John T. Groves

Princeton University, Princeton, New Jersey, United States

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Publications (191)1456.51 Total impact

  • Xiongyi Huang, Tova M Bergsten, John T Groves
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    ABSTRACT: We report a manganese-catalyzed aliphatic C-H azidation reaction that can efficiently convert secondary, tertiary, and benzylic C-H bonds to the corresponding azides. The method utilizes aqueous sodium azide solution as the azide source and can be performed under air. Besides its operational simplicity, the potential of this method for late-stage functionalization has been demonstrated by successful azidation of various bioactive molecules with yields up to 74%, including the important drugs pregabalin, memantine, and the antimalarial artemisinin. Azidation of celestolide with a chiral manganese salen catalyst afforded the azide product in 70% ee, representing a Mn-catalyzed enantioselective aliphatic C-H azidation reaction. Considering the versatile roles of organic azides in modern chemistry and the ubiquity of aliphatic C-H bonds in organic molecules, we envision that this Mn-azidation method will find wide application in organic synthesis, drug discovery, and chemical biology.
    Journal of the American Chemical Society 04/2015; DOI:10.1021/jacs.5b01983 · 11.44 Impact Factor
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    ABSTRACT: A kinetic and spectroscopic characterization of the ferryl intermediate (APO-II) from APO, the heme-thiolate peroxygenase from Agrocybe aegerita, is described. APO-II was generated by reaction of the ferric enzyme with metachloroperoxybenzoic acid in the presence of nitroxyl radicals and detected with the use of rapid-mixing stopped-flow UV-visible (UV-vis) spectroscopy. The nitroxyl radicals served as selective reductants of APO-I, reacting only slowly with APO-II. APO-II displayed a split Soret UV-vis spectrum (370 nm and 428 nm) characteristic of thiolate ligation. Rapid-mixing, pH-jump spectrophotometry revealed a basic pKa of 10.0 for the Fe(IV)-O-H of APO-II, indicating that APO-II is protonated under typical turnover conditions. Kinetic characterization showed that APO-II is unusually reactive toward a panel of benzylic C-H and phenolic substrates, with second-order rate constants for C-H and O-H bond scission in the range of 10-10(7) M(-1)⋅s(-1). Our results demonstrate the important role of the axial cysteine ligand in increasing the proton affinity of the ferryl oxygen of APO intermediates, thus providing additional driving force for C-H and O-H bond scission.
    Proceedings of the National Academy of Sciences 03/2015; DOI:10.1073/pnas.1503340112 · 9.81 Impact Factor
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    ABSTRACT: We describe the first catalytic decarboxylative fluorination reaction based on the nucleophilic fluoride ion. The reported method allows the facile replacement of various aliphatic carboxylic acid groups with fluorine. Moreover, the potential of this method for PET imaging has been demonstrated by the successful (18) F labeling of a variety of carboxylic acids with radiochemical conversions up to 50 %, representing a targeted decarboxylative (18) F labeling method with no-carrier-added [(18) F]fluoride. Mechanistic probes suggest that the reaction proceeds through the interaction of the manganese catalyst with iodine(III) carboxylates formed in situ from iodosylbenzene and the carboxylic acid substrates. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Angewandte Chemie International Edition in English 03/2015; 54(17). DOI:10.1002/anie.201500399 · 13.45 Impact Factor
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    ABSTRACT: We describe the first catalytic decarboxylative fluorination reaction based on the nucleophilic fluoride ion. The reported method allows the facile replacement of various aliphatic carboxylic acid groups with fluorine. Moreover, the potential of this method for PET imaging has been demonstrated by the successful 18F labeling of a variety of carboxylic acids with radiochemical conversions up to 50 %, representing a targeted decarboxylative 18F labeling method with no-carrier-added [18F]fluoride. Mechanistic probes suggest that the reaction proceeds through the interaction of the manganese catalyst with iodine(III) carboxylates formed in situ from iodosylbenzene and the carboxylic acid substrates.
    Angewandte Chemie 03/2015; 127(17). DOI:10.1002/ange.201500399
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    ABSTRACT: The efficient and selective partial oxidation of light alkanes using potassium periodate and potassium chloride is reported. Yields of methane functionalization in trifluoroacetic acid reach >40% with high selectivity for methyl trifluoroacetate. Periodate and chloride also functionalize ethane and propane in good yields (>20%).
