Earth-Abundant Mixed-Metal Catalysts for Hydrocarbon Oxygenation

Article abstract of DOI:10.1021/acs.inorgchem.8b00420

The oxygenation of aliphatic and aromatic hydrocarbons using earth-abundant Fe and Cu catalysts and "green" oxidants such as hydrogen peroxide is becoming increasingly important to atom-economical chemical processing. In light of this, we describe that dinuclear Cu^II complexes of pyrrolic Schiff-base macrocycles, in combination with ferric chloride (FeCl₃), catalyze the oxygenation of π-activated benzylic substrates with hydroperoxide oxidants at room temperature and low loadings, representing a novel design in oxidation catalysis. Mass spectrometry and extended X-ray absorption fine structure analysis indicate that a cooperative action between Cu^II and Fe^III occurs, most likely because of the interaction of FeCl₃ or FeCl₄^- with the dinuclear Cu^II macrocycle. Voltammetric measurements highlight a modulation of both Cu^II and Fe^III redox potentials in this adduct, but electron paramagnetic resonance spectroscopy indicates that any Cu-Fe intermetallic interaction is weak. High ketone/alcohol product ratios, a small reaction constant (Hammett analysis), and small kinetic isotope effect for H-atom abstraction point toward a free-radical reaction. However, the lack of reactivity with cyclohexane, oxidation of 9,10-dihydroanthracene, oxygenation by the hydroperoxide MPPH (radical mechanistic probe), and oxygenation in dinitrogen-purge experiments indicate a metal-based reaction. Through detailed reaction monitoring and associated kinetic modeling, a network of oxidation pathways is proposed that includes "well-disguised" radical chemistry via the formation of metal-associated radical intermediates.

Full text of DOI:10.1021/acs.inorgchem.8b00420

Article
pubs.acs.org/IC
Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
Earth-Abundant Mixed-Metal Catalysts for Hydrocarbon
Oxygenation
James R. Pankhurst,† Massimiliano Curcio,† Stephen Sproules,*,‡ Guy C. Lloyd-Jones,*,†
and Jason B. Love*,†
†EaStCHEM School of Chemistry, The University of Edinburgh, Joseph Black Building, David Brewster Road, Edinburgh EH9 3FJ,
U.K.
‡WestCHEM School of Chemistry, University of Glasgow, Glasgow G12 8QQ, U.K.
S
* Supporting Information
ABSTRACT: The oxygenation of aliphatic and aromatic hydrocarbons using earth-abundant Fe and Cu catalysts and “green”
oxidants such as hydrogen peroxide is becoming increasingly important to atom-economical chemical processing. In light of this,
we describe that dinuclear CuII complexes of pyrrolic Schiff-base macrocycles, in combination with ferric chloride (FeCl3),
catalyze the oxygenation of π-activated benzylic substrates with hydroperoxide oxidants at room temperature and low loadings,
representing a novel design in oxidation catalysis. Mass spectrometry and extended X-ray absorption fine structure analysis
indicate that a cooperative action between CuII and FeIII occurs, most likely because of the interaction of FeCl3 or FeCl4 with
−
the dinuclear CuII macrocycle. Voltammetric measurements highlight a modulation of both CuII and FeIII redox potentials in this
adduct, but electron paramagnetic resonance spectroscopy indicates that any Cu−Fe intermetallic interaction is weak. High
ketone/alcohol product ratios, a small reaction constant (Hammett analysis), and small kinetic isotope effect for H-atom
abstraction point toward a free-radical reaction. However, the lack of reactivity with cyclohexane, oxidation of 9,10-
dihydroanthracene, oxygenation by the hydroperoxide MPPH (radical mechanistic probe), and oxygenation in dinitrogen-purge
experiments indicate a metal-based reaction. Through detailed reaction monitoring and associated kinetic modeling, a network of
oxidation pathways is proposed that includes “well-disguised” radical chemistry via the formation of metal-associated radical
intermediates.
Simple transition-metal salts of Cu and Fe have also been
used in nonbiomimetic approaches to oxygenation catalysis,
mainly in combination with H2O2 or tert-butyl hydroperoxide
(tBuOOH or TBHP) as the oxidant. The reaction between
CuBr and TBHP forms mixtures of tBuO• (alkoxyl) and
tBuOO• (peroxyl) radicals that carry out H-atom abstraction
(HAA) from hydrocarbons.34 CuCl2, CuCl, and Cu metal
catalyze the oxygenation of π-activated benzylic substrates using
TBHP.35,36 Furthermore, copper acetate catalyzes the oxidation
of aromatic C−H bonds using O2 as an oxidant.37 The related
Kharasch−Sosnovsky reaction of dialkyl peroxides leads to
etherification of hydrocarbon substrates and is typically
catalyzed by CuI salts,38−41 and coordination complexes of
CuI have also been implemented in radical reactions.42 Simple
Fe salts (most commonly FeCl3) and their complexes catalyze
oxygenation reactions of hydrocarbon substrates with high
INTRODUCTION
■
The combination of earth-abundant metals such as Fe or Cu,
with oxidants such as dioxygen (O2) or hydrogen peroxide
(H2O2) offers “green” alternatives to more traditional, toxic,
stoichiometric, or catalytic chromium and manganese reagents
for the oxygenation of alkanes. The process has a strong
foundation in understanding the enzymatic oxygenation of
hydrocarbons.1−7 Cytochrome P450 and peroxidase enzymes
react aerobically through high-oxidation-state iron oxo (FeIV
O, “ferryl heme”) complexes.8−10 Tyrosinase enzymes feature
bimetallic CuI active sites that oxidize catechol to o-
quinone.11,12 Methane monooxygenase enzymes contain either
Cu or Fe13,14 and oxidize the strong C−H bonds of methane
(HDiss = 439 kJ mol−1).15,16 This has led to the development of
oxygenation catalysts based on Cu and Fe complexes17 that
incorporate the M(μ-O2)M diamond motif,18−21 reactive iron
oxo- and peroxoporphyrins,22−27 and nonheme FeIVO28−32
or FeVO33 functionalities.
