Mechanistic Investigation of Oxygen Rebound in a Mononuclear Nonheme Iron Complex

Article abstract of DOI:10.1021/acs.inorgchem.9b01208

An iron(III) methoxide complex reacts with para-substituted triarylmethyl radicals to give iron(II) and methoxyether products. Second-order rate constants for the radical derivatives were obtained. Hammett and Marcus plots suggest the radical transfer rea

Full text of DOI:10.1021/acs.inorgchem.9b01208

Communication
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Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
Mechanistic Investigation of Oxygen Rebound in a Mononuclear
Nonheme Iron Complex
‡
‡
,‡
Thomas M. Pangia,†,∇ Vishal Yadav,†,∇ Emilie F. Gerard, Yen-Ting Lin, Sam P. de Visser,*
́
Guy N. L. Jameson,§ and David P. Goldberg*,†
†Department of Chemistry, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, United States
‡Manchester Institute of Biotechnology and School of Chemical Engineering and Analytical Science, The University of Manchester,
131 Princess Street, Manchester M1 7DN, United Kingdom
§School of Chemistry, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 30 Flemington Road,
Parkville, Victoria 3010, Australia
S
* Supporting Information
Scheme 1. Comparison of Heme and Nonheme Iron
Enzymes
ABSTRACT: An iron(III) methoxide complex reacts
with para-substituted triarylmethyl radicals to give iron-
(II) and methoxyether products. Second-order rate
constants for the radical derivatives were obtained.
Hammett and Marcus plots suggest the radical transfer
reactions proceed via a concerted process. Calculations
support the concerted nature of these reactions involving
a single transition state with no initial charge transfer.
These findings have implications for the radical “rebound”
step invoked in nonheme iron oxygenases, halogenases,
and related synthetic catalysts.
he preferential formation of C−O bonds by heme and
Tnonheme iron enzymes typically occurs through C−H
bond cleavage by a high-valent FeIVO species, followed by a
radical “rebound” step in which the newly formed carbon
radical (R•) and Fe(OH) intermediate combine to give R−
OH and a reduced Fe product.1−4 However, alternate
outcomes are sometimes observed, including desaturation or
decarboxylation (e.g., heme: Cytochrome P450 (CYP) OleT;
nonheme: AsqJ, NapI, VioC, UndA).5−12 In the nonheme iron
halogenases (e.g., CytC3, WelO5, SyrB2),13−17 the radical
selectively combines with a halide ligand rather than an OH
ligand, leading to halogenation. Interestingly, the nonheme
iron enzyme isopenicillin N synthase (IPNS) may operate
through a similar pathway, in which a CVal radical combines
selectively with a coordinated thiolate ligand, instead of a
bound OH group, to give the final thiazolidine ring.18 Studies
on biomimetic, high-valent metal-oxo complexes showed that
different outcomes can occur from the carbon radical stage,
including conventional hydroxylation as well as simple radical
dissociation away from the Fe(OH) species.4,19,20 The factors
that control the rates and selectivities of these reactions remain
poorly understood.
FeIV(OH)(porphyrin) to an FeIII(porphyrin). The analogous
nonheme chemistry, exemplified by the hydroxylation
performed by TauD shown in Scheme 1, occurs via the
lower-valent FeIII(OH) to FeII transformation.1,23 Recently, we
showed that a nonheme FeIII(OMe) complex reacts with trityl
radical via homolytic cleavage of the Fe−OMe bond to give
Ph3COMe and FeII.24 However, no kinetic data were obtained
and the mechanism was not examined in detail. To our
knowledge, experimentally determined rates of the rebound
reaction in nonheme enzymes or models are not known.
Herein, we show that [FeIII(N3PyO2Ph)(OCH3)](ClO4) (1)
reacts with a series trityl radical derivatives, and a detailed
kinetic study provides key insights regarding the mechanism of
these reactions. Density functional theory (DFT) calculations
help support the observed reactivity.
In our initial report, we employed triphenylmethyl radical
(Ph3C•), a stable carbon radical, for reaction with 1. In the
current work, we varied the electronic character of the radical
derivatives by para substitution.25 A series of para-X-
substituted radicals (X = OCH3, tBu, Ph, CN) were prepared.