    Dalton Transactions 02/2015; DOI:10.1039/c5dt00558b · 4.10 Impact Factor
  • Nicholas C Boaz, Seth R Bell, John T Groves
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    ABSTRACT: Ferryl porphyrins, P-Fe(IV)=O, are central reactive intermediates in the catalytic cycles of numerous heme proteins and a variety of model systems. There has been considerable interest in elucidating factors, such as terminal oxo basicity, that may control ferryl reactivity. Here, the sulfonated, water-soluble ferryl porphyrin complexes tetramesitylporphyrin, oxoFe(IV)TMPS (FeTMPS-II), 2,6-dichlorophenyl analog, oxoFe(IV)TDClPS (FeTDClPS-II) and two analogs are shown to be protonated under turnover conditions to produce the corresponding (bis-aqua)iron(III) porphyrin cation radicals. The results reveal a novel internal electromeric equilibrium, P-Fe(IV)=O ⇆ P+-Fe(III)(OH2)2. Reversible pKa values in the range of 4-6.3 have been measured for this process by pH-jump, UV-vis spectroscopy. Ferryl protonation has important ramifications for C-H bond cleavage reactions mediated by oxoiron(IV) porphyrin cation radicals in protic media. Both solvent O-H and substrate C-H deuterium kinetic isotope effects are observed for these reactions, indicating that hydrocarbon oxidation by these oxoiron(IV) porphyrin cation radicals occurs via a solvent proton coupled hydrogen atom transfer from the substrate that has not been previously described. The effective FeO-H BDEs for FeTMPS-II and FeTDClPS-II were estimated from similar kinetic reactivities of the corresponding oxoFe(IV)TMPS+ and oxoFe(IV)TDClPS+ species to be ~92-94 kcal/mol. Similar values were calculated from the two-proton P+-Fe(III)(OH2)2 pKaobs and the porphyrin oxidation potentials, despite a 230 mV range for the iron porphyrins examined. Thus, the iron porphyrin with the lower ring oxidation potential has a compensating higher basicity of the ferryl oxygen. The solvent-derived proton adds significantly to the driving force for C-H bond scission.
    Journal of the American Chemical Society 02/2015; DOI:10.1021/ja508759t · 11.44 Impact Factor
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    ABSTRACT: Background Peroxynitrite, a product of the reaction of superoxide with nitric oxide, causes oxidative stress with concomitant inactivation of enzymes, poly(ADP-ribosylation), mitochondrial dysfunction and impaired stress signalling, as well as protein nitration. In this study, we sought to determine the effect of preventing protein nitration or increasing peroxynitrite decomposition on diabetic neuropathy in mice after an extended period of untreated diabetes. MethodsC57Bl6/J male control and diabetic mice were treated with the peroxynitrite decomposition catalyst Fe(III) tetramesitylporphyrin octasulfonate (FeTMPS, 10mg/kg/day) or protein nitration inhibitor (-)-epicatechin gallate (20mg/kg/day) for 4weeks, after an initial 28weeks of hyperglycaemia. ResultsUntreated diabetic mice developed motor and sensory nerve conduction velocity deficits, thermal and mechanical hypoalgesia, tactile allodynia and loss of intraepidermal nerve fibres. Both FeTMPS and epicatechin gallate partially corrected sensory nerve conduction slowing and small sensory nerve fibre dysfunction without alleviation of hyperglycaemia. Correction of motor nerve conduction deficit and increase in intraepidermal nerve fibre density were found with FeTMPS treatment only. Conclusions Peroxynitrite injury and protein nitration are implicated in the development of diabetic peripheral neuropathy. The findings indicate that both structural and functional changes of chronic diabetic peripheral neuropathy can be reversed and provide rationale for the development of a new generation of antioxidants and peroxynitrite decomposition catalysts for treatment of diabetic peripheral neuropathy. Published in 2014. This article is a U.S. Government work and is in the public domain in the USA.
