Structurally Modelling the 2-His-1-Carboxylate Facial Triad with a Bulky N,N,O Phenolate Ligand

Article abstract of DOI:10.1002/chem.202004633

We present the synthesis and coordination chemistry of a bulky, tripodal N,N,O ligand, Im^Ph2NNO^tBu (L), designed to model the 2-His-1-carboxylate facial triad (2H1C) by means of two imidazole groups and an anionic 2,4-di-tert-butyl-s

Full text of DOI:10.1002/chem.202004633

Accepted Article
Accepted Article
Title: Structurally Modelling the 2-His-1-Carboxylate Facial Triad with a
Bulky N,N,O Phenolate Ligand
Authors: Emily C. Monkcom, Daniël de Bruin, Annemiek J. de Vries,
Martin Lutz, Shengfa Ye, and Robertus Johannes Klein
Gebbink
This manuscript has been accepted after peer review and appears as an
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202004633
Link to VoR: https://doi.org/10.1002/chem.202004633
01/2020

10.1002/chem.202004633
Chemistry - A European Journal
FULL PAPER
Structurally Modelling the 2-His-1-Carboxylate Facial Triad with a
Bulky N,N,O Phenolate Ligand
Emily C. Monkcom,[a] Daniël de Bruin,[a] Annemiek J. de Vries,[a] Martin Lutz,[b] Shengfa Ye,[c] Robertus
J. M. Klein Gebbink*[a]
[a]
E. C. Monkcom, D. de Bruin, A. J. de Vries, Prof. Dr. R. J. M. Klein Gebbink
Organic Chemistry and Catalysis
Debye Institute for Nanomaterials Science, Utrecht University
Universiteitsweg 99, 3584 CG Utrecht (The Netherlands)
E-mail: r.j.m.kleingebbink@uu.nl
[b]
[c]
Dr. M. Lutz
Crystal and Structural Chemistry
Bijvoet Centre for Biomolecular Research, Utrecht University
Padualaan 8, 3584 CH Utrecht (The Netherlands)
Prof. Dr. S. Ye
State Key Laboratory of Catalysis
Dalian Institute of Chemical Physics, Chinese Academy of Sciences
457 Zhongshan Road, Dalian 116023 (China)
and
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany)
Email: shengfa.ye@dicp.ac.cn, shengfa.ye@kofo.mpg.de
Supporting information containing all experimental details for this article is given via a link at the end of the document.
Abstract: We present the synthesis and coordination chemistry of a
bulky, tripodal N,N,O ligand, ImPh2NNOtBu (L), designed to model the
2-His-1-carboxylate facial triad (2H1C) by means of two imidazole
groups and an anionic 2,4-di-tert-butyl-subtituted phenolate.
Reacting K-L with MCl2 (M = Fe, Zn) affords the isostructural,
tetrahedral non-heme complexes [Fe(L)(Cl)] (1) and [Zn(L)(Cl)] (2) in
high yield. The tridentate N,N,O ligand coordination observed in their
X-ray crystal structures remains intact and well-defined in MeCN and
CH2Cl2 solution. Reacting 2 with NaSPh affords a tetrahedral zinc
thiolate complex, [Zn(L)(SPh)] (4), that is relevant to isopenicillin N
synthase (IPNS) biomimicry. Cyclic voltammetry studies demonstrate
the ligand’s redox non-innocence, where phenolate oxidation is the
first electrochemical response observed in K-L, 2 and 4. However, the
first electrochemical oxidation in 1 is iron-centred, the assignment of
which is supported by DFT calculations. Overall, ImPh2NNOtBu
provides access to well-defined mononuclear, monoligated, N,N,O-
bound metal complexes, enabling more accurate structural modelling
of the 2H1C to be achieved.
similar reactivity and selectivity remains a long-standing goal in
homogeneous catalysis.
More recently, the 3-His facial triad (3His) has emerged as a
recurring bioinorganic motif at the active site of, amongst others,
a
small group of mononuclear non-heme iron enzymes
collectively known as thiol dioxygenases (TDO), which activate O2
and catalyse the dioxygenation of thiols to their corresponding
sulfinic acids.[6] Similarly to the 2H1C, the 3His involves the facial
coordination of three amino acid residues to a single iron(II) centre.
However, unlike the 2H1C, the 3His comprises three neutral
histidine residues, and no carboxylate ligand is required for
catalytic activity. In this regard, the different reactivities of
isopenicillin N synthase (IPNS), a 2H1C-containing oxidase
enzyme, and cysteine dioxygenase (CDO), a TDO enzyme, make
for a particularly interesting comparison. In both cases, the native
substrate’s anionic thiolate binds directly to the iron centre trans
to a His residue. Yet, in IPNS, O2 subsequently binds trans to an
Asp and the d-(L-a-aminoadipoyl)-L-cysteine-D-valine (ACV)
substrate undergoes a 4-electron oxidative bicyclisation,[7-9]
whereas in CDO, O2 binds trans to a His residue and the cysteine
substrate undergoes sulfur oxygenation (Figure 1).[6,10] This has
stimulated a deeper examination of the carboxylate’s mechanistic
role in 2H1C-containing enzymes. An important strategy to this
end is the study of synthetic complexes that model
metalloenzyme active sites.
Introduction
The 2-His-1-Carboxylate facial triad (2H1C) is a bioinorganic motif
characterised by the facial, tripodal N,N,O coordination of two
neutral histidine (His) residues and an anionic carboxylate group,
(Asp or Glu), to a single metal centre.[1-3] It occurs at the active
site of many oxygen-activating mononuclear non-heme iron
enzymes, and is considered one of the most versatile platforms
with which nature performs oxidation catalysis.[4,5] The ability of
this motif to activate O2 and mediate a highly diverse set of highly
selective biocatalytic oxidations reactions has attracted the
interest of the bioinorganic and catalytic research communities.
Many of these reactions are synthetically challenging, and
developing small molecular iron-based catalysts that can achieve
H
S
H
H
IPNS
H3N
O
N
H3N
O
N
H
S
H
N
H
O
O
N
O
O
O
O
O2
2 H2O
COO
OOC
isopenicillin N
ACV
NH3
CDO
NH3
O
S
O
SH
O
OH
O2
O
O
cysteine
cysteine sulfinic acid
1
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10.1002/chem.202004633
Chemistry - A European Journal
FULL PAPER
N,N,O coordination due to lability of a neutral N-/O-donor.[31] The
primary strategy to overcome these issues has been to increase
the ligand’s bite angle and steric demand,[26,31,32] or to use an
organic co-ligand.[25,33] In the few cases where monoligation and
tripodal N,N,O coordination were successfully achieved (Figure 2,
bottom),[25,26,31-36] little or no further exploration of the solution
state behaviour was conducted. The robustness of the ligands’
facial N,N,O coordination to iron in solution therefore remains
largely unknown, making the use of their respective complexes
disadvantageous from a practical point of view compared to the
well-established coordination chemistry of polydentate N-donor
ligands. Previously, our group has explored the facial capping
potential of bis-imidazole derived N,N,O phenolate ligands,
ImNNO and BenzImNNO.[23,25] However, these were shown to
readily form bisligated complexes in the absence of a co-ligand.
