Hydrogen atom abstraction by synthetic heme ferric superoxide and hydroperoxide species

Article abstract of DOI:10.1039/c9cc01423c

To date, artificial dioxygen adducts of heme have not been demonstrated to be able to oxidize organic substrates in sharp contrast to their non-heme analogues and naturally occurring enzymes like heme dioxygenases. To address this apparent anomaly, an iro

Full text of DOI:10.1039/c9cc01423c

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DOI: 10.1039/C9CC01423C
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Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Hydrogen Atom Abstraction by Synthetic Heme Ferric Superoxide
and Hydroperoxide Species
Asmita Singha, Abhishek Dey*
proteins have been actively pursued over six decades.12-14 The
Till date artificial dioxygen adducts of heme have not been
demonstrated to be able to oxidize organic substrates in sharp
contrast to their non-heme analogues and naturally occurring
enzymes like heme dioxygenases. To address this apparent
anomaly an iron porphyrin complex is synthesized which includes a
pendant quinol group. The corresponding dioxygen bound iron
porphyrin species is demonstrated to perform Hydrogen atom
transfer (HAT) from a quinol group appended to the porphyrin
ligand. The resultant ferric peroxide, formed by the first HAT,
performs a 2nd HAT generating a ferryl species (FeIV=O) and
O2 adducts can be reduced by electron transfer from a reducing
agent like a metallocene or from a reductant poised in the 2nd
sphere (e.g. distal CuB type site) resulting in formation of
peroxide species; thus, emulating the reaction pathways of
CytP450 and CcO.15 However, to date, synthetic analogues of
dioxygen heme (O2 adducts iron porphyrins) have not been
reported to be chemically reactive towards organic substrates.
This is in sharp contrast to synthetic models to dioxygen bound
non-heme iron proteins, where their reactivity towards organic
17
substrates have been demonstrated.16,
HAT by a heme-
resulting in the 2e-/2H+ oxidation of the pendant hydroquinol to dioxygen species remains to elude attempts using bio-inspired
iron based metalloenzyme mimics.
quinone.
Heme proteins are ubiquitous in nature and serve diverse
functions in physiology.1-4 The globin proteins like haemoglobin
(Hb) traffic O2 to all living cells while myoglobin (Mb) and
4
neuroglobin (Ngb) store O2 in tissues.3, The member of
cytochrome P450 (CytP450) family of protein catalyse oxidation
of organic molecules with O2 and this reactivity is key for
breakdown of food and other organics in the liver as well as for
the biosynthesis of several hormones.1, 5 Cytochrome c oxidase
(CcO) is the terminal oxidase present in complex IV in the
respiratory chain and it reduces O2 to H2O and generates a
proton gradient across the mitochondrial membrane which
7
drives the synthesis of ATP.6,
Heme dioxygenases like
Indoleamine 2,3 dioxygenase (IDO), Tryptophan 2,3
dioxygenases (TDO) are involved in the breakdown of pyrrole
ring of L-tryptophan.8-11 A dioxygen bound ferrous heme species
is common to all of these enzymes involved in vital biological
processes (Figure 1).
Dioxygen adducts of heme have attracted considerable
attention from the scientific community. In nature, these
adducts can be inert, as in Hb/Mb, or active as IDO/TDO.8-11 In
CytP450 the dioxygen bound heme is not the key active species,
rather it is an intermediate in the catalytic cycle, which then has
to be further reduced and protonated to form ferric peroxide
(compound 0) species eventually forming a high valent iron oxo
species (compound I in case of CytP450). This reduction is
achieved by ET from a reductase component, as in CytP450.1
Due to its occurrence across all O2 activating heme enzymes,
synthesis and electronic structure of dioxygen bound heme
Figure 1: Crystal structure of heme dioxygen adduct complex of
cytochrome P450 cam (A), and tryptophan dioxygenase (C). Catalytic
cycle of cytochrome P450 (B) and tryptophan 2,3 dioxygenase (D). The
Fe porphyrin (FeQH2) with a hydroquinone moiety covalently attached
to porphyrin ring (E).
