Direct Observation of Primary C?H Bond Oxidation by an Oxido-Iron(IV) Porphyrin π-Radical Cation Complex in a Fluorinated Carbon Solvent

Article abstract of DOI:10.1002/anie.201901608

Oxido-iron(IV) porphyrin π-radical cation species are involved in a variety of heme-containing enzymes and have characteristic oxidation states consisting of a high-valent iron center and a π-conjugated macrocyclic ligand. However, the short lifetime of the complex has hampered detailed reactivity studies. Reported herein is a remarkable increase in the lifetime (80 s at 10 °C) of Fe^IV(TMP^+.)(O)(Cl) (2; TMP=5,10,15,20-tetramesitylporphyrin dianion), produced by the oxidation of Fe^III(TMP)(Cl) (1) by ozone in α,α,α-trifluorotoluene (TFT). The lifetime is 720 times longer compared to that of the currently most stable species reported to date. The increase in the lifetime improves the reaction efficiency of 2 toward inert alkane substrates, and allowed observation of the reaction of 2 with a primary C?H bond (BDE_C-H=ca. 100 kcal mol^?1) directly. Activation parameters for cyclohexane hydroxylation were also obtained.

Full text of DOI:10.1002/anie.201901608

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Accepted Article
Title: Direct Observation of Primary C–H Bond Oxidation by An Oxido-
iron(IV) Porphyrin π-Radical Cation Complex in a Fluorinated
Carbon Solvent
Authors: Yuma Morimoto, Yuki Shimaoka, Yuri Ishimizu, Hiroshi Fujii,
and Shinobu Itoh
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Direct Observation of Primary C–H Bond Oxidation by An Oxido-
iron(IV) Porphyrin π-Radical Cation Complex in a Fluorinated
Carbon Solvent
Yuma Morimoto,[a],* Yuki Shimaoka,[a] Yuri Ishimizu,[b] Hiroshi Fujii,[b],* Shinobu Itoh,[a],*
Abstract: Oxido-iron(IV) porphyrin π-radical cation species are
involved in a variety of heme-containing enzymes, which has been
attracting considerable attentions due to its biological importance and
characteristic oxidation states consisting of the high-valent iron center
and the π-conjugated macrocyclic ligand. However, the short lifetime
of the complex due to its high reactivity has hampered detailed
reactivity study. We herein report remarkable lifetime elongation (80 s
temperature to be very low (e.g. –80 °C). Usage of water solvent
with hydrophilic porphyrins can encumber solvent oxidation
problem. However, synthesis of modified porphyrins is
demanding, and substrates are limited to hydrophilic ones.
Moreover, experimental temperature must be above 0 °C. To
overcome these limitations, we herein utilize α,α,α-trifluorotoluene
(TFT) as a solvent to accomplish remarkable elongation of lifetime
of 2. Miscibility of TFT with organic compounds is close to that of
dichloromethane according to the Hildebrand solubility parameter
() (9.2 for TFT and 9.9 for dichloromethane, respectively),[7] and
TFT does not have any sp3 C–H bond. Also reported are the
reactivity study of 2 in TFT toward inert alkane substrates
including primary C–H bonds.
at
10
°C)
of
FeIV(TMP+•)(O)(Cl)
(TMP:
5,10,15,20-
tetramesitylporphyrin dianion) (2) produced by the oxidation of
FeIII(TMP)(Cl) (1) by ozone in α,α,α-trifluorotoluene (TFT), which is
720 times longer lifetime as compared to that of the currently most
stable one reported by Groves et al. (J. Am. Chem. Soc. 2009, 131,
9640-9641). The drastic elongation of the lifetime improves reaction
efficiency of 2 toward inert alkane substrates, and allows us to
observe the reaction of 2 with a primary C–H bond (BDEC–H = ca. 100
kcal mol–1) directly. We also succeeded to obtain activation
parameters for cyclohexane hydroxylation.
