Mechanism of Oxidative Activation of Fluorinated Aromatic Compounds by N-Bridged Diiron-Phthalocyanine: What Determines the Reactivity?

Article abstract of DOI:10.1002/chem.201902934

The biodegradation of compounds with C?F bonds is challenging due to the fact that these bonds are stronger than the C?H bond in methane. In this work, results on the unprecedented reactivity of a biomimetic model complex that contains an N-bridged diiron-phthalocyanine are presented; this model complex is shown to react with perfluorinated arenes under addition of H₂O₂ effectively. To get mechanistic insight into this unusual reactivity, detailed density functional theory calculations on the mechanism of C₆F₆ activation by an iron(IV)-oxo active species of the N-bridged diiron phthalocyanine system were performed. Our studies show that the reaction proceeds through a rate-determining electrophilic C?O addition reaction followed by a 1,2-fluoride shift to give the ketone product, which can further rearrange to the phenol. A thermochemical analysis shows that the weakest C?F bond is the aliphatic C?F bond in the ketone intermediate. The oxidative defluorination of perfluoroaromatics is demonstrated to proceed through a completely different mechanism compared to that of aromatic C?H hydroxylation by iron(IV)-oxo intermediates such as cytochrome P450 Compound I.

Full text of DOI:10.1002/chem.201902934

A Journal of
Accepted Article
Title: Mechanism of Oxidative Activation of Fluorinated Aromatic
Compounds by N-Bridged Diiron-Phthalocyanine. What
determines the reactivity?
Authors: Samuel de Visser, Anthonio Tobing, Gourab Mukherjee,
Cedric Colomban, Chiviluka Sastri, and Alexander Sorokin
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To be cited as: Chem. Eur. J. 10.1002/chem.201902934
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Mechanism of Oxidative Activation of Fluorinated Aromatic
Compounds by N-Bridged Diiron-Phthalocyanine. What
determines the reactivity?
Cédric Colomban,[a] Anthonio H. Tobing,[b] Gourab Mukherjee,[b,c] Chivukula V. Sastri,[c] Alexander B.
Sorokin,*,[d] and Sam P. de Visser*[a]
Abstract: The biodegradation of compounds with C–F bonds is
challenging due to the fact that these bonds are stronger than the C–
exceptional stability; however, creates a major environmental
burden to society, as natural biodegradation of these
compounds is very limited. Consequently, there is major
scientific research on going into the activation and degradation
of fluorinated compounds considered as emerging pollutants.
Due to its small size (van der Waals radius of 1.47 Å) as well as
its low atomic polarizability volume, fluorine is a suitable
replacement of hydrogen in molecular design and as such has
been inserted into a large variety of organic molecules.[4] The
activation of a C–F bond requires the breaking of a bond with a
strength of about 130 kcal mol‒1, which is challenging in
H
bond in methane. Herein, we present results on the
unprecedented reactivity of a biomimetic model complex that
contains an N-bridged diiron-phthalocyanine and show it to react
with perfluorinated arenes under addition of H2O2 effectively. To get
mechanistic insight into this unusual reactivity, detailed density
functional theory calculations on the mechanism of C6F6 activation
by an iron(IV)-oxo active species of the N-bridged diiron
phthalocyanine system were performed. Our studies show that the
reaction proceeds through a rate-determining electrophilic C–O
addition reaction followed by a 1,2-fluoride shift to give the ketone
product that can further rearrange to the phenol. A thermochemical
analysis shows that the weakest C–F bond is the aliphatic C–F bond
in the ketone intermediate. We demonstrate that the oxidative
defluorination of perfluoroaromatics proceeds via a completely
different mechanism compared to that of aromatic C–H hydroxylation
chemical
catalysis.[5]
These
bonds
are
thermally,
photochemically, electrooxidatively and often chemically stable;
hence are difficult to break. To activate these C–F bonds, one
needs the use of an electron-rich species, e.g., an electron-rich
transition metal complex, a strong reductant or nucleophile, are
usually applied.[5] Similarly to the activation of C–H bonds,
by iron(IV)-oxo intermediates such as cytochrome P450 Compound I. organometallic activation of C–F bonds has been the subject of
extensive research.[5d] Alternatively, the C–H bonds can be
transformed by oxidative pathways. By contrast to the extensive
research on C–H bond oxidation reactions done over the past
century, very few studies have reported C–F bond activation
Introduction
under oxidative conditions. The latter reactivity represents a
particular case because strong oxidants, which are electron-
deficient species, should be involved in the reaction with C–F
bonds formed by the most electronegative element.
One of the strongest chemical bonds in nature is the C–F bond,
which arises due to the large difference in electronegativity (EN)
between carbon and fluorine (EN = 2.5 vs 4.0).[1] The strength of
these C–F bonds means they are generally inert in nature and
are very difficult to break. For instance, the extensively used
Consequently, there are major gaps in our understanding of the
mechanism and driving forces of these reactions.
polyfluorinated compound Teflon or polytetrafluoroethylene is a
Nature employs a variety of iron-containing enzymes for the
highly robust synthetic polymer with strong thermal and chemical
selective oxidation of strong C–H bonds. In particular, the
resistance.[2] Consequently, molecules with multiple C–F bonds
cytochromes P450 are heme monooxygenases that form a high-
are highly stable and inert, which makes them highly desirable
valent iron(IV)-oxo heme cation radical known as Compound I in
as insulators.[3] Fluorinated compounds find increasing use in
their catalytic cycle.[6] Compound I reacts with substrates
many areas, for instance, 40% of agrochemicals and 25% of
pharmaceuticals currently used contain C–F bonds. Their
through hydrogen atom abstraction of aliphatic C–H bonds, but
also can activate C=C double bonds, arenes and sulfides.[7]
Interestingly, P450 Compound I (Cpd I) is unable to react with
methane although there is evidence of ethane and propane
[a]
[b]
[c]
Dr. C. Colomban, Dr. A. B. Sorokin
oxidation.[8] Clearly, P450 Cpd I cannot cleave the methane C–H
bond of 105 kcal mol–1 and, therefore, is not expected to be able
to activate even stronger bonds, such as the C–F bonds in
perfluoroarenes by an oxidative pathway.