Here, we describe the synthesis of a new N,N,O ligand,
ImPh2NNOtBu (Figure 3), whose constituent groups have been
functionalised with sterically demanding substituents to promote
the thermodynamic formation of monoligated, mononuclear metal
complexes. While the ligand’s imidazole groups are the most
biologically relevant heterocycle for modelling histidine residues,
the incorporation of a phenol deviates somewhat from the
carboxylate residue of the 2H1C due to its redox-active properties.
However, the ease with which phenols can be functionalised
opens up more possibilities for ligand design and helps avoid
certain drawbacks associated to carboxylic acids, such as
decarboxylation, poor solubility,[31] or the formation of coordination
oligomers.[23] Moreover, the t-butyl substituents on the 2,4-
positions of the phenol can help prevent radical side reactions.
The coordination chemistry of ImPh2NNOtBu is explored with iron
and zinc, the latter serving as a convenient diamagnetic analogue
with which to conduct detailed studies of the complexes in their
solution state. Finally, the synthesis and solution state behaviour
of a zinc thiolate complex relevant to IPNS biomimicry is
described. In this way, the robustness of the ligand’s N,N,O facial
triad in the presence of biorelevant co-ligands is established,
making ImPh2NNOtBu an ideal platform with which to model and
further investigate the 2H1C.
IPNS
CDO
His214
His270
His86
His140
Asp216
His88
Fe
ACV
H2O
Fe
cysteine
Figure 1. Top: native reactions catalysed by IPNS and CDO. Bottom: The
substrate-bound active site structures of IPNS from Aspergillus nidulans (PDB
1BK0)[7] and CDO from Homo sapiens (PDB 2IC1)[6]. Carbon, iron, nitrogen and
oxygen are depicted in grey, orange, blue and red, respectively.
The 2H1C has been an inspiration for the design of many
biomimetic ligands,[13] some of the most well-known being the
Tp,[14] TPA,[15] 14-TMC,[16] PyTACN,[17] PyNMe3,[18] BPBP,[19] and
N4Py[20] ligands (Figure 2, top). These polydentate N-donor
ligands support the formation of high-valent iron-oxo species and
have greatly helped the scientific community understand the role
of such entities in enzymatic reactions and oxidation
catalysis.[21,22] However, these ligands can, arguably, be
considered structurally more similar to the 3His than the 2H1C
due to lack of an anionic O-donor. Moreover, many of these
ligands have a denticity greater than three, deviating somewhat
from the tricoordinate nature of the 2H1C.
In order to structurally model the 2H1C with greater accuracy, it
remains of interest to develop facial, tridentate N,N,O ligands.
While numerous examples of such ligands with systematically
varied donor group constituents have been reported,[23] the
number of N,N,O ligands that can coordinate in a tripodal manner
and support the formation of mononuclear, monoligated metal
complexes is small. Typically, difficulties in achieving the desired
coordination mode are encountered due to the formation of
homoleptic bis-ligand complexes,[24-26] the increase in nuclearity
due to anionic O-donor bridging modes,[27-30] or rupture of the
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
BH
N
N
O
N
N
N
N
N
N
N
N
Tp
TPA
14-TMC
PyNMe3
S,S-BPBP
N4Py
PyTACN
O
O
R
O
O
O
O
O
N
R
R
O
N
O
N
N
N
N
N
N
N
N
N
O
N
O
N
N
O
N
N
N
N
N
N
N
N
bpatBu2,Me2 (R = Me)
(R = Me)
L2
L3 (R = tBu)
BMMeBIPnPr
ImNNO
BEiPrIP
L1
t
bdtbpza
(R = Bu)
Figure 2. Selected N-donor ligands (top)[11] and tripodal N,N,O ligands (bottom)[12] that have been used to synthesise mononuclear, monoligated biomimetic metal
complexes. Mononuclear, monoligated iron complexes of BEiPrIP and ImNNO have only been reported in combination with an organic co-ligand, e.g. a catecholate.
No mononuclear, monoligated iron complexes have been crystallographically characterised with ligands bpatBu2,Me2, bdtbpza, L2 and L3.
2
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10.1002/chem.202004633
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form compound LS4 in 82% yield. The final step involves the
deprotection of the phenol in acidic conditions to yield the ligand
H-ImPh2NNOtBu as a pale off-white solid in 71% yield. The overall
isolated yield of the ligand synthesis is 24%
O
N
N
O
The phenol can easily be deprotonated using KH as a base.
Stirring the ligand with an excess of KH in THF resulted in the fast
release of hydrogen gas as well as a bright yellow solution,
indicative of phenol deprotonation. The reaction was left to stir two
hours, after which it was filtered to remove any unreacted KH. The
solvent was removed under vacuum, affording an off-white crude
solid. The solid was washed with hexane and dried, producing the
N
N
Figure 3. Ligand ImPh2NNOtBu with an N,N,O donor set.
1
desired potassium ligand salt (K-ImPh2NNOtBu) in 92% yield. H
Results and Discussion
NMR analysis of the ligand salt in acetonitrile-d3 (Figure S19)
clearly demonstrates the anionic nature of the phenolate through
the absence of any OH signal. This is further corroborated by the
absence of an O-H stretch in the IR analysis (Figure S21).
However, the singlet assigned to the N-methyl groups at 3.29 ppm
is severely broadened, indicating fluxional exchange of the two
imidazole groups at 25 ºC. Cooling the measurement to -30 ºC
produces a spectrum with two distinct singlets of equal integration
at 3.49 and 2.92 ppm, assigned to the N-methyl groups (Figure
S20). This suggests that a temperature-dependent fluxional
process occurs, possibly involving the dissociation of the
imidazole groups from the potassium ion. Crystals of K-
ImPh2NNOtBu suitable for X-ray diffraction were grown from slow
vapour diffusion of diethyl ether into a dichloromethane solution
of the ligand salt at –40 ºC. The crystal structure of the ligand salt
(Figure 4) reveals the coordination of two potassium ions within a
centrosymmetric dimeric diamond core structure, involving two
ligand molecules whose phenolic O atoms coordinate by means
of a µ2-bridging mode. Each potassium ions is further stabilised
by the coordination of the methoxy group from one ligand
molecule and one of the imidazole groups from the other ligand
molecule. Each ligand molecule features one non-coordinated
imidazole group. Coordination of a molecule of diethyl ether
completes the overall pentacoordinate geometry of each
potassium ion. Selected bond lengths and bond angles are given
in Table S1. The C-O bond length of the phenolate is measured
as 1.306(3) Å. This bond length is somewhat shortened compared
to the C-O bond length of a neutral phenol (1.36 Å).
Ligand Synthesis and Characterisation
Ligand H-ImPh2NNOtBu can be readily synthesised in five steps
using a procedure adapted from Jameson et al. (Scheme 1).[25,37]
An additional alkylation step has been incorporated to install tert-
butyl substituents on the phenolate ring.[38] The synthesis also
involves the use of 1-methyl-4,5-diphenylimidazole instead of the
sterically less encumbered 1-methylimidazole, as our group has
previously demonstrated that a higher degree of substitution on
the imidazole favours the formation of monoligated complexes.[31]
Overall, the synthesis involves the use of readily available starting
materials, and the ligand can easily be prepared on a multigram
scale. The synthesis begins with the electrophilic aromatic
substitution reaction of methyl salicylate with tert-butanol in
methanol, using sulfuric acid as a catalyst. This results in the
formation of LS1, which can be recrystallised from methanol and
isolated as a white crystalline solid in 51% yield. Next, the
salicylate’s phenol group is protected using a methyl methoxy
ether (MOM), producing LS2 as a viscous yellow oil in 90% yield.
