Evaluation of the Synthetic Scope and the Reaction Pathways of Proton‐Coupled Electron Transfer with Redox‐Active Guanidines in C−H Activation Processes

Abstract Proton‐coupled electron transfer (PCET) is currently intensively studied because of its importance in synthetic chemistry and biology. In recent years it was shown that redox‐active guanidines are capable PCET reagents for the selective oxidation of organic molecules. In this work, the scope of their PCET reactivity regarding reactions that involve C−H activation is explored and kinetic studies carried out to disclose the reaction mechanisms. Organic molecules with potential up to 1.2 V vs. ferrocenium/ferrocene are efficiently oxidized. Reactions are initiated by electron transfer, followed by slow proton transfer from an electron‐transfer equilibrium.


General information
All synthetic work was carried out using standard Schlenk techniques under argon atmosphere. Solvents were dried with an MBraun MB-SPS-800 Solvent Purification System and stored over molecular sieves.
Elemental analyses were carried out at the Microanalytical Laboratory of the University of Heidelberg. NMR spectra were recorded on a Bruker DPX 200, Bruker DRX 200, Bruker Avance II 400 or Bruker AVANCE III 600 system. Solvent resonances were taken as references for all 1 H NMR spectra. UV-vis spectra were recorded with a Cary 5000 spectrophotometer and cyclic voltammetry (CV) measurements relied on a Metrohm Autolab potentiostate PGSTAT204, ( n Bu4N)(PF6) (electrochemical grade (>99.0), Fluka) was employed as supporting electrolyte. Stopped flow measurements were made with an "Applied Photophysics SX 18MV-R". MS-ESI measurements relied on a Bruker microTOF II ESI mass spectrometer.

X-ray crystallography
Suitable crystals for single-crystal structure determination were taken directly from the mother liquor, taken up in perfluorinated polyether oil and fixed on a cryo loop. Full shells of intensity data were collected at low temperature with a Nonius Kappa CCD diffractometer (Mo-Kα radiation, sealed X-ray tube, graphite monochromator) for compound (2+2H)(PF6)2, and Bruker D8 Venture, dual source (Mo-or Cu-K radiation, microfocus X-ray tube, Photon III detector) for all other compounds. Data were processed with the standard Nonius and Bruker (SAINT, APEX3) software package. [5] [ Multiscan absorption correction was applied using the SADABS program. [ 6 ] The structures were solved by intrinsic phasing [7] and refined using the SHELXTL software package (Version 2014/6 and 2018/3). [8] Graphical handling of the structural data during solution and refinement were performed with OLEX2. [9] All non-hydrogen atoms were given anisotropic displacement parameters. Hydrogen atoms bound to carbon were input at calculated positions and refined with a riding model. Hydrogen atoms bound to nitrogen were located in difference Fourier syntheses and refined, either fully or with appropriate distance and/or symmetry.

General protocol
In a Schlenk flask, a HBF4·OEt2 solution (5% in CH3CN; c = 0.364 mol·l -1 ) was added under ice cooling in an argon atmosphere to the reactants 1 2+ and N-ethylcarbazole.
The reaction was stirred for 15 min under ice cooling and then allowed to warm up to room temperature.
The reaction was stopped by the addition of an aqueous saturated NaHCO3 solution.
The small amount of CH3CN and HBF4•OEt2 was removed under high-vacuum. Then an aqueous diluted solution of NaOH (8%) was added (pH > 9), converting all formed (1+4H) 4+ to (1+2H) 2+ (for subsequent transfer into the organic phase). A clear solution was obtained that was extracted several times with CH2Cl2. The combined organic phases were dried over Na2SO4, filtrated and condensed.

General protocol
In a Schlenk flask, 0.5 ml of a HBF4·OEt2 solution (5% in CH3CN, c = 0.364 mol·l -1 ) was added under ice cooling in an argon atmosphere to the reactants 1 2+ and to an appropriate volume of a 3,3''-dimethoxy-3',4'-dimethyl-o-terphenyl -solution (c = 0.284 mol·l -1 in CH3CN). The reaction was stirred for 10 min under ice cooling and then allowed to warm up to room temperature.
The reaction was stopped by the addition of an aqueous saturated NaHCO3 solution.
The small amount of CH3CN and HBF4·OEt2 was removed under high-vacuum. Then an aqueous diluted solution of NaOH (8%) was added (pH > 9), converting all formed (1+4H) 4+ to (1+2H) 2+ (for subsequent transfer into the organic phase). A clear solution was obtained that was extracted several times with CH2Cl2. The combined organic phases were dried over Na2SO4, filtrated and condensed.
Workup [2] : the reaction mixture was quenched by H2O, extracted several times with ethylacetate and dried over MgSO4. After the organic layer had been filtered and concentrated the crude product was purified by column chromatography on silica gel (d
Workup [2] : the reaction mixture was quenched by H2O, extracted several times with ethylacetate and dried over MgSO4. After the organic layer had been filtered and concentrated the crude product was purified by column chromatography on silica gel (d

General protocol (NMR experiments)
In a Schlenk flask 1 2+ , HMB and 9,10-dihydroanthracene were dissolved in 0.45 ml CD3CN and transferred via syringe into a flame-sealable NMR tube. HBF4·OEt2 (10% in CD3CN, c = 0.729 mol·l -1 ) was added via microliter syringe. The NMR tube was flame-sealed in vacuum at -196 °C. Plot showing the conversion as a function of time for the reaction between 1(PF6)2 and 9,10-dihydroanthracene in the presence of 5 eq. and 9 eq. HBF4·OEt2 Please note that the conversion in this plot refers to the decay of the dihydroanthracene (AnH2) signals in the 1 H NMR spectrum. By contrast, the conversion to anthracene (NMR yield) given in the tables are determined from the anthracene (An) signal integrals relative to the guanidine signal integrals. The different procedures are necessary due to the formation of the radical AnH · as reaction intermediate, leading to temporary broad product signals not applicable for integration in the course of the reaction.

Stopped flow UV-vis measurements:
First, stock solutions of (1+2H)(PF6)2 (solution I) and 2(PF6)2 (solution II) were prepared. By stepwise dilution of solution II, three further solutions (III-V) of 2(PF6)2 with decreasing concentrations were obtained. Then the two storage vessels of the instrument were charged with solution I and one of the solutions II-V, and the measuring cell filled with equal volumes of both solutions.
The following concentrations and molar ratios between the two reactants result.

General protocol (NMR experiments)
Under an argon atmosphere 0.25 ml of a solution of 10-methyl-9,10-dihydroacridine (c = 0.0258 mol·l -1 in CH3CN) was transferred into a flame-sealable NMR tube and the solvent was removed under high-vacuum. In a Schlenk flask 2(PF6)2 and HMB were dissolved in 0.45 ml CD3CN and added via syringe to the 10-methyl-9,10dihydroacridine. The NMR tube was flame-sealed in vacuum at -196 °C. 10