Institut de Recherches sur la Catalyse et l’Environnement de Lyon,
IRCELYON, UMR 5256, CNRS Université Lyon 1,
2 av. Albert Einstein, 69626 Villeurbanne Cedex, France
E-mail: alexander.sorokin@ircelyon.univ-lyon1.fr
Mr. A. H. Tobing, Dr. S. P. de Visser
The Manchester Institute of Biotechnology and School of Chemical
Engineering and Analytical Science, The University of Manchester
131 Princess Street, Manchester M1 7DN, United Kingdom
E-mail: sam.devisser@manchester.ac.uk
Mr. G. Mukherjee, Dr. Chivukula V. Sastri
Department of Chemistry
Indian Institute of Technology Guwahati
Guwahati-781039, Assam, India
Although several studies on C–F bond oxygenation reactions by
iron(IV)-oxo species have been reported,[9] actually little is
known on the defluorination of poly- or perfluoro aromatic
compounds. Some of us recently reported an excellent
defluorination oxidant for poly- and perfluoro aromatic
compounds, namely a -nitrido diiron phthalocyanine (Pc)
complex (tBu4PcFe)2N (1), Scheme 1.[10] A range of aromatic
compounds with fluoride substituents (SubF) were investigated
with widely ranging yields and turnover numbers (TON).
Complex 1 is shown to be able to activate and hydroxylate
strong aromatic C–F bonds under oxidation conditions
E-mail: sastricv@iitg.ac.in
Supporting information for this article is given via a link at the end of
the document.
1
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efficiently; hence 1 appears to be a more powerful oxidant than
P450 Cpd I. The question, therefore, is how that is possible and
what makes it so efficient. Therefore, we decided to pursue a
CN, ‒NO2, ‒CF3) substrates (0.1 M) were conducted in CD3CN,
in the presence of (tBu4PcFe)2N (0.4 mol%) and H2O2 (16
equiv.) at 60°C for 15 hours. Identification and quantification of
phenolic products was achieved by 19F NMR analyses of the
reaction mixture after concentration of the reaction mixture using
an argon flow (Scheme 2). Detailed procedures for the
determination of phenol product ratios are given in the
Supporting Information. For all the substrates, a preference for
the transformation of the C–F bond in the meta-position is
observed, which is a normal trend for electrophilic aromatic
substitution reactions where the electron withdrawing
substituents act as potential meta-directing groups.[12]
detailed
mechanistic
study
using
experimental
and
computational techniques. Our study proposes
a
novel
mechanism for aromatic hydroxylation of fluorinated arenes that
is completely different from that of non-fluorinated arenes. In
particular, the reaction takes place through the initial formation
of a ketone. In the ketone structure an aliphatic C–F bond is
broken in the re-aromatization step to give the fluorinated
phenols.
Scheme 2. Ratio of different phenolic products formed as quantified by 19F-
NMR analysis.
In order to check the possible effect of the concentration step on
the ratio of the produced phenol, we also performed the
analyses of the reaction mixtures by GC/MS using two
substrates, namely C6F5CN and C6F5NO2 without the
concentration step. The GC/MS analyses were performed after
treatment
of
the
reaction
mixtures
with
trimethylsilyldiazomethane to obtain methylated phenol
derivatives (Supporting Information, Table S1). The distributions
of phenol isomers obtained using the GC/MS method is very
similar to those from the 19F NMR analysis. In particular, for
C6F5CN the two techniques give differences in the ratio of
phenols less than 0.3%, hence both methods give quantitatively
identical results.
Scheme 1. Oxidant and reaction cycle with fluorinated substrate (SubF)
studied.
Results
Table 1. Catalytic degradation of C6F6 catalysed by 1-H2O2 in CD3CN in the
presence of various amounts of trifluoroacetic acid (TFA).[a]
A combination of experimental and computational studies was
performed on the activation of polyfluorinated arenes, namely
C6F5Y (Y = F, NO2, CN, CF3) with the -nitrido diiron-
phthalocyanine complex (tBu4PcFe)2N (1) as described in
Scheme 1. The high reactivity of 1 is associated with the
formation of high-valent diiron-oxo species. These species
supported by phthalocyanine, porphyrin and porphyrazine
ligands have been characterized by spectroscopic methods and
DFT calculations.[10b,10c,11] Particular focus of the work is on
establishing the reaction mechanism and the origin of C‒F bond
cleavage in the reaction.
[TFA]
(mM)
Conversion
(%)
TON [b]
Defluorination degree
(%)[c]
0
29
36
44
45
49
226
344
412
460
514
52 (3.1 over 6)
63 (3.8 over 6)
62 (3.7 over 6)
68 (4.1 over 6)
71 (4.2 over 6)
5
15
70
100
[a] The solution containing the catalyst (0.4 mM), substrate (0.1 M), and
H2O2 (1.6 M) was stirred in CD3CN at 60°C for 15 h. The substrate
conversions and yields of F‒ were determined by 19F NMR spectroscopy. [b]
Turnovers numbers (TONs) were calculated as the molar amount of F‒
formed per mole of catalyst. [c] The degree of defluorination is the ratio of
the amount of F‒ formed to the total amount of fluorine in the converted
substrate.
Experimental reactivity study
To determine the regioselectivity of the initial reaction step
involving the diiron-oxo species, we performed the oxidation of
perfluorinated aromatic substrates bearing electron-withdrawing
substituents, namely pentafluorocyanobenzene (C6F5CN),
pentafluoronitrobenzene (C6F5NO2) and octafluorotoluene
(C6F5CF3) to explore the reaction mechanism for defluorination.
