Tuning the Circumference of Six-Porphyrin Nanorings

Article abstract of DOI:10.1021/jacs.9b02965

Most macrocycles are made from a simple repeat unit, resulting in high symmetry. Breaking this symmetry allows fine-tuning of the circumference, providing better control of the host-guest behavior and electronic structure. Here, we present the template-di

Full text of DOI:10.1021/jacs.9b02965

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Article
Tuning the Circumference of Six-Porphyrin Nanorings
Renee Haver, Lara Tejerina, Hua-Wei Jiang, Michel Rickhaus, Michael Jirasek,
Isabell Gruebner, Hannah J. Eggimann, Laura M. Herz, and Harry L. Anderson
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 24 Apr 2019
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Tuning the Circumference of Six-Porphyrin Nanorings
Renée Haver,†# Lara Tejerina,†# Hua-Wei Jiang,†# Michel Rickhaus,†# Michael Jirasek,# Isabell Grüb-
ner,# Hannah J. Eggimann,§ Laura M. Herz,§ and Harry L. Anderson*#
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†These authors contributed equally.
#Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Oxford OX1 3TA, United Kingdom
§Department of Physics, University of Oxford, Clarendon Laboratory, Parks Road, Oxford OX1 3PU, United Kingdom
ABSTRACT: Most macrocycles are made from a simple repeat unit, resulting in high symmetry. Breaking this symmetry allows
fine tuning of the circumference, providing better control of the host-guest behavior and electronic structure. Here we present the
template-directed synthesis of two unsymmetrical cyclic porphyrin hexamers with both ethyne (C2) and butadiyne (C4) links, and
we compare these nanorings with the symmetrical analogues with six ethyne or six butadiyne links. Inserting two extra carbon at-
oms into the smaller nanoring causes a spectacular change in binding behavior: the template-affinity increases by a factor of 3 ×
109, to a value of ca. 1038 M–1 and the mean effective molarity is ca. 830 M. In contrast, removing two carbon atoms from the larg-
est nanoring results in almost no change in its template-affinity. The strain in these nanorings is 90–130 kJ mol–1, as estimated both
from DFT calculation of homodesmotic reactions and from comparing template-affinities of linear and cyclic oligomers. Breaking
the symmetry has little effect on the absorption and fluorescence behavior of the nanorings: the low radiative rates that are charac-
teristic of a circular delocalized S1 excited state are preserved in the low-symmetry macrocycles.
Introduction
Symmetry confers beauty and simplicity. Most large syn-
thetic macrocycles are constructed from a repeating monomer
unit, resulting in a highly symmetric structure (Cn or Dnh),
which expedites their synthesis and spectroscopic characteri-
zation, for example, it gives simple NMR spectra.1 Converse-
ly, a less symmetrical design brings structural versatility: it
allows the diameter of the macrocycle to be adjusted in small-
er increments, to optimize binding to a specific guest. In π-
conjugated macrocycles, if the singlet electronic excited state
is delocalized over the whole ring, high symmetry makes the
S0-S1 transition forbidden; thus reducing the symmetry is ex-
pected to increase the radiative rate and increase the fluores-
cence quantum yield.2,3 Previously, we reported the template-
directed synthesis of two 6-fold symmetric cyclic porphyrin
hexamers, c-P6[b6] and c-P6[e6], linked via butadiyne (C4)
and ethyne (C2) bridges, using templates T6 and T6*, respec-
tively (Figure 1).4-6 Here we show that low-symmetry (C2v)
versions of these macrocycles, c-P6[b5e] and c-P6[be5] can be
synthesized using the same T6 and T6* templates. We demon-
strate that the ability to adjust the circumference, by adding or
removing two carbon atoms, has a dramatic effect on the bind-
ing behavior of these nanorings. In contrast, the changes in
Figure 1. Molecular structures, schematic representation and
labels of the porphyrin nanorings used throughout this study. The
label in [brackets] indicates the number of butadiyne [bx] or eth-
symmetry are too subtle to have a strong effect on the radia-
tive rates of the singlet excited states, and the photophysical
behavior of the parent structures are preserved.
ylene [ey] linkages present in the nanoring. Ar
bis(trihexylsilyl)phenyl.