Deprotonation of 1-methyl-4,5-diphenyl-1H-imidazole using n-
BuLi, generates a lithium imidazolium salt, two equivalents of
which can subsequently perform a nucleophilic attack on the
carbonyl group of LS2. In doing so, the carbonyl group is reduced
to a tertiary alcohol in LS3, which is formed in a yield of 89%. Due
to its sterically encumbered nature, the subsequent methylation
of the tertiary alcohol is kinetically slow and requires a two-fold
excess of NaH and MeI as well as overnight stirring in order to
Ph
N
N
O
O
O
1) NaH
tBuOH
H2SO4
Li
(2 eq.)
2)
Cl
O
O
O
O
Ph
OH
OH
O
O
THF
MeOH
THF
LS1 (51%)
LS2 (90%)
OH
O
N
O
O
N
O
1) NaH
2) MeI
N
N
N
N
HCl / MeOH
reflux
O
O
OH
N
N
N
N
N
N
THF
H-ImPh2NNOtBu (71%)
LS4 (82%)
LS3 (89%)
Scheme 1. Synthesis of H-ImPh2NNOtBu
.
3
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10.1002/chem.202004633
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tridentate N,N,O motif, involving both neutral imidazole N-donors
and the anionic phenolate O-donor. The fourth coordination site
is occupied by a chloride ligand, which completes the distorted
tetrahedral geometry of each metal centre. Based on these results,
ImPh2NNOtBu can be regarded as a heteroscorpionate ligand that
imparts a metallobicyclo[2.2.3]nonane topology to each complex.
The ability of the ligand to monoligate is proposed to be principally
due to the steric demands of its constituent groups, where the 4,5-
diphenyl-substituted imidazole groups hinder the coordination of
a second ligand equivalent and the ortho-tBu substituent on the
phenolate reduces the accessibility of the lone pair of the phenolic
oxygen atom and prevents any bridging coordination modes from
occurring.[23,28,35] Together, these bulky groups contribute to the
relatively large buried volume of the ligand (58.9 and 59.6%Vburied
in 1 and 2, Figure 6).
i
i
i
i
i
i
Figure 4. Displacement ellipsoid plot of [K2(ImPh2NNOtBu)2(OEt2)2] drawn at the
50% probability level. Only the major form of the disordered tBu groups is drawn,
Symmetry code i: 1-x, 1-y, 1-z. Hydrogen atoms and severely disordered solvent
molecules are omitted for clarity. Ph and tBu substituents of the imidazole and
phenolate groups, respectively, are depicted in the wireframe format for clarity.
Synthesis and Solid State Characterisation of 1 and 2
The facial capping potential of anionic ImPh2NNOtBu was
investigated by exploring its coordination chemistry with Fe2+ and
Zn2+. Both iron and zinc complexes were prepared using
analogous methods, depicted in Scheme 2. K-ImPh2NNOtBu was
dissolved in acetonitrile, and one equivalent of the desired
metal(II) chloride precursor was added to the solution.[39] The
mixture was stirred for two hours and was subsequently filtered
and dried under vacuum. The crude solid was washed three times
with hexane and was then dried under vacuum. The final reaction
products were identified as mononuclear complexes
[Fe(ImPh2NNOtBu)(Cl)] (1) and [Zn(ImPh2NNOtBu)(Cl)] (2), which
were obtained in yields of 97% and 94%, respectively. IR analysis
of both samples supports the anionic coordination of the
phenolate ligand in each complex through the absence of an O-H
stretching vibration. Solid-state zero-field 57Fe Mössbauer
analysis (80 K) of 1 produced a single quadrupole doublet with an
isomer shift (d) of 0.94 mm/s and a quadrupole splitting (|DEQ|) of
2.58 mm/s, consistent with high-spin (S = 2) iron(II) (Figure S22).
1
2
O
N
N
N
Figure 5. Displacement ellipsoid plots of 1 and 2 drawn at the 50% probability
level. Only the major form of the disordered Bu groups is drawn. Hydrogen
atoms and severely disordered solvent molecules are omitted for clarity.
OK
MCl2
t
N
N
N
O
MeCN
- KCl
O
N
N
M
4
3
2
1
0
4
3
2
1
0
4
O
O
Cl
3
2
1; M = Fe
2; M = Zn
K-ImPh2NNOtBu
1
0
Fe
Zn
Scheme 2. Synthesis of [Fe(ImPh2NNOtBu)(Cl)] (1) and [Zn(ImPh2NNOtBu)(Cl)] (2).
-1
-2
-3
-1
-1
-2
-3
-4
-2
N
-3 N
N
N
Crystals of 1 and 2 suitable for X-ray diffraction were grown from
the slow vapour diffusion of n-hexane into a THF solution of each
complex at ambient conditions. The crystal structures of
complexes 1 and 2 are isostructural (Figure 5). Selected bond
lengths and bond angles are given in Table 1. In each complex,
ImPh2NNOtBu chelates to a single metal(II) ion by means of a
-4
-4
-3 -2 -1
0
1
2
3
4
-3 -2 -1
0
1
2
3
4
Figure 6. Steric maps of ImPh2NNOtBu in 1 (left) and 2 (right) generated using
the SambVca software.[40] Spheres are defined with a radius of 4 Å from the
metal centre and H-atoms are included in the calculation.
4
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The tetrahedral distortion in 1 and 2 is characterised by the
N-M-O and N-M-N angles of the ligand being smaller than in the
ideal tetrahedron, while the O-M-Cl and N-M-Cl angles are
larger than ideal. This is due to the strain caused by the “cage”
effect of the tripodal ligand scaffold, whose donor groups are
linked by a single quaternary carbon atom, thereby imposing a
certain degree of rigidity on the tripod and contracting the bite
angles between its three donor atoms. The slightly elongated
Fe-N bonds (>2.0 Å) in 1 are consistent with the high spin nature
of the iron(II) centre and lie within the range of Fe-N bond lengths
previously obtained for other high spin non-heme iron(II)
complexes bearing imidazole-derived N,N,O ligands.[31,41] The
Fe1-O1 bond length of 1.8915(19) Å in 1 is relatively short and
reflects the anionic nature of the phenolic oxygen atom. For
comparison, an Fe-O bond length of 2.1979(14) Å was previously
reported in our group for the pentacoordinate complex
[Fe(BMMeBIPnPr)(OTf)2], whose supporting N,N,O ligand features
a neutral n-propyl ester group.[31] Similarly, the Zn-N bond lengths
in 2 fall well within the expected range for a zinc(II) nucleus of
tetrahedral geometry bound to neutral N-donors.[26] The Zn1-O1
bond distance of 1.9266(12) Å in 2 is shorter than those reported
by Burzlaff and co-workers for similar tetrahedral zinc complexes
To the best of our knowledge,
1
is one of only three
crystallographically characterised mononuclear non-heme iron(II)
complexes featuring a tripodal N,N,O ligand and that does not
require additional stabilisation from an organic co-ligand. The
tetrahedral nature of 1 differs somewhat from the typically penta-
or hexacoordinate nature of enzymatic resting states that contain
the 2H1C. A comparison of the crystallographic parameters of 1
with those of deacetoxycephalosporin C synthase (DOACS,
octahedral)[42] and 2,3-dihydroxybiphenyl dioxygenase (BphC,
square pyramidal)[43] is given in Table 1. Overall, 1 shows the
greatest similarity to DAOCS, both in terms of the Fe-N bond
lengths and the bond angles between the constituent atoms of the
facial triad and the iron nucleus. However, the short Fe-O bond
in 1 differs strongly from the Fe-O bond lengths in both enzymes,
each of which is >2 Å.