Homogeneous catalytic oxidative defluorinations of C6F5Y (Y = ‒
Next, the influence of the presence of acid on the defluorination
efficiency was studied. The 1-H2O2 system mediates another
2
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challenging reaction, namely the mild oxidation of methane in
water.[13] The efficiency of the methane oxidation strongly
increases upon addition of a small amount of acid and shows a
bell-shaped dependence on the acid concentration.[13b] While a
turnover number (TON) of 26 was observed in pure water, using
a 75 mM H2SO4 aqueous solution results in the boosting of the
turnover number of methane oxidation up to 223. This
enhancement can be explained by the more efficient formation
of the diiron-oxo species from the hydroperoxo complex due to
the protonation of peroxide oxygen leading to easier heterolytic
cleavage of the O–O bond with release of a water molecule. In
line with these previous studies, therefore, we decided to
investigate the influence of trifluoroacetic acid (TFA) on the
defluorination reaction. In particular, the work focused on the
efficiency of defluorination of hexafluorobenzene in the presence
of TFA (see Table 1 and Figure 1).
Indeed, upon progressive increase of the TFA concentration
from 0 to 100 mM, the conversion of C6F6 gradually increased
from 29% to 49% and is accompanied by a more than two-fold
increase of turnover number from 226 to 514 (Figure 1).
Importantly, the ratio of the amount of F‒ formed during the
reaction to the total amount of fluorine in converted substrate
(defluorination degree) was also increased from 52% to 71%
indicating the higher reaction efficiency in the presence of acid.
This enhancement of the reactivity is expected to be correlated
to the acceleration of the formation of the N-bridged diiron-oxo
species involved in the reaction with fluorinated aromatic
substrates, but involvement of protons in the reaction sequence
leading to defluorination cannot be excluded (vide infra).
to an epoxide or alternatively an ipso-proton abstraction and
reshuttle creates either ketone or phenol products.[14] An
interconversion between the latter two structures through the so-
called NIH-shift with additional protons may be possible as well.
As such, acid is involved in some steps of the reaction cycle and
the pH of the reaction mixture should affect product distributions.
Importantly, the 1–H2O2 system showed the mechanistic
features similar to those of P450 Cpd I in the oxidation of
benzene (intermediate formation of benzene epoxide and NIH
shift evidenced using benzene-1,3,5-[D3]).[15] Thus, it is likely that
the reaction of the perfluoroarene with N-bridged diiron-oxo
phthalocyanine will be initiated by a similar electrophilic addition
reaction through oxygen atom transfer to the arene.
Subsequently, epoxide or ketone products are formed through
either a common intermediate or sequentially. These epoxide
and ketone products could escape the oxidant environment
mixture and into solution. In order to obtain the phenol product,
however, one of the fluoride atoms will need to be removed and
a proton provided. Hence, this offers a mechanistic challenge
with respect to the aromatic hydroxylation mechanism at the top
part of Scheme 3, where this proton comes from the original C‒
H bond that is broken. Thus, oxygen atom transfer to a
fluorinated arene to form the epoxide will not need the breaking
of a C‒F bond and as such should be the thermodynamically
easiest pathway.
Therefore, based on our experimental work on fluorinated
arenes by an iron-oxo species we propose a mechanism
whereby an initial epoxide is formed that through an NIH-fluoride
shift leads to the ketone prior to fluoride release to form phenol.
Alternatively, a fluoride transfer from epoxide to the N-bridged
diiron complex can lead to pentafluorophenolate directly. These
mechanistic possibilities would make the reactivity of fluorinated
arenes different from hydrogenated arenes. Consequently, we
decided to pursue
perfluoroarene activation
a
density functional theory study on
by N-bridged diiron-oxo
phthalocyanine complexes to shed more light on the
experimental results.
Thus, the mechanistic possibilities given in the bottom panel of
Scheme 3 provide an initial reaction step for hexafluorobenzene
epoxidation. The fluoroarene epoxide could rearrange to ketone
intermediate through a rare fluorine NIH-shift. This shift was
experimentally shown using 1,4-difluorobenzene as
a
substrate.[10a] Escape of the ketone intermediate into solution
may lead to the loss of F‒ to generate a cationic species
followed by the addition of a hydroxide group to form quinone
after elimination of HF. Thus, there is a significant difference in
the behavior of the ketone intermediates generated from
aromatic hydrocarbons and perfluorinated aromatics. While the
former species loses H+ to form finally phenol, namely through a
2-electron oxidation reaction, on the other hand, the fluorinated
ketone intermediate undergoes fluoride anion elimination leading
to direct formation of fluoranil (6-electron oxidation product)
without intermediate formation of fluorinated phenol (Scheme 3).
However, GC-MS and 19F NMR analysis unambiguously shows
fluorinated phenols as intermediate products. In order to gain
insight into how the formation of phenols in the oxidative
defluorination of perfluoroarenes could be explained, we decided
to do a computational study on the various possible reaction
mechanisms.
Figure 1. Evolution of the conversion of C6F6 catalysed by the 1-H2O2 system
as a function of the concentration of TFA. The inset shows the dependence of
TON as a function of the TFA concentration.
Mechanistic considerations
To highlight the mechanistic possibilities of ketone and phenol
observation in a reaction of an iron(IV)-oxo intermediate with
C6F6 we show a possible reaction mechanism of the aromatic
hydroxylation in Scheme 3. Thus, computational modelling of the
mechanism of aromatic hydroxylation by a P450 Cpd I model,
namely an iron(IV)-oxo heme cation radical, showed that the
reaction starts with an electrophilic C–O bond formation to one
of the carbon atoms of the arene, leading to a radical
intermediate (Scheme 3).[14] Thereafter, a ring-closure step leads
3
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Scheme 3. Mechanistic scenarios for the evolution of ketone intermediates from aromatic hydrocarbon and fluorocarbon oxidation by iron(IV)-oxo intermediates:
(top panel) P450 Cpd I reaction with benzene. (bottom panel) N-bridged diiron-oxo phthalocyanine reaction with C6F6.
