John T. Groves

Princeton University, Princeton, New Jersey, United States

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Publications (218)1673.32 Total impact

  • Xiongyi Huang · John T. Groves

    No preview · Article · Dec 2015 · ACS Catalysis
  • Xiongyi Huang · Tova M. Bergsten · John T. Groves
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    ABSTRACT: No abstract is available for this article.
    No preview · Article · Sep 2015 · ChemInform
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    John T. Groves
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    ABSTRACT: Cytochrome P450 (CYP) enzymes are the primary proteins of drug metabolism and steroid biosynthesis. These crucial proteins have long been known to harbor a cysteine thiolate bound to the heme iron. Recent advances in the field have illuminated the nature of reactive intermediates in the reaction cycle. Similar intermediates have been observed and characterized in novel heme-thiolate proteins of fungal origin. Insights from these discoveries have begun to solve the riddle of how enzyme biocatalyst design can afford a protein that can transform substrates that are more difficult to oxidize than the surrounding protein architecture.
    Preview · Article · Jul 2015 · F1000 Research
  • Wei Liu · John T Groves
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    ABSTRACT: The remarkable aliphatic C–H hydroxylations catalyzed by the heme-containing enzyme, cytochrome P450, have attracted sustained attention for more than four decades. The effectiveness of P450 enzymes as highly selective biocatalysts for a wide range of oxygenation reactions of complex substrates has driven chemists to develop synthetic metalloporphyrin model compounds that mimic P450 reactivity. Among various known metalloporphyrins, manganese derivatives have received considerable attention since they have been shown to be versatile and powerful mediators for alkane hydroxylation and olefin epoxidation. Mechanistic studies have shown that the key intermediates of the manganese porphyrin-catalyzed oxygenation reactions include oxo- and dioxomanganese(V) species that transfer an oxygen atom to the substrate through a hydrogen abstraction/oxygen recombination pathway known as the oxygen rebound mechanism. Application of manganese porphyrins has been largely restricted to catalysis of oxygenation reactions until recently, however, due to ultrafast oxygen transfer rates.
    No preview · Article · Jun 2015 · Accounts of Chemical Research
  • 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.
    No preview · Article · Apr 2015 · Journal of the American Chemical Society
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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.
    Full-text · Article · Mar 2015 · Proceedings of the National Academy of Sciences
  • Xiongyi Huang · Wei Liu · Jacob M Hooker · John T Groves
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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.
    No preview · Article · Mar 2015 · Angewandte Chemie International Edition in English
  • Xiongyi Huang · Wei Liu · Jacob M. Hooker · John T. Groves
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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.
    No preview · Article · Mar 2015 · Angewandte Chemie
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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%).
    Preview · Article · Feb 2015 · Dalton Transactions
  • 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.
    No preview · Article · Feb 2015 · Journal of the American Chemical Society
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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.
    Full-text · Article · Nov 2014 · Diabetes/Metabolism Research and Reviews
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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.
    No preview · Article · Sep 2014 · Angewandte Chemie International Edition
  • John T Groves · Nicholas C Boaz

    No preview · Article · Jul 2014 · Science
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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.
    No preview · Article · May 2014 · Journal of the American Chemical Society
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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.
    Full-text · Article · Apr 2014 · Journal of the American Chemical Society
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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.
    No preview · Article · Apr 2014 · Dalton Transactions
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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.
    No preview · Article · Apr 2014 · Organometallics
  • 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.
    No preview · Article · Jan 2014 · Nature Chemistry
  • 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.
    No preview · Article · Dec 2013 · Nature Protocol
  • 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).
    No preview · Article · Oct 2013 · ChemInform

Publication Stats

15k Citations
1,673.32 Total Impact Points


  • 1986-2015
    • Princeton University
      • Department of Chemistry
      Princeton, New Jersey, United States
    • Stanford University
      • Department of Applied Physics
      Palo Alto, California, United States
  • 2008
    • Louisiana State University
      Baton Rouge, Louisiana, United States
  • 2003
    • University of Washington Seattle
      • Division of Cardiothoracic Surgery
      Seattle, Washington, United States
  • 2002
    • University Hospital of Lausanne
      Lausanne, Vaud, Switzerland
  • 1972-1987
    • University of Michigan
      • • Department of Chemistry
      • • Department of Biological Chemistry
      Ann Arbor, Michigan, United States
  • 1975
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States