Functional models of nonheme diiron enzymes: Reactivity of the μ-oxo-μ-1,2-peroxo-diiron(iii) intermediate in electrophilic and nucleophilic reactions

Article abstract of DOI:10.1039/c9dt04551a

The reactivity of the previously reported peroxo-adduct [FeIII2(μ-O)(μ-1,2-O₂)(IndH)₂(solv)₂]²⁺ (1) (IndH = 1,3-bis(2-pyridyl-imino)isoindoline) has been investigated in nucleophilic (e.g., deformylation of alkyl and aryl alkyl aldehydes) and electrophilic (e.g. oxidation of phenols) stoichiometric reactions as biomimics of ribonucleotide reductase (RNR-R2) and aldehyde deformylating oxygenase (ADO) enzymes. Based on detailed kinetic and mechanistic studies, we have found further evidence for the ambiphilic behaviour of the peroxo intermediates proposed for diferric oxidoreductase enzymes.

Full text of DOI:10.1039/c9dt04551a

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Functional models of nonheme diiron enzymes: reactivity of -
oxo--1,2-peroxo-diiron(III) intermediate in electrophilic and
nucleophilic reactions.
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Balázs Kripli, Miklós Szávuly, Flóra Viktória Csendes, and József Kaizer*
Dedicated to Professor Gábor Speier on the occasion of his 80th birthday.
www.rsc.org/
Abstract: The reactivity of the previously reported peroxo-adduct more insight into the versatility of this family of enzymes. It
[FeIII2(-O)(-1,2-O2)(IndH)2(solv)2]2+ (1) (IndH = 1,3-bis(2-pyridyl- can be found some biologically relevant mononuclear end-on
imino)isoindoline) has been investigated in nucleophilic (e.g., copper(II)-,8 and iron(III)-superoxides,9 and dinuclear
deformylation of alkyl and aryl alkyl aldehydes) and electrophilic diiron(II,III)-superoxide that was capable of electrophilic
(e.g. oxidation of phenols) stoichiometric reactions as biomimics hydrogen atom abstraction (HAA) from phenols,10
of ribonucleotide reductase (RNR-R2) and aldehyde deformylating intramolecular C-H activation and oxygen atom transfer
oxygenase (ADO) enzymes. Based on detailed kinetic and reactions (OAT), but only few examples can be found in the
mechanistic studies we have found further evidence for the literature, where peroxo-metal complexes are directly involved
ambiphilic behaviour of the peroxo intermediates proposed for in a nucleophilic reaction (e.g., the deformylation of
diferric oxidoreductase enzymes.
aldehydes).11 McDonald and Que had previously reported the
first example of a reactive dimanganese(II,III)-peroxide as
nucleophilic oxidant.12
To date, around 30 synthetic spectroscopically
characterized peroxo-diferric complexes are known as possible
stuctural models of diiron enzymes.13 As a possible functional
model of RNR-R2 and ADO enzymes we have investigated the
reactivity of peroxo adduct [Fe2(-O2)(MeBzim-Py)4(CH3CN)]4+
Nonheme dinuclear oxidoreductases such as ribonucleotide
reductase (RNR),1 arylamine N-oxygenase (CmII),2 deoxyhypusine
hydroxylase (hDOHH),3 soluble methane monooxygenase (sMMO),4
and toluene monooxygenase (TMO)5 generate high-valent FeIIIFeIV
(RNR-R2) or FeIVFeIV (CmII, hDOHH, sMMO and TMO) oxoiron
species via peroxo-diiron(III) intermediates as a result of dioxygen
activation.6 These intermediates are responsible for many types of
electrophilic and nucleophilic oxidative process in the
aforementioned enzymes and their synthetic models. For example,
the sMMO and RNR enzymes catalyse the oxidation of alkanes and