An iron porphyrin with a covalently attached hydroquinol group
(Figure 1e) is reduced to its ferrous state and reacted with O2
and the reaction is followed using UV-Visible spectroscopy,
electron paramagnetic resonance (EPR) and resonance Raman
(rR) spectroscopy at -80 °C in dry and degassed solvents.
a.School of Chemical Science, Indian Association for the Cultivation of Science,
Kolkata, India. Email: icad@iacs.res.in .
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
·-
Immediately, upon reaction with O2, a FeIII-O2 species is
produced. This species is characterized by ν4 (oxidation state
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marker) and ν2 (spin state marker) vibrations at 1367 cm-1 and species decays with time (Figure S8B , S.I.). TheseVsieuwgAgrteicsletOtnhlianet
1567 cm-1, respectively. These are diagnostic of a low spin ferric the FeIV-oxo species is formed after HATDfOroI:m10.1t0h3e9/pCe9nCdCa0n14t2S3QC
porphyrin.18 The Fe-O vibration appears at 581 cm-1, which by the ferric hydroperoxide which leads to the homolytic O-O
shifts to 555 cm-1 upon using labelled 18O2 (Figure 2A)18, 19, i.e. bond cleavage forming a ferryl species and the SQ, in turn, gets
isotope shift (16O2-18O2) is 26 cm-1 (expected 33 cm-1). EPR data oxidized to Q (FeIV=O[Q] species). Room temperature FTIR data
of this species show no signal at 77 K consistent with a of the reaction before and after O2 addition show shift of a
diamagnetic ground sate (GS) expected for this FeIII-O2·- species quinolic band at 1316 cm-1 to quinone vibration at 1520 cm-1
(Figure 3B, red). UV-visible spectra of this species show Soret (Figure S9, S.I.).
band at 422 nm (Figure S3, S.I. in orange), and Q band at 545,
582 nm along with a weak absorption at 623 nm (Figure S4, in
orange). These absorption are characteristic of heme ferric
superoxide complexes.20 The O-O stretching frequency of ferric
superoxide is not observed here which is not uncommon for
21
these species.15,
The band at 545 and 582 nm in the
absorption spectra disappear eventually indicating the decay of
FeIII-O2˙- and two bands grow in at 574 nm and 617 nm (Figure
S4, in blue) suggesting the formation of a ferric hydroperoxide
species.15, 20, 22 The rR data of this intermediate shows two 18O2
sensitive vibrations. One at 531 cm-1 and the other at 783 cm-1,
which shift to 511 cm-1 and 748 cm-1 on using 18O2, respectively
(Figure 2B, blue to red). Furthermore, the vibration at 783 cm-1
shifts to 780 cm-1, on using deuterated MeOH i.e CH3OD (Figure
2C, blue to green). These 16O2/18O2 and H/D isotope shifts
suggest that a ferric hydroperoxide (FeIII-OOH) species is
formed, where the vibration at 531 cm-1 (Δ16-18 observed= 20
cm-1, expected= 30 cm-1) and 783 cm-1 (Δ16-18 observed= 35 cm-
1, calculated= 45 cm-1) represent the Fe-O and O-O vibration,
respectively (Figure 2B) consistent with previous reports on
similar species.23 Additionally when CH3OH is replaced with
CH3OD during reduction of ferric porphyrin, along with the Fe-
O and O-O stretch at 531 cm-1 and 783 cm-1, respectively two
peaks at 834 and 816 cm-1 are found to shift at 830 and 811 cm-
1
respectively. The position of these peaks remain unaltered
upon 18O2 exchange. These peaks originate from semiquinone
ring formed after 1st HAT (see DFT section below). The X-band
EPR data of FeIIIOOH-SQ species show signals originating from
two paramagnetic species which grow in together (Figure 3A).