=
3,5-
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tection of the hexamer followed by palladium-catalyzed oxida-
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Results and Discussion
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tive coupling in the presence of T6 template gave the target
porphyrin nanoring c-P6[b5e]·T6 in 37% yield.
Molecular Modeling. Density functional theory (DFT;
B3LYP, 6-31G* basis set, in vacuum) was used to calculate
optimized geometries of the free nanorings and their template
complexes, to estimate the level of strain and to predict which
templates would be effective for nanoring synthesis.7 The
strain in each nanoring (ΔHstrain) was estimated by calculating
the free energy change for a homodesmotic reaction:8 cyclic
hexamer + linear dimer → linear octamer. The results (Table
1) show a gradual reduction in strain with ring expansion.
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The complementarity of the templates was estimated from
the average distances of the six zinc atoms from the centroid
(RZn) for the template-free nanorings (Table 1). The ideal tem-
plate radius (RN,ideal) for each nanoring was calculated by sub-
tracting the crystallographic out-of-plane distance of the zinc
atom (0.37 Å) and the Zn-N(pyridine) bond length (2.15 Å)
from RZn.5 The calculated radii of T6 and T6* (RN) are 10.03
and 8.30 Å, respectively, allowing us to calculate the misfit
(RN – RN,ideal) as listed in Table 1. These data lead to the sur-
prising conclusion that, if we ignore the angular deviation
from D6h symmetry in the low-symmetry nanorings, then T6*
and T6 are expected to fit the unsymmetrical rings better than
the symmetrical rings for which they were originally de-
signed.4,6 T6 is slightly too small for c-P6[b6] and slightly too
big for c-P6[b5e], while T6* is slightly too big for c-P6[be5]
and substantially too big for c-P6[e6].
Table 1. Calculated Strains and Geometries from DFT.a
ΔHstrain
RZn
(Å)
RN,ideal
(Å)
RN – RN,ideal
molecule
c-P6[e6]
(kJ mol–1)
(Å)
131
115
105
100
10.33
10.72
12.38
12.82
7.81
8.20
0.49 (T6*)
0.10 (T6*)
0.17 (T6)
–0.27 (T6)
c-P6[be5]
c-P6[b5e]
c-P6[b6]
9.86
Figure 2. DFT calculated geometries of (a) c-P6[b5e]·T6, (b) c-
P6[b6]·T6, (c) c-P6[be5]·T6*, and (d) c-P6[e6]·T6* (two orthog-
onal views of each complex; B3LYP/6-31G*, aryl groups re-
placed by H to facilitate geometry optimization).
10.30
a
B3LYP/6-31G*; aryl groups replaced by H to facilitate calcula-
tions.
The smaller unsymmetrical nanoring c-P6[be5]·T6* was
synthesized in 25% yield, by palladium-catalyzed oxidative
coupling of the linear C2-linked hexamer HC2-l-P6[e5]-C2H
in the presence of the T6* template. This linear hexamer was
prepared from a known bromo-porphyrin hexamer6 by So-
nogashira coupling as shown in Scheme 1. The unsymmetrical
nanoring c-P6[be5] is easier to synthesize than c-P6[e6], both
because oxidative Glaser coupling is a more efficient reaction
than Sonogashira coupling, for the final cyclization step, and
because the T6* template matches the cavity of c-P6[be5]
better than that of c-P6[e6] (Table 1).
The DFT optimized geometries of the nanoring-template
complexes (Figure 2) show that when the template is too large
for the cavity, it adopts a domed conformation, rising above
the plane of the nanoring, as seen clearly in c-P6[e6]·T6* and
to a more subtle extent in c-P6[b5e]·T6.