phenols via electrophilic C-H and O-H activation, respectively, whilst
the aldehyde deformylating oxygenases (ADO)7 catalyse the
(2, MeBzim-Py
=
2-(2’-pyridyl)-N-methylbenzimidazole)
towards various phenols and aldehydes.13a,b In the former case
we have found direct kinetic and computational evidence for
the formation of low-spin oxoiron(IV) species and its
involvement as an electrophilic species in the O-H activation
process,13a whilst in the latter case the -1,2-peroxo-diiron(III)
intermediate proved to be a nucleophilic oxidant in the
aldehyde deformylation, that occurs by Baeyer-Villiger type
mechanism including rate-limiting AN or Creege-type
aldehyde deformylation with
a nucleophilic mechanism. The
ambiphilic feature of these enzymes can be interpreted with the
involvement of two distinct oxidants, namely the electrophilic high-
valent oxoiron(IV) and the nucleophilic peroxo-diferric
intermediates. While, the reactivity of oxoiron(IV) species in
various electrophilic reactions have been studied in details,
only few examples can be seen in the literature, where peroxo-
metal species are the key reactive intermediates. Furthermore,
understanding the factors that lead to O–O bond cleavage at
nonheme diiron centers resulting electrophilic intermediate
has also been a major goal of researchers in this field, to get
Department of Chemistry, University of Pannonia, H-8201 Veszprém,
Hungary
E-mail: kaizer@almos.uni-pannon.hu.†Electronic Supplementary Information
(ESI) available: Experimental details of oxidations, and kinetic data. See
DOI: 10.1039/x0xx00000x
Scheme 1. Electrophilic (phenol oxidation) and nucleophilic
(aldehyde deformylation) reactions of 1.
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rearrangement steps depending on the substrate used.13b As a and ΔH‡ = 27(4) kJ mol-1, ΔS‡ = -175(14) J mol-1 K-1, ΔG‡ = 79(8)
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-1
DOI: 10.1039/C9DT04551A
continuity of this study we have choosed the previously kJ mol at 10 °C, respectively (Fig. 2B). The activation enthalpy
reported and fully characterized (-oxo)-(-1,2-peroxo)- of 28 kJ mol-1 and the calculated Gibbs energy of 69 kJ mol-1
diiron(III) species, [FeIII (-O)(-1,2-O2)(IndH)2(solv)2]2+ (1, IndH for PhC(O)H are smaller than those observed for 2/PhC(O)H
2
= 1,3-bis(2-pyridylimino)isoindoline) as model compound,14 system (ΔH‡ = 42 and ΔG‡ = 71 kJ mol-1), which is consistent
where the dissociation of the diiron(III) core may be excluded with the higher reactivity of 1 with PhC(O)H.13b Similarly, under
due to the -oxo-bridge, and investigated its reactivity identical conditions the ΔH‡ = 27 kJ mol-1 and ΔG‡ = 79 kJ mol-1
compared to our earlier system ([Fe2(-O2)(MeBzim- values are smaller than that was obtained for 2/DTBPH (64 and
Py)4(CH3CN)]4+)13a,b (2) in both electrophilic and nucleophilic 96 kJ mol-1),13a but larger than that calculated for
reactions to get further evidence for the ambiphilic behaviour [FeIV(N4Py*)(O)]2+/DTBPH (ΔH‡ = 21 and ΔG‡ = 42 kJ mol-1,
of a -1,2-peroxo-diiron intermediates proposed for diiron N4Py*
oxygenases.6 ethylamine).15 Compared to the self-decay process, the much
Initially we have investigated the electrophilic and smaller ΔH‡ and the large, negative ΔS‡ values are consistent
nucleophilic reactivity of the in situ generated [FeIII (-O)(- with an associative-type bimolecular reactions.