An alternative scenario would be that the ketone intermediate is
retained by the -nitrido diiron-phthalocyanine complex in its
coordination sphere. Again, the loss of fluoride anion F‒ leads to
a coordinated cationic species followed by two electron transfer
from [(Pc)FeIII-N-FeIV(Pc)] to the cationic intermediate. In this
way, a high-valent F–(Pc)FeIV-N-FeIV(Pc+•)–F complex will be
formed, which was isolated from the reaction mixture and fully
characterized by spectroscopic techniques.[10] In turn, reduced
fluoroarene residue furnishes phenol, which is obtained as a
reaction product. An intramolecular electron transfer and the
formation of phenol can be facilitated if the carbonyl group would
be protonated. Thus, the presence of acid should be beneficial
for the reaction.
(model B). These structures are found to have a doublet spin
ground state in agreement with experimental electron
paramagnetic resonance (EPR) and Mössbauer spectroscopic
studies.[16] Previous modelling on N-bridged diiron-oxo
porphyrins and porphyrazines also found a doublet spin ground
state with a singly occupied -orbital with molecular orbital
coefficients located along the Fe2–N–Fe1–O axis.[11] Several
papers by other groups have reported studies on this chemical
system and found
structure.[17]
a similar electronic configuration and
For the smallest chemical system (2A), we calculated three
electromers for the doublet spin state (Supporting Information,
Figure S8). The most stable configuration for both A and B is a
doublet spin state structure with an iron(IV)-oxo terminal group,
i.e. Fe1–O, with spin densities of 1.1 on Fe1 and 1.0 on O. This
is similar to heme and nonheme iron(IV)-oxo species calculated
Computational modelling of C6F6 activation by N-bridged
diiron(IV)-oxo
To gain further insight into the details of the reaction mechanism, previously that all were shown to have two three-electron bonds
2
1
2
and particularly on the order of formation of epoxide, ketone and
phenol products, we performed a computational study using
density functional theory methods. We started our work with
calculations on the iron(IV)-oxo species of N-bridged diiron-
porphyrazine (model A) and N-bridged diiron-phthalocyanine
along the Fe–O axis due to occupation xz *xz yz *yz .
1 [16,17] In
structures A and B these  and * orbitals mix further with
orbitals on the bridging nitrogen and Fe2 atoms and, therefore,
are more delocalized.
4
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(a)
(b)
1.803 (1.809) [1.800] {1.921}
1.743 (1.743) [1.745] {1.864}
2.418 (2.545) [2.343] {1.734}
1.656 (1.643) [1.834] {1.643}
i815 (i803) [i832] {i601} cm1
2TS1A (4TS1A) [6TS1A] {2TS1A’}
1.843 (1.916)
1.751 (1.866)
2.011 (1.693)
1.660 (1.630)
i757 (i595) cm1
2TS1B (2TS1’B)
Figure 2. (a) Optimized geometries of electrophilic addition transition states TS1A and TS1B as obtained at UB3LYP/BS1 in Gaussian-09. Bond lengths are given
in angstroms and the imaginary frequency in the transition state in cm‒1. (b) Potential energy profile for the epoxidation of C6F6 by 2,4,6[(PzFe)2N]O (2A) and
2[(PcFe)2N]O (2B) as calculated in Gaussian-09 at UB3LYP/BS1 level of theory. Energies (in kcal mol‒1) reported are UB3LYP/BS2//UB3LYP/BS1 with zero-point
and solvent corrections included, while free energies at 298K are given in parenthesis.
Thus, in 2A1 we find short Fe1–O and Fe2‒N distances of 1.648
and 1.662Å in analogy to previous calculations. Very similar
distances are found for the phthalocyanine optimized geometry
2B1, where the Fe1–O and Fe2–N distances are 1.649 and
1.678Å, respectively. In addition, the electronic configuration of
2B1 resembles that of 2A1 (Supporting Information, Figure S8)
with group spin densities within a few hundredth of an atomic
unit of each other. As such, replacing the phthalocyanine units
with porphyrazine has no major structural and electronic effect
on the system.
spin states, respectively. An alternative doublet spin barrier
(2TS1A’) is about 21.9 kcal mol‒1 above reactants. The latter has
a distinct electronic configuration and structure from 2TS1A
(Table S4, Supporting Information) and connects to the radical
intermediate 2IM1’A, while 2TS1A has a configuration closer to
2
2IM1A. Thus, IM1A has one unpaired electron on the substrate
and no spin on the diiron-oxo porphyrazine moiety, whereas
2IM1’A has two unpaired electrons on the metal coupled to a
substrate radical. As such, there are competing pathways on the
doublet and quartet spin state surfaces with various possible
electronic configurations that are close in energy and most likely
2
Subsequently, we investigated C6F6 activation by 2,4,6A and B
leading to epoxide products and the results are given in Figure 2. the system will react through multistate reactivity patterns on
The reaction occurs stepwise with an electrophilic transition
state (TS1) leading to a radical intermediate (IM1) followed by a
ring-closure transition state (TS2) to form epoxide products
(IM2). This mechanism resembles previous computational
studies on substrate epoxidation by metal-oxo oxidants.[18] The
rate determining reaction step is via the first transition state for
both models A and B. Barriers of E+ZPE+Esolv = 18.6, 18.6 and
32.6 kcal mol‒1 are obtained in the doublet, quartet and sextet
competing barriers. In general, the sextet spin state is high in
energy and is not expected to play a major role of importance in
the reaction mechanism. Although 4TS1A is low in energy,
actually the mechanism beyond 4IM1A is well higher in energy
than that on the doublet spin state. Consequently, the main
reaction mechanism will take place on the doublet spin state
surface, although there are several close-lying doublet spin
configurations that still give rise to multistate reactivity patterns.
5
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Figure 3. Reaction mechanisms explored for the reaction of C6F6 with 2[(PzFe)2N]O, i.e. 2A as calculated in Gaussian-09. Energies refer to
UB3LYP/BS2//UB3LYP/BS1+ZPE values in kcal mol‒1
.