Addition of (4-tBu-C6H4)3C• (5 equiv) to 1 (Scheme 2) led
to the conversion of dark purple 1 to yellow-orange within 5
1
min. Analysis by H NMR spectroscopy of the same reaction
The synthesis of a heme-like Fe(OH) corrole complex
provided us with a platform to examine reactions with carbon
radicals (trityl radical derivatives).21,22 These model reactions
could be compared to the rebound hydroxylation process seen
in CYP, involving protonated Compound II (Cpd-II, Scheme
1).21 The heme-based CYP undergoes reduction of a formal
mixture in toluene-d8 showed formation of the methoxy group
of (p-tBu-C6H4)3COCH3. Quantitation gave a 70% yield of
Received: April 24, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.inorgchem.9b01208
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Inorganic Chemistry
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Scheme 2. Reaction of 1 with para-X-Substituted
Triphenylmethyl Radicals
methoxyether (see Figure S8 in the Supporting Information).
The 57Fe-labeled 1 in THF/toluene revealed a broad doublet
−1
̈
in the Mossbauer spectrum (δ = 0.5 mm s , |ΔEQ| = 1.29 mm
s−1), which is indicative of an FeIII complex in an intermediate
relaxation regime, as reported earlier.24 This doublet
disappears following the addition of (4-tBu-C6H4)3C•, giving
rise to two new high-spin FeII subcomponents: δ = 1.16 mm
s−1, |ΔEQ| = 2.68 mm s−1 (80% of total fit) and δ = 1.34 mm
s−1, |ΔEQ| = 3.29 mm s−1 (20% of total fit) (see Figure S10 in
the Supporting Information). The latter component exhibits
parameters that are similar to the FeII species formed after
reaction with the unsubstituted Ph3C•,24 although the latter
reaction was carried out in pure THF. The solvent mixture
employed here (toluene/THF 1:2) likely leads to different
solvent binding equilibria that produces two, related high-spin
Figure 1. (A) Plot of kobs versus [(p-tBu-C6H4)3C•], where the slope
of the best fit (red line) gives k2 = 13.4(1) M−1 s−1. (B) Hammett
plot. (C) Marcus plot. (D) Eyring plot of (ln(kobs/T) vs 1/T for the
reaction of 1 and (p-tBu-C6H4)3-C• from −10 °C to 25 °C.
possible noninnocent behavior of the corrole ligand, but the
overall redox level is one unit above the nonheme system
(formally FeIV(OH)), and this difference in redox levels may,
in part, help to explain the enhanced reactivity of the corrole
complex. Alternatively, the difference in reactivity may be due
to the steric demands of the axial OMe versus OH ligand, or
may arise from an inherent difference in Fe−OMe versus Fe−
OH homolytic bond strengths. Further work is needed on both
heme and nonheme systems to resolve these fundamental
questions.
FeII products, which, in turn, gives rise to the two overlapping
III
̈
Mossbauer signals. There is no evidence of any Fe starting
material remaining. When acetonitrile is added to the product
mixture, the spectrum resolves to a single high-spin FeII
component, δ = 1.16 mm s−1, ΔEQ = 2.66 mm s−1, matching
that for [FeII(N3PyO2Ph)(CH3CN)]+,24 and indicating that 1
is quantitatively reduced to iron(II) via the radical reaction.
+
A Hammett plot (Figure 1B) consisting of log k2 vs 3σ ,
1
t
The H NMR and Mossbauer spectra indicate that (4- Bu-
C6H4)3C• reacts with 1 in good yield via the radical reaction
shown in Scheme 2.
where σ+ is the Hammett parameter for the para-X substituents
in (p-X-C6H4)3C•. The rates decrease linearly with the σ+
values, indicating that 1 is behaving as an electrophile, as
expected. However, the slope is small (ρ = −0.25). In fact, it is
less than half the slope seen for the Hammett plot for
Fe(OH)(ttppc) (ρ = −0.55) with the same trityl radical
derivatives. Both ρ values suggest little charge separation in the
transition state,21,26 and 1 is even less sensitive to the
electrophilicity of the radical derivatives.
̈
Mechanistic information was obtained from kinetic studies.