Received: February 16, 2018
© XXXX American Chemical Society
A
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bond dissociation energies (BDEs), including cyclohexane.43−56
The bulk of these reactions are described by Fenton
mechanisms,57,58 in which the role of Fe is to generate highly
reactive hydroxyl,59 tert-butoxyl,60 and tert-butyl peroxyl61 free
radicals from the hydroperoxide.
the variation of various components in these macrocycles,
important parameters such as internuclear separation and cavity
size can be controlled.84,85 The macrocyclic clefts offered by
these complexes are reminiscent of supramolecular flasks,
where catalytic and stoichiometric reactions that are disfavored
in the bulk phase can take place within the host structure
because of the increased effective concentration and lowered
entropy.86−89 Dinuclear FeII Pacman diporphyrin complexes
activate O2, leading to reactive FeIVO complexes (through
photolysis) that oxidize hydrocarbon substrates to generate
alcohols.22 We anticipated that reactions between complexes A,
B, or C (Figure 1) and hydroperoxides might form reactive
species akin to diamond MO2M complexes21,90,91 because the
structurally related Schiff-base Pacman complexes of CoII
catalyze the microscopic reverse O2-reduction reaction.92−94
Electrochemical measurements have indicated that the CuIII
oxidation state is also accessible for these complexes, leading to
the possibility of the formation of CuIII−OH complexes, which
could take place in HAA reactions.95−98
Mixtures of metal compounds can act as tandem catalysts for
oxygenation reactions.62−65 Combinations of FeII and CrII
diketonates carry out tandem oxygenation and epoxidation
catalysis of cyclohexene.66,67 Additionally, copper acetate and
FeCl3 mixtures act as catalysts for a complex series of C−C and
C−O bond-forming reactions, although these reactions require
high catalyst loadings.68 A mixture of Fe2SO4 and CuCl2
catalyzes the oxidation and isomerization of alkene-containing
organoperoxides, yielding ketone products, with the postulated
mechanism showing the two metal ions participating in
tandem.69 In terms of cooperative catalysis, mixtures of Cu
and Fe (in the form of salts, complexes, or nanoparticles) have
been used to successfully promote cross-coupling reactions,70
including those that form new C−C bonds,71−74 C−O
bonds,75,76 C−S bonds,77 and also N-arylation.78−80 In
contrast, there is surprisingly little use of mixtures of metals
and their complexes in cooperative catalysis for the direct
functionalization of hydrocarbon C−H bonds. In one example,
amination of an allylic C−H bond was achieved by a palladium
acetate catalyst but only when a CrIII catalyst was also present
to aminate the palladium allyl intermediate.81
We report here the use of dinuclear CuII complexes for the
catalytic oxygenation of π-activated, benzylic hydrocarbon
substrates, using hydroperoxide oxidants. We find that the
activity, stability, and operating temperature of the catalyst
improves substantially by the addition of FeCl3, and we report
the attempted characterization of the catalytically active species
through detailed spectroscopic and voltammetric methods, as
well as the elucidation of a plausible reaction network through
kinetic studies. To the best of our knowledge, there are no
previous reports of mixtures of Cu and Fe compounds being
used to catalyze the oxygenation of hydrocarbon bonds.
On the basis of these precedents, we sought to employ
dinuclear CuII complexes of Schiff-base pyrrole macrocycles as
catalysts for hydrocarbon oxygenation (Figure 1).82,83 Through
RESULTS AND DISCUSSION
■
Catalysis with Bimetallic CuII Macrocycles. Initial
oxygenation reactions using the bimetallic CuII complexes A−
C (0.2 mol %) were carried out in deuterated acetonitrile
(MeCN-d3), using TBHP as the oxidant (Scheme 1). Xanthene
was chosen as the substrate because of the low BDE of its
benzylic C−H bond (HDiss = 75.5 kcal mol−1).99 All three
complexes are catalytically inactive at room temperature, but
upon heating at 333 K, the substrate is consumed, as is
evidenced by the loss of the benzylic proton resonance at 4.05
1
ppm in the H NMR spectrum.
The three products formed were identified by NMR/mass
spectrometry (MS) as the benzylic alcohol (xanthydrol, ROH),
organoperoxide [(tert-butyl)xanthyl peroxy ether, ROOtBu],
and benzylic ketone (xanthone, RO) after isolation of the
products on a preparative scale. One coproduct of the reaction
is tert-butanol, identified by the singlet resonance at 1.17 ppm
of the methyl protons. Importantly, no 9,9′-bixanthene, a
homocoupling product that might be expected to form if an
Figure 1. Dinuclear CuII macrocycles used as precatalysts for benzylic
hydrocarbon oxygenation and the proposed precatalyst arising from A
+ FeCl3. Complexes A and B adopt Pacman configurations and feature
different spacer groups [Cu···Cu = 3.695/3.738 Å for A and 4.818(3)
Å for B]. Complex C adopts a bowl geometry [Cu···Cu = 6.493(6) Å].
a
Scheme 1. Oxygenation of Xanthene Catalyzed by the Dinuclear CuII Complexes A−C at 333 K
a
1
The yields were determined by H NMR spectroscopy.
B
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organic free-radical reaction mechanism operates through HAA
from xanthene, is seen.100
complexes B and C could potentially undergo oxidation
chemistry to dipyrrins,101,102 only complex A was used to
study the catalytic reactions in detail.
The concentration profiles for xanthene and its three
Mixed-Metal Catalysis. While the CuII complexes are
highly active xanthene oxygenation catalysts, this activity
quickly arrests. In order to address this issue, FeCl3 was
employed initially as a simple FeIII cocatalyst because it has
been demonstrated previously to catalyze the oxidation of
benzylic alcohol substrates.46 We hypothesized that this mixed-
metal system would carry out tandem catalysis, with the CuII
complex catalyzing xanthene oxygenation to form a mixture of
ROH and ROOtBu and FeCl3 catalyzing the formation of RO
in improved yields with shorter reaction times.
1
oxygenated products were determined by H NMR spectros-
copy (Figure 2) with 93% conversion of the substrate seen
within 30 min, giving a formal initial turnover frequency (TOF)
of 930 h−1.
Surprisingly, at catalyst loadings of 0.1 mol % A and 0.1 mol
% FeCl3, the reaction proceeds at room temperature; A shows
negligible activity at room temperature and FeCl3 achieves only
13% conversion after 2 h, whereas the A/FeCl3 mixture
achieves 80% conversion within 2 h. Reaction monitoring by
1H NMR spectroscopy revealed that the substrate is consumed
after 4 h (Scheme 2 and Figure 3), forming 72% ROOtBu, 19%
RO, and 9% ROH. Longer reaction times (12 h) and higher
relative concentrations of TBHP are found to drive the
selectivity toward the ketone product (in excess of 80%; Figure
3). It is significant that the addition of FeCl3 both limits
deactivation of the CuII catalyst and enhances the reaction rate,
implying that cooperative catalysis is taking place.
