Secondary coordination sphere influence on the reactivity of nonheme iron(II) complexes: An experimental and DFT approach

Article abstract of DOI:10.1021/ja402688t

The new biomimetic ligands N4Py^2Ph (1) and N4Py ^2Ph,amide (2) were synthesized and yield the iron(II) complexes [Fe^II(N4Py^2Ph)(NCCH₃)](BF₄) ₂ (3) and [Fe^II(N4Py^2Ph,amide)](BF ₄)₂ (5). Controlled orientation of the Ph substituents in 3 leads to facile triplet spin reactivity for a putative Fe^IV(O) intermediate, resulting in rapid arene hydroxylation. Addition of a peripheral amide substituent within hydrogen-bond distance of the iron first coordination sphere leads to stabilization of a high-spin Fe^IIIOOR species which decays without arene hydroxylation. These results provide new insights regarding the impact of secondary coordination sphere effects at nonheme iron centers.

Full text of DOI:10.1021/ja402688t

Communication
pubs.acs.org/JACS
Secondary Coordination Sphere Influence on the Reactivity of
Nonheme Iron(II) Complexes: An Experimental and DFT Approach
Sumit Sahu,† Leland R. Widger,† Matthew G. Quesne,‡ Sam P. de Visser,*,‡ Hirotoshi Matsumura,§
Pierre Moenne-Loccoz,*,§ Maxime A. Siegler,† and David P. Goldberg*,†
̈
†Department of Chemistry, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, United States
‡Manchester Institute of Biotechnology and School of Chemical Engineering and Analytical Science, The University of Manchester,
131 Princess Street, Manchester M1 7DN, United Kingdom
§Division of Environmental and Biomolecular Systems, Institute of Environmental Health, Oregon Health & Science University,
Beaverton, Oregon 97006, United States
S
* Supporting Information
ABSTRACT: The new biomimetic ligands N4Py2Ph (1)
and N4Py2Ph,amide (2) were synthesized and yield the
iron(II) complexes [FeII(N4Py2Ph)(NCCH3)](BF4)2 (3)
and [FeII(N4Py2Ph,amide)](BF4)2 (5). Controlled orienta-
tion of the Ph substituents in 3 leads to facile triplet spin
reactivity for a putative FeIV(O) intermediate, resulting in
rapid arene hydroxylation. Addition of a peripheral amide
substituent within hydrogen-bond distance of the iron first
Figure 1. Structures of new ligands 1 and 2.
coordination sphere leads to stabilization of a high-spin
FeIIIOOR species which decays without arene hydrox-
ylation. These results provide new insights regarding the
impact of secondary coordination sphere effects at
nonheme iron centers.
group as a hydrogen-bond donor for interaction with metal−
oxygen intermediates. An iron(II) complex from 1 undergoes
rapid, regioselective arene hydroxylation at one Ph ring, and a
novel reaction channel appears accessible by the positioning of
the phenyl ring in the second coordination sphere. In contrast,
the FeII complex from 2 does not undergo arene hydroxylation
but rather leads to the formation of a metastable FeIII-OOR
complex. The latter result suggests a significant influence of the
amide-derived H-bond donor group on the stability of the FeIII-
OOR species. Computational studies, in combination with the
experimental data, provide key insights regarding the
importance of the second-coordination sphere effects intro-
duced by 1 and 2.
onheme iron oxygenases are potent and selective
Ncatalysts, typically operating through iron-peroxo
(FeOO(H/R)) and iron-oxo (Fe(O)) intermediates. For
example, arene hydroxylation is mediated by a class of
mammalian nonheme iron enzymes known as aromatic
amino acid hydroxylases (e.g., Tyr, Phe, and Trp hydroxylases),
and both FeIIOOR and FeIV(O) species are postulated as key
intermediates in their catalytic cycles.1 Much effort has gone
into the preparation of synthetic analogs of FeOO(H/R) and
FeIV(O) intermediates, employing ligands designed to stabilize
these species through the use of oxidatively inert, biologically
relevant donor groups and steric shielding of the metal center.
Enzymes, however, also have at their disposal the ability to
control the second coordination sphere through the juxtapo-
sition of substrates at appropriate distances from the metal
center and through interacting residues that can tune reactivity
via hydrogen bonds. In contrast, model complexes that are
designed to incorporate these second-coordination sphere
effects are less developed.
