Research ArticleChemistry

A new strategy to efficiently cleave and form C–H bonds using proton-coupled electron transfer

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Science Advances  13 Jul 2018:
Vol. 4, no. 7, eaat5776
DOI: 10.1126/sciadv.aat5776
  • Fig. 1 C–H and O–H bond cleavage by removal of a proton (red arrow) and an electron (curved arrow) in a single elementary step.

    (A) HAT to X. (B) MS-CPET from O–H hydrogen-bonded to a base. (C) MS-CPET from a C–H bond with a positioned base.

  • Fig. 2 Kinetics of the oxidation of 1 with various oxidants.

    (A) Computed structure of 1 indicating PT (red arrow) to a benzoate oxygen. Nontransferring protons omitted for clarity. (B) C–H bond oxidation in compound 1 forms 1, which is further oxidized to 2. (C) Overlaid optical spectra over time, from a stopped-flow instrument, showing the disappearance of the oxidant N(ArOMe)3•+ in the presence of excess 1; the inset shows the exponential decay of the absorbance at 716 nm. (D) Plot of log(kMS-CPET) versus Δlog(KMS-CPET) including kH for aminium (Embedded Image) and ferrocenium oxidants (Embedded Image) and kD (Embedded Image); Δlog(KMS-CPET) = FEox)/2.303RT; the top axis shows Eox. The fit lines have unitless slopes of 0.21 ± 0.01 (kH) and 0.17 ± 0.02 (kD). Thermochemical estimates (section S4) indicate that ΔGMS-CPET ≅ 0 for the reaction with FeCp*2+, so that point was set to Δlog(KMS-CPET) = 0.

  • Fig. 3 Mechanistic possibilities for the C–H bond oxidation of 1.

    Stepwise transfers of proton and electron from 1 are ruled out (horizontal and vertical arrows from top left, respectively), implicating the MS-CPET pathway (diagonal). Ruled-out pre-equilibrium steps are indicated with dashed arrows. ΔGMS-CPET for the oxidation with FeCp*2+ is estimated from literature values for related compounds (Supplementary Materials); ΔG°PT and ΔG°ET are rough estimates using the pKa (where Ka is the acid dissociation constant) and potentials of the separated fluorene and benzoate units (9, 15). ΔG°ET and ΔG°MS-CPET for other oxidants are each more negative by −23.1[(EoxEox(FeCp*2+)].

  • Fig. 4 Reductive MS-CPET to form C–H bonds.

    (A) Reduction of rhodamine B (3+) with CoCp*2; (B) Reduction of an alkene with CoCp*2. “AH” is an additional equivalent of 5. (C) The trans-selective alkene reduction of protochlorophyllide by DPOR occurs via long-distance ET from an iron-sulfur cluster ≥10 Å away from the substrate. Short-range PT occurs from the propionic acid side chain and a proximal aspartic acid (Asp274). (D) Crystal structure of DPOR active site, showing the Fe4S4 redox cofactor and heme-derived substrate; PT from the propionic acid side chain to the C17═C18 bond is indicated with an arrow. Figure made using VMD (Visual Molecular Dynamics) and adapted from Muraki et al. (20). ADP, adenosine 5′-diphosphate; ATP, adenosine 5′-triphosphate.

  • Table 1 Rate constants for the reaction of 1 with oxidants of varying potential (Eox) in MeCN.

    1 generated in situ from 1H using 1 eq of TBAOH. See section S5 for experimental details.

    EntryOxidantEox (V)kMS-CPET (M−1 s−1)§KIE||
    1N(ArBr)3•+0.677.2×105~4.5
    2N(ArOMe)(ArBr)2•+0.485.4×104
    3N(ArOMe)2(ArBr)•+0.321.9×1042.4
    4N(ArOMe)3•+0.169.5×1033.7
    5FeCp2+0.001.9 × 103
    6FeCp*Cp+−0.273.8×1021.6
    7FeCp*2+−0.482.3×101
    8CoCp2+−1.33No reactionn/a

    †ArX = p-C6H4-X; Cp = η5-C5H5; Cp* = η5-C5Me5; all oxidants are PF6 salts.

    E1/2 versus FeCp2+/0 in MeCN.

    §In MeCN with 0.2 vol% MeOH (NAr3•+) or 0.4 vol% MeOH (Fc+), uncertainty in kMS-CPET ca. ±10%.

    ||kH/kD.

    ¶Approximate value, kH and kD, measured under slightly different conditions, see section S5.

    Supplementary Materials

    • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/4/7/eaat5776/DC1

      Section S1. Calculations

      Section S2. Representative NMR spectra for MS-CPET reactions

      Section S3. Characterization of lactone 2

      Section S4. Reaction mechanism and thermodynamics

      Section S5. Kinetics

      Section S6. DFT-calculated coordinates

      Fig. S1. Summary of DFT-calculated thermodynamics.

      Fig. S2. DFT-calculated structures.

      Fig. S3. Representative 1H-NMR spectra for the oxidation of 1.

      Fig. S4. Representative 1H-NMR spectra for the reduction of 3+.

      Fig. S5. Representative 1H-NMR spectra for the reduction of 5.

      Fig. S6. IR spectra for the oxidation of 1.

      Fig. S7. 1H-NMR investigation of proton exchange in 1-d1.

      Fig. S8. Representative stopped-flow data.

      Fig. S9. Dependence of kobs on [MeOH] for the reaction of 1 + N(ArOMe)2(ArBr)+•.

      Table S1. Summary of key structural and energetic results from DFT screening calculations.

      References (2940)

    • Supplementary Materials

      This PDF file includes:

      • Section S1. Calculations
      • Section S2. Representative NMR spectra for MS-CPET reactions
      • Section S3. Characterization of lactone 2
      • Section S4. Reaction mechanism and thermodynamics
      • Section S5. Kinetics
      • Section S6. DFT-calculated coordinates
      • Fig. S1. Summary of DFT-calculated thermodynamics.
      • Fig. S2. DFT-calculated structures.
      • Fig. S3. Representative 1H-NMR spectra for the oxidation of 1.
      • Fig. S4. Representative 1H-NMR spectra for the reduction of 3+.
      • Fig. S5. Representative 1H-NMR spectra for the reduction of 5.
      • Fig. S6. IR spectra for the oxidation of 1.
      • Fig. S7. 1H-NMR investigation of proton exchange in 1-d1.
      • Fig. S8. Representative stopped-flow data.
      • Fig. S9. Dependence of kobs on MeOH for the reaction of 1 + N(ArOMe) 2(ArBr) +•.
      • Table S1. Summary of key structural and energetic results from DFT screening calculations.
      • References (2940)

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