Complex 1 was reacted with (p-X-C6H4)3C• derivatives under
pseudo-first-order conditions (excess radical) in toluene at 23
°C. The consumption of 1 could be followed by UV-vis
spectroscopy, leading to decay curves that give a pseudo-first-
order rate constant (kobs) (see Figures S2−S5 in the
Supporting Information). Measuring the kobs values at different
radical concentrations led to second-order rate constants (k2)
(Figure 1A) with a range of k2 values between 2−25 M−1 s−1
(X = CN < Ph < tBu < OMe), which increased with the
electron-donating ability of the para-substituent.
The reaction for 1 with the carbon radicals could occur as a
concerted process in which C−O bond formation occurs with
concomitant Fe−O bond cleavage and reduction of FeIII to
FeII, or it could proceed following a stepwise electron-transfer/
cation transfer (ET/CT) pathway shown in Scheme 3. The
possibility of an ET/CT mechanism was addressed by a
Marcus plot (Figure 1C). The plot shows reasonable linearity,
but the slope (ρ = −0.098) is quite small, showing only a weak
dependence on the redox potentials of the radical substrates. In
comparison, a rate-limiting, outer-sphere ET process gives
typical slopes on the order of −0.5 provided ΔGET/λ is
relatively small.21,27 The same plot for the reaction of
Fe(OH)(ttppc) also gave a small slope (ρ = −0.15). This
analysis indicates the mechanism for 1 is best-described as a
concerted process (i.e., the diagonal path in Scheme 3). The
same Marcus analysis has also been applied to metal-mediated
H atom transfer reactions, with small slopes indicating a
concerted proton electron-transfer (CPET) process.28,29
Although there are no other analogous rate constants
available for nonheme iron complexes for comparison, we can
compare these rate constants to those measured previously for
a heme-like corrole complex. The iron corrole Fe(OH)(ttppc)
(ttppc = tris(2,4,6-triphenylphenyl corrole) undergoes similar
t
radical reactivity with (p-X-C6H4)3C• (X = OCH3, Bu, Ph,
Cl) to give (p-X-C6H4)3COH and FeIII(ttppc), with rate
constants ranging from 12.6(1) to 357(4) M−1 s−1.21 The ttppc
complex is sterically encumbered by large triphenylphenyl
groups, but appears to react significantly faster than 1; e.g.,
Fe(OH)(ttppc) reacts 14 times faster than 1 with the para-
OMe derivative. The physical oxidation state of the iron center
in the ttppc complex is not easily assigned, because of the
B
DOI: 10.1021/acs.inorgchem.9b01208
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Communication
mol−1, respectively. The calculated enthalpy values (see Table
S9 in the Supporting Information) are relatively close to the
experimental value obtained from the Eyring analysis.
Scheme 3. Concerted versus ET/CT Pathways
The transition state (TS) structures for the FeIII(OMe) and
FeIII(OH) complexes are similar in both geometry and relative
energies, although one of the py donors appears dissociated
from the metal in both structures (Figure 2) due to steric clash,
The pseudo-first-order rate constants (kobs) were measured
between −10 °C and 25 °C, and a plot of ln(k/T) versus 1/T
(Figure 1D) gave activation parameters: ΔH⧧ = 13.2(1.6) kcal
Figure 2. Transition-state structures for [FeIII(OCH3)(N3PyO2Ph)]+
(left) and [FeIII(OH)(N3PyO2Ph)]+ (right) with (4-Cl-C6H4)3C•.
The C−O and Fe−O distances (in Å), and imaginary frequencies, are
listed for each structure.
mol−1 and ΔS⧧ = −22.1(0.4) cal mol−1 K−1, and ΔG⧧
=
19.7(1.7) kcal mol−1 at 298 K. These values are consistent with
a bimolecular rate-determining step.