A key step in the synthesis of diphenyl-substituted 1 was a
Suzuki−Miyaura coupling between bis(6-bromo-2-pyridyl)
ketone and C6H5B(OH)2, with the final ligand 1 prepared as
in Figure S1. Stirring of 1 equiv of Fe(BF4)2 and 1 in CH3CN
(Scheme 1) leads to X-ray quality crystals of [FeII(N4Py2Ph)-
(NCCH3)](BF4)2 (3) (92%) from Et2O/CH3CN. X-ray
Scheme 1
Herein we report the synthesis of two new polydentate
ligands, N4Py2Ph (1) and N4Py2Ph,amide (2) (N4Py = N,N-bis(2-
pyridylmethyl)-N-bis(2-pyridyl)methylamine) (Figure 1),
which have been designed to examine second-coordination
sphere effects in nonheme Fe model complexes. The new
ligand 1 incorporates phenyl substituents as constrained
substrates for oxidation, while 2 includes an additional amide
Received: March 15, 2013
© XXXX American Chemical Society
A
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Communication
i
diffraction reveals the structure of 3 as shown in Figure 2, which
[FeIII(N4PyPh,PhO)](BF4)2 (4) from Pr2O/CH3CN (Figure 2).
The structure confirmed that arene hydroxylation had occurred
to give a phenolato-iron(III) complex. The Fe-N bond lengths
(1.9193(15)−2.0358(15) Å) and EPR spectrum (g 2.39, 2.12,
1.90) indicate 4 is an ls-FeIII complex.
has a six-coordinate FeII center bound to the pentadentate
t
The reaction of 3 with BuOOH, PhIO or IBX-ester results
in a regioselective intramolecular arene hydroxylation to give a
single ortho-hydroxylated product. This selectivity for the same
product points to a common metal-based intermediate for all
three oxidants, which is most likely the proposed [FeIV(O)-
(N4Py2Ph)]2+ species (Scheme 2).4b,c Further support for the
Scheme 2
Figure 2. Displacement ellipsoid plots (50% probability) of the cations
of 3 and 4. H atoms are omitted for clarity.
N4Py2Ph ligand and one CH3CN molecule. The Fe-Npy
distances for 3 (2.165(1)−2.379(1); 2.172(1)−2.442(1) Å)
are indicative of high-spin (hs) FeII-Npy bond lengths.2 The
1
involvement of [FeIV(O)(N4Py2Ph)]2+ comes from UV−vis and
NMR spectral titrations, where maximal formation of 4 is
clearly seen following the addition of 1 equiv of IBX-ester
(Figures S9, S10). These data are consistent with two-electron
OAT from IBX-ester to 3 to give an FeIV(O) species that then
hydroxylates the phenyl ring. Reaction of PhI18O + 3 leads to
18O incorporation (88%) in 4 as seen by LDI-MS (Figure S16),
indicating that the O atom in 4 is derived exclusively from the
organic oxidant, and providing additional evidence for the
FeIV(O) species as a key intermediate.
paramagnetically shifted H NMR spectrum (from 151 to −7
ppm) as well as a magnetic moment measurement by Evan’s
method in CD3CN (exptl μeff = 5.2; calcd (spin-only, S = 2) μeff
= 4.9) confirmed that 3 is hs-FeII. Thus the addition of phenyl
substituents to the N4Py scaffold causes a spin state change
from low-spin (ls) FeII for [FeII(N4Py)(CH3CN)]2+ to hs-FeII
for 3.3
t
Addition of a small excess (4−5 equiv) of BuOOH to 3 in
CH3CN at room temperature results in an immediate color
change from yellow to green and a new UV−vis band (λmax
=
758 nm, ε = 1880 M−1 cm−1) (Figure 3). Characterization by
Attempts were made to trap the FeIV(O) intermediate
derived from 3. Reaction of 3 with IBX-ester and tBuOOH was
examined at low temperature but led only to the slow
formation of 4 (−35 °C/CH3CN, Figure S11) or decom-
position (−60 °C/CH2Cl2), suggesting that the FeIV(O)
species rapidly reacts with the C6H5 substituent even at low
6
temperature. In contrast, the stable [FeIV(O)(N4Py)]2+ does
not react with C6H6 (500 equiv) even over prolonged reaction
times (>14 h). Thus [FeIV(O)(N4Py)]2+ is not competent to
mediate benzene hydroxylation.7
A few examples of aromatic hydroxylation mediated by
nonheme Fe complexes are known, and some have implicated
the importance of orienting the aromatic substrate near the
metal.4,8 However, the mechanism of hydroxylation and
identity of the active oxidant in these systems remain poorly
understood. In the case of 3, rapid intramolecular phenyl
hydroxylation is observed, but there is a complete lack of
reactivity between [FeIV(O)(N4Py)]2+ and C6H6. Similar
contradictory observations have been discussed for intra- vs
intermolecular phenyl hydroxylations in the Fe-TPA (TPA =
tris(2-pyridylmethyl)amine) system, but no explanation has
been given.4a,b,8g To gain insight into the mechanism of intra-
vs intermolecular arene hydroxylation, we performed density
functional theory (DFT) calculations on [FeIV(O)(N4Py2Ph)]2+
and compared the results with those previously obtained for
[FeIV(O)(N4Py)]2+ + C6H6.7
Figure 3. UV−vis spectral changes (0−17 min) (left) and LDIMS(+)
t
(inset: calcd for 4) (right) for 3 + BuOOH (5 equiv) in CH3CN.