One species has g values 2.38, 2.20 and 1.90, typical of low spin
ferric hydroperoxide species,20, 24-27 and other has a sharp signal
at g=2.004 typical of a semi-quinone (SQ) radical (Figure 3B,
blue). Quantification of these two signals against CuSO4
standard indicates approximately 1.6 spins consistent with the
presence of two paramagnetic centres in this intermediate.
Thus, this intermediate is a low spin ferric hydroperoxide bound
semi-quinone i.e. FeIII-OOH[SQ]. The formation of the LS FeIII-
·-
OOH[SQ] species from a FeIII-O2 [QH2] by HAT is consistent with
the simultaneous growth in the EPR signal at g= 2.38, 2.20 and
1.90 and g=2.004 (Figure 3A). To ensure an intra-molecular HAT
process, a control experiment is performed with FeTPP in the
presence of 1 equivalent hydroquinone added externally. Upon
addition of O2 and keeping it for 13 minutes at -80 ºC neither
the EPR signal of FeIII low spin nor the radical signal of
semiquinone (Figure S6, S.I.) is observed. This suggests that the
ferric superoxide species reacts intra-molecularly with
hydroquinone to form a ferric hydroperoxide species.
Figure 2: Resonance Raman data of intermediates involved in oxygen
reduction mechanism by FeQH2. All Raman data are recorded at 77 K
using 413.1 nm excitation. (A) Fe-O stretching frequency of 16O2 adduct
of FeQH2 in blue, 18O2 adduct of FeQH2 in red, the difference spectrum
of 16O2 and 18O2 rR data in black, and resonance Raman data of FeQH2
(in green). Fe-O (B) and O-O (C) stretching frequencies of 16O2
substituted (in blue), 18O2 substituted (in red) and deuterated (in green)
FeIII-hydroperoxide intermediates and the difference spectrum of 16O2
and 18O2 in black recorded in DCM. (D) Fe-O stretching frequency of 16O2
(in blue) and 18O2 (in red) substituted FeIV-oxo intermediate and
difference spectra (in black) recorded at 77 K in DCM.
The FeIII-OOH[SQ] reacts intra-molecularly and a new vibration
grows in at 754 cm-1 which is replaced by a Fermi doublet at 729
cm-1 and 698 cm-1 on using labelled 18O2 (Figure 2D). This
represents the Fe-O stretch of a Fe(IV)=O species.28, 29 The peak
at 754 cm-1 increases as the population of the FeIII-OOH[SQ]
species decreases (Figure S7A, S.I.). Simultaneously the two
signals at g= 2.38, 2.20 and 1.90 and g=2.004 of FeIIIOOH-SQ
2 | J. Name., 2012, 00, 1-3
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superoxide. The spin density of the TS shows that the anti-
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ferromagnetic coupling between the irDoOnI:a10n.d103s9u/pCe9CroCx0i1d4e23iCs
maintained (Figure S12, SI); albeit the spin density from the
superoxide is transferred to the QH2 group indicating the
3
formation of a SQ radical. The DFT optimised structure of II’
(scheme 1) show a vibration at 826 cm-1 involving asymmetric
stretching vibration of two C-O bonds of semiquinone ring,
which shifts to 820 cm-1 upon deuteration (Figure S14A, B, S.I.).
The same vibration is observed for 3II in its DFT optimised
structure at 796 cm-1, which shifts to 794 cm-1 upon deuteration
(Figure S14C, D, S.I.). These calculated frequencies at 826 cm-1
and 796 cm-1 correspond to experimentally found vibrations at
834 cm-1, 816 cm-1, respectively. The TS for the next HAT by the
ferric hydroperoxide species result in the homolytic O-O bond
cleavage and the formation of a FeIV=O and Q. The optimized TS
structure (Figure S11C, SI) shows that the O-O bond is being
cleaved and a HAT from the O-H group of the pendant SQ is in
progress. An imaginary frequency at 1728 cm-1 involves the
transfer of H-atom from the SQ as the O-O bond is cleaved
(Figure S11C, SI). The O-O bond is elongated to 2.16 Å in the TS
relative to 1.45 Å in the reactant suggesting that the O-O
cleavage precedes the HAT from the SQ in the TS. The TS is
calculated to be 13.4 kcal/mol higher than the reactant which is
reasonably close to the experimental estimate of 13.7 kcal/mol.