BphC
DAOCS
His183
His145
His209
His243
Glu260
OH2
Asp185
OH2
[Zn(bdtbpza)(Cl)] and [Zn(bpatBu2,Me2)(CH3)], featuring
a
Fe
Fe
carboxylate O-donor in the N,N,O ligand (1.990(2) and 2.054(6)
Å, respectively).[26,34] This indicates a greater degree of charge
localisation on the phenolate oxygen atom of 2 compared to a
carboxylic acid oxygen donor.
H2O
H2O
OH2
Figure 8. Active site structures of BphC from Pseudomonas sp. KKS102 (PDB
1EIL)[43] and DAOCS from Streptomyces clavuligerus (PDB 1RXF)[42]. Carbon,
iron, nitrogen and oxygen are depicted in grey, orange, blue and red,
respectively.
In both complexes, the M-N bonds are observed to have slightly
different lengths, contributing to the overall distortion of the
tetrahedron. This asymmetry correlates with the different angles
between the plane of the imidazole heterocycles and their
respective M-N bond vectors (Figure 7). Angles of 146.13(13)º
and 167.99(13)º are observed for Cim-N1-Fe1 and Cim-N3-Fe1
in 1, which correspond to Fe-N bond lengths of 2.131(2) Å and
2.089(2) Å, respectively. In other words, the greater the distortion
away from co-planarity, the longer the observed M-N bond length
and the weaker the strength of the coordination bond. A similar
phenomenon is observed for 2. We attribute this effect to the
inherent geometric restrictions imposed by the tripodal nature of
the ligand, which force the metal out of plane relative to the
imidazole rings and cause a slight twisting of the phenolate ring
out of the approximate mirror plane.
Table 1: Selected bond lengths and angles observed in the X-ray crystal
structures of 1, 2, BphC (PDB 1EIL)[43] and DAOCS (PDB 1RXF)[42]
.
Bond
1
2
BphC
DAOCS
Length (Å)
Length (Å)
Length (Å)
Length (Å)
2.131(2)
2.089(2)
1.8915(19)
2.0754(14)
2.0248(14)
1.9265(12)
2.24 (His145
)
)
2.19 (His183
)
)
M-N1
M-N3
M-O1
Angle
2.30 (His209
2.15 (His243
2.09 (Glu260
)
2.15 (Asp185)
1
2
BphC
Angle (º)
DAOCS
Angle (º)
Angle (º)
Angle (º)
95.10(8)
98.92(9)
84.05(9)
95.91(5)
100.97(5)
88.23(5)
106.7
103.9
87.0
86.3
99.4
89.3
N1-M-O1
N3-M-O1
N1-M-N3
Solution State Behaviour of 2
In order to establish the rigidity of the ImPh2NNOtBu ligand’s
tripodal N,N,O binding motif, we investigated the solution state
behaviour of 2 in solvents of different binding affinities and varying
steric bulk (CD3CN, CD2Cl2, THF-d8, and pyridine-d5), using
(variable temperature, VT) 1H NMR and electronic absorption
spectroscopy. In this way, the sensitivities of our newly developed
biomimetic complexes can be elucidated, and further coordination
chemistry can be controlled with greater precision.
1
1
Figure 7. Views perpendicular (left) and parallel (right) to the Fe-Cl bond in the
molecular structure of 1. Displacement ellipsoids are drawn at the 50%
probability level. Phenyl substituents are drawn in the wireframe format for
clarity.
5
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*
tBu
CH3CN
*
NCH3
OCH3
*
*
H1
H2
CD3CN
*
tBu
*
NCH3
OCH3
tBu
*
H1
H2
CD2Cl2
*
*
*
THF
*
*
*
*
THF
THF-d8
*
*
Py
tBu
tBu
Py
Hexane
*
*
Py-d5
ꢅꢁꢃ
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ꢆꢁꢀ
ꢅꢁꢂ
ꢅꢁꢀ
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ꢇꢃꢈꢉꢊꢊꢋꢌ
ꢄꢁꢀ
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ꢃꢁꢀ
ꢀꢁꢂ
Figure 9. Stacked 1H NMR (400 MHz) spectra of 2 in different deutero solvents, recorded at 298 K. The region between 4.5 and 6.5 ppm has been omitted for
clarity and the signal intensity of the aromatic region has been amplified. Spectra are clipped vertically for clarity. Green asterisks indicate tBu resonances. Purple
asterisks indicate N-methyl and O-methyl resonances. Red asterisks denote aromatic protons on the phenyl groups. H1 and H2 are aromatic phenol ring protons.
The 1H NMR analysis of 2 in various deutero solvents is depicted
in Figure 9. One of the most noticeable features of this data-set is
the similarity between the spectra recorded in CD3CN and CD2Cl2,
despite their different coordination affinities. In comparison, the
spectra recorded in THF-d8 or pyridine-d5 are more complex and
contain a larger number of peaks, possibly stemming from
solvent-specific interactions or complex speciation in solution that
arise from the sterically more demanding nature of these solvents.
(Figure S46) demonstrates that no temperature-dependent
fluxional processes occur in these solvents and that the structural
integrity of 2 remains intact across a wide temperature range.
The 1H NMR spectrum of 2 in THF-d8 differs significantly from the
previously discussed spectra. Most strikingly, four singlets are
observed between 1.25 and 1.50 ppm in the region of the tert-
butyl groups. The two central signals occur very close together at
1.30 and 1.28 ppm, which is similar in chemical shift to the tert-
butyl resonances observed in CD3CN and CD2Cl2. The two outer
singlets at 1.38 and 1.22 ppm have equal integral values, and
together have a 1:2 integral ratio relative to the two large singlets.
Overall, this would suggest that two species are present in
solution. Further evidence to support this can be found in the
spectral region between 3.10 and 3.70 ppm associated to the N-
methyl and O-methyl groups, where four signals are observed
instead of the expected two. In addition, the aromatic region of the
spectrum is very disordered, which also suggests that multiple
species may be present in solution. Over the course of several
days, the relative intensities and chemical shifts of these different
NMR signals do not change. Similarly, the spectrum remains
unchanged after cooling or heating the sample and repeating the
measurement at room temperature, suggesting that the two
species present in THF solution are in thermal equilibrium. VT
NMR of 2 in THF-d8 reveals a temperature-dependent fluxional
process that occurs on the NMR time-scale (see Figure S47). This
is most pronounced in the region around 3.5 ppm where two
signals are seen to converge as the temperature increases.