To test the stability of the catalyst further, recycling was
attempted. The reaction between xanthene and 4 equiv of
TBHP at room temperature, catalyzed by 0.1 mol % A/FeCl3,
affords RO as a colorless precipitate in 90% yield after 16 h.
However, filtering and recharging the solution with xanthene
and TBHP led to no further conversion of the substrate. In
contrast, the catalyst was much more stable at very low loading
and could be recycled multiple times. The reaction between
xanthene and 4 equiv of TBHP, catalyzed by 0.002 mol % A/
Figure 2. Monitoring the oxygenation of xanthene by 2.2 equiv of
TBHP, catalyzed by 0.2 mol % complex C at 333 K in MeCN-d3
(concentrations determined by H NMR integration). Interpolation
1
between the datapoints is provided solely as an aid to the eye.
After 2 h, the oxidation products ROOtBu and RO are
formed in yields of 60% and 33%, respectively, with ROH in 7%
yield. After this period, the concentrations of both ROOtBu
and RO almost plateau for 10 h before the peroxy ether slowly
converts to the ketone through autooxidation at an
approximate initial rate of 2 × 10−7 mol dm−3 s−1. At room
temperature, the background (non-catalyzed) oxidation of
isolated ROOtBu is found to be slow (1 × 10−8 mol dm−3 s−1)
but is accelerated in the presence of 0.2 mol % C (2 × 10−6 mol
dm−3 s−1). The slow oxidation of ROOtBu during the first 10 h
(Figure 2) suggests that the active catalyst inhibits autoox-
idation during this stage but is ultimately deactivated.
Variation of the ligand scaffold in the macrocyclic complexes
A−C causes dramatic changes in terms of their geometric and
electronic properties, as is evident from their solid-state
structures and electrochemical behavior.82,83 Despite these
differences, varying the catalysts A−C did not change the
activity or distribution of products, nor did it make the catalyst
more or less susceptible to deactivation or inhibition. Because
the dipyrromethane groups containing meso-H substituents in
1
FeCl3, was monitored by H NMR spectroscopy (Figure 4,
top). Under these conditions, the catalyst is surprisingly active,
with 90% conversion of the substrate in 30 h; the TOF at 50%
conversion is high at 1595 h−1. Under low catalyst conditions,
RO does not precipitate, and instead ROOtBu is formed as the
major product (78% selectivity at 30 h). The reaction is slower
in the second cycle, but 80% conversion of xanthene is achieved
after an additional 96 h. In the third cycle, the catalyst activity
depreciates significantly, and only 13% conversion is seen in the
next 48 h. Nevertheless, the mixed-metal catalyst is able to carry
out more than 100000 turnover numbers (TONs) under these
conditions. Steady catalyst deactivation is seen over time, with
the TOF diminishing by approximately 10 h−2 (Figure 4,
bottom).
To investigate the role of FeCl3, a catalytic reaction was
carried out using A (0.1 mol %) and InCl3 (0.5 mol %) as a
chloride-containing, redox-inactive Lewis acid. After 24 h, the
room temperature reaction between xanthene and TBHP (2
a
Scheme 2. Xanthene Oxygenation Catalyzed by a Mixture of FeCl3 and A, at 300 K
a
1
The yields after 4 h are shown and were determined by H NMR spectroscopy.
C
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Figure 4. Assessing the stability of the A/FeCl3 catalyst in the
xanthene oxygenation reaction through multiple reaction cycles.
Reaction conditions: stirring MeCN-d3, room temperature, [xan-
thene]0 = 170 mM, [TBHP]0 = 680 mM, [A]0 = 3.4 μM, and [FeCl3]0
= 3.4 μM (0.002 mol %). Top: monitoring the xanthene concentration
1
by H NMR spectroscopy to determine the percent conversion and
TON. Bottom: monitoring the changes in TON and TOF during the
course of the reaction. Interpolation between the datapoints is
provided solely as an aid to the eye.
Figure 3. Monitoring the xanthene oxygenation by TBHP catalyzed by
mixtures of A and FeCl3 at 300 K in MeCN-d3 (concentrations
determined by 1H NMR spectroscopy). Top: [xanthene]0 = 150 mM,
[TBHP]0 = 575 mM, [A]0 = 150 μM, and [FeCl3]0 = 150 μM.
Bottom: [xanthene]0 = 75 mM, [TBHP]0 = 300 mM, [A]0 = 150 μM,
and [FeCl3]0 = 150 μM. Interpolation between the datapoints is
provided solely as an aid to the eye.
complex A upon the addition of FeCl3 is a direct consequence
of the macrocyclic ligand.
Scope of the Catalytic Reaction. The catalytic reaction is
found to be tolerant of the choice of solvent, with identical
conversion and product distributions seen after 2 h in
acetonitrile (polar, coordinating), dichloromethane (polar,
noncoordinating), and benzene (apolar).
A number of peroxide oxidants were tested in the xanthene
oxygenation reaction, although TBHP is the best by far (Figure
5). Whereas 100% conversion of xanthene is seen after 2 h
when TBHP is used, the conversion is lowered to 60% when
H2O2 is used. Use of the organoperoxides di-tert-butyl peroxide
(DTBP), tert-butyl peroxybenzoate, or dicumyl peroxide gives
no reaction. Similarly, no reaction is seen when carried out in
air in the absence of a hydroperoxide oxidant. Finally, adding
cyclohexanecarboxaldehyde as a co-oxidant to promote aerobic
oxidation103,104 does not yield any oxygenated products.
A range of hydrocarbon substrates was tested in reactions
with TBHP, catalyzed by A only, at loadings between 0.2 and
0.1 mol %. No reaction occurs with cyclohexane105 or n-
decanol.106 Only trace amounts of oxygenated products are
seen with cyclohexene,105 namely, cyclohexene oxide, cyclo-
equiv) shows only 3% conversion. A similar reaction involving
scandium(III) triflate (0.5 mol %) achieves a higher conversion
of 18% after 24 h, forming ROOtBu as the sole product. Under
the same conditions, reactions involving A and FeCl3 achieve
90% conversion at lower catalyst loading (0.1 mol %), yielding
higher amounts of alcohol and ketone products in just 3 h.
These experiments indicate that FeCl3 does not simply act as a
Lewis acid or a chloride source but that its redox properties
may also be important.