The calculated geometry of the TS, 3IITS, show partial oxidation
of the pendant SQ ring as evident by shortening of the C-O bond
(1.31 Å) and elongation of the O-H bond (1.11 Å) relative to the
reactant (C-O =1.36 Å and O-H 0.95 Å). Hence the O-O bond
cleavage in the FeIII-OOH[SQ] intermediate proceeds
concomitantly with the HAT from the pendant SQ group.
Figure 3: (A) Kinetic trace of formation of X-band EPR signal (77K) of FeIII-
OOH[SQ] species in THF at -80 °C. Both the FeIII low spin and radical
grows and decays simultaneously. (B) X-band EPR spectra (4K) of FeQH2
kept at -80 °C for 13 min (in blue) and for 2min (in orange) after addition
of O2.
The time trace of the radical signal (at -80°C, THF solvent) show
a faster appearance of these EPR signals in protonated QH2
(2.5±0.1 × 10-3 s-1) than deuterated QD2 (6.1±0.5 × 10-4 s-1)
(Figure 4). Thus, there is a prominent kinetic isotope effect in
·-
the formation of FeIII-OOH[SQ] from FeIII-O2 [QH2] and it is
estimated to be 4.2±0.2. A KIE of ~4 is suggestive of a HAT by
·-
the preceding FeIII-O2 [QH2] species consistent with the
spectroscopic data. Both the FeIII-OOH and SQ EPR signals decay
with time and a HS FeIII signal grows in. The decay of the SQ EPR
signal is faster for QH2 (1.3±0.1 x 10-3 s-1) than QD2 (5.8±0.3 x 10-
4 s-1) consistent with a 2nd HAT responsible for the oxidation of
SQ to quinone with a KIE of 2.2±0.2.
Figure 4: Kinetic trace of formation and decay of radical signal in CH3OH
(blue) and CH3OD (red) at -80 oC. The EPR measurements are performed
at 77 K.
Based on spectroscopic and kinetic data it can be proposed that
·-
a heme FeIII-O2·- adduct in the FeIII-O2 [QH2] species abstracts a
H-atom from the pendant quinol group to form a FeIII-OOH[SQ]
intermediate species (scheme 1A,B). FeIII-OOH[SQ] species then
performs the 2nd HAT from pendant semiquinone ring and
decays to a FeIV=O[Q] species (scheme 1B). The FeIV=O[Q]
decays to a FeIII-OH[Q] with a rhombically split axial EPR at
around g=6 (Figure S8A, S.I.). O2 reduction to H2O requires 4e-
/4H+. In this case 2e-/2H+ are obtained from iron (FeII gets
oxidised to FeIV) and 2e-/2H+ are obtained from QH2
(Hydroquinone is oxidised to quinone).
The optimized structure of FeIII-O2˙--[QH2] shows that the bound
superoxide is involved in H-bonding with the pendant QH2
group offering a pre-organized geometry set-up for HAT (Figure
S10, S.I.). The singlet TS energy is computed to be 26 kcal/mol
which is substantially higher than what may be expected from
the experimental rate of 2.5±0.1 × 10-3 s-1 at -80°C. The triplet
TS energy, calculated to be 13.6 kcal/mol, is consistent with
activation barrier obtained from the experimental rate (13.4
kcal/mol) using Eyring equation (Figure S11A). The optimized
triplet TS for the HAT show a single imaginary frequency at -
1597.57 cm-1, which involves the shift of the H atom from QH2
to superoxide (Figure S11B, SI). The O-O bond lengths is
elongated to 1.35 Å at the TS relative to 1.29 Å in the reactant
indicating incipient formation of a hydroperoxide from a
Scheme 1: (A) The schematic representation of mechanistic pathway of
O2 reduction by the Fe(II)[QH2] complex mediated by hydroquinone
probed at -80 oC (B) The schematic representation of 2 consecutive
HAT’s performed by hydroquinol group appended in porphyrin ring
(FeQH2) to reduce O2 to H2O probed at -80 °C.