The transition states 2TS1A and 4TS1A are very similar in
structure with a very short Fe2–N distance of 1.656 and 1.643 Å,
which implicate an Fe(IV)-nitrido bond. By contrast, the Fe1–O
distances have elongated from 1.648 Å in the isolated reactant
to 1.743 Å in the transition state. Hence, the Fe1–O interaction
has weakened. Indeed electron density has accumulated on Fe1
in 2TS1A and a spin density of 2.14 is found. The imaginary
frequencies are very high, in the order of i800 cm‒1, although for
2TS1A’ a value of i601 cm‒1 is calculated. These values are well
larger than those typically found for aromatic hydroxylation or
epoxidation transition states by iron(IV)-oxo complexes.[14,15,19]
On the doublet spin state an alternative transition state was
structures and energetics, whereby the barrier is lowered from
18.6 to 14.7 kcal mol‒1 but does not affect the overall results.
Electrophilic addition of C6F6 to the iron(IV)-oxo species leads to
elongation of the Fe‒O distance in 2,4,6TS1A to 1.743 – 1.745 Å.
These changes are often seen in aromatic hydroxylation
reactions calculated previously.[14,20] The group spin densities on
Fe2 and bridging N are similar to those in the isolated reactant,
2
while the substrate spin increases to ‒0.26 in TS1A and 0.94 in
2IM1’A. Therefore, the reaction will not be completely radical in
nature and significant charge-transfer will have occurred from
the substrate moiety to the metal. The imaginary frequencies are
relatively large for C‒O bond formation transition states and of
the order of i815 cm‒1.
2
located, namely TS1A’, which is about 3.3 kcal mol‒1 higher in
energy than 2TS1A. Structurally, it has a much shorter Fe1–N
The radical intermediates (IM1A and IM1B) can lead to epoxide
distance of 1.734 Å and hence the metal-metal distance is closer. products (IM2A and IM2B) through a ring-closure step via a
This structure also has elongated Fe1–O and O–C distances to
transition state TS2. The lowest energy epoxide product is in the
doublet spin state and –15.5 kcal mol–1 below isolated reactants
for model A, while the reaction is –21.8 kcal mol–1 exothermic for
model B. The optimized geometries of 2IM2A and 2IM2B are
almost identical with Fe1–N distances of 1.655Å for both
structures and N–Fe2 distances of 1.78Å for both structures. As
such they have very similar electronic configuration and
properties and hence the equatorial ligand has little effect on the
structure and chemical properties of the epoxide product
complexes.
1.864 and 1.921 Å. As
a consequence, the electronic
configuration of 2TS1A’ is distinct from that of 2TS1A.
The transition state structures and energies of the larger
phthalocyanine model via 2TS1B are similar to those seen for the
small porphyrazine model A with barriers of 14.7 and 21.0 kcal
mol‒1 for 2TS1B and 2TS1B’. The electronic configuration of 2TS1A
2
and 2TS1B match each other well and so does the pair of TS1A’
and 2TS1B’ structures. Therefore, a change from porphyrazine to
phthalocyanine ligand has a small stabilizing effect on the
6
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The electrophilic intermediates (2,4,6IM1A) are on bifurcation
pathways that connect to a variety of possible products (Figure
3). Firstly, they can form epoxide products (2,4,6IM2A) via a ring-
closure barrier (TS2), Figures 2 and 3. On the doublet spin state
surface this barrier is significant; however, and a value of 16.6
arenes showed the reaction to start with an initial electrophilic
addition, like structure IM2 in Figure 3. However, the reaction
proceeds through proton-shuttle from the ipso-proton via a
nitrogen of the equatorial ligand to the oxygen atom to form
phenol.[14,20] A similar mechanism in fluorinated arenes would
require an F– transfer to the equatorial ring via TS8 to form
intermediate IM5. We estimated the energy for this step from
constraint geometry scans (Supporting Information, Figure S20)
and predict this pathway to be well higher in energy than 45 kcal
mol‒1 and hence fluorinated arenes will react through a different
mechanism than aromatic hydrocarbons.
2
kcal mol‒1 above IM1A is obtained. Consequently, we searched
for lower-energy pathways leading to phenol and ketone
products directly. Firstly, 2IM1A can react to form the ketone
2
products by a 1,2-fluoride shift and a barrier TS9A of 3.8 kcal
mol–1 higher in energy than 2IM1A was found. The optimized
geometry of 2TS9A is given in Figure 4. Its imaginary mode
represents fluoride transfer from the ipso position to its
neighboring carbon atom and indeed the intrinsic reaction
coordinate scan (Figure S19, Supporting Information) leads to
the radical intermediate (2IM1A) in one direction and ketone
products in the other direction. Long C‒F bonds of 2.092 and
A substrate-swing mechanism via transition state TS6 was also
explored, where the Fe–O bond in the electrophilic intermediate
IM1 breaks and is replaced by an Fe–F bond simultaneously to
form the radical intermediate IM4. Again, a constraint geometry
scan was performed (see Supporting Information, Figure S22).
2
2
2.225Å are obtained in TS9A and hence the transition state is
The calculations predict that TS6A is well higher in energy than
close to central.
24 kcal mol‒1 with respect to isolated reactants. This energy is
higher than epoxide product formation and, therefore, the
substrate-swing mechanism can be ruled out as a viable
reaction pathway.
A final pathway investigated was fluoride abstraction from the
epoxide product followed by ring-opening to give phenol
Next, we looked into alternative reaction pathways for C6F6
activation by N-bridged diiron(IV)-oxo complexes leading to
phenol products and explored a range of possible mechanisms
as shown in Figure 3. Firstly, we tested the NIH-fluoride shift
from carbon 1 to carbon 2 in the epoxide structure with ring-
opening via transition state TS3 to give the ketone product (IM3). products. For this pathway, we located transition states for
We find a small barrier (2TS3A) of 12.2 kcal mol‒1 higher in
energy than IM2A leading in a highly exothermic step to ketone
fluoride abstraction (2TS5A) and subsequent ring-opening
(2TS5’A), see Supporting Information Scheme S4 and Figure
S22. Energetically, the energies are very high, namely 29.1 and
34.1 kcal mol‒1 above isolated reactants, hence will be
inaccessible under room temperature conditions.