CuCl2 is known to catalyze the oxygenation of benzylic
substrates,36 and we find that the room temperature oxygen-
ation of xanthene by TBHP, catalyzed by CuCl2, proceeds with
a reaction profile almost identical with that of catalytic reactions
involving A/FeCl3. However, an equimolar mixture of FeCl3
and CuCl2 leads to no enhancement of the CuCl2-catalyzed
reaction, indicating that the improved activity and stability of
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chromatography (GC)/MS and in some cases were carried out
on a preparative scale to isolate the products by column
chromatography (Figure 6).
First, a series of simple substituted benzylic substrates were
tested at a catalyst loading of 0.2 mol %, with heating at 60 °C
for 16 h. The substrates with high benzylic C−H BDEs, i.e.,
toluene, p-nitrotoluene, and benzyl sulfoxide, are not oxidized.
Low-to-moderate conversion is seen for benzyl alcohol (51%),
ethylbenzene (26%), cumene (20%), bibenzyl (11%), benzyl
phenyl ether (24%), diphenylmethane (3%), 2-benzylpyridine
(21%), and 4-benzylpyridine (42%). Of these, a few yield single
carbonyl products with high selectivity: benzyl alcohol affords
benzaldehyde (100%); ethylbenzene affords acetophenone
(90%); benzyl phenyl ether affords phenyl benzoate (69%);
diphenylmethane affords benzophenone (100%); both 2- and
4-benzylpyridines afford the corresponding benzoylpyridines
(100%). Three substrates in particular undergo high con-
version. Benzylamine is consumed quantitatively but only
affords 28% of the carbonyl product (benzyl amide), with
benzaldehyde (55%) and benzonitrile (16%) seen as the other
products. Benzyl methyl ether undergoes 91% conversion and
is 94% selective for the ester, methyl benzoate. Triphenyl-
methane also undergoes 100% conversion and affords (tert-
butyl)triphenyl methylperoxy ether as the sole product.
A series of bicyclic benzylic substrates were tested, all of
which undergo high conversion, with the exception of α-
tetralone (40%). The N-heterocyclic compounds indoline and
1,2,3,4-tetrahydroquinoline both afford the aromatic com-
pounds indole and quinolone quantitatively, with no oxygen-
ation of the substrate taking place following HAA. In contrast,
the O-containing heterocycle isochroman quantitatively affords
the monoketone product 4-chromanone. Likewise, 94% of
indane reacts to afford the monoketone indanone with 89%
selectivity. For 1,2,3,4-tetrahydronaphthalene, 100% of the
substrate is converted, forming a mixture of the monoketone α-
tetralone (51%) and p-quinone products 1,4-naphthoquinone
(9.5%) and 2,3-dihydro-1,4-naphthoquinone.
Figure 5. Screening different oxidants in the xanthene oxygenation
reaction, catalyzed by 0.1 mol % A and 0.1 mol % FeCl3. Reaction
conditions: 0.15 M xanthene, 2 equiv of oxidant, stirring MeCN, room
temperature, 3 h (conversion of xanthene determined by H NMR
spectroscopy). I is a co-oxidant with 2 equiv TBHP.
1
hexenol, and cyclohexenone. The aromatic alkene, trans-
stilbene, reacts to yield the epoxide in 72% selectivity and
97% conversion; 17% of the remaining products are
benzaldehyde and benzoic acid, which result from C−C bond
breaking. Neither the Baeyer−Villiger reaction of cyclo-
pentanone107 nor the oxidation or oxidative coupling of the
ortho-directed phenol, 2,4-di-tert-butylphenol,108−110 is cata-
lyzed by A. Similarly, the para-directed phenol, 2,6-di-tert-
butylphenol, does not react to give the expected p-quinone or
diphenoquinone products.111,112 Application of the mixed-
metal system of A and FeCl3 does not improve any of these
reactions.
Because the catalytic reaction involving A and FeCl3 is
restricted mainly to π-activated benzylic substrates, a wider
screening of these substrates was undertaken (Scheme 3). The
1
reactions were assessed by H NMR spectroscopy and gas
Scheme 3. General Reaction and a List of π-Activated Benzylic Substrates Tested in the CuII/FeIII-Catalyzed Oxygenation
Reaction
E
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Figure 6. Application of the mixed-metal A/FeCl3 catalytic system to a range of π-activated benzylic hydrocarbon substrates. Reaction conditions:
0.15 M substrate, 4 equiv of TBHP per benzylic position, 0.2 mol % A, 0.2 mol % FeCl3, stirring MeCN, 60 °C, 16 h (yields determined by GC/MS
using mesitylene as an internal standard). *Reaction carried out at room temperature. †Isolated yields reported after the reaction was performed on a
1 mmol scale and purification by column chromatography.
The tricyclic benzylic substrates xanthene, fluorene, 9,10-
dihydroanthracene (DHA), and 9,10-dihydrophenanthrene
were all screened on a preparative scale. All four substrates
react with 100% conversion, and the carbonyl products are
isolated in high yields: xanthone, 90%; fluorenone, 89%;
anthraquinone, 87%; phenanthraquinone, 80%. Only 9,10-
dihydrophenanthrene required heating at 60 °C.
Finally, three furan derivatives of benzylic substrates were
tested because this would hold some relevance to natural
product synthesis.113,114 Phthalan reacts quantitatively at room
temperature, with 45% selectivity for the monoketone
phthalide. A second unidentified product was also formed in
significant quantity (representing 30% of the total GC trace).
Dihydrobenzofuran only undergoes 44% conversion at 60 °C
to give a mixture of products; benzofuran is identified as the
major product at 39% selectivity. Finally, menthofuran
undergoes 75% conversion, but the products could not be
identified by GC/MS and the selectivity for the major product
is low at 34%.
hand, the two ether-containing compounds undergo very
different conversions, at 33% for benzyl phenyl ether and 81%
for benzyl methyl ether.
Characterization of the Catalyst. Because of the strong
paramagnetism exhibited by both complex A and FeCl3,
structural characterization of the catalytically active species by
NMR spectroscopy was not possible. Furthermore, we were
unable to grow single crystals of the (pre)catalyst from a wide
range of solvent combinations and crystallization conditions
and, as such, the structure has not been determined by X-ray
crystallography.
