Aromatic C−F Hydroxylation by Nonheme Iron(IV)−Oxo Complexes: Structural, Spectroscopic, and Mechanistic Investigations
Sumit Sahu,† Bo Zhang,‡,§ Christopher J. Pollock,‡,§ Maximilian Dürr,∥ Casey G. Davies,⊥ AlexM.Confer,† IvanaIvanovic-́Burmazovic,́∥ MaximeA.Siegler,† GuyN.L.Jameson,*,⊥ Carsten Krebs,*,‡,§ and David P. Goldberg*,†
†Department of Chemistry, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, United States ‡Department of Chemistry and §Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University
Park, Pennsylvania 16802, United States
∥Department of Chemistry and Pharmacy, University of Erlangen-Nürnberg, 91058 Erlangen, Germany
⊥Department of Chemistry & MacDiarmid Institute for Advanced Materials and Nanotechnology, University of Otago, PO Box 56, Dunedin 9054, New Zealand
http://pubs.acs.org/doi/abs/10.1021/jacs.6b03346
ABSTRACT:
The synthesis and reactivity of a series of mononuclear nonheme iron complexes that carry out intramolecular aromatic C−F hydroxylation reactions is reported. The key intermediate prior to C−F hydroxylation, [FeIV(O)- (N4Py2Ar1 )](BF4)2 (1-O, Ar1 = −2,6-difluorophenyl), was characterized by single-crystal X-ray diffraction. The crystal structure revealed a nonbonding C−H···OFe interaction with a CH3CN molecule. Variable-field Mö ssbauer spectroscopy of 1-O indicates an intermediate-spin (S = 1) ground state. The Mö ssbauer parameters for 1-O include an unusually small quadrupole splitting for a triplet FeIV(O) and are reproduced well by density functional theory calculations. With the aim of investigating the initial step for C−F hydroxylation, two new ligands were synthesized, N4Py2Ar2 (L2, Ar2 = −2,6-difluoro-4-methoxyphenyl) and N4Py2Ar3 (L3, Ar3 = −2,6-difluoro-3-methoxyphenyl), with −OMe substituents in the meta or ortho/para positions with respect to the C−F bonds. FeII complexes [Fe(N4Py2Ar2 )(CH3CN)]- (ClO4)2 (2) and [Fe(N4Py2Ar3 )(CH3CN)](ClO4)2 (3) reacted with isopropyl 2-iodoxybenzoate to give the C−F hydroxylated FeIII−OAr products. The FeIV(O) intermediates 2-O and 3-O were trapped at low temperature and characterized. Complex 2-O displayed a C−F hydroxylation rate similar to that of 1-O. In contrast, the kinetics (via stopped-flow UV−vis) for complex 3-O displayed a significant rate enhancement for C−F hydroxylation. Eyring analysis revealed the activation barriers for the C−F hydroxylation reaction for the three complexes, consistent with the observed difference in reactivity. A terminal FeII(OH) complex (4) was prepared independently to investigate the possibility of a nucleophilic aromatic substitution pathway, but the stability of 4 rules out this mechanism. Taken together the data fully support an electrophilic C−F hydroxylation mechanism.
†Department of Chemistry, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, United States ‡Department of Chemistry and §Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University
Park, Pennsylvania 16802, United States
∥Department of Chemistry and Pharmacy, University of Erlangen-Nürnberg, 91058 Erlangen, Germany
⊥Department of Chemistry & MacDiarmid Institute for Advanced Materials and Nanotechnology, University of Otago, PO Box 56, Dunedin 9054, New Zealand
http://pubs.acs.org/doi/abs/10.1021/jacs.6b03346
ABSTRACT:
The synthesis and reactivity of a series of mononuclear nonheme iron complexes that carry out intramolecular aromatic C−F hydroxylation reactions is reported. The key intermediate prior to C−F hydroxylation, [FeIV(O)- (N4Py2Ar1 )](BF4)2 (1-O, Ar1 = −2,6-difluorophenyl), was characterized by single-crystal X-ray diffraction. The crystal structure revealed a nonbonding C−H···OFe interaction with a CH3CN molecule. Variable-field Mö ssbauer spectroscopy of 1-O indicates an intermediate-spin (S = 1) ground state. The Mö ssbauer parameters for 1-O include an unusually small quadrupole splitting for a triplet FeIV(O) and are reproduced well by density functional theory calculations. With the aim of investigating the initial step for C−F hydroxylation, two new ligands were synthesized, N4Py2Ar2 (L2, Ar2 = −2,6-difluoro-4-methoxyphenyl) and N4Py2Ar3 (L3, Ar3 = −2,6-difluoro-3-methoxyphenyl), with −OMe substituents in the meta or ortho/para positions with respect to the C−F bonds. FeII complexes [Fe(N4Py2Ar2 )(CH3CN)]- (ClO4)2 (2) and [Fe(N4Py2Ar3 )(CH3CN)](ClO4)2 (3) reacted with isopropyl 2-iodoxybenzoate to give the C−F hydroxylated FeIII−OAr products. The FeIV(O) intermediates 2-O and 3-O were trapped at low temperature and characterized. Complex 2-O displayed a C−F hydroxylation rate similar to that of 1-O. In contrast, the kinetics (via stopped-flow UV−vis) for complex 3-O displayed a significant rate enhancement for C−F hydroxylation. Eyring analysis revealed the activation barriers for the C−F hydroxylation reaction for the three complexes, consistent with the observed difference in reactivity. A terminal FeII(OH) complex (4) was prepared independently to investigate the possibility of a nucleophilic aromatic substitution pathway, but the stability of 4 rules out this mechanism. Taken together the data fully support an electrophilic C−F hydroxylation mechanism.
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