LDI-MS(+) revealed a parent ion at m/z 590.167, correspond-
ing to [Fe(N4Py2Ph)-H+O]+. Isolation of the modified ligand
and analysis by FAB-MS is consistent with ligand mono-
hydroxylation. The product N4Py2PhOH was isolated in 65%
yield following purification.
t
Hydroxylation of the ligand in the reaction of 3 + BuOOH
suggests a reactive oxidant, such as a high-valent FeIV(O)
species, is formed as a transient intermediate via O-O bond
cleavage from an Fe-OOtBu precursor.4 We turned toward
oxygen-atom transfer (OAT) agents in an attempt to generate
an FeIV(O) species directly. Addition of PhIO or the more
soluble analog isopropyl 2-iodoxybenzoate (IBX-ester)4d,5 (1
equiv) to 3 in CH3CN resulted in the rapid formation of a
The [FeIV(O)(N4Py2Ph)]2+ structure has close lying triplet
and quintet spin configurations, with a favorable triplet spin
state in the gas phase and almost degenerate spin states at free
energy level at 298 K. This spin state splitting is much smaller
than that found for [FeIV(O)(N4Py)]2+, where the triplet spin
state was found to be at least 8 kcal mol−1 more stable than the
green species with an almost identical UV−vis signature (λmax
=
763 nm, ε = 2190 M−1 cm−1) and LDI-MS spectrum (m/z
t
589.892) as that seen for the product obtained from BuOOH.
The IBX-ester reaction afforded X-ray quality crystals of
B
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Journal of the American Chemical Society
Communication
quintet.7 Electrophilic attack of the oxo group on the ortho-
carbon atom leads to electron transfer from Ph to the π*xz
orbital in the triplet spin state (3π-pathway), whereas in the
investigations have asserted the importance of substrate
positioning (σ vs π) in controlling nonheme Fe(O) reactivity,9
but to our knowledge the results herein provide the first
combined experimental/theoretical evidence for the impor-
tance of σ vs π substrate orientation in a synthetic nonheme
iron system.
quintet spin state the virtual σ*z (5σ-pathway) or π*xz (5π-
2
3
pathway) are the possible acceptor orbitals. The π-pathway
↑
2
2
generates an intermediate with configuration π*xy π*xz π*yz
↑
5
↑
↑
↑
↑
↑
2
2
2
ϕL↓, while the σ-channel gives π*xy π*xz π*yz σ*z σ*x↑−y
Addition of another secondary coordination sphere element,
in the form of a potential H-bond donor group,11 dramatically
changes the reactivity of the nonheme FeII complex. The
complex [FeII(N4Py2Ph,amide)](BF4)2 (5) was readily prepared
from 2, and an X-ray structure reveals a six-coordinate, hs-FeII
complex with the new amide group bound in the open site
5
↑
↑
↑
2
2
2
ϕL , and the π-pathway gives π*xz π*xy π*yz σ*x −y ϕL .
As seen in Figure 4, the gas-phase energies predict that the 3π
channel is the lowest in energy, although the quintet transition
t
(Figure 5). Reaction of 5 with BuOOH (10 equiv) at room
Figure 5. Generation of the FeIII(OOtBu) complex 6.
temperature does not induce arene hydroxylation as seen for
3
12 but instead gives rise to a transient green intermediate that
Figure 4. Potential energy landscape (kcal/mol) for arene
hydroxylation of [FeIV(O)(N4Py2Ph)]2+ (a) and molecular orbitals
for the electron transfer pathways (b).
rapidly decays (∼t1/2 < 30 s). This intermediate can be trapped
at −30 °C, revealing a long-lived, dark-blue species with λmax
=
606 nm (ε = 2100 M−1 cm−1 based on total Fe), which rapidly
decays upon warming without any ligand hydroxylation
(Figures S22, S23). Resonance Raman spectroscopy of the
606 nm species (6) shows vibrations at 642 and 876 cm−1,
which are typical of hs-FeIIIOOR species and can be assigned to
ν(Fe−O) and ν(O−O) (Figure S21), respectively.13 EPR
revealed hs-FeIII peaks (g 7.89, 5.55, 4.24), along with a minor,
unidentified ls-FeIII component (∼20%). Based on these data, a
reasonable structure for the blue species is proposed for
complex 6 as shown in Figure 5.