It was thought that the addition of FeCl3 to A might cause (i)
transmetalation to dinuclear FeIII or heterodinuclear CuII/FeIII
complexes, (ii) the formation of an ate complex, with FeCl3/
FeCl4− incorporated within the CuII macrocycle through one or
more bridging chloride ligands (see Figure 1), reminiscent of
dinuclear ZnII macrocycles that bind chloride in the macrocyclic
cleft,115 or (iii) the formation of CuCl2, which has been shown
to catalyze the oxygenation reaction (see above).
The benzylic substrates that were screened span a benzylic
C−H BDE range between 75 and 105 kcal mol−1. While that
with the lowest BDE (xanthene) undergoes full conversion and
that with the highest BDE (toluene) does not react, there is no
linear correlation between the percent conversion and BDE
between these extremes. Likewise, there is no correlation
between the percent conversion and benzylic C−H pKa or the
ionization energies of the substrates. Comparing a set of
substituted benzylic substrates of similar BDE values (85−87.5
kcal mol−1) reveals that, even in a narrow BDE range, there are
vast differences in the percent conversion, which is ascribed to
functional group sensitivity. The two alkyl-substituted sub-
strates in this subset, ethylbenzene and cumene, undergo
similar conversions at 26% and 22%, respectively. In
comparison, the conversion of benzyl alcohol is higher (57%)
and that of benzylamine is higher still (100%). On the other
In the positive-ion electrospray ionization MS (ESI-MS)
spectrum of a 1:1 mixture of A and FeCl3 in MeCN, no ions
corresponding to transmetalated products are seen. Signifi-
cantly, however, a low-intensity ion at m/z 980 is assigned to
the ate complex [A-FeCl4]+ (Figure 7), which might arise from
an A/FeCl3 complex or, alternatively, because FeCl3 is known
to form [FeCl2(MeCN)4]+[FeCl4]− in MeCN,116 the formation
of an adduct between A and the [FeCl4]− anion. A further ion
is seen at m/z 853, consistent with [A(Cl)2]+, and supports the
ability of the CuII centers to bind chloride in the presence of
FeCl3. The base peak at m/z 697 is assigned to [KH4L]+, and
its observation may suggest the demetalation and formation of
CuCl2.
The electronic absorption spectrum of A in MeCN shows
three absorption bands at 240, 298, and 367 nm, as well as a
shoulder at 400 nm (Figure 8). These are assigned to a mixture
F
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(Figure S57). In the square-wave voltammograms (SWVs) of
the mixtures (Figure 9), it is more apparent that this new
Figure 7. Fourier transform ion cyclotron resonance positive-ion ESI-
MS spectrum of a 1:1 solution of A and FeCl3 in CH3CN showing the
highest molecular-ion peak only (a simulated spectrum is below).
Figure 9. SWVs for CuCl2, FeCl3, A, and A/FeCl3. All measured at
124 mV s−1 as 1 mM MeCN solutions in 0.1 M [nBu4N][PF6], using a
glassy-carbon working electrode, a platinum gauze counter electrode,
and a silver-wire quasi-reference electrode.
c
reduction process (Ep = −0.29 V), with its lower-intensity
a
anodic wave on the return scan (Ep = −0.15 V), resembles the
SWV signal of FeCl3, albeit 166 mV more positive than that for
FeCl3 measured in isolation. The presence of even trace
amounts of CuCl2 would be immediately obvious in the SWV
because of the nanomolar detection limit inherent with that
technique.117−119 The 166 mV anodic shift of the FeCl3
reduction wave in the SWV is also accompanied by a 44−88
mV cathodic shift in the oxidation waves for A and, therefore,
lends support to the formation of a CuII/FeIII ate complex.
The EPR spectra of dinuclear CuII Pacman complexes that
are structurally similar to A have been reported previously.83
The frozen MeCN/tetrahydrofuran solution X-band EPR
spectrum of A shows a signal consistent with two weakly
Figure 8. Electronic absorption spectra for CuCl2, FeCl3, A, and A/
FeCl3 at equimolar concentration in MeCN.
120,121
1
coupled CuII (S = /2) ions (Figure S59).
The spectral
of charge-transfer and π−π* transitions, and with εmax of 30000
profile is dominated by an axial g splitting synonymous with
CuII, plus the addition of the small exchange coupling gives rise
to the weakly resolved seven-line hyperfine pattern at low field,
characteristic of coupled 63,65Cu nuclei (I = 3/2; 100%
abundant). A signature half-field signal is seen, arising from
the forbidden ΔMS = 2 transition of the spin triplet (S = 1)
formed by coupling of the two CuII ions, in agreement with the
electrochemical measurements discussed above. The X-band
EPR spectrum of FeCl3 measured under the same conditions
dm3 mol−1 cm−1 (at 240 nm), these bands would obscure the
low-intensity charge-transfer bands of CuCl2 and FeCl3 (εmax
=
2700 at 310 nm for CuCl2 and 8300 at 240 nm for FeCl3).
Nonetheless, the absorption spectrum of A/FeCl3 in MeCN is
near-identical with that of A and does not support
demetalation.
In the cyclic voltammogram (CV), A undergoes two
c
irreversible CuII/CuI reduction processes at Ep = −1.40 and
−1.71 V versus ferrocenium/ferrocene (Fc+/Fc) and two
features a broad single signal with g = 2, commensurate with an
irreversible CuIII/CuII oxidation processes at Ep = +0.36 and
S =
/ ferric species with intrinsically minute zero-field
2
a
5
+0.60 V (Figure S55). These stepwise redox processes indicate
that electronic communication between the two metal centers
occurs and is consistent with its electron paramagnetic
resonance (EPR) spectrum (see below). FeCl3 undergoes
splitting.122 Mixing equimolar amounts of A and FeCl3
produces a spectrum consistent with the sum of the two
paramagnetic components. The half-field transition is still seen
and is unperturbed by the presence of FeCl3. Furthermore,
there is no detectable indication of coupling between the CuII
and FeIII centers; the stronger coupling between the two CuII
centers masks any interaction and dominates the spectral
profile.
