), [CoIII(SMe2N4(tren))(NHC(O)CH3)]+ (2), and [CoIII(OMe2N4(tren))(NHC(OH)CH3)]2+ (5). Iminol−bound 5 represents the first example of a Co(III)-iminol compound in any ligand environment. Kinetic parameters (k1(298 K)= 2.98(5) M−1 s−1, ΔH‡ = 12.65(3) kcal/mol, ΔS‡ = −14(7) e.u.) for nitrile hydration by 1 are reported, and the activation energy Ea = 13.2 kcal/mol is compared with that (Ea= 5.5 kcal/mol) of the NHase enzyme. A mechanism involving initial exchange of the bound MeCN for OH− is ruled out by the fact that nitrile exchange from 1 (kex(300 K) = 7.3(1) × 10−3 s−1) is 2 orders of magnitude slower than nitrile hydration, and that hydroxide bound 3 does not promote nitrile hydration. Reactivity of an analogue that incorporates an alkoxide as a mimic of the highly conserved NHase serine residue shows that this moiety facilitates nitrile hydration under milder conditions. Hydrogen-bonding to the alkoxide stabilizes a Co(III)-iminol intermediate. Comparison of the thiolate versus alkoxide intermediate structures shows that CN bond activation and CO bond formation proceed further along the reaction coordinate when a thiolate is incorporated into the coordination sphere