2
products (‒39.1 kcal mol‒1 with respect to isolated reactants)
2IM3A. Subsequently, one of the aliphatic fluoride atoms of the
ketone molecule can be abstracted by the iron atom to form
phenol product (P1) with a barrier (2TS4A) of 15.8 kcal mol‒1.
Interestingly, formation of phenol from ketone is an endothermic
process by 9.1 kcal mol‒1. Nevertheless, the activation of C6F6
through epoxide and ketone to form phenol has a rate-
In conclusion, the mechanism of oxygen atom transfer to
fluorinated arenes has been studied with experimental and
computational techniques. It is found to be different to what was
established for benzene and its derivatives. Nevertheless, both
mechanisms start with an initial electrophilic addition step where
a chemical bond between the oxo and one of the carbon atoms
of the arene is formed. The latter geometry for a biomimetic
mononuclear iron system was characterized by Goldberg and
co-workers for a nonheme iron complex.[9ab] Our calculations
show that this intermediate in the N-bridged diiron-
phthalocyanine system will isomerize into a ketone that can lose
a fluoride substituent from the aliphatic C–F group readily. As
such, defluorination is a series reaction where products are
formed in a sequential process, while in aromatic hydroxylation
of arenes all products appear to arise from a common
intermediate. Our mechanism compares favorably to the one
proposed for oxygen atom transfer by cytochrome P450 CpdI to
fluorinated arenes.[21] Thus, the mechanism of Hadad and co-
workers[21] proceeds with an electrophilic addition followed by F–
migration to form the ketone. As the latter has a low electron
affinity they propose a quick F release to form pentafluorophenol
products.
To understand the regioselectivity reactions seen in the
experimental studies from Scheme 2, we decided to calculate
substrate epoxidation of C6F5CF3 by 2A reactant through an
electrophilic attack on either the ortho-, meta- or para-positions.
Optimized geometries of 2TS1A,CF3,ortho and 2TS1A,CF3,meta are
given in Figure 5. The two structures are very close in energy
with the meta-attack configuration slightly lower by 0.7 kcal mol–1.
These relative energies imply that a mixture of products leading
to ortho- and meta-hydroxylation of C6F5CF3 will be formed with
dominant meta-products as indeed observed experimentally. As
2
determining step for C‒O bond formation via TS1A of 18.6 kcal
mol‒1 and all subsequent barriers are well lower in energy. As
such this should be a feasible pathway.
CF: 2.225
CF: 2.092
FeO: 1.998
i122 cm1
2TS9A
Figure 4. UB3LYP/BS1 optimized geometry of 2TS9A with bond lengths in
angstroms and the imaginary frequency in the transition state in cm‒1
.
In addition, several other pathways for oxygen atom transfer to
hexafluorobenzene to form pentafluorophenol products were
explored (Figure 3). Earlier studies of aromatic hydroxylation of
7
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10.1002/chem.201902934
Chemistry - A European Journal
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such the calculations on C6F5CF3 predict the correct
chemoselectivity as seen experimentally.
nature a diiron or dicopper complex is typically utilized in the
methane monoxygenases.[22]
Geometrically, the transition states 2TS1A,CF3,ortho and
2TS1A,CF3,meta are very much alike with Fe–O and C–O distances
of 1.884/1.880 and 1.898/1.914Å for attack on the ortho/meta
position of the substrate, respectively. As a consequence of the
similarity in transition state geometry also the imaginary
frequency in the transition state are close in value, which implies
analogous potential energy surfaces for the two processes. In
addition, the charge and spin distributions in the two transition
states are alike as well with a small positive spin density building
up on the substrate (0.28 for the ortho and 0.29 for the meta
structure) and a radical on the oxo group (O = 0.72 for the ortho
and 0.70 for the meta structure). The difference in energy
between the two transition state structures, therefore, is most
likely caused by stereochemical interactions of the CF3 group
with the porphyrin/phthalocyanine ligand that raises the ortho
pathway slightly in energy.
Computational modelling on the properties and reactivities of
[(Pc)2Fe2N]O showed that orbital interactions along the Fe–N–
Fe–O axis lowered the redox potential of the oxidant and pulled
electron density away from the oxo group, thereby affecting the
pKa of the iron-hydroxo species, which enabled it to hydroxylate
methane.[11,16] These studies rationalized the enhanced reactivity
of -nitrido bridged diiron(IV)-oxo phthalocyanine complexes
over mononuclear nonheme and heme iron(IV)-oxo complexes.
The work described here shows that the mechanisms of
aromatic hydroxylation of arenes and fluoroarenes are
distinctively different and in the following we will try to rationalize
these differences. Thus, aromatic hydroxylation of arenes
(Scheme 3 and 4) typically starts with an aromatic addition of the
diiron(IV)-oxo species to
a carbon atom of the arene.
Subsequently, the mechanism bifurcates into the epoxide
pathway through a ring-closure step to form epoxide or
alternatively an ipso-proton abstraction by the heme to produce
a phenolate bound iron(III) complex. The heme proton can
thereafter reshuttle to phenolate to either form phenol or ketone
products, which explains the experimentally observed NIH-shift.
With fluoroarenes the latter mechanism is not feasible as it
would have required the removal of an F+ ion from the ipso-
position. Indeed, DFT finds a high-energy pathway for F+
abstraction. Therefore, the only feasible pathway for fluoroarene
activation by an iron(IV)-oxo species is the formation of an
ketone intermediate. Consequently, we find a novel mechanism
for the hydroxylation of fluorinated arenes that passes through
an electrophilic addition intermediate first and is then converted
into a ketone. Only thereafter the phenol is formed through a
defluorination step. The initial electrophilic attack of the diiron
oxo species at the carbon atom of perfluoroarenes is supported
by preferential formation of meta-phenols in course of C6F5X
oxidation (Scheme 2).