irreversible FeIII/FeII reduction at Ep = −0.56 V, and CuCl2
c
undergoes reversible CuIII/CuII oxidation at E1/2 = +0.11 V,
c
with the cathodic wave appearing at Ep = +0.05 V. In A/FeCl3,
c
a new, irreversible cathodic wave is seen in the CV, at Ep
=
−0.31 V, approximately midway between the cathodic waves of
CuCl2 and FeCl3 (Figure S56). The peak height of this new
wave is directly proportional to the concentration of FeCl3 and
increases steadily upon the addition of FeCl3 in portions
The X-ray absorption near-edge structure spectra at the Cu
K-edge are dominated by the effective nuclear charge at Cu and
in this case are persistently CuII. The edge position is unaffected
by the inclusion of FeCl3 and, furthermore, the potential
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changes to the coordination sphere about Cu from local square-
planar to pyramidal geometry due to the presence of Cl have no
bearing on the pre-edge profile, with no departure from
centrosymmetry. The Fourier transform of the extended X-ray
absorption fine structure (EXAFS) region of the Cu K-edge X-
ray absorption spectrum for A measured in MeCN at 95 K
(Figure 10) is well-reproduced using the crystal structure
Attempts were made to identify the product of the reactions
between either A or A/FeCl3 and TBHP. In all cases, we were
unable to isolate any pure material, with reactions often leading
to biphasic mixtures of oily residues. All crystallization attempts
were unsuccessful. In contrast, positive-ion ESI-MS of the
reaction between A and an excess of TBHP shows an ion at m/
z 873 that is consistent with the formation of an A(TBHP)
complex (Figure S48), in which we surmise that TBHP is
bound within the macrocyclic cleft. Unfortunately, no further
evidence of potentially catalytically active species, especially in
the presence of FeCl3, could be gained.
Reaction Mechanism, Initial Rates, and Simulation of
the Pathways. The nature of catalytic hydrocarbon oxygen-
ation reactions remains contentious as to whether the reaction
proceeds through a reactive metal complex or freely diffusing
radicals. A number of iron oxo complexes were once thought to
carry out HAA and oxygenation of substrates (Gif chem-
istry),123−125 but HAA was later attributed to hydroxyl radicals,
which, in turn, formed organic radicals (i.e., Fenton
chemistry).126−129 The oxygenation was shown by isotopic
labeling130,131 and argon-purge experiments100 to proceed
through an autooxidation mechanism involving O2.
The formation of highly reactive, freely diffusing hydroxyl,
tert-butoxyl, or tert-butylperoxyl radicals should lead to HAA
from substrates with high C−H BDEs, such as toluene or
cyclohexane. However, no reactions with these substrates were
observed during this work. Furthermore, the rate of the
decomposition reaction of the free tert-butoxyl radical by β-
scission is rapid (k = 2.1 × 104 s−1).132 Thus, the generation of
tert-butanol as a coproduct from the reactions studied herein
indicates that, if a tert-butoxyl radical is present, it is closely
associated with, and stabilized by, the catalyst.
Concerning the radical nature of the substrate following
HAA, the quantitative conversion of DHA is seen with high
selectivity for anthraquinone (90%) over anthracene (10%).
Similarly, the reaction of 9,10-dihydrophenanthrene produces
phenanthraquinone in 80% yield. In a reaction mechanism that
involves freely diffusing benzylic radicals, anthracene or
phenanthrene would be expected as the sole products.
Reactions catalyzed by A at 80 °C, or by A/FeCl3 at room
temperature, are unaffected by the presence of O2, with
identical yields of oxygenated xanthene products seen from
reactions carried out under air or dinitrogen (N2). In contrast
to previous studies, no homocoupled 9,9′-bixanthene product is
seen, even when the reaction is carried out under N2.100 This
provides further evidence that freely diffusing organic radicals
are not present and also indicates that the hydroperoxide is
responsible for oxygenation of the substrate, rather than O2
through an autocatalysis radical mechanism.
Assertions in the literature claim that high selectivity for
peroxy ether and ketone products is a signature for a free-
radical mechanism.133 While we have observed high selectivities
for these products in our work, our other observations show
that the HAA and oxygenation steps do not result from free
radicals. As such, the mechanistic probe 2-methyl-1-phenyl-
propan-2-yl hydroperoxide (MPPH) was used134 because, in
this case, the alkoxyl free radical formed following homolytic
O−O bond fission in MPPH is unstable and undergoes very
rapid β-scission, forming acetone and benzyl radical (k ∼ 2.2 ×
108 s−1). In the case of a free-radical mechanism, the only
products from a reaction involving xanthene and MPPH should
therefore be acetone and those derived from benzyl free
radicals. The room temperature reaction between xanthene and
Figure 10. EXAFS for complex A (top) and a 1:1 mixture of A and
FeCl3 (bottom) following Fourier transform. Measured as MeCN
solutions at 95 K. Experimental data are black; simulations are red.
The asterisk marks the new peak observed following the addition of
FeCl3.
metrics (Table S5). Crystallographic Cu−N distances in the
first coordination sphere are 1.903(2) and 1.919(3) Å for
pyrrolide donors and 1.987(2) and 2.073(3) Å for imine
donors and compare well with the fitted EXAFS-predicted Cu−
N distances of 1.926, 2.016, and 2.066 Å, respectively. The
Cu···Cu separation of 3.95 Å in the EXAFS is slightly longer
than that determined crystallographically [3.6157(6) Å] but in
close agreement with the distance previously determined by
EPR in a frozen solution (3.8 Å).83 Cu K-edge EXAFS recorded
after the addition of FeCl3 to A (Figure 10) further shows that
the Cu ion remains complexed by the macrocycle. A prominent
scattering peak evident in the Fourier transform was modeled
−
by including a single Cl atom from FeCl3/FeCl4 . The best fit
places this Cl atom 3.524 Å away from the Cu ion (Table S6).
As such, the EPR and EXAFS data indicate that A and FeCl3/
FeCl4− form a weakly associated adduct in solution rather than
a formal ate complex (Figure 1). The formation of such a
heterometallic adduct, resulting in improved catalytic activity, is
likely directed by the macrocyclic setting.
H
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a
Scheme 4. Reaction of Xanthene with 1 equiv of MPPH
a
Selectivities (%) for xanthene oxidation products are with respect to xanthene. Selectivities (%) for MPPOL and benzyl-radical-derived products are
with respect to MPPH.
1 equiv of MPPH catalyzed by 0.1 mol % A/FeCl3 (Scheme 4)
results in 90% conversion of xanthene, while that with 2 equiv
of MPPH results in quantitative conversion. In line with the
TBHP reactions above, the stoichiometry of MPPH influences
the product distribution; the use of 1 equiv of MPPH gives
ROH (30%), peroxy ether (37%), and RO (33%), whereas 2
equiv of MPPH gives ROH (6%), peroxy ether (52%), and RO
(42%).