Another important observation is the appearance of a small
shoulder at 1.75 ppm next to the residual THF-d8 peak at low
temperature. This suggests that the solvent participates in the
coordination equilibrium, possibly through direct coordination to
The 1H NMR spectrum of 2 in CD3CN features two sharp singlets
at 3.51 and 3.45 ppm, assigned to the N-methyl and O-methyl
protons, respectively, of the supporting ligand framework. The 2:1
ratio of integral intensities is consistent with a metallobicyclo-
[2.2.3]nonane topology, indicating that the tripodal N,N,O
coordination of ImPh2NNOtBu is retained in solution. Analogous
peaks at 3.52 and 3.45 ppm are observed in CD2Cl2, which show
a high degree of structural similarity between the solute structure
of 2 in acetonitrile and dichloromethane. Indeed, only minor
differences are observed in the aromatic region of the spectra as
well as the tert-butyl signals, which are ascribed to non-specific
solvent interactions. Strikingly, selective excitation of the N-
methyl signal by means of 1D NOE NMR experiments in CD3CN
produced correlation signals to the O-methyl signal (3.45 ppm) as
well as the tBu signal (1.28 ppm), whereas selective excitation of
OCH3 did not produce any correlation response to the tBu signals
(Figure S45). In three-dimensional space, this places the methoxy
t
group further away from the Bu groups than the imidazole N-
methyl groups, which is in line with the observed H…H distances
within the crystal structure (approximately 5.8 Å and 4.8 Å for the
O-methyl and N-methyl groups, respectively). We therefore
conclude that the solute structure of 2 in acetonitrile and
dichloromethane is equivalent to its structure in the solid state.
1
Additionally, VT H NMR conducted in both CD3CN and CD2Cl2
6
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the metal centre. By coordinating to the metal, it hypothesised that
THF could initiate the dissociation of one of the two imidazoles.
observed in CD3CN (e.g. the signals at 51, 36, 33, and 23 ppm)
that are not present in CD2Cl2. VT H NMR analysis of 1 in both
1
solvents showed normal Curie behaviour with highly linear Curie
plots (Figure 10) that converge to the diamagnetic region upon
extrapolation to infinite temperature, thereby excluding the
presence of any spin crossover phenomena or reversible solvent
coordination in solution (see Figures S28-S31). This suggests
that the differences between the 1H NMR spectra may simply
arise from the different solvent-specific effects. Moreover, the
electronic absorption spectra of 1 in CH3CN and CH2Cl2 are
Dissolving 2 in pyridine-d5 produces a yellow solution, whose 1H
NMR spectrum indicates that a disruption in the complex
symmetry has taken place. This is most clearly identified by the
presence of three singlets at 3.98, 3.89 and 3.44 ppm, each with
an integral value of 3H. This suggests that the imidazole groups
no longer coordinate to the metal iron in an equivalent manner.
Slow diffusion of hexane into a pyridine solution of 2 under
ambient conditions resulted in the formation of yellow needles that
were identified as the simple [Zn(Cl)2(py)2] complex, which is
known from the literature.[44] Based on this data, we hypothesise
that the strongly coordinating and sterically demanding nature of
pyridine disrupts the N,N,O coordination of ImPh2NNOtBu and
enables pyridine to scavenge a portion of the available zinc. This
causes a mixture of decomposition products to form, possibly
including a bisligated compound of the type [Zn(ImPh2NNOtBu)2]
(vide infra).
almost identical, featuring
a very weak, broad band at
approximately 500 nm as well as a broad band at 380 nm that
shoulders the intense ligand-based p-p* transitions (<350 nm).
No change of the optical spectrum was observed upon conducting
variable temperature measurements to low temperature (Figure
S34).
Unlike 2, the 1H NMR spectrum of 1 in THF-d8 does not reveal the
presence of multiple species in solution at 298 K. Indeed, the UV-
vis spectrum of 1 in THF is very similar to those recorded in
CH3CN and CH2Cl2, which suggests that an electronically similar
Solution State Behavior of 1
1
species is present in solution. However, conducting VT H NMR
By analogy to 2, complex 1 is expected to retain the same
structure in acetonitrile and dichloromethane solution. Using
Evans’ NMR method,[45] the magnetic moment of 1 in CD3CN was
determined to be 4.50 BM, which corresponds to a high-spin (S =
2) electronic configuration and is consistent with the solid state
geometry and Mössbauer parameters previously described. The
analysis in THF-d8 reveals more deviation from ideal Curie
behaviour, which is indicative of additional processes occurring in
solution at low temperature (Figure S32 and S33). Recording a 1H
NMR spectrum at 298 K after having either cooled or heated the
sample produced the same spectrum as that recorded prior to any
temperature change. This suggests that a reversible solvent-
related coordination equilibrium in THF solution occurs. Similarly
to 2, dissolving complex 1 in pyridine-d5 produces a yellow
solution (lmax = 420 nm), indicating the formation of a FeCl2-
pyridyl adduct in solution.[46,47] Moreover, the paramagnetic 1H
NMR spectrum of 1 in pyridine-d5 contains fewer peaks and bears
little resemblance to the spectra recorded the other deutero
solvents, which suggests a new species has formed in solution.
1H NMR spectra of
1 in CD3CN and CD2Cl2 contain
paramagnetically shifted signals (Figure 10), and certain
resonances are observed to have almost identical chemical shifts
in both solvents (e.g. the signals at 58, 50 and 10 ppm). This
supports the assumption that the hyperfine interactions between
protons of the ligand scaffold and the paramagnetic iron centre
are similar in both solvents. However, additional broad signals are
75
CD3CN
60
45
30
15
CD3CN
0
2.8 3.0 3.2 3.4 3.6 3.8 4.0 4.2 4.4
90
CD2Cl2
75
60
45
30
15
0
CD2Cl2
-15
3.1 3.4 3.7 4.0 4.3 4.6 4.9 5.2
THF-d8
100
THF-d8
75
50
25
0
Pyridine-d5
-25
-50
2.9 3.2 3.5 3.8 4.1 4.4 4.7 5.0 5.3
1/T (K-1) x 10-3
Figure 10. Left: Stacked paramagnetic 1H NMR (400 MHz) spectra of 1 in different deutero solvents, recorded at 298 K. Spectra have been clipped for clarity. Right:
Curie plots showing the inverse temperature dependence of the paramagnetic 1H NMR chemical shifts (ppm) for 1 in CD3CN, CD2Cl2 and THF-d8.
7
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The crystal structure of 4 (Figure 12) reveals the formation of a
mononuclear zinc(II) complex with
a distorted tetrahedral
geometry. Selected bond lengths and bond angles are given in
Table S5. ImPh2NNOtBu has retained its N,N,O binding mode
involving both neutral imidazole N-donors and the anionic
phenolic O-donor. The ligand’s buried volume in 4 is calculated
as 59.4%Vburied, which is almost identical to that in 2. The
thiophenolate binds through its anionic sulfur atom to the zinc’s
fourth coordination site. The Zn1-S1-C49 angle of 101.67(11)º is
typical for an arylthiolate coordinated to a transition metal and the
Zn-S bond length of 2.2249(9) Å is comparable to those other
tetrahedral zinc(II) thiophenolate complexes (2.2201(13)–
2.418(1) Å).[48-54] Similarly to 2, the tetrahedral distortion in 4 is
characterised by N-Zn-O and N-Zn1-N angles that are
significantly smaller than the ideal tetrahedron angle, and N-Zn-S
and O-Zn-S angles that are larger than 109.5º. Interestingly, the
thiolate appears to be coordinated in such a way that its aryl
substituent “bends” towards one of the two imidazole groups,
effectively imparting chirality to the complex. However, the overall
crystal structure of 4 must be considered racemic as can be seen
by the centrosymmetric space group (Figure 13). Overall, the low
coordination number, the single metal-sulfur bond, and the facial
N,N,O triad qualify 4 as an accurate (diamagnetic) structural
model of the ACV-bound active site of IPNS.