Synthesis. The unsymmetrical nanorings were prepared
from linear porphyrin hexamers, as summarized in Scheme 1.
The key intermediate in the synthesis of c-P6[b5e] is the C2-
linked porphyrin dimer TMS-l-P2[e]-CPDMS, which was
prepared by Sonogashira coupling of monomers Br-P1-TMS
and HC2-P1-CPDMS. This combination of silicon protecting
groups with different polarities9 was used to enable the C2-
linked dimer to be separated from any C4-linked dimer by-
product, CPDMS-l-P2[b]-CPDMS, produced by oxidative
Glaser coupling of HC2-P1-CPDMS. Traces of the butadiyne-
linked byproduct must be removed, otherwise they lead to
contamination of c-P6[b5e] with symmetric c-P6[b6], which is
inseparable. Complete deprotection of TMS-l-P2[e]-CPDMS
followed by palladium-catalyzed oxidative coupling with ex-
cess HC2-P1-CPDMS yielded porphyrin tetramer CPDMS-l-
P4[b2e]-CPDMS in 50% yield. This deprotection/coupling
sequence was repeated to give porphyrin hexamer CPDMS-l-
P6[b4e]-CPDMS in good yield (68% over two steps). Depro-
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Scheme 1. Synthesis of c-P6[b5e]·T6 and c-P6[be5]·T6*
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Ar
Zn
Ar
Ar
Zn
Ar
Ar
Zn
Ar
Ar
Zn
Ar
Ar
Ar
N
N
N
Zn
N
(i)
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Zn
Ar
N
N
Br
TMS
H
CPDMS
TMS
CPDMS
N
+
Ar
N
N
(ii)
N
N
N
Br-P1-TMS
HC2-P1-CPDMS
TMS-l-P2[e]-CPDMS
Ar
Ar
N
N
Zn
N
Zn
N
N
Ar
Ar
N
N
8
9
Ar
Ar
Ar
Zn
Ar
Ar
Zn
Ar
Ar
Zn
Ar
Ar
(vii)
Ar
N
N
N
N
N
N
N
N
(iii)
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Ar
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N
N
H
Zn
Ar
Zn
Ar
H
R
Zn
Ar
R
N
N
N
N
N
N
N
N
Zn
Zn
N
N
Ar
n
n
Ar
c-P[b5e]·T6
CPDMS-l-P4[b2e]-CPDMS (R = CPDMS, n = 1)
HC2-l-P4[b2e]-C2H (R = H, n = 1)
HC2-l-P2[e]-C2H
(iv)
(v)
Ar
Ar
N
N
CPDMS-l-P6[b4e]-CPDMS (R = CPDMS, n = 2)
HC2-l-P6[b4e]-C2H (R = H, n = 2)
N
N
N
Zn
Zn
Ar
N
(vi)
N
N
Ar
N
N
N
N
Ar
N
N
N
Ar
Ar
Ar
Ar
Zn
N
N
N
Ar
Zn
N
Ar
N
(viii)
(ix)
(x)
N
N
N
N
N
N
N
N
N
N
N
Br
Zn
Ar
CPDIPS
CPDIPS
Zn
Ar
CPDIPS
H
Zn
Ar
H
N
Ar
N
N
Ar
6
N
6
6
N
Zn
Zn
N
N
N
N
N
N
Ar
Br-l-P6[e5]-CPDIPS
CPDIPS-l-P6[e5]-CPDIPS
HC2-l-P6[e5]-C2H (R = H)
Ar
c-P[be5]·T6*
Reaction conditions: (i) Pd2(dba)3, AsPh3, 64%. (ii) TBAF, 94%. (iii) HC2-P1-CPDMS, Pd(PPh3)2Cl2, CuI, 1,4-benzoquinone, 50%. (iv)
TBAF, 100%. (v) HC2-P1-CPDMS, Pd(PPh3)2Cl2, CuI, 1,4-benzoquinone, 68%. (vi) TBAF, 100%. (vii) T6, Pd(PPh3)2Cl2, CuI, 1,4-
benzoquinone, 37%. (viii) CPDIPS-acetylene, Pd(PPh3)2Cl2, CuI, 95%. (ix) TBAF, 96%. (x) T6*, Pd(PPh3)2Cl2, CuI, 1,4-benzoquinone,
25%. Ar = 3,5-bis(trihexylsilyl)phenyl. TMS = SiMe3. CPDMS = SiMe2(CH2)3CN. CPDIPS = Si(i-Pr)2(CH2)3CN. The syntheses of the
starting materials are detailed in the SI.