In TFT, a treatment of FeIII(TMP)(Cl) (1) (28 µM) with a slightly
excess amount of ozone gas at 10 °C generated a green species
with a broad absorption band around 670 nm (Figure 1a, red line),
which is similar to that of 2 observed in dichloromethane (667
nm).[6f, 6g, 8] In EPR spectrum of the generated complex, signals
assignable to quartet species (S = 3/2) were detected around g =
4 and 2 (see Supporting Information, Figure S1a).[9] The
resonance Raman spectrum measured at room temperature
showed a band around 800 cm–1 ascribed to an Fe=O vibration
(Figure S1b).[10] All of these spectroscopic features are consistent
with a formation of 2 in TFT (Scheme 1). The UV-vis absorption
band of 2 gradually decreased obeying first-order kinetics with the
first-order rate constant (kdec) of 1.2 × 10–2 s–1 (lifetime [1/kdec] =
80 s) (Figure 1b). The lifetime is much longer than those of the
compound I generated in protein pockets of CPO, CYP119, and
AaeAPO by several orders.[4d, 4f, 11] Remarkably, the lifetime of 2
is 720 times longer than that of FeIII(4-TMPyP)(Cl) generated in
water at 10 °C, which is the currently longest lifetime of compound
I in model systems (Table 1).[4c] We could clearly observe 2 even
at 30 °C with the lifetime of 19 s (Figure S2). The lifetime of 2 can
be extended to 2.2 × 103 s by decreasing the temperature to –
20°C (Table S1). We further examined the stability of 2 in the
other solvents at 30 °C. 1,4-Di-trifluoromethylbenzene and
perfluorotoluene also prompted the formation of 2 (Figure S3,S4).
Alkane hydroxylation is a difficult process due to the high bond
dissociation energy of C–H bond (BDEC–H).[1] The reaction,
usually requiring high temperature conditions, has been attracted
huge attentions of organic and inorganic chemist.[2] In biological
systems, heme and non-heme enzymes perform such difficult
oxidation reactions of alkanes by means of a high-valent metal-
oxide species as the key reactive intermediate.[3] Among those
reactive oxidants, oxido-iron(IV) porphyrin π-radical cation
species, compound I, in cytochrome P450 is one of the most
important species responsible to metabolisms of versatile
lipophilic compounds.[4] After the first report of a direct observation
of compound I model complex, FeIV(O)(TMP•+)(Cl) (2) (TMP:
5,10,15,20-tetramesitylporphyrin) at –78 °C,[5] its reactivity has
been extensively studied along with its application to synthetic
organic chemistry.[6] Dichloromethane is often used as a solvent
in those studies, but the solvent oxidation limits the substrates
with higher reactivity as compared to the solvent and the reaction
[a]
Dr. Y. Morimoto, Y. Shimaoka, Prof. Dr. S. Itoh
Department of Material and Life Science,
Graduate School of Engineering, Osaka University
2-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
E-mail: y-morimoto@mls.eng.osaka-u.ac.jp,
shinobu@mls.eng.osaka-u.ac.jp
Scheme 1. Formation of 2 by the reaction of 1 with O3 in TFT
[b]
Y. Ishimizu, Prof. Dr. H. Fujii
Department of Chemistry, Graduate School of Humanities and
Sciences, Nara Women’s University, Kitauoyanishi, Nara 630-8506,
Japan.
E-mail: fujii@cc.nara-wu.ac.jp
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:ꢀ
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(a)
(b)
0.14
0.13
0.12
0.11
0.10
0.09
0.08
–3
–4
–5
–6
–7
2.0
1.5
1.0
0.5
0
0
100
Time (s)
200
× 5
300
400
500
600
700
800
0
100
200
Time (s)
300
Wavelength (nm)
Figure 1. (a) Spectral changes for the oxidation of 1 (28 µM) (black line) to 2
(red line) with ozone in TFT at 10 °C. (b) Time course of the absorbance change
at 670 nm in the self-decomposition of 2 in TFT at 10 °C. The inset shows first-
order plot based on the absorption changes at 670 nm.