Reaction of 1 and trityl cation, Ph3C+, gives very different
results. Combining 1 and (Ph3C)BF4 (4 equiv) in THF at 23
°C led to a reaction that was over within seconds, as seen by
UV-vis. The ether product (Ph3COCH3) was formed in 80%
yield (Figure S9 in the Supporting Information), and the iron
complex did not change oxidation state, as seen by UV-vis
as a result of substrate approach. However, this Fe-py bond is
restored during product formation, giving the expected FeII
product. The structures shown in Figure 2 indicate relatively
early transition states, consistent with facile, exothermic
reactions. The DFT results show that a concerted, radical
group transfer mechanism is favored for both the FeIII(OMe)
and FeIII(OH) complexes, and the electronic changes are
similar for both species. Calculations for other heme and
nonheme iron-hydroxo complexes have also shown a single
transition state, implicating a concerted process.31−33
The combined experimental and computational data suggest
that the radical rebound step in nonheme iron enzymes or
synthetic catalysts may proceed by a concerted process, with
little or no charge transfer prior to C−O bond formation. The
sizable reaction barrier for the rebound process for complex 1
is significantly different from the considerably smaller rebound
processes predicted for nonheme iron enzymes. However, the
model complex reacts via a bimolecular process, whereas the
radicals in the enzymes are trapped in the active site pocket
and react directly via a first-order process. In addition, the trityl
radical derivatives are significantly more stable than typical
primary or secondary alkyl radicals generated in the biological
systems. The conclusion that a concerted “rebound” pathway is
operative for 1 suggests that radical rebound in nonheme iron
enzymes also may be concerted, which could help determine
product selectivity. The substrate radical must be held in a
close, appropriate orientation for a concerted pathway to lead
to a productive reaction. Obtaining such information from
model systems should further our understanding of the
selectivity of rebound processes in nonheme iron enzymes
such as the halogenases, IPNS, and related systems.
̈
(Figure S7 in the Supporting Information) and Mossbauer
spectroscopy (see Figure S10 in the Supporting Information).
The nucleophilic reactivity of 1 with trityl cation is consistent
with the reactivity observed for other metal-alkoxide
complexes.30 It appears as though heterolytic cleavage of the
Fe−O bond in 1 is facile, compared to homolytic cleavage,
although the origins of this difference are not well understood
at this time.
DFT calculations on [Fe(OCH3)(N3PyO2Ph)]+, and the
related hypothetical hydroxide complex [Fe(OH)-
(N3PyO2Ph)]+, led to optimized geometries for the sextet
spin ground states of these species (see Figure S11 in the
6
Supporting Information). The metrical parameters for [Fe-
(OCH3)(N3PyO2Ph)]+ match reasonably well with the
reported crystal structure, except for Fe−N1(py), which is
elongated by ∼0.10 Å in the DFT structure. The initial
reactant complex (Re) involves the association of the FeIII
complex with a radical substrate whose unpaired spin is aligned
parallel (septet) or antiparallel (quintet) to the Fe d electrons.
The quintet states were uniformly lower in energy. No charge
transfer in the Re was observed. Attempts to interchange
molecular orbitals to generate a charge-transfer state (e.g.,
5[Fe(OH)(N3PyO2Ph)]0−(4-Cl-C6H4)3C+) for 5ReOH,Cl) al-
ways converged back to the structure with a radical on the
carbon moiety. The [FeII(N3PyO2Ph)+ + ROCAr3)] (R = H,
Me) products (Pr) were also calculated, and their relative
energies showed similar exothermicities (5Pr(ΔE + ZPE) −
(5Re(ΔE + ZPE)) = −7 to −8 kcal mol−1) for the FeIII(OMe)
and FeIII(OH) complexes, suggesting similar reaction pathways
for these species. Transition state (TS) structures were located
for the FeIII(OMe) and FeIII(OH) complexes and the (p-Cl-
C6H4)3C• radical, and free energies of activation with the
Wertz entropy correction give values of 25.0 and 23.9 kcal
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.9b01208.
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DOI: 10.1021/acs.inorgchem.9b01208
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̈
Experimental procedures, UV-vis data, kinetics, Moss-
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AUTHOR INFORMATION
Corresponding Authors
*E-mail: dpg@jhu.edu (D. P. Goldberg).
*E-mail: sam.devisser@manchester.ac.uk (S. P. de Visser).
ORCID
Vishal Yadav: 0000-0002-7016-2991
Sam P. de Visser: 0000-0002-2620-8788
Guy N. L. Jameson: 0000-0001-9416-699X
David P. Goldberg: 0000-0003-4645-1045
■
Author Contributions
∇These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NIH (GM119374) to D.P.G. The
BBSRC is acknowledged for a studentship to E.F.G. and
S.P.d.V. (under Grant No. BB/M011208/1).
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