John T Groves

Princeton University, Princeton, New Jersey, United States

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Publications (124)707.35 Total impact

  • [Show abstract] [Hide abstract]
    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 08/2014; · 11.34 Impact Factor
  • John T Groves, Nicholas C Boaz
    Science (New York, N.Y.). 07/2014; 345(6193):142-3.
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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; · 10.68 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; · 10.68 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; · 3.81 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. · 4.15 Impact Factor
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    ABSTRACT: Peroxynitrite, a product of the reaction of superoxide with nitric oxide, causes oxidative stress with concomitant inactivation of enzymes, poly(ADP-ribosylation), mitochondrial dysfunction, impaired stress signaling, 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. C57Bl6/J male control and diabetic mice were treated with the peroxynitrite decomposition catalyst Fe(III) tetramesitylporphyrin octasulfonate (FeTMPS, 10 mg/kg/d) or protein nitration inhibitor (-)-epicatechin gallate (20 mg/kg/d) for 4 weeks, after an initial 28 weeks of hyperglycemia. Untreated diabetic mice developed motor and sensory nerve conduction velocity deficits, thermal and mechanical hypoalgesia, tactile allodynia, and loss of intraepidermal nerve fibers. Both FeTMPS and epicatechin gallate partially corrected sensory nerve conduction slowing and small sensory nerve fiber dysfunction without alleviation of hyperglycemia. Correction of motor nerve conduction deficit and increase in intraepidermal nerve fiber density were found with FeTMPS treatment only. In conclusion, peroxynitrite injury and its component, 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. This article is protected by copyright. All rights reserved.
    Diabetes/Metabolism Research and Reviews 03/2014; · 2.97 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. · 21.76 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. · 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).
  • 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; · 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 07/2013; · 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 04/2013; · 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; · 9.81 Impact Factor
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    ABSTRACT: Six aerobic alkanotrophs (organism that can metabolize alkanes as their sole carbon source) isolated from deep-sea hydrothermal vents were characterized using the radical clock substrate norcarane to determine the metalloenzyme and reaction mechanism used to oxidize alkanes. The organisms studied were Alcanivorax sp. strains EPR7 and MAR14, Marinobacter sp. strain EPR21, Nocardioides sp. strains EPR26w, EPR28w, and Parvibaculum hydrocarbonoclasticum strain EPR92. Each organism was able to grow on n-alkanes as the sole carbon source and therefore must express genes encoding an alkane-oxidizing enzyme. Results from the oxidation of the radical-clock diagnostic substrate norcarane demonstrated that five of the six organisms (EPR7, MAR14, EPR21, EPR26w, and EPR28w) used an alkane hydroxylase functionally similar to AlkB to catalyze the oxidation of medium-chain alkanes, while the sixth organism (EPR92) used an alkane-oxidizing cytochrome P450 (CYP)-like protein to catalyze the oxidation. DNA sequencing indicated that EPR7 and EPR21 possess genes encoding AlkB proteins, while sequencing results from EPR92 confirmed the presence of a gene encoding CYP-like alkane hydroxylase, consistent with the results from the norcarane experiments.
    Frontiers in Microbiology 01/2013; 4:109. · 3.90 Impact Factor
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    ABSTRACT: An alkane hydroxylase from the marine organism Alcanivorax borkumensis (AbAlkB) was purified. The purified protein retained high activity in an assay with purified rubredoxin (AlkG), purified maize ferredoxin reductase, NADPH, and selected substrates. The reaction mechanism of the purified protein was probed using the radical clock substrates bicyclo[4.1.0]heptane (norcarane), bicyclo[3.1.0]hexane (bicyclohexane), methylphenylcyclopropane and deuterated and non-deuterated cyclohexane. The distribution of products from the radical clock substrates supports the hypothesis that purified AbAlkB hydroxylates substrates by forming a substrate radical. Experiments with deuterated cyclohexane indicate that the rate-determining step has a significant CH bond breaking character. The products formed from a number of differently shaped and sized substrates were characterized to determine the active site constraints of this AlkB. AbAlkB can catalyze the hydroxylation of a large number of aromatic compounds and linear and cyclic alkanes. It does not catalyze the hydroxylation of alkanes with a chain length longer than 15 carbons, nor does it hydroxylate sterically hindered CH bonds.
    Journal of inorganic biochemistry 12/2012; 121C:46-52. · 3.25 Impact Factor