1.898
1.884
1.914
1.880
1.688
1.627
1.691
1.629
i583 cm‒1
i591 cm‒1
2TS1A,CF3,ortho
2TS1A,CF3,meta
Figure 5. UB3LYP/BS1 optimized geometries of 2TS1A,CF3 structures for ortho
or meta attack on C6F5CF3 by 2A. Bond lengths are in angstroms and the
The rate-determining step in the reaction mechanism is C‒O
bond formation via TS1 and to understand the electron transfer
2
imaginary frequency in the transition state in cm‒1
.
mechanisms and the factors that influence this step, we
delineated the process in a valence bond diagram (Figure 6).
These valence bond diagrams have been used previously to
rationalize reaction mechanisms and confirmed trends in, e.g.
hydrogen atom abstraction and substrate sulfoxidation reaction
by metal-oxo oxidants.[23] Furthermore, these VB diagrams
helped to explain regioselectivity patterns and reaction
mechanisms by giving details of the electronic configuration and
electron migration steps.[24] Thus, the reactant species has a
number of -type orbitals along the O‒Fe1‒N‒Fe2 axis through
interactions of the 2px/2py on O/N with the 3dxz/3dyz on Fe1/Fe2.
The full set of bonding combinations are the almost degenerate
Discussion
This work describes the experimental and computational
investigation of defluorination of fluoroarenes by a high-valent
diiron(IV)-oxo intermediate. Overall, our combined experimental
and computational study shows that -nitrido bridged diiron-
phthalocyanine complexes are versatile oxidants that can initiate
substrate activation of C–X bond strengths well over 100 kcal
mol‒1. As such, these oxidants are more powerful than the active
species of most mononuclear metalloenzymes in nature.
Furthermore, they are environmentally benign and utilize an iron
catalyst with hydrogen peroxide as oxygen donor. In previous
work, we and others showed that the iron(IV)-oxo species of the
-nitrido bridged diiron-phthalocyanine, [(Pc)2Fe2N]O, efficiently
reacts with methane and arenes through oxygen atom transfer
to form alcohol products.[11,16] This species is the only known
iron(IV)-oxo oxidant to be able to activate methane, whereas in
1,x/1,y orbitals that are both doubly occupied. Higher lying are
the 2,x and 2,y orbitals that have a single node and are also
doubly occupied. The 3,x and 3,y orbitals are depicted on the
left-hand-side of Figure 6 and are in the valence region and
dependent on the spin state and electronic configuration contain
one or more electrons.
8
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10.1002/chem.201902934
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Figure 6. Valence bond description of arene activation step of C6F6 by N-bridged diiron-phthalocyanine complexes. Electrons are represented with a dot and a
chemical bond as two dots separated by a line. Key orbital occupations during the mechanism are shown.
As shown previously[11] and confirmed for our models here the
3,x orbital is doubly occupied and the 3,y is singly occupied
leading to an overall doublet spin state ground state with orbital
2
2
2
2
2
configuration 1,x 1,y 2,x 2,y *3,x *3,y1. Two doublet spin
transition states and radical intermediates (IM1) were located
that have different electronic configuration. Thus, in 2TS1/2IM1
there is positive spin density on the OFeNFe unit and negative
spin density on the substrate, whereas in 2TS1’/2IM1’ the
substrate spin is positive. This implies that there are different
electron transfer processes in these pathways, which are
explained in Figure 6.
In the C‒O bond forming transition states TS1 and TS1’ one of
the -bonds in the arene breaks (CC) homolytically. One of
those electrons of the arene CC orbital forms the C‒O bond with
the incoming oxidant, while the other one remains on the
substrate in orbital Sub. The C‒O bond is formed between an
electron in a 2pC orbital on the substrate with a 2pO orbital on
oxygen. The latter comes from the set of y orbitals (1,y, 2,y, 3,y
*4,y), which split into a new set of orbitals that only covers the
,
2
Fe1, N and Fe2 atoms: ’1,y, ’2,y and ’*3,y. As such, in IM1 a
Figure 7. Homolytic (in red) and heterolytic (in blue) C‒F bond cleavage free
energies for C6F6 and C6F6O as calculated at UB3LYP/6-311++G** level of
theory. Free energies are in kcal mol‒1 and include thermal (at 298 K) and
entropic corrections.
radical intermediate is formed with electronic configuration
3dyz,Fe1 ’1,yz,Fe2 ’2,y,Fe2 Sub, with Sub the orbital that hosts the
radical on the arene. The alternative mechanism via 2TS1’ and
2IM1’ by contrast, results in the pairing of a down-spin electron
on the carbon atom of the substrate with an up-spin electron in
2pO. As a consequence, the 3dxy,Fe1 electron is down-spin and
the overall spin densities along the O‒Fe1‒N‒Fe2 axis virtually
cancel out.
2

To further understand the mechanism of fluoroarene
hydroxylation, we did a detailed thermochemical analysis on the
individual bonds that are broken and formed in substrate,
9
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Liquid-state 1H and 19F nuclear magnetic resonance (NMR) spectra were
obtained using an AM 250 Bruker spectrometer using a protocol as
previously described.[10a] The UV-vis spectra were recorded with an
Agilent 8453 diode-array spectrophotometer. The reaction products were
identified by GC-MS technique using a Hewlett Packard 5973/6890
system equipped with an electron impact (EI) ionization source at 70 eV.
Helium gas was used as the carrier gas and a capillary column with
dimensions of 30m  0.25 mm (HP-INNOWax) with poly-ethylene glycol
(0.25 m coating) or DB 5MS 50 m capillary column (0.250 mm  0.25
m) were used. Data were analysed using the NIST Mass Spectral
Search Program.[25] The reaction mixtures were prepared for analysis
epoxide, ketone and phenol products. Eqs 1 and 2 describe the
homolytic (Eq 1) and heterolytic (Eq 2) C‒F bond cleavage
reactions calculated here. Thus, the homolytic C‒F bond
breaking will produce an F radical with free energy Ghomolytic
while the heterolytic cleavage will give F‒ anion with free energy
Gheterolytic
,
.