=
N,N-bis(2-pyridylmethyl)-1,2-di(2-pyridyl)-
A
2
1,2-O2)(IndH)2(solv)2]2+ (1) (derived from the reaction of krel(PhC(O)H/DTBPH) value of 5.4 was also determined by
[FeII(IndH)(solv)3]2+ with stoichiometric amounts of H2O2) comparing the individual reactions under identical conditions.
towards benzaldehyde (PhC(O)H) as electrophilic and 2,6-di- The kinetics of benzaldehyde and phenol oxidation have also
tert-butylphenol (DTBPH) which may behave either as been measured with PhC(O)D and DTBPD to investigate the C-
nucleophilic or electrophilic model substrates in CH3CN at 10 H and O-H kinetic isotope effects (KIE). In the former case the
˚C, and obtained the same results that benzoic acid13b and almost identical rate constant when compared with PhC(O)H
3,3’,5,5’-tetra-tert-butyl-4,4’-diphenoquinone13a
were suggests that the benzylic (aldehydic) hydrogen atom is
produced as major products (80-80 % based on 1, Fig. S2 and innocent, its involvement in the rate-determining step can be
S3, ESI), respectively. The distinction between nucleophilic excluded. In the latter case the involvement of the phenolic O-
versus radical peroxo character can be proved with phenols H bond in the rate-determining step is indicated by the
since deprotonation leads to phenoxide coordination, whereas magnitude of the kO-H
/
kO-D
KIE (SIE) of 1.8 in CH3CN/H2O and
HAA provides a phenoxyl radical, which can lead to an easily- CH3CN/D2O. The observed isotope effect is not large, but SIE in
identifiable 2,2’-biphenol-coupled product after the HAA reactions are not necessarily large due to the involvement
disproportionation of the forming semiquinones. Based on our of proton transfer and/or disruption of hydrogen bonding in
previous kinetic and computational results peroxo O─O bond the presence of water. This value is almost identical with the
cleavage resulting in oxoiron(IV) intermediate (1a) may also data reported for the previously published 2/DTBPH system
occur prior to HAA in these reactions. Complex 1 decays over (KIE = 1.78),13a and comparable to those obtained with
the course of 200 s at 10 °C with kdecay = 3.5(5) × 10-3 s-1 with a mononuclear complexes [FeIV(N4Py*)(O)]2+ (KIE = 4.5 for
large H‡ of 81(3) kJ mol-1 and a small S‡ of -10(10) J mol-1 K-1 DTBPH),15 and [FeIV(TMC)(O)(X)]2+ (KIE = 2.7 for H2Q16 (H2Q =
(Fig. S1), which is consistent with an unimolecular decay 1,4-hydroquinone, TMC
=
1,4,8,11-tetramethyl-1,4,8,11-
process. The decay rate of 1, which was monitored by UV-vis tetraaza-cyclotetradecane). These values are much smaller
spectroscopy at 690 nm (Fig. 1, ESI),14 is significantly increased than those for corresponding oxidations, where the reactions
by the addition of PhC(O)H or DTBPH, and the extent of which
is linearly dependent on the concentration of the substrate in
both cases (Fig. 2A). These results indicate a direct reaction
between 1 and PhC(O)H, and 1a and DTBPH with k2
=
2.16±0.08 M-1 s-1 and k2 = 0.40±0.01 M-1 s-1, respectively at 10
°C. The activation parameters for PhC(O)H and DTBPH are ΔH‡
= 28(1) kJ mol-1, ΔS‡ = -138(3) J mol-1 K-1, ΔG‡ = 69(2) kJ mol-1,
Fig. 2. Reactions of [FeIII2(-O)(-1,2-O2)(IndH)2(solv)2]2+ (1)
with 4R-PhC(O)H and 4R-DTBPH (R = CH3O, CH3, H, Cl, CN and
t-Bu, CH3, H, Br, CN) in CH3CN at 10 °C. (A) Plot of kobs’ versus
[substrate] for reactions of 1 (1 mM) with PhCHO, and DTBPH.
(B) Eyring plots of logk2/T versus 1/T for PhC(O)H and DTBPH.