Significantly, a resonance for the benzylic proton of 2-
methyl-1-phenylpropan-2-ol (MPPOL) is seen at 2.72 ppm in
1
the H NMR spectrum, in a ratio of 4:5 with MPPH. The
presence of significant amounts of MPPOL supports a metal-
associated mechanism because coordination of the alkoxide or
alkoxyl radical to a metal center stabilizes the radical against β-
scission. Furthermore, the presence of unreacted MPPH
indicates that a metal hydroxide is also responsible for HAA,
in order to account for the 90% conversion of the xanthene
substrate. However, analysis of the reaction mixtures involving
MPPH by GC/MS reveals that the benzyl-radical-derived
products benzaldehyde, benzyl alcohol, and bibenzyl are also
formed, albeit in low concentration (approximately 15%
compared with that of MPPH). Overall, a predominantly
metal-associated mechanism best fits with the observations
above.
Figure 11. Monitoring the oxygenation of xanthene-d2 by 4 equiv of
TBHP, catalyzed by 0.1 mol % A and 0.1 mol % FeCl3 at 300 K in
MeCN-d3 (concentrations determined by 1H NMR integration).
Interpolation between the datapoints is provided solely as an aid to the
eye.
It is therefore apparent that the oxygenation reactions
catalyzed by A/FeCl3 feature elements of both free-radical and
radical-free mechanisms.48,54,135 We therefore suggest that the
the benzylic reaction center, and is consistent with both radical
reaction mechanism in this work involves “well-disguised”,
and radical-free mechanisms.137,138
metal-associated radical species,8−10,133 in which the organic
radical of the substrate that is formed following HAA is
associated with the intermediate as a “cage radical”.136
In order to further explore the system, the reactant
concentrations were varied from the standard conditions.
However, this rapidly led to major deviations from what had
appeared as approximately first-order kinetics; indeed, no
simple correlations were evident. The initial rates were thus
analyzed as a function of all components (xanthene, TBHP, A,
and FeCl3), which were independently varied. The initial rate
was found to have a linear dependence on the initial
concentrations of xanthene (albeit with a small nonzero
intercept), the Cu catalyst (A), and FeCl3, suggesting first-
order kinetics with respect to each component (Figures S98,
S100, and S101). Importantly, the initial rates become
independent of the Cu catalyst (A) and FeCl3 when the
concentration of one precatalyst becomes superstoichiometric
over the other. In other words, A and FeCl3 appear to operate
cooperatively (1:1 ratio). The initial rate as a function of the
TBHP concentration was approximately first-order at low
concentrations, becoming independent above approximately
200 mM, indicative of saturation in this reagent (Figure S99).
The temporal evolution of the xanthene oxygenation
reaction, from a series of around 40 experiments in which the
initial concentrations of the reactants were varied, was
qualitatively analyzed to identify trends and relationships
between the components. Three important features arose
from these studies:
To further elucidate the reaction pathways for the overall
oxidation process, the reaction kinetics were explored in situ by
1H NMR spectroscopy. Under the standard reaction conditions
employed earlier (0.15 M xanthene, 0.30 M TBHP, 0.1 mol %
A, and 0.1 mol % FeCl3), xanthene consumption approximately
fitted to a first-order integrated rate law, albeit coincidently (see
below). Deuteration of xanthene at the benzylic 9 position
slows the rate of xanthene consumption marginally (Figures 11
and S95), indicative of a small primary kinetic isotope effect
(KIE; νH/νD = 1.5). Deuteration has a pronounced impact on
the product distribution, with a substantial KIE estimated for
the conversion of xanthene into xanthydrol/ketone (νH/νD ≈
6). Deuteration at the 9 position of xanthene therefore has a
more pronounced effect on the second oxidation step(s). The
2
oxygenation reaction of xanthene-d2 was also monitored by H
NMR spectroscopy (Figure S96), which confirms that tBuOD
forms as a coproduct. No D2O/HDO was detected.
The influence of the electronic properties of the substrate on
the rate of the reaction was briefly investigated using a series of
xanthene substrates substituted at the 2 position (Figure S97).
The reaction constant, ρ, is small but positive (1.2
0.2),
implying only marginal accumulation of the electron density at
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(i) The concentration of ROOtBu reaches a maximum value
at the point that the xanthene substrate is entirely consumed.
After this, it is converted to a ketone (RO), indicative of the
competition between xanthene and ROOtBu for the catalyst, or
a reactive intermediate.
(ii) ROH and ROOtBu form at identical rates when the
initial concentrations of xanthene and TBHP are equimolar.
Increasing the ratio of [TBHP]/[xanthene] results in ROOtBu
being formed at a faster rate than ROH, indicating that
ROOtBu and ROH arise from separate pathways or
intermediates.
(iii) In cases where there is sufficient oxidant for the
conversion of ROH/ROOtBu to ketone (RO), the concen-
tration of the alcohol (ROH) reaches a maximum shortly after
the point where [xanthene] = [ROOtBu]. This final aspect was
explored in a more quantitative way, by coplotting temporal
concentrations of xanthene, ROH, and ROOtBu (Figures
S102−S107 and Table S6).
The three features outlined above were then employed as the
starting point for a series of models for reaction pathways that
might account for the overall transformations. Extensive kinetic
simulations were conducted to explore a very diverse series of
models of increasing complexity. The failure of any of these
models to provide a satisfactory global fit to the entire data set
(40 experiments) is indicative of the complex and interlinked
nature of the reaction pathways. Nonetheless, the most effective
model tested (outlined schematically in Scheme 5 and full
Scheme 5. Schematic Representation of the Reaction
Network Employed To Explore the Kinetics of Oxidation of
a
Xanthene, Catalyzed by a Mixture of Complex A and FeCl3
Figure 12. Simulation of the xanthene oxygenation reaction, catalyzed
by A/FeCl3, using the generalized reaction pathway presented in
Scheme 5 (full details in Scheme S1). Top: [xanthene]0 = 150 mM,
[TBHP]0 = 300 mM, [A]0 = 150 μM, and [FeCl3]0 = 150 μM.