3
5
states are not that far above TSπ. The σ-pathway is slightly
3
favored over the π-pathway at the free-energy level. These
results differ dramatically from calculations on [FeIV(O)-
(N4Py)]2+, which show that the 3π-pathway is highly
destabilized compared to the σ-pathway (δΔG‡ > 15 kcal/
5
mol).7
Much effort has gone into determining the factors that
control the reactivity of FeIV(O) species. For both nonheme
iron models and enzymes, the triplet (low-spin) state for
FeIV(O) is described as generally unreactive, whereas quintet
(high-spin) FeIV(O) is considered a powerful oxidant.9 The
high reactivity for the quintet species has been attributed to the
DFT calculations (see Supporting Information) fully support
the proposed, hs-FeIII−OOR structure with an amide N−H···O
bond. The influence of H-bond donors on the stability of iron−
oxygen species in nonheme Fe systems is of great interest but is
still not well-understood.11 We conclude that the amide group
in 5 helps to trap an FeIII−OOR complex, in contrast to 3,
which likely forms an FeIII−OOR species as a transient
intermediate during arene hydroxylation.
We have employed an experimental and computational
approach to examine the influence of secondary coordination
sphere modifications in nonheme iron model complexes. The
results herein give new insights regarding how nonheme Fe
enzymes may utilize two critical secondary coordination sphere
effects, substrate orientation, and hydrogen bonding, to control
reactivity.
5
accessibility of the σ-reaction channel, with an approximate
collinear approach (Fe−O−C(or H) = 180°) of the substrate
donor orbital with the FeO unit. The triplet FeIV(O), on the
other hand, is limited to the 3π-reaction channel with an
approximate perpendicular approach for overlap with the
π*xz/yz orbital. The ligands in the equatorial plane of triplet
FeIV(O) complexes typically provide a steric barrier to this
channel and make it prohibitively high in energy, and a low-
lying quintet excited state is often invoked to explain the
observed reactivity for triplet FeIV(O).
The DFT calculations for [FeIV(O)(N4Py2Ph)]2+ indicate
that the low-spin, 3π-pathway becomes a viable reaction
channel by positioning the phenyl substrate in the second
coordination sphere. In comparison, triplet [FeIV(O)(N4Py)]2+
is completely unreactive toward C6H6, consistent with the fact
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental and DFT details. This material is available free of
charge via the Internet at http://pubs.acs.org.
7,9g,10
3
that the π-pathway is sterically blocked.
Computational
C
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Journal of the American Chemical Society
Communication
F.; Neese, F. Angew. Chem., Int. Ed. 2010, 49, 5717−5720. (f) Ye, S.;
Neese, F. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 1228−1233.
(g) Srnec, M.; Wong, S. D.; England, J.; Que, L., Jr.; Solomon, E. I.
Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 14326−14331. (h) Wilson, S.
AUTHOR INFORMATION
Corresponding Author
dpg@jhu.edu; sam.devisser@manchester.ac.uk; ploccoz@ebs.
ogi.edu
■
́
A.; Chen, J.; Hong, S.; Lee, Y.-M.; Clemancey, M.; Garcia-Serres, R.;
Nomura, T.; Ogura, T.; Latour, J.-M.; Hedman, B.; Hodgson, K. O.;
Notes
Nam, W.; Solomon, E. I. J. Am. Chem. Soc. 2012, 134, 11791−11806.
The authors declare no competing financial interest.
(10) McDonald, A. R.; Guo, Y.; Vu, V. V.; Bominaar, E. L.; Munck,
̈
E.; Que, L., Jr. Chem. Sci. 2012, 3, 1680−1693.
ACKNOWLEDGMENTS
■
(11) (a) Shook, R. L.; Borovik, A. S. Inorg. Chem. 2010, 49, 3646−
3660. (b) Berreau, L. M.; Makowska-Grzyska, M. M.; Arif, A. M. Inorg.
Chem. 2001, 40, 2212−2213. (c) Yeh, C.-Y.; Chang, C. J.; Nocera, D.
G. J. Am. Chem. Soc. 2001, 123, 1513−1514. (d) Wada, A.; Harata, M.;
Hasegawa, K.; Jitsukawa, K.; Masuda, H.; Mukai, M.; Kitagawa, T.;
Einaga, H. Angew. Chem., Int. Ed. 1998, 37, 798−799. (e) Latifi, R.;
Sainna, M. A.; Rybak-Akimova, E. V.; de Visser, S. P. Chem.Eur. J.
2013, 19, 4058−4068.
The NIH (D.P.G., GM62309; P.M.L., GM074785) is gratefully
acknowledged for financial support. S.d.V. thanks the NSCCS
for CPU time and M.G.Q. thanks BBSRC for a studentship.
H.M. acknowledges support from the JSPS.
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