(C) Plot of logk2 versus BDEO-H for DTBPH. (D) Hammett plots of
log krel against p of 4R-PhC(O)H and 4R-DTBPH. (E)
Competitive oxidation of PhC(O)H and DTBPH: [1] = 1 mM;
[PhC(O)H + DTBPH] = 60 mM.
Fig. 1. Reactions of 1 with benzaldehyde in CH3CN at 10 ˚C: UV-
vis spectral change of 1 (1 mM) upon addition of 20 equiv.
PhCHO. Inset shows time course of the decay of 1 monitored
at 690 nm upon addition of 20 equiv. PhCHO.
2 | J. Name., 2012, 00, 1-3
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occur by proton-coupled electron transfer (PCET) mechanism
(e.g., KIE = 29 for cis-[RuIV(bpy)2(py)(O)]2+/H2Q).17a Consistent
with a HAA mechanism, studies with para-substituted 2,6-di-
tert-butylphenols (4R-DTBPH, R = t-Bu, CH3, H, Br, CN) afforded
a linear correlation between the reaction rates and the O-H
bond dissociaton energy (BDEO-H) values of the substrates. The
slope of -0.17 is little bit smaller (Fig. 2C), but comparable to
those obtained in the oxidation of 4R-DTBPHs by
[FeIV(N4Py*)(O)]2+ (-0.48),16 and [FeIV(TMC)(O)(X)]2+ (X = N3 (-
0.36), CF3CO2 (-0.42) and CH3CN (-0.55)) via HAA
mechanism.17b Further evidence for a HAA derives from the
Hammett analysis of the rate data from the DTBPH derivatives.
Plotting the relative rates (log(Rk2/Hk2)) as a function of p and
p+ values of the substituents afford  value of -0.63 and -0.58,
which is almost identical with the data observed for 2/DTBPH
(-0.71),13a and suggests that the metal-based oxidant is
electrophilic (Fig. 2D). Furthermore, these relatively small
negative values suggest that there is a small development of
positive charge on the substrate in the transition state, and
that the phenol oxidation in our case occurs by H atom
abstraction, excluding the electron transfer process, which
typically shows a more negative  value due to the more polar
transition state.
View Article Online
DOI: 10.1039/C9DT04551A
Scheme 2. Proposed mechanism for the nucleophilic reactions
of 1 with series of aldehydes.
To probe the nucleophilic reactivity of 1 we have
investigated the electronic effect of substrates with para-
substituted benzaldehydes (4R-PhC(O)H, R = CH3O, CH3, H, Cl,
CN), and a good linear correlation was obtained with small
positive Hammett  value of +0.48 by plotting the relative
rates as a function of p of the para-substituents. This result
demonstrates that electron-donating groups on the substrate
decrease and electron-withdrawing groups increase the
reaction rate, and that the metal-based oxidant in that case is
nucleophilic (Fig. 2D). This value is comparable to those
obtained previously in the Baeyer-Villiger type deformylation
of PhCHO by [MnIIMnIII(O2)(BPMP)]2+ ( = +0.64; HBPMP = 2,6-
bis[(bis(2-pyridylmethyl)amino)methyl]-4-methylphenol),12
and 2 (  +0.67),13b suggesting a similar mechanism including
a nucleophilic attack of the peroxide on the aldehyde C-atom
in the rate-determining step (Scheme 2). These results above
serve strong evidence for the ambiphilic behavior of 1. As it is
able to assist both nucleophilic and electrophilic oxidations, we
have carried out competitive reactions of PhC(O)H and DTBPH,
and found that nucleophilic oxidation of benzaldehyde
competes with the O–O bond cleavage step required to
generate the electrophilic O=FeIV–O–FeIV=O (1a) oxidant in a
preequlibrium process with steady-state kinetics (+d[1a]/dt = -
d[1a]/dt; K = k1/k-1, where k1 << k-1, k2), responsible for the
phenol oxidation in the rate-determining step (krds). 1a is
formed by analogy to what Kodera has demonstrated for his
diferric-peroxo intermediate by a dinucleating octadentate
6,6-(ethylene-bridged)bis(TPA) ligand.18 The equlibrium
between 1a and 1 can also be supported based on the
previously published [FeII(IndH)(solv)3]2+-catalyzed H2O2
oxidation of thioanisole and benzyl alcohol via electrophilic
OAT ( = -0.4) and HAA ( = -0.85, KIE = 9) process,
respectively.14
Fig. 3. Second-order rate constants (k2) determined in the
reactions of 1 (1 mM) at 10 ˚C with alkyl aryl (A) and alkyl
aldehydes (B). (C) Isokinetic plot and (D) Plot of G‡ versus lnk2
for the reaction between 1 and various aldehydes.