Bottom: [xanthene]0 = 75 mM, [TBHP]0 = 300 mM, [A]0 = 150 μM,
and [FeCl3]0 = 150 μM. Simulated data plotted as solid curves;
experimental data plotted as dots.
a
deactivation, the addition of FeCl3 improves the catalyst
stability and efficacy, resulting in much higher TONs and
allowing the reaction to proceed at room temperature. A
combined spectroscopic and voltammetric study indicates that
the catalyst is likely a weakly associated adduct, with an FeCl3
Each step in the network involves the exogenous oxidant TBHP. The
primary catalyst initially generated from A + FeCl3 is represented as
cat A; a secondary, higher-oxidation-state species, generated by
branching from the primary catalytic cycle, is represented as cat B. Not
shown in the network is an irreversible oxidative degradation of the
primary catalyst and its reversible inhibition by xanthone complexation
(see the SI for full details).
−
or FeCl4 moiety bound within the macrocyclic cleft. It is the
macrocyclic ligand that encourages cooperative action between
CuII and FeIII in the oxygenation reaction, which is a novel
strategy in oxidation catalysis.
details provided in the Supporting Information, SI) is able to
provide a qualitative tool for the prediction of temporal product
distributions as a function of all initial concentrations.
Consistent with the complexity of the system and the
qualitative nature of the model, some initial sets of conditions
give better fits than others; two examples are given in Figure 12.
The catalytic reaction involving A/FeCl3 is limited to π-
activated benzylic substrates, achieving oxygenation in high
conversion for those with low-to-moderate C−H BDEs. The
observation of oxygenated products indicates that a nonradical
mechanism is operative, which is reinforced by N2-purge
experiments and the use of a MPPH mechanistic probe.
However, the high selectivity for ketone, small KIE, and
Hammett analysis indicate that the mechanism features radical
elements, and the mechanism is therefore thought to be driven
by metal-associated radicals.
CONCLUSIONS
■
The dinuclear CuII complexes A−C catalyze the oxygenation of
hydrocarbon substrates using hydroperoxide oxidants at
elevated temperature. While these complexes undergo rapid
J
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Article
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possible, albeit complex reaction network (Scheme 5) has been
deduced through the analysis of qualitative trends and kinetic
modeling. This is presented in its current form to illustrate the
complexity of the kinetics of the reaction catalyzed by A/FeCl3
and as a basis for more detailed mechanistic work in the future.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.8b00420.
(9) Groves, J. T. Enzymatic C-H bond activation: Using push to get
pull. Nat. Chem. 2014, 6, 89.
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Capture, Characterization, and C-H Bond Activation Kinetics. Science
2010, 330, 933.
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Syntheses and Reactivity of Cu2O2 Active-Site Models. Acc. Chem. Res.
2015, 48, 2424.
Full experimental details, catalysis procedures, substrate
screening data, MS spectra, UV/vis data, cyclic
voltammetry, EPR data, EXAFS analysis, and full kinetic
data (PDF)
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states of the active site and their relevance to enzymatic activation,
oxidation and inactivation. Bioorg. Med. Chem. 2014, 22, 2388.
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to methanol. Nature 2015, 518, 431.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: jason.love@ed.ac.uk (J.B.L.).
*E-mail: guy.lloyd-jones@ed.ac.uk (G.C.L.J.).
*E-mail: stephen.sproules@glasgow.ac.uk (S.S.).
(14) Culpepper, M. A.; Cutsail, G. E.; Hoffman, B. M.; Rosenzweig,
A. C. Evidence for Oxygen Binding at the Active Site of Particulate
Methane Monooxygenase. J. Am. Chem. Soc. 2012, 134, 7640.
(15) Rosenzweig, A. C. Biochemistry: Breaking methane. Nature
2015, 518, 309.
ORCID
Stephen Sproules: 0000-0003-3587-0375
Guy C. Lloyd-Jones: 0000-0003-2128-6864
Jason B. Love: 0000-0002-2956-258X
(16) Ervin, K. M.; DeTuri, V. F. Anchoring the Gas-Phase Acidity
Scale. J. Phys. Chem. A 2002, 106, 9947.
Author Contributions
The manuscript was written through contributions of all
authors.
(17) Que, L.; Tolman, W. B. Biologically inspired oxidation catalysis.
Nature 2008, 455, 333.
(18) Que, J. L.; Tolman, W. B. Bis(μ-oxo)dimetal “Diamond” Cores
in Copper and Iron Complexes Relevant to Biocatalysis. Angew. Chem.,
Int. Ed. 2002, 41, 1114.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(19) Holland, P. L.; Cramer, C. J.; Wilkinson, E. C.; Mahapatra, S.;
Rodgers, K. R.; Itoh, S.; Taki, M.; Fukuzumi, S.; Que, L.; Tolman, W.
B. Resonance Raman Spectroscopy as a Probe of the Bis(μ-
oxo)dicopper Core. J. Am. Chem. Soc. 2000, 122, 792.
(20) Shimizu, K.; Maruyama, R.; Hatamachi, T.; Kodama, T. O2-
Bridged Multicopper(II) Complex in Zeolite for Catalytic Direct
Photo-oxidation of Benzene to Diphenols. J. Phys. Chem. C 2007, 111,
6440.
(21) Garcia-Bosch, I.; Cowley, R. E.; Diaz, D. E.; Siegler, M. A.; Nam,
W.; Solomon, E. I.; Karlin, K. D. Dioxygen Activation by a Macrocyclic
Copper Complex Leads to a Cu2O2 Core with Unexpected Structure
and Reactivity. Chem. - Eur. J. 2016, 22, 5133.
(22) Rosenthal, J.; Luckett, T. D.; Hodgkiss, J. M.; Nocera, D. G.
Photocatalytic Oxidation of Hydrocarbons by a Bis-iron(III)-μ-oxo
Pacman Porphyrin Using O2 and Visible Light. J. Am. Chem. Soc. 2006,
128, 6546.
(23) Groves, J. T.; Nemo, T. E. Epoxidation reactions catalyzed by
iron porphyrins. Oxygen transfer from iodosylbenzene. J. Am. Chem.
Soc. 1983, 105, 5786.
■
We thank the University of Edinburgh for the award of a
Principal’s Career Development Scholarship (Ph.D. studentship
to J.R.P.) and the EPSRC CRITICAT Centre for Doctoral
Training (Ph.D. studentship to M.C.; Grant EP/L016419/1)
for financial support. The research leading to these results has
received funding from the European Research Council under
the European Union’s Seventh Framework Programme (FP7/
2007−2013)/ERC Grant 340163. We thank the Diamond
Light Source for the data collected on beamline B18 (Rapid
Access Proposal Number SP15756). We also thank Dr. Lorna
Murray for NMR support and Dr. Logan Mackay for mass
spectrometry support.
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