Figure 11. Displacement ellipsoid plot of 3 drawn at the 50% probability level.
Only the major form of the disordered tBu group is drawn. Hydrogen atoms, non-
coordinated pyridine molecules and severely disordered solvent molecules are
omitted for clarity. Phenyl substituents are depicted in the wireframe format for
clarity.
Slow vapour diffusion of n-hexane into a pyridine solution of 1
resulted in the growth of needle-like pale yellow crystals that were
suitable for X-ray diffraction. The resulting crystal structure
reveals the formation of a mononuclear, bisligated complex,
[Fe(kN,O-ImPh2NNOtBu)2] (3) (Figure 11). Selected bond lengths
and bond angles are given in Table S4. The iron centre has a
distorted tetrahedral geometry, bound by two ligand molecules,
each of which chelates by means of a new bidentate N,O
coordination mode involving the anionic phenolic oxygen atom
and a neutral imidazole N-donor. The second imidazole group is
unbound, orientated away from the iron in such a way that the
methoxy group is forced into relatively close proximity to the metal
(Fe...O21 and Fe1...O22 distances of 2.4598(18) and 2.513(2) Å,
respectively). This result confirms the disrupting effect that
pyridine has on the facial coordination of ImPh2NNOtBu
.
Synthesis of a Zinc Thiolate Complex (4)
The substitutional lability of the chloride ligand in 2 was
investigated using a monodentate thiophenolate. Complex 2 was
dissolved in CH2Cl2 and a slight excess of NaSPh was added. The
reaction mixture stirred 3 h and was subsequently filtered and
dried under vacuum. The crude solid was washed with hexane
and dried under vacuum, affording [Zn(ImPh2NNOtBu)(SPh)] (4) in
95% yield (Scheme 3). Crystals suitable for X-ray diffraction were
grown from slow vapour diffusion of n-hexane into a THF solution
of 4 at room temperature.
Figure 12. Displacement ellipsoid plot of 4 drawn at the 50% probability level.
Hydrogen atoms and disordered THF molecules are omitted for clarity.
0,a
c
O
NaS
O
N
N
N
N
N
N
N
N
O
O
CH2Cl2
- NaCl
Zn
Zn
b
Cl
2
S
4
Scheme 3. Synthesis of [Zn(ImPh2NNOtBu)(SPh)] (4).
Figure 13. Packing of 4 in the crystal, shown along the a-axis. H-atoms are
omitted for clarity. Two independent THF molecules in the asymmetric unit are
depicted in red and green. Only the major form of the disordered THF is shown.
8
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coordination of a pyridine molecule to the zinc centre has taken
place (Figure 15). This has caused the zinc’s coordination
environment to expand from four- to five-coordinate, and has also
lead to a disruption of the N,N,O coordination of ImPh2NNOtBu. The
steric demands of the pyridine ligand have caused one of the
imidazole groups of the supporting ligand to dissociate, resulting
in a closer proximity of the methoxy group to the zinc ion. This
results in the coordination of the supporting ligand by means of
an alternative facial N,O,O coordination mode to the zinc metal
centre, comprising an anionic phenolic O-donor, one of the neutral
imidazole N-donors and the loosely bound neutral methoxy O-
donor (Zn1-O2 distance of 2.455(3) Å). Selected bond lengths
and bond angles are given in Table S6.
Solution State Behaviour of 4
The 1H NMR spectrum of 4 in different deutero solvents is
1
depicted in Figure 14. The H NMR spectra of 4 in CD3CN and
CD2Cl2 both feature sharp singlets at 3.51 ppm and 3.44 ppm,
assigned to the N-methyl and O-methyl groups of the supporting
ligand framework, respectively. Their relative integral ratio of 2:1
supports the metallobicyclo[2.2.3]nonane topology associated to
the facial binding motif of the ImPh2NNOtBu ligand. In both spectra,
the thiolate ligand can be identified by the presence of two
multiplets in the aromatic region of the spectra, the most
deshielded being assigned to the two protons ortho to the sulfur
atom. Interestingly, the chemical shifts of the phenolic protons
have not changed compared to those of 2, which suggests that
chloride substitution for the thiophenolate does not have a
significant impact on the electronic properties of the phenolate
ring. VT 1H NMR analysis in CD3CN and CD2Cl2 (see Figures S57
and S58) demonstrates that 4 retains its structural integrity across
a wide temperature range, as no fluxional behaviour of the
supporting ligand nor any thiophenolate dissociation was
observed in either solvent. Finally, 1D NOE 1H NMR experiments
in CD3CN confirmed the three-dimensional structure of 4 as being
the same in solution as it is in the solid state (see Figures S55 and
S56).
Dissolving 4 in pyridine-d5 produced a pale pink solution whose
1H NMR spectrum reveals a number of significant changes
compared to the spectra obtained in CD3CN and CD2Cl2. Most
importantly, three singlets are observed at 3.93, 3.87, and 3.41
ppm, each with a relative integral of 3H. This strongly suggests
that the supporting ligand’s facial binding motif has been disrupted
and that a break in symmetry has occurred. Furthermore, a
significant increase in the number of observed aromatic signals
has occurred, which is in accordance with both imidazole groups
having different chemical environments. Colourless crystals
suitable for X-ray diffraction were grown from slow vapour
diffusion of hexane into a pyridine solution of 4 at room
temperature. The resulting crystal structure reveals the formation
of a new complex, [Zn(ImPh2NNOtBu)(SPh)(py)] (5), where direct
Figure 15. Displacement ellipsoid plot of 5 drawn at the 50% probability level.
Hydrogen atoms and partially occupied non-coordinated pyridine molecules are
omitted for clarity. Phenyl substituents are depicted in the wireframe format for
clarity.
p-tBu
*
*
*
NMe
H2
o-tBu
*
H1
CH3CN
OMe
*
CD3CN
*
tBu
*
*
tBu
NMe
H2
*
OMe
H1
*
CD2Cl2
tBu
Py
Py
Py
tBu
Hexane
*
*
*
C5D5N
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ꢅꢁꢄ
ꢇꢈꢉꢊꢋꢋꢌꢍ
ꢃꢁꢂ
ꢃꢁꢄ
ꢀꢁꢂ
ꢆꢁꢂ
ꢆꢁꢀ
ꢅꢁꢂ
ꢅꢁꢀ
ꢄꢁꢂ
ꢇꢃꢈꢉꢊꢊꢋꢌ
ꢄꢁꢀ
ꢃꢁꢂ
ꢃꢁꢀ
ꢀꢁꢂ
Figure 14. Stacked 1H NMR (400 MHz) spectra of 4 in different deutero solvents, recorded at 298 K.