Figure 2. (a) Spectral changes for the reaction of 2 with 2,2,3,3-tetra-
methylbutane (TMB) (150 mM) in TFT at 0 °C (red: 0 s, blue: 400 s). (b) Time
courses of the absorbance change at 670 nm in the reactions of 2 with TMB
(150 mM: blue, 100 mM: orange, 50 mM: red, and 25 mM: green). Inset: plots
of the kobs vs [TMB], The plot for [TMB] = 0 is the self-decay rate of 2.
Table 1. Comparison of lifetime (1/kdec) of compound I in enzymatic systems
and its model complexes around room temperature.
(BDEC–H: 101 kcal mol–1), is the first example of primary carbon
oxidation with a compound I model compound.[14][15][16]
enzyme or complex
temp. (°C)
1/kdec (s)
2.0
ref.
Reactivity of 2 toward cyclohexane (c-C6H12), cycloheptane (c-
C7H14), cyclooctane (c-C8H16), and butane (n-C4H10) were also
examined to yield cyclohexanol, cycloheptanone, cyclooctanone,
and butanone as the major product, respectively. The second-
order rate constants (kC–H) for the oxidation of these substrate
were determined as well (Figure S12, Table S3). Notably, kC–H
values for gaseous alkane substrate, butane is adequately
obtained to be 1.5 × 10–1. The kinetic isotope effect (KIE) value
for cyclohexane oxidation was determined to be 4.1 by using
cyclohexane-d12 (c-C6D12) (Figure S12e, S13).[17],[18] The obtained
kC–H value was normalized by dividing it with the number of
identical C–H bonds to give k’C–H, and log k’C–H values are plotted
against BDE values of the substrates (Figure 3a).[16] The log k’
values becomes smaller with increase of the BDEC–H of the
substrates, which is consistent with the occurrence of hydrogen
atom abstraction in the rate-determining step (R.D.S.) of the
hydroxylation reaction. Obviously, the plots in figure 3a cannot be
fitted with single linear line, indicating that the free energy
relationship between the activation energy of the reaction and
BDEC–H of the substrates cannot be approximated as first order
with the range of BDEC–H values of the substrates (ca. 7 kcal mol–
1) in this system. Groves and co-workers reported a similar curved
plot for compound I in protein AaeAPO.[4f] The bent log k’ vs
BDEC–H plot even without protein cavity supports the curvature
should be resulted from intrinsic property of the reaction center
rather than the cavity of the enzyme. There is no other report of
such a bent plot for metal-oxide reactive species to date,[19]
CPO a
25
4
30
CYP119 a
0.11
0.24
0.11
80
16, 31
18
AaeAPO a
4
FeIV(O)(4-TMPyP+•)(Cl) a
10
10
30
15
2 b
2 b
this work
this work
19
a measured in water. b measured in TFT.
However, the lifetime of 2 in those fluorocarbon solvents were
much shorter than that in TFT. The lower polarity of those solvents
than TFT may decrease stability of the high-valent species. In
contrast, in dichloromethane, the reaction of 1 with ozone gas
didn’t yield observable amount of 2 (Figure S5). The reactivity
between 2 and dichloromethane was examined in TFT, and the
second-order rate constant was determined to be 7.4 × 10–3 M–1
s–1 at 0 °C (Figure S6). Solvents having an electron-withdrawing
substituent like nitrobenzene, benzonitrile, and fluorobenzene
cannot extend the lifetime of 2 (Figure S7–S9).[12] In addition,
usage of m-chloroperbenzoic acid (m-CPBA) as the oxidant
instead of ozone did not result in accumulation of oxido-iron(IV)
porphyrin radical complex both in TFT and CH2Cl2 (Figure S10–
S11). Probably, m-CPBA or generated m-chlorobenzoic acid (m-
CBA) further reacts with 2.