Finally, we have investigated the scope of substrates for
the Baeyer-Villiger reaction of 1 by the use of various aryl alkyl
(Fig. 3A) and alkyl aldehyde (Fig. 3B) derivatives (Scheme 2).
The reactions with 2-phenylpropionaldehyde (PPA) and
phenylacetaldehyde (PAA) afforded acetophenone and
benzaldehyde, respectively as major reaction products based
on gas chromatography mass spectrometry. The relative
reactivity of 1 toward the aryl and aryl alkyl aldehydes shows
the following order PhCHO > PAA > PPA (Table 1, Fig. 3A). 1
was also able to deformylates various alkyl aldehydes such as
pivalaldehyde (TBA), cyclohexanecarboxaldehyde (CCA) and
propionaldehyde (PA) affording tert-butanol, cyclohexanone
and acetaldehyde, respectively as major products (Fig. S4-S8,
ESI). The relative reactivity order; TBA (3˚) > CCA (2˚) > PA (1˚)
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reaction with significantly larger rates than thoseVoiebwsAertricvlee dOnflioner
the previously reported -1,2-peroxo-dDifOerI:r1ic0.1s0p3e9/cCie9sD.T0B4a5s5e1dA
on detailed kinetic studies, a plausible mechanism has been
proposed for both systems, and the relative reactivity values
have been discussed in details. Studies on the oxidation of
hydrocarbons as further evidence for the formation of 1a
including DFT calculations are in progress.
Table 1. Rate constants and activation parameters for the
reaction of 1 and 2 towards aldehydes and phenols.
[a]
Substrate/
Complex
k2

H‡
[kJmol-1]
S‡
[Jmol-1K-1]
G‡
[kJmol-1]
[M-1s-1]
TBA/1
2.96±0.15
2.34±0.10
2.39±0.06
0.59
21±1
27±1
28±1
42
-163±3
-144±5
-138±3
-98
69±2
69±3
69±2
71
CCA/1
PhCHO/1
PhCHO/213b
PAA/1
+0.48
+0.67
Notes and references
Conflicts of interest: There are no conflicts of interest to
declare.
§ This work was supported by a grant from The Hungarian
National Research Fund (OTKA) K108489 and GINOP-2.3.2-15-
2016-00049.
0.95±0.06
0.04
18±1
52
-181±2
-87
72±1
77
PAA/213b
PA/1
0.77±0.03
0.68±0.04
0.002
29±2
25±1
72
-145±6
-162±5
-34
72±4
73±2
82
1
2
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PPA/1
PPA/213b
DTBPH/1
DTBPH/213a
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-0.62
-0.71
27±4
-175±14
79±8
64
-108
96
aIn CH3CN at 10 ºC; k2 = (kobs – ksd) / [S] from –d[1]/dt = kobs [1]
= (ksd + k2 [S])[1] (Table S1-S9, ESI).