9
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involving imidazole lability, solvent coordination to the potassium
ion and possible coordination equilibria between monomeric and
dimeric states, all of which contribute to the diffuse and
irreversible nature of the electrochemical events. The
electrochemical responses B and D (that occur at approximately
-0.75 V) are very minor and become less well defined at higher
scan rates (Figure S70). We therefore tentatively ascribe them
either to the presence of small amounts of structural isomers or to
the presence of a minor impurity.
Electrochemistry
Phenolate ligands are known to be redox non-innocent in
character, which prompted us to investigate the electrochemical
properties of complexes 1, 2 and 4, and examine the effect of
combining the redox non-innocent character of the supporting
ligand with zinc (redox inert), iron (redox non-innocent), as well as
a redox non-innocent thiophenolate ligand. The redox properties
of the complexes were investigated by cyclic voltammetry (CV)
under an inert N2 (g) atmosphere in acetonitrile, using [n-
Bu4N]PF6 as a supporting electrolyte. All quoted potentials are
referenced versus the ferrocene/ferrocenium couple (Fc/Fc+). The
redox behaviour of the ligand salt was investigated for comparison.
The voltammograms are displayed in Figure 16.
The voltammogram of complex 2 features a single irreversible
redox couple within the potential range of -1.0 V to +0.8 V with
the oxidation (A) and reduction (B) occurring at Ep,a = +0.56 V and
Ep,c = +0.07 V, respectively. Given the redox-inert nature of
divalent zinc, these electrochemical responses are assigned as
phenolate-based electron transfers. The phenolate oxidation
potential is comparable to that of other zinc(II) phenolate
complexes bearing mixed N,O-donor ligands.[60,61] Compared to
the ligand salt, the phenolate oxidation in 2 has undergone a 100
mV anodic shift. This is likely due to a depletion in the electron
density on the phenolate’s oxygen atom as a result of its
coordination to the Lewis acidic zinc ion.[62] Additionally, we
ascribe the smaller peak-to-peak separation of A and B in 2
(compared to A and C in K-ImPh2NNOtBu) to the rigid, tripodal
coordination of the ligand to zinc in acetonitrile solution, which
may help to increase the (electro)chemical reversibility of the
phenolate-centred electron transfers. Scanning beyond +0.85V,
additional irreversible oxidations were observed with no reduction
events taking place on the return scan, indicating decomposition
of the complex on the surface of the working electrode.
Scanning across the potential range of –2.1 V to +1.1 V, the
voltammogram of K-ImPh2NNOtBu features a strong oxidation
wave, A (Ep,a = +0.46 V), that we ascribe to the phenolate
oxidation to its phenoxyl form.[55-57] This is approximately 0.5 V
lower compared to the oxidation potential of tri-substituted
phenols such as 2,4,6-tri-tert-butylphenol or 2,4,6-trimethylphenol
that oxidize at ca. 1.0 V (vs. Fc/Fc+),[58,59] which reflects the
anionic state of the phenolic oxygen atom in K-ImPh2NNOtBu. A
reduction event, C (Ep,c = –1.66 V), is observed that only occurs
after A has taken place (see Figure S71), prompting us to assign
it to the electrochemical reduction of the phenoxide radical. The
large peak separation between A and C (ca. 2 V) and the
relatively diffuse nature of both signals reflects the highly
irreversible nature of this redox couple and is consistent with
previous observations made for the electrochemical behaviour of
substituted phenols in coordinating solvents.[58,59] Moreover, the
structure of the ligand salt in solution is likely very dynamic,
K-ImPh2NNOtBu
A
[Zn(L)(Cl)] (2)
[Fe(L)(Cl)] (1)
[Zn(L)(SPh)] (4)
D
A
B
C
C
B
B
20 µA
A
D
A
C
E
F
B
G
D
E
G
F
-2.2
-1.8
-1.4
-1.0
-0.6
-0.2
0.2
0.6
1.0
1.4
1.8
2.2
Potential vs. Fc/Fc+ (V)
Figure 16. Cyclic voltammograms of K-ImPh2NNOtBu, 2, 1 and 4, recorded in a 0.1 M solution of [n-Bu4N]PF6 in acetonitrile at ambient temperature and with a scan
rate of 100 mV/s.
10
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The presence of
a
redox-active metal in
1
produces
a
innocent nature of both the iron and the phenolate. A more
definitive assignment of these electrochemical processes has
been made by means of computational studies.
voltammogram of greater complexity than that of 2, with three
oxidative waves (A-C) and four reductive responses (D-G)
observed within the potential range of -1.0 V and +1.0 V. The
voltammogram is reproducible over at least 20 cycles, which
implies that the electrochemical cycle it represents is overall
chemically reversible. The first oxidation event, A (Ep,a = +0.18 V)
is assigned to iron oxidation on the basis of its low oxidation
potential. It forms an irreversible redox couple to G (Ep,c = -0.25),
which suggests that the formation of a ferric ion is accompanied
by additional chemical or structural changes in solution. One
possibility is that the preference for an octahedral geometry may
drive the ferric ions into coordination equilibria with acetonitrile,
deviating from the original tetrahedral geometry of the complex.
Indeed, this is reflected by the diffuse nature of the subsequent
oxidation, B (Ep,a = +0.42 V), ascribed to phenolate oxidation.[63]
By means of segmentation experiments (Figure S74), B was
shown to be redox-coupled to both E (+0.23 V) and F (+0.04 V),
supporting the hypothesis that a mixture of species is present in
solution after the initial oxidation event A. Finally, a quasi-
reversible redox couple comprising C and D (E1/2 = +0.88 V) is
observed that we tentatively assign to a FeIV/FeIII couple, based
on similar potentials reported for other non-heme iron complexes
supported by tripodal ligands.[64,65]
Computational Studies
In order to better understand the electronic structure of complexes
1, 2 and 4, we resorted to density functional theory (DFT)
calculations. For ease of comparison, we also performed DFT
calculations on the theoretical monomeric structure of the ligand’s
potassium salt (K-Lopt), where a tripodal N,N,O ligand binding
mode to the potassium cation has been imposed. Overall, the
geometries (1opt, 2opt and 4opt) obtained from the gas-phase
geometry optimisations are consistent with the solid-state X-ray
crystal structures. The electron density was therefore recalculated
at the B3LYP / 6-311g(d,p) level of theory. For K-Lopt, 2opt and
4opt, the energies of the Kohn-Sham molecular orbitals (MOs)
were extracted from these geometries. The a and b MOs in 1opt
,
were biorthogonalised with the Multiwfn program,[67] using the
Fock matrix from natural bonding orbital (NBO) analysis in order
to evaluate their energies. The MO energies calculated for K-Lopt
,
1opt, 2opt and 4opt are given in Table S7 and are depicted
schematically in Figure 17. The MO energies for 1opt have been
ordered according to the average energy of the a and b orbitals
generated upon biorthogonalization.