    Diabetes/Metabolism Research and Reviews 11/2014; 30(8). DOI:10.1002/dmrr.2549 · 3.59 Impact Factor
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    ABSTRACT: Direct partial oxidation of methane, ethane, and propane to their respective trifluoroacetate esters is achieved by a homogeneous hypervalent iodine(III) complex in non-superacidic (trifluoroacetic acid) solvent. The reaction is highly selective for ester formation (>99 %). In the case of ethane, greater than 0.5 M EtTFA can be achieved. Preliminary kinetic analysis and density functional calculations support a nonradical electrophilic CH activation and iodine alkyl functionalization mechanism.
    Angewandte Chemie International Edition 09/2014; 53(39). DOI:10.1002/anie.201406185 · 11.34 Impact Factor
  • John T Groves, Nicholas C Boaz
    Science 07/2014; 345(6193):142-3. DOI:10.1126/science.1256754 · 31.48 Impact Factor
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    ABSTRACT: We describe an efficient system for the direct partial oxidation of methane, ethane, and propane using iodate salts with catalytic amounts of chloride in protic solvents. In HTFA (TFA = trifluoroacetate), >20% methane conversion with >85% selectivity for MeTFA have been achieved. The addition of substoichiometric amounts of chloride is essential, and for methane the conversion increases from <1% in the absence of chloride to >20%. The reaction also proceeds in aqueous HTFA as well as acetic acid to afford methyl acetate. (13)C labeling experiments showed that less than 2% of methane is overoxidized to (13)CO2 at 15% conversion of (13)CH4. The system is selective for higher alkanes: 30% ethane conversion with 98% selectivity for EtTFA and 19% propane conversion that is selective for mixtures of the mono- and difunctionalized TFA esters. Studies of methane conversion using a series of iodine-based reagents [I2, ICl, ICl3, I(TFA)3, I2O4, I2O5, (IO2)2S2O7, (IO)2SO4] indicated that the chloride enhancement is not limited to iodate.
    Journal of the American Chemical Society 05/2014; 136(23). DOI:10.1021/ja502657g · 11.44 Impact Factor
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    ABSTRACT: We describe the first late-stage 18F labeling chemistry for aliphatic C-H bonds with no-carrier-added [18F]fluoride. The method uses Mn(salen)OTs as an F-transfer catalyst and enables the facile labeling of a variety of bioactive molecules and building blocks with radiochemical yields (RCY) ranging from 20% to 72% within 10 minutes without the need for pre-activation of the labeling precursor. Notably, the catalyst itself can directly elute [18F]fluoride from an ion exchange cartridge with over 90% efficiency. Using this feature, the conventional and laborious dry-down step prior to reaction is circumvented, greatly simplifying the mechanics of this protocol and shortening the time for automated synthesis. Eight drug molecules, including COX, ACE, MAO and PDE inhibitors have been successfully [18F]-labeled in this way.
    Journal of the American Chemical Society 04/2014; 136(19). DOI:10.1021/ja5039819 · 11.44 Impact Factor
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    ABSTRACT: Net reductive elimination (RE) of MeX (X = halide or pseudo-halide: Cl(-), CF3CO2(-), HSO4(-), OH(-)) is an important step during Pt-catalyzed hydrocarbon functionalization. Developing Rh(i/iii)-based catalysts for alkane functionalization is an attractive alternative to Pt-based systems, but very few examples of RE of alkyl halides and/or pseudo-halides from Rh(III) complexes have been reported. Here, we compare the influence of the ligand donor strength on the thermodynamic potentials for oxidative addition and reductive functionalization using [(t)Bu3terpy]RhCl () {(t)Bu3terpy = 4,4',4''-tri-tert-butylpyridine} and [(NO2)3terpy]RhCl () {(NO2)3terpy = 4,4',4''-trinitroterpyridine}. Complex oxidatively adds MeX {X = I(-), Cl(-), CF3CO2(-) (TFA(-))} to afford [(t)Bu3terpy]RhMe(Cl)(X) {X = I(-) (), Cl(-) (), TFA(-) ()}. By having three electron-withdrawing NO2 groups, complex does not react with MeCl or MeTFA, but reacts with MeI to yield [(NO2)3terpy]RhMe(Cl)(I) (). Heating expels MeCl along with a small quantity of MeI. Repeating this experiment but with excess [Bu4N]Cl exclusively yields MeCl, while adding [Bu4N]TFA yields a mixture of MeTFA and MeCl. In contrast, does not reductively eliminate MeX under similar conditions. DFT calculations successfully predict the reaction outcome by complexes and . Calorimetric measurements of [(t)Bu3terpy]RhI () and [(t)Bu3terpy]RhMe(I)2 () were used to corroborate computational models. Finally, the mechanism of MeCl RE from was investigated via DFT calculations, which supports a nucleophilic attack by either I(-) or Cl(-) on the Rh-CH3 bond of a five-coordinate Rh complex.