Taking the advantage of the drastic elongation of the lifetime of
2 in TFT, we further examined reactivity of 2 toward alkane
substrates at 0 °C. Upon an addition of 150 mM of 2,2,3,3-
tetramethylbutane (TMB) to a solution of 2 (28 µM), absorption
bands of 2 decayed to give almost identical spectrum to that of 1
with clear isosbestic points (Figure 2a). The reaction was
significantly faster than the natural decay of 2, and obeyed first
order kinetics (Figure 2b). The product of the reaction was
determined to be 2,2,3,3-tetramethylbutanol with the yield of 10%
based on 1.[13] The second-order rate constant of the reaction (kC–
H) was determined to be 2.4 × 10–2 M–1 s–1 from the slope of the
linear plot of pseudo-first-order rate constants (kobs) against the
concentration of TMB (Figure 2b, inset). The reaction of 2 with
2,2,3,3-tetramethylbutane, only bearing primary C–H bonds
(a)
(b)
–7
–8
1
2
–1
–2
–3
3
4
–9
5
6
–10
94
96
98
100
102
3.6
3.7
3.8
3.9
4.0
BDEC–H (kcal mol–1
)
103 × 1/T (K–1
)
Figure 3. (a) Plots of log k’ against the BDEC–H values of substrates (1: c-C7H14
,
2: c-C8H16, 3: n-C4H10, 4: c-C6H12, 5: cyclohexane-d12, 6: TMB). (b) Eyring plot
for hydroxylation of c-C6H12 (T: –20 – 0 °C), which yields ΔH‡ and ΔS‡ values of
12.3 kcal mol–1 and –17.7 cal K–1 mol–1, respectively.
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which implies very small reorganization energies in hydrogen
atom transfer from alkanes to 2.[20] Quantitative evaluation of the
plot is under investigations.
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The high thermostability of 2 in TFT also enabled us to conduct
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various temperatures.[21] An Eyring plot is shown in Figure 3b
(Table S4), from which the activation enthalpy (ΔH‡) and the
activation entropy (ΔS‡) values were determined as 12.3 kcal mol–
[2]
[3]
[4]
1
and –17.7 cal K–1 mol–1, respectively. These activation
parameters are compared to those for cyclohexane hydroxylation
by [FeV(O)(OAc)(PyNMe3)]2+ and [FeV(O)(TAML)]– and listed in
Table S5 together with those data for t-butyl alkoxy radical.[22][23]
The ΔH‡ values decreased from 14.3 to 8.8 kcal mol–1 with slight
increase of ΔS‡ values (corresponds to 4.6–5.0 kcal mol–1 at 0 °C)
as the total charge of the iron complex becomes positive. The
aliphatic hydroxylation reactions by formal oxide-iron(V)
complexes can be regarded as ΔH‡-controlled process generally
depending on the total charge of the complex, and smaller
activation entropy term (–TΔS‡) (e.g. 4.8 kcal mol–1 for 2 at 0 °C)
is interpreted as the result of a transition state not requiring
specific alignment of the substrate and the reactive species.
[5]
[6]
J. T. Groves, R. C. Haushalter, M. Nakamura, T. E. Nemo, B. J.
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K. Czarnecki, S. Nimri, Z. Gross, L. M. Proniewicz, J. R. Kincaid, J.
Am. Chem. Soc. 1996, 118, 2929-2935.
In summary, we have found a drastic elongation of the lifetime
of an oxido-iron(IV) porphyrin π-cation radical species by
employing TFT as a solvent. Such a stability enables us to detect
the reactive species even at room temperature (30 °C) without
any special protections but preserving its high reactivity. This
solvent system elongated a lifetime of FeIV(O)(TMP+•)(Cl) over
720 times longer as compared to that of the most stable artificial
oxido-iron(IV) porphyrin radical cation system, FeIV(O)(4-
TmPyP+•)(Cl), observed in water. This system enabled us to
directly observe the reactions of FeIV(O)(TMP+•)(Cl) with various
inert alkanes, resulting in the first example of the determination of
reaction-rate constant for hydrogen abstraction reaction from
primary carbons, and gaseous alkane substrate. The present
simple method will provide an immense opportunity for chemists
interested in compound I, and also a wide variety of reactive
oxygen complexes.