4
5
(Fig. 3B), is typical for the Baeyer-Villiger mechanism, where
the migratory ability on the Criegee intermediate is ranked
tertiary (3˚) > secondary (2˚) > primary (1˚). The more electron-
rich (most-substituted) alkyl group migrates in preference.,
which can be explained by the buildup of positive charge in the
transition state for breakdown of the Criegee intermediate.19
These results above suggest that in the case of
benzaldehydes the nucleophilic attack of the peroxide on the
aldehyde C-atom, while in the case of the investigated aryl-
alkyl and alkyl aldehydes the Criegee-rearrangement can be
postulated as rate-determining step. Based on kinetic and
activation parameters presented herein demonstrate that the
-oxo--1,2-peroxo-diferric species, 1 is much more reactive
than the -1,2-peroxo-diferric species, 2 in the deformylation
reactions (Table 1); e.g., the relative rate is 24 for PAA (ΔΔG‡ =
5 kJ mol-1), and significantly larger for PPA (krel = 340 with ΔΔG‡
= 9 kJ mol-1). Based on the temperature dependence of the
reaction rates of the investigated formylation reactions we
have also found that the values of -TΔS‡ in the studied
temperature range, were larger than ΔH‡, indicating an
6
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that observed for 2 (Table 1, enthalpy-controlled reaction with
ΔH‡ > TΔS‡). Arbitrary fitting of a linear relationship to
available entropy and enthalpy data yields ΔH‡ = 63.4 kJ mol-1
at the intercept, which is little bit smaller than that was
obtained for the deformylation reaction of 2. Furthermore, the 13 (a) M. I. Szávuly, M. Surducan, E. Nagy, M. Surányi, G. Speier,
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MacMurdo, A. Mairata i Payeras, L. Que, Jr., Inorg. Chem.,
2005, 44, 85; (d) M. A. Cranswick, K. K. Meier, X. Shan, A.
Stubna, J. Kaizer, M. P. Mehn, E. Münck, L. Que, Jr., Inorg.
calculated Gibbs energy values correlate very well with the
reaction rates (Fig. 3D).
Efforts have been made to find strong evidence for the
ambiphilic behavior of non-heme peroxo-diferric intermediate.
We have found that the -oxo--1,2-peroxo-diferric
intermediate is capable of deformylating aldehydes via
nucleophilic, and able to oxidize phenols via an electrophilic
4 | J. Name., 2012, 00, 1-3
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Dalton Transactions
Journal Name
COMMUNICATION
Chem., 2012, 51, 10417; (e) A. T. Fiedler, X. Shan, M. P.
Mehn, J. Kaizer, S. Torelli, J. R. Frisch, M. Kodera, L. Que, Jr.,
J. Phys. Chem. A. 2008, 112, 13037; (f) J. S. Pap, A.
Draksharapu, M. Giorgi, W. R. Browne, J. Kaizer, G. Speier,
Chem. Commun., 2014, 50, 1326.
View Article Online
DOI: 10.1039/C9DT04551A
14 J. S. Pap, M. A. Cranswick, É. Balogh-Hergovich, G. Baráth, M.
Giorgi, G. T. Rohde, J. Kaizer, G. Speier, L. Que, Jr., Eur. J.
Inorg. Chem., 2013, 3858;
15 D. Lakk-Bogáth, G. Speier, J. Kaizer, Polyhedron, 2018, 145,
227.
16 K. Nehru, Y. Jang, S. Oh, F. Dallemer, W. Nam, J. Kim, Inorg.
Chim. Acta, 2008, 361, 2557.
17 (a) R. A. Binstead, M. E. McGuire, A. D. Dovletoglou, W. K.
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Functional models of nonheme diiron enzymes: reactivity of -oxo--1,2-peroxo-diiron(III)
View Article Online
DOI: 10.1039/C9DT04551A
intermediate in electrophilic and nucleophilic reactions.
Balázs Kripli, Miklós Szávuly, Flóra Viktória Csendes, and József Kaizer*
The ambiphilic behavior (electrophilic versus nucleophilic character) of peroxo-diferric complex,
and its relative reactivity towards aldehydes and phenols has been discussed.