    Dalton Transactions 04/2014; 43(22). DOI:10.1039/c4dt00234b · 4.10 Impact Factor
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    ABSTRACT: A density functional theory (DFT) study was performed to understand the factors that control the reactivity of bipyridine (bpy)-ligated Rh(III) methyl complexes toward nucleophiles to produce functionalized methane and Rh(I) complexes. The effect of the structure of the complex, the nucleophile, the identity of the ancillary ligand, the electronic properties of the bipyridine ligand, and the identity of the metal were considered. Many similarities were found between the reaction of Rh(III) methyl complexes supported by bipyridyl ligands and classic organic SN2 reactions, including a strong dependence of the reaction on the nucleophile identity and modifications to the complex that facilitate rhodium as a leaving group. Using these concepts, a comparison of reductive functionalization of Rh(III) alkyl complexes supported by porphyrin versus two bipyridyl ligands was made, and modifications that could lead to more active complexes were proposed.
    Organometallics 04/2014; 33(8):1936–1944. DOI:10.1021/om4010093 · 4.25 Impact Factor
  • John T Groves
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    ABSTRACT: Cytochrome P450 enzymes are able to oxidize substrates that are more inert than their own surrounding protein framework. Now, a quantitative understanding has emerged as to how the enzymes accomplish this remarkable feat.
    Nature Chemistry 01/2014; 6(2):89-91. DOI:10.1038/nchem.1855 · 23.30 Impact Factor
  • Wei Liu, Xiongyi Huang, John T Groves
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    ABSTRACT: Fluorination is a reaction that is useful in improving the chemical stability and changing the binding affinity of biologically active compounds. The protocol described here can be used to replace aliphatic, C(sp(3))-H hydrogen in small molecules with fluorine. Notably, isolated methylene groups and unactivated benzylic sites are accessible. The method uses readily available manganese porphyrin and manganese salen catalysts and various fluoride ion reagents, including silver fluoride (AgF), tetrabutylammonium fluoride and triethylamine trihydrofluoride (TREAT·HF), as the source of fluorine. Typically, the reactions afford 50-70% yield of mono-fluorinated products in one step. Two representative examples, the fragrance component celestolide and the nonsteroidal anti-inflammatory drug ibuprofen, are described; they produced useful isolated quantities (250-300 mg, ∼50% yield) of fluorinated material over periods of 1-8 h. The procedures are performed in a typical fume hood using ordinary laboratory glassware. No special precautions to rigorously exclude water are required.
    Nature Protocol 12/2013; 8(12):2348-54. DOI:10.1038/nprot.2013.144 · 8.36 Impact Factor
  • Wei Liu, John T. Groves
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    ABSTRACT: Applicability of this method is demonstrated by benzylic fluorination of several bioactive molecules (not shown).
    ChemInform 10/2013; 44(44). DOI:10.1002/chin.201344052
  • Dong Wang, John T Groves
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    ABSTRACT: A series of cationic cobalt porphyrins was found to catalyze electrochemical water oxidation to O2 efficiently at room temperature in neutral aqueous solution. Co-5,10,15,20-tetrakis-(1,3-dimethylimidazolium-2-yl)porphyrin, with a highly electron-deficient meso-dimethylimidazolium porphyrin, was the most effective catalyst. The O2 formation rate was 170 nmol⋅cm(-2)⋅min(-1) (kobs = 1.4 × 10(3) s(-1)) with a Faradaic efficiency near 90%. Mechanistic investigations indicate the generation of a Co(IV)-O porphyrin cation radical as the reactive oxidant, which has accumulated two oxidizing equivalents above the Co(III) resting state of the catalyst. The buffer base in solution was shown to play several critical roles during the catalysis by facilitating both redox-coupled proton transfer processes leading to the reactive oxidant and subsequent O-O bond formation. More basic buffer anions led to lower catalytic onset potentials, extending below 1 V. This homogeneous cobalt-porphyrin system was shown to be robust under active catalytic conditions, showing negligible decomposition over hours of operation. Added EDTA or ion exchange resin caused no catalyst poisoning, indicating that cobalt ions were not released from the porphyrin macrocycle during catalysis. Likewise, surface analysis by energy dispersive X-ray spectroscopy of the working electrodes showed no deposition of heterogeneous cobalt films. Taken together, the results indicate that Co-5,10,15,20-tetrakis-(1,3-dimethylimidazolium-2-yl)porphyrin is an efficient, homogeneous, single-site water oxidation catalyst.