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    ABSTRACT: A purified and highly active form of the non-heme diiron hydroxylase AlkB was investigated using the diagnostic probe substrate norcarane. The reaction afforded C2 (26%) and C3 (43%) hydroxylation and desaturation products (31%). Initial C-H cleavage at C2 led to 7% C2 hydroxylation and 19% 3-hydroxymethylcyclohexene, a rearrangement product characteristic of a radical rearrangement pathway. A deuterated substrate analog, 3,3,4,4-norcarane-d4, afforded drastically reduced amounts of C3 alcohol (8%) and desaturation products (5%), while the radical rearranged alcohol was now the major product (65%). This change in product ratios indicate a large kinetic hydrogen isotope effect of ~20 for both the C-H hydroxylation at C3 and the desaturation pathway with all of the desaturation must have originated via hydrogen abstraction at C3 and not C2. The data indicates that AlkB reacts with norcarane via initial C-H hydrogen abstraction from C2 or C3 and that the three pathways, C3 hydroxylation and desaturation, C2 hydroxylation/radical rearrangement, are parallel and competitive. Thus, the incipient radical at C3 either reacts with the iron-oxo center to form an alcohol or proceeds along the desaturation pathway via a second H-abstraction to afford both 2-norcarene and 3-norcarene. Subsequent reactions of these norcarenes led to detectable amounts of hydroxylation products and toluene. By contrast, the 2-norcaranyl radical intermediate leads to C2 hydroxylation and the diagnostic radical rearrangement, but this radical apparently did not afford desaturation products. The results indicate that C-H hydroxylation and desaturation follow analogous stepwise reaction channels via carbon radicals that diverge at the product-forming step.
    Journal of the American Chemical Society 11/2012; · 10.68 Impact Factor
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    ABSTRACT: Despite the growing importance of fluorinated organic compounds in drug development, there are no direct protocols for the fluorination of aliphatic C-H bonds using conveniently handled fluoride salts. We have discovered that a manganese porphyrin complex catalyzes alkyl fluorination by fluoride ion under mild conditions in conjunction with stoichiometric oxidation by iodosylbenzene. Simple alkanes, terpenoids, and even steroids were selectively fluorinated at otherwise inaccessible sites in 50 to 60% yield. Decalin was fluorinated predominantly at the C2 and C3 methylene positions. Bornyl acetate was converted to exo-5-fluoro-bornyl acetate, and 5α-androstan-17-one was fluorinated selectively in the A ring. Mechanistic analysis suggests that the regioselectivity for C-H bond cleavage is directed by an oxomanganese(V) catalytic intermediate followed by F delivery via an unusual manganese(IV) fluoride that has been isolated and structurally characterized.
    Science 09/2012; 337(6100):1322-5. · 31.20 Impact Factor
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    ABSTRACT: The extracellular heme-thiolate peroxygenase from Agrocybe aegerita (AaeAPO) has been shown to hydroxylate alkanes and numerous other substrates using hydrogen peroxide as the terminal oxidant. We describe the kinetics of formation and decomposition of AaeAPO compound I upon its reaction with mCPBA. The UV-vis spectral features of AaeAPO-I (361, 694 nm) are similar to those of chloroperoxidase-I and the recently described cytochrome P450-I. The second-order rate constant for AaeAPO-I formation was 1.0 (±0.4) × 10(7) M(-1) s(-1) at pH 5.0, 4 °C. The relatively slow decomposition rate, 1.4 (±0.03) s(-1), allowed the measurement of its reactivity toward a panel of substrates. The observed rate constants, k(2)', spanned 5 orders of magnitude and correlated linearly with bond dissociation enthalpies (BDEs) of strong C-H bond substrates with a log k(2)' vs BDE slope of ∼0.4. However, the hydroxylation rate was insensitive to a C-H BDE below 90 kcal/mol, similar to the behavior of the tert-butoxyl radical. The shape and slope of the Brønsted-Evans-Polanyi plot indicate a symmetrical transition state for the stronger C-H bonds and suggest entropy control of the rate in an early transition state for weaker C-H bonds. The AaeAPO-II Fe(IV)O-H BDE was estimated to be ∼103 kcal/mol. All results support the formation of a highly reactive AaeAPO oxoiron(IV) porphyrin radical cation intermediate that is the active oxygen species in these hydroxylation reactions.
    Journal of the American Chemical Society 07/2012; · 10.68 Impact Factor
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    ABSTRACT: Flavins and related molecules catalyze organic Baeyer-Villiger reactions. Combined experimental and DFT studies indicate that these molecules also catalyze the insertion of oxygen into metal-carbon bonds through a Baeyer-Villiger-like transition state.
    Journal of the American Chemical Society 07/2012; · 10.68 Impact Factor

Publication Stats

3k Citations
707.35 Total Impact Points

Institutions

  • 1991–2014
    • Princeton University
      • Department of Chemistry
      Princeton, New Jersey, United States
  • 2012
    • University of Virginia
      • Department of Chemistry
      Charlottesville, VA, United States
  • 2003–2012
    • Bates College
      • Department of Chemistry
      Lewiston, Maine, United States
  • 2010
    • University of Kentucky
      Lexington, Kentucky, United States
  • 2007–2008
    • Pennington Biomedical Research Center
      Baton Rouge, Louisiana, United States
  • 2006
    • Università degli Studi di Perugia
      Perugia, Umbria, Italy
  • 2005
    • University of Michigan
      • Department of Internal Medicine
      Ann Arbor, MI, United States