A‒F  A• + F• + Ghomolytic
A‒F  A+ + F‒ + Gheterolytic
(1)
(2)
with
a preliminary procedure treated with 2.0 M solution of (tri-
We calculated the adiabatic C‒F bond cleavage free energy for
hexafluorobenzene, hexafluoroarene epoxide and the ketone
isomer. Figure 7 and Supporting Information Figures S27 and
S28 describe the homolytic and heterolytic free energies of C‒F
bond cleavage of these compounds. As mentioned above, the
C‒F bond is very strong and homolytic and heterolytic C‒F bond
free energies of G = 106.8 and 126.4 kcal mol‒1 are found,
respectively. Similar C‒F bond strengths are seen for the
epoxide complex, which matches the DFT studies above that
found high barriers for C‒F bond breaking in the epoxide
complex. However, both heterolytic and homolytic C‒F bond
cleavage from the ketone intermediate is low in energy from the
aliphatic (sp3)C‒F bond for which we find adiabatic free energies
of 62.9 and 61.0 kcal mol‒1, respectively. Therefore, the C‒F
bond strength in the ketone intermediate is considerably weaker
than the aromatic C–F bonds in hexafluorobenzene and epoxide
isomers. Consequently, the lowest energy hexafluorobenzene
hydroxylation will have to pass the ketone intermediate so that
the weaker C–F bond can be cleaved to form pentafluorophenol
products. With release of products from the iron centre, the
vacant iron ligand site will be occupied by the fluoride anion.
However, as the -nitrido bridged diiron-phthalocyanine complex
only has two vacant iron sites (on each iron center) it means the
complex can only do two turnovers with substrates. To perform
catalytic reaction, the formed F–(Pc)FeIV-N-FeIV(Pc+•)–F
species should be reduced back to the starting (Pc)FeIII-N-
FeIV(Pc) complex. We have previously shown that F‒(Pc)FeIV-
N-FeIV(Pc+•)‒F reacted with H2O2 to regenerate (Pc)FeIII-N-
FeIV(Pc) for new catalytic cycles.[10a]
methylsilyl)diazomethane in diethyl ether to convert carboxylic acids to
the corresponding methyl esters. The response factors of phenolic
products were determined using authentic compounds. When authentic
compounds were not available, phenol products were analysed assuming
that they have similar response factors as their available isomers.
Theory
Calculations were performed using density functional theory methods as
implemented in the Gaussian-09 software package.[26] In a previous
study,[11] we extensively tested several density functional and ab initio
methods for the description of the electronic configuration of N-bridged
diiron(IV)-oxo complexes and obtained good results against experimental
data with the unrestricted B3LYP hybrid density functional method.[27]
Therefore, the same procedures were followed in this work.
We initially tested two density functional methods for the electrophilic
addition pathway, namely the unrestricted B3LYP and B3LYP-D3
methods.[27,28] Although both methods give similar optimized geometries
for the local minima and transition states (see Supporting Information for
details), the full mechanism with all possible reaction pathways was done
with the UB3LYP method only. These models and methods were
extensively benchmarked and calibrated for analogous models and
shown to reproduce experimental free energies of activation and
spectroscopic parameters well.[29]
The geometry optimizations, constraint reaction scans, frequency
calculations and intrinsic reaction coordinate scans were done with
continuum polarized conductor model included at the UB3LYP level of
theory and the LANL2DZ basis set with core potential on iron and 6-31G
on the rest of the atoms: basis set BS1.[30] Single point energy
calculations were done on the optimized geometries with an LANL2TZ
basis set on iron with core potential and 6-311+G* on the rest of the
atoms: basis set BS2. All calculations were performed with a solvent
included through the CPCM model with dielectric constant mimicking
acetonitrile.[31]
Conclusions
This work reports a combined experimental and computational
study into the defluorination of fluoroarenes by a high-valent
diiron(IV)-oxo species. It is shown that the reaction happens with
an initial electrophilic addition step to form an epoxide that can
rearrange to a ketone form. The latter loses a fluoride to the
diiron complex to form phenolate. Overall, defluorination is
mechanistically different from aromatic hydroxylation as an
aromatic C–H versus C–F bond is broken. Computational
modelling shows that the C–F aliphatic bond in the ketone is
significantly weaker than the aromatic C–F bonds in epoxide and
arenes and hence it is essential to pass through the ketone
intermediate, which is not needed for aromatic hydroxylation.
We used two different models, namely model A and B. Model A had the
two phthalocyanine (Pc) groups abbreviated to porphyrazine (Pz) and all
side-chains as hydrogen atoms, whereas model B represented the full
phthalocyanine equatorial ligand without peripheral substituents. These
systems were reacted with C6F6 as substrate. The full reaction profile
was explored for all low-lying doublet, quartet and sextet spin states as
identified with a value 2, 4 or 6 in superscript before the label. Transition
states were characterized with a single imaginary frequency representing
the correct mode, while local minima had real frequencies only. A
selection of intrinsic reaction coordinate (IRC) scans was performed on
key reaction steps of the mechanism, which confirmed the assigned
pathways and connected the transition state to the two local minima.
Experimental Section
Acknowledgements
Experiment
SdV and CVS thank the British Council for a UK-India Education
Research Initiative (UKIERI) award (DST/INT/UK/P-151/2017).
10
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ANR-16-CE29-0018-01).
Keywords: biomimetic models • reaction mechanism •
epoxidation • hydroxylation • enzyme models
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Entry for the Table of Contents
Layout 2:
FULL PAPER
Cédric Colomban, Anthonio H. Tobing,
Gourab Mukherjee, Chivukula V. Sastri,
Alexander B. Sorokin,* and Sam P. de
Visser*
+ C6H6
+ C6F6
Parallel reactions
Series reactions
Page No. – Page No.
Mechanism of Oxidative Activation of
Fluorinated Aromatic Compounds by
N-Bridged Diiron-Phthalocyanine.
What determines the reactivity?
A combined experimental and computational study shows that N-bridged diiron
phthalocyanine oxidants can react with fluorinated arenes by defluorination
reactions. The mechanism is shown to be distinct from typical aromatic
hydroxylation reactions and proceeds via a ketone intermediate.
13
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