[7]
[8]
[9]
[10]
[11]
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Solvent parameters are compared in Supporting Information, Table
S2.
[12]
[13]
[14]
Based on the ratio of kdec and kobs, maximum yield in the conditions
is ca. 50%
Groves and co-workers determined the rate constant for the reaction
between a compound I and 3,3-dimethylbutanoic acid, which has
both of primary C–H bonds and secondary C–H bonds.
BDEC–H of TMB was estimated from that of 2,2-dimetylpropane.
Y.-R. Luo, Comprehensive Handbook of Chemical Bond Energies,
CRC Press, Boca Raton, FL, 2007.
[15]
[16]
Experimental Section
[17]
The KIE value is different by more than 10 from the value obtained
from the oxidation reaction with KHSO5 and NaOCl, respectively
(see refs. 33 and 34). Their values were determined from the
product analysis of the resulting solution of competition reactions of
alkanes and deuterated alkanes, where another reactive species
can be involved in the reaction.
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Soc. 1993, 115, 7293-7299.
Reaction of FeIII(TMP)(Cl) (1) with Ozone in Various Solvents.
Typically to a solution of FeIII(TMP)(Cl) (1) (28 µM) in a 1.0 cm path length
UV–vis cuvette closed with a rubber septum cap, ozone containing oxygen
gas (10 mL) was added using a syringe through the rubber septum cap.
Excess ozone gas and remaining oxygen gas were removed by bubbling
nitrogen gas.
[18]
[19]
Further details are shown in the Supporting Information.
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[20]
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Reactivity of the compound I analog was not largely changed in TFT
compared to that in CH2Cl2 at –20 °C (ca. 3 times decrease, see
Figure S16).
Acknowledgements
[22]
[23]
PyNMe3: tris((N-methyl-benzimidazol-2-yl)methyl)amine, TAML:
tetraamido macrocyclic ligand
This work is supported by JST (the CREST program,
a) S. Kundu, J. V. K. Thompson, L. Q. Shen, M. R. Mills, E. L.
Bominaar, A. D. Ryabov, T. J. Collins, Chem.–Eur. J. 2014, 21,
1803-1810; b) J. Serrano-Plana, W. N. Oloo, L. Acosta-Rueda, K. K.
Meier, B. Verdejo, E. García-España, M. G. Basallote, E. Münck, L.
Que, A. Company, M. Costas, J. Am. Chem. Soc. 2015, 137, 15833-
15842; c) M. Finn, R. Friedline, N. K. Suleman, C. J. Wohl, J. M.
Tanko, J. Am. Chem. Soc. 2004, 126, 7578-7584.
JPMJCR16P1, for H.F. and S.I.) and
a Grant-in-Aid for
challenging Exploratory Research (JP16K13963) from JSPS
(S.I.).
Keywords: fluorocarbon solvent • oxidation reaction • reactive
intermediate • oxido-iron complex • porphyrin
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Entry for the Table of Contents
Layout 2:
COMMUNICATION
Yuma Morimoto,* Yuki Shimaoka,
Yuri Ishimizu, Hiroshi Fujii,*
Shinobu Itoh*
Page No. – Page No.
Title: Direct Observation of Primary
C–H Bond Oxidation by An Oxido-
iron(IV) Porphyrin π-Radical Cation
Complex in a Fluorinated Carbon
Solvent
The extremely short lifetime of oxido-iron(IV) porphyrin π-radical cation species has
hampered detailed reactivity study of the complex. We herein report a remarkably
long lifetime (80 s at 10 °C) of FeIV(TMP+•)(O)(Cl) (TMP = 5,10,15,20-
tetramesitylporphyrin dianion) (2) produced by the oxidation of FeIII(TMP)(Cl) (1) by
ozone in α,α,α-trifluorotoluene (TFT). The drastic elongation allows us to directly
observe the reactions of 2 with a primary C–H bond (BDEC–H = ca. 100 kcal mol–1).
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