Reactivity of dioxygen adducts of heme is well documented in
heme dioxygenases. However, lack of clear evidence in
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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10.
H. Sugimoto, S.-i. Oda, T. Otsuki, T. Hino, T. Yoshida and Y. Shiro,
synthetic systems, where several other aspects of these species
had already been mimicked, have prompted proposals justifying
inertness of heme-dioxygen adducts.13, 15, 30, 31 In this report, it
is demonstrated that a synthetic analogue of a heme dioxygen
adduct is kinetically competent in performing HAT abstraction
from QH2 unit with BDFE of 80 kcal/mol. Similarly a ferric
hydroperoxide species is demonstrated to performing HAT of a
SQ species (BDFEO-H = 65.2 kcal/mol32). These reactivities
demonstrate that the heme bound superoxide and peroxide
species are as reactive as their non-heme analogues.33 The
architecture of the porphyrin ligand ensures direct hydrogen
bonding interaction between the ferric superoxide and ferric
hydroperoxide with the -OH groups of quinol and semiquinone,
respectively. Such a favourable pre-organization is likely
responsible for the facile reactivity observed here.
The Ferric superoxide and hyroperoxide species are much
weaker oxidants relative to the high-valent ferryl species which
can hydroxylate C-H bonds having BDEC-H >100 kcal/mol. Thus,
these are not likely to be the reactive species involved in
oxidations catalysed by Cyt P450. The BDEO-H of these species is
determined by a) pKa of compound II and b) Eo of compound I
following equation 1.
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Proceedings of the National Academy of Sciences of the United States of
DOI: 10.1039/C9CC01423C
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18.
19.
20.
21.
22.
23.
24.
25.
26.
BDEOH = CH + 1.37pka + 23.06xEo --------------------- (1)
Where CH represents the enthalpic constant and includes free
energy of formation of hydrogen radical, free energy of
solvation of hydrogen radical in the solvent and an entropy
term. In aprotic organic solvents CH in equation 1 changes by 10-
15 kcal/mol relative to water.32, 34 In general, the high valent
metalloporphyrin/non-heme species have much higher Eo than
the ferric superoxides investigated here which enables them to
perform HAT from much stronger C-H bonds. The pKa of the
superoxide bound to a ferric centre is likely to be less than that
of free superoxide (4.8 in water).35, 36 A rough estimate of pKa of
a ferric superoxide in water was obtained to be 3.537 whereas
that of compound II in P450 is 11.9.38 The Eo of the Ferric site
bound to superoxide is around -280 mV vs NHE24 which is ~1.5
V lower than that of compound I (+1.22V vs NHE in pH7).39 Thus,
the BDEX-H that these iron superoxide species can abstract
should be ~28 kcal/mol less than that of compound I in P450
(1.37xΔpKa + 23.06xΔE) in an aqueous solvent i.e. a highest
BDEX-H of ~70 kcal/mol may be abstracted. However, in an
organic solvent, the difference in CH between aprotic organic
and aqueous solvents is (~10-15 kcal/mol). Thus, HAT from
substrates with BDEX-H of ~80-90 kcal/mol can be achieved in
aprotic organic solvents; as is the case here.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
In summary, both heme dioxygen adducts and heme
hydroperoxides are demonstrated to be capable of HAT from
suitably oriented organic substrates.
T. H. Yosca, J. Rittle, C. M. Krest, E. L. Onderko, A. Silakov, J. C. Calixto, R. K.
Behan and M. T. Green, Science, 2013, 342, 825.
K. Mittra and M. T. Green, Journal of the American Chemical Society, 2019,
Conflicts of interest
There are no conflicts to declare
DOI: 10.1021/jacs.9b00242.
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