Substitution of the chloride ligand in 2 for the thiophenolate ligand
in 4 can be regarded as the addition of a redox centre within the
Our calculations show that the HOMO in K-Lopt, 2opt and 4opt is
consistently localised on the phenolate group. This demonstrates
clearly that ImPh2NNOtBu has redox non-innocent character and
supports our assignment of the first electrochemical oxidation of
these compounds as being ligand-centred. The calculations also
show that the HOMO in K-Lopt (-4.26 eV) is more energetically
accessible than that in 2opt and 4opt, which reflects the electronic
effect imparted by the more Lewis acidic zinc centre. In contrast,
the HOMO in 1opt is localised on the iron centre and lies much
higher in energy than for the other complexes. Indeed, the
occupied MOs of highest energy in 1opt are calculated as being
the five iron d-orbitals, four of which are singly occupied and one
of which is filled. NBO calculations also show the natural spin
density to be almost entirely localised on the iron centre (Figure
17 and Table S8). Together, these calculations indicate that the
ferrous centre in 1 is most prone to oxidation despite the redox-
active nature of the phenolate group, and support our assignment
of the first electrochemical oxidation in 1 to the FeII/FeIII oxidation.
zinc complex framework. Scanning oxidatively,
a strong
irreversible oxidation, A (Ep,a = +0.65 V), is observed that is
followed by a second more diffuse oxidation, B (Ep,a = +1.07 V).
We ascribe these to the sequential oxidation of the phenolate and
thiophenolate moieties, on the basis of literature precedent.[56,62,66]
The presence of the thiolate ligand has therefore caused the
phenolate oxidation to shift anodically by approximately 0.1 V
compared to 2. Scanning beyond +1.4 V, a quasi-reversible redox
couple is observed, C and D (E1/2 = +1.57 V), which we assign to
a ligand-centred electron transfer, although we are unable to
assign it definitively to the thiolate or to the phenolate. Reduction
F (Ep,c = -0.89 V) was observed not to occur without A having
previously taken place (Figure S78), which prompted our
assignment of F to the phenoxide reduction. Interestingly,
segmentation experiments revealed that F is less broad when C
has not taken place (Figure S79), demonstrating that sequential
electrochemical oxidations of 4 provoke structural changes in
solution that increase the activation energy required for F.
Presumably, these structural changes account for the overall
irreversibility of the electrochemical events.
Computations also reveal that the HOMOs in 2opt and 4opt are
similar in energy (-4.97 eV and -4.84 eV, respectively), thereby
supporting the hypothesis that the oxidation potential of the
supporting phenolate is not significantly affected by the
exogenous ligand substitution on the zinc centre. Similarly, the
presence of a thiolate ligand in 4opt has no effect on the energy of
the LUMO compared to 2opt. We attribute this to the highly
aromatic character of the LUMO, which is delocalised across the
bis-imidazole ligand backbone in both cases and is, presumably,
highly energetically inaccessible. Finally, the HOMO-1 in 4opt is
calculated as being localised on the sulfur atom, which indicates
that the thiolate is slightly less prone to oxidation than the
phenolate and supports our assignment of the sequential
oxidations in the CV of 4.
Overall, these results demonstrate the redox non-innocence of
ImPh2NNOtBu and show that phenolate to phenoxide oxidation is
the first electrochemical response observed upon subjecting K-
ImPh2NNOtBu, 2 and 4 to oxidative conditions. The thiolate ligand
in 4 is slightly more difficult to oxidise than phenolate, which
suggests that its soft nature may help create more covalent bonds
with transition metals than the phenolic oxygen, thereby reducing
its charge localisation and rendering it less prone to oxidation.
Moreover, the 2,4-disubstitution of the phenolate group helps
stabilise the phenoxide radical and make its oxidation more
thermodynamically favourable. The cyclic voltammogram of 1,
however, is more difficult to interpret due to the redox non-
11
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K-Lopt
0.0
-1.0
-2.0
-3.0
-4.0
-5.0
-6.0
HOMO
LUMO
2opt
HOMO
SOMO
LUMO
K-Lopt
4opt
1opt
2opt
HOMO
LUMO
1opt
1opt
spin density
LUMO
HOMO (SOMO)
4opt
HOMO-1
HOMO
LUMO
Figure 17. Calculated MO energies for L-Kopt, 1opt, 2opt and 4opt. LUMOs for 1opt are not depicted as they occur higher in energy than the given scale. Relevant MO
diagrams for each complex are also provided (isosurface: ±0.05). HOMO: highest occupied molecular orbital; LUMO: lowest unoccupied MO; SOMO: singly occupied
MO.
solution-state dependencies of ImPh2NNOtBu, this ligand has now
been established as a robust platform from which to structurally
model the 2H1C bioinorganic motif. Cyclic voltammetry studies,
Conclusion
This work has established ImPh2NNOtBu as a synthetically
accessible, bioinspired ligand that can structurally model the
2H1C by means of a facial N,N,O binding motif. Reacting K-
ImPh2NNOtBu with iron(II) or zinc(II) chloride afforded the
supported by DFT calculations, demonstrated the redox non-
innocence of ImPh2NNOtBu as phenolate oxidation was the first
electrochemical response observed in K-ImPh2NNOtBu, 2 and 4.
However, the initial electrochemical oxidation of 1 was shown to
occur at the iron centre and not at the phenolate. Therefore, 1 is
an interesting complex with which to investigate the spectroscopy
and oxidative transformations of derivative iron complexes that
model 2H1C-containing iron enzymes. Our group currently
focuses on the development of mononuclear non-heme iron
thiolate complexes that structurally model the substrate-bound
active site of IPNS.
isostructural
complexes
[Fe(ImPh2NNOtBu)(Cl)]
(1)
and
[Zn(ImPh2NNOtBu)(Cl)] (2) in high yield. These complexes can be
regarded as highly convenient synthons from which a range of
biomimetic complexes bearing biorelevant co-ligands could be
created. In this work, the substitutional lability of the chloride
ligand in 2 was investigated using a simple thiophenolate ligand,
producing complex [Zn(ImPh2NNOtBu)(SPh)] (4) in high yield. The
low coordination number, the single metal-sulfur bond, and the
facial N,N,O supporting ligand qualify
4 as an accurate
(diamagnetic) structural model of the substrate-bound IPNS
active site. Detailed investigation of the solution state behaviour
of 1, 2, and 4 showed that the complexes retained their structural
integrity in acetonitrile and dichloromethane solutions, while
coordinating solvents of greater bulk such as THF and pyridine
provoke structural rearrangements and lead to alternative
bidentate (k2-N,O) and tridentate (k3-N,O,O) coordination modes
of the supporting ligand. Having elucidated the sensitivities and
Acknowledgements
Financial support was provided by the European Union through
the Marie Sklodowska-Curie NoNoMeCat ITN network (675020-
MSCA-ITN-2015-ETN). The X-ray diffractometer was financed by
the Netherlands Organisation for Scientific Research (NWO). S.Y.
gratefully acknowledges the financial support from the Max-
12
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Entry for the Table of Contents
2-His-1-Carboxylate Facial Triad
Model Complexes
His
R
O
N
N
His
H
N
Glu/Asp
R
H
N
R
N
N
N
O
N
O
O
M
Fe
OH2
H2O
Cl
OH2
M = Fe, Zn
How N,N,O can you go? A new bulky, tripodal N,N,O phenolate ligand provides access to well-defined mononuclear, monoligated
non-heme iron and zinc complexes that accurately model the 2-His-1-Carboxylate facial triad. These complexes are ideal synthons
from which to create a range of biomimetic N,N,O-bound complexes featuring biorelevant cofactors.
Institute and/or researcher Twitter usernames: EMonkcom
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