    Proceedings of the National Academy of Sciences 09/2013; 110(39). DOI:10.1073/pnas.1315383110 · 9.81 Impact Factor
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    ABSTRACT: Absolutely: Redox potentials for three redox couples in AaeAPO-catalyzed reactions have been measured, thus placing these heme-thiolate reactive intermediates on an absolute energy scale for the first time. The importance of the axial thiolate ligand and the basic nature of compound II ferryl oxygen atom are discussed in terms of these redox potentials.
    Angewandte Chemie International Edition 08/2013; 52(35). DOI:10.1002/anie.201302137 · 11.34 Impact Factor
  • Wei Liu, John T Groves
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    ABSTRACT: An efficient protocol for the selective fluorination of benzylic CH bonds is described. The process is catalyzed by manganese salen complexes and uses nucleophilic fluorine sources, such as triethylamine trihydrofluoride and KF. Reaction rates are sufficiently high (30 min) to allow adoption for the incorporation of (18) F fluoride sources for PET imaging applications.
    Angewandte Chemie International Edition 06/2013; 125(23). DOI:10.1002/anie.201301097 · 11.34 Impact Factor
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    ABSTRACT: The release of cytochrome c from mitochondria is a key signaling mechanism in apoptosis. Although extramitochondrial proteins are thought to initiate this release, the exact mechanisms remain unclear. Cytochrome c (cyt c) binds to and penetrates lipid structures containing the inner mitochondrial membrane lipid cardiolipin (CL), leading to protein conformational changes and increased peroxidase activity. We describe here a direct visualization of a fluorescent cyt c crossing synthetic, CL-containing membranes in the absence of other proteins. We observed strong binding of cyt c to CL in phospholipid vesicles and bursts of cyt c leakage across the membrane. Passive fluorescent markers such as carboxyfluorescein and a 10-kDa dextran polymer crossed the membrane simultaneously with cyt c, although larger dextrans did not. The data show that these bursts result from the opening of lipid pores formed by the cyt c-CL conjugate. Pore formation and cyt c leakage were significantly reduced in the presence of ATP. We suggest a model, consistent with these findings, in which the formation of toroidal lipid pores is driven by initial cyt c-induced negative spontaneous membrane curvature and subsequent protein unfolding interactions. Our results suggest that the CL-cyt c interaction may be sufficient to allow cyt c permeation of mitochondrial membranes and that cyt c may contribute to its own escape from mitochondria during apoptosis.
    Proceedings of the National Academy of Sciences 04/2013; 110(16). DOI:10.1073/pnas.1303819110 · 9.81 Impact Factor

Publication Stats

9k Citations
1,456.51 Total Impact Points

Institutions

  • 1988–2015
    • Princeton University
      • • Institute for Science and Technology of Materials
      • • Department of Chemistry
      Princeton, New Jersey, United States
  • 2008
    • Pennington Biomedical Research Center
      Baton Rouge, Louisiana, United States
  • 2003
    • University of Washington Seattle
      • Division of Cardiothoracic Surgery
      Seattle, Washington, United States
  • 2002
    • Columbia University
      • Department of Chemistry
      New York, New York, United States
  • 1980–2002
    • University of Michigan
      • Department of Chemistry
      Ann Arbor, Michigan, United States
  • 1986
    • Stanford University
      • Department of Applied Physics
      Palo Alto, California, United States
  • 1985
    • William Penn University
      SCE, Pennsylvania, United States