Table 2. Thermodynamic Parameters from UV-vis-NIR Titrations
ΔGf (kJ mol–1)
–90 ± 2
ΔGstrain (kJ mol–1)
ligand
porphyrin hexamer
HC2-l-P6[e5]-C2H
HC2-l-P6[b4e]-C2H
HC2-l-P6[b5]-C2H
c-P6[e6]
log Kf
log ꢀꢁ
–1.6 ± 0.1
–1.7 ± 0.1
–1.5 ± 0.1
1.0 ± 0.1
2.9 ± 0.1
1.4 ± 0.1
1.7 ± 0.1
T6*
T6
15.8 ± 0.3
19.9 ± 0.3
20.8 ± 0.3
29.0 ± 0.3
38.5 ± 0.3
35.6 ± 0.3
37.0 ± 0.3
—
–113 ± 2
–119 ± 2
–166 ± 2
–220 ± 2
–203 ± 2
–211 ± 2
—
T6
—
T6*
T6*
T6
76 ± 3 (cf. HC2-l-P6[e5]-C2H)a
130 ± 3 (cf. HC2-l-P6[e5]-C2H)
90 ± 3 (cf. HC2-l-P6[b4e]-C2H)
92 ± 3 (cf. HC2-l-P6[b5]-C2H)
c-P6[be5]
c-P6[b5e]
c-P6[b6]
T6
a The poor complementary between c-P6[e6] and T6* mean that this value does not accurately reflect the strain in c-P6[e6].
1
NMR Spectroscopy. The H NMR spectra of the four na-
noring-template complexes are compared in Figure 3. Reso-
nances from β-pyrrole protons nearest to an ethyne bridge are
easy to identify by virtue of their high chemical shifts (ca. 10
ppm).10 The spectra were fully assigned using 2D NMR tech-
niques (as detailed in the SI). The complexes c-P6[b6]·T6 and
c-P6[e6]·T6* have D6h symmetry on the NMR timescale, as
reported previously,4-6 whereas c-P6[b5e]·T6 and c-
P6[be5]·T6* have effective C2v symmetry, resulting in split-
ting of the porphyrin and template resonances, as expected.
The shielding of the α- and β-pyridine template protons is
substantially greater in c-P6[be5]·T6* than in c-P6[e6]·T6*,
which probably reflects the tighter N-Zn interaction and less
distorted geometry of c-P6[be5]·T6* (Figure 2c,d).
Stabilities of Template Complexes: UV-vis-NIR and
NMR Titrations. The stabilities of the nanoring-template
complexes c-P6[b6]·T6, c-P6[b5e]·T6, c-P6[be5]·T6* and c-
P6[e6]·T6* were determined by UV-vis-NIR titration, in tolu-
ene at 298 K, and compared with the corresponding complexes
of linear porphyrin hexamers HC2-l-P6[b5]-C2H·T6, HC2-l-
P6[b4e]-C2H·T6 and HC2-l-P6[e5]-C2H·T6*. All the for-
mation constants, Kf, are too high to be determined by direct
titration, so they were measured by denaturation titrations,
using a monovalent ligand to displace the template (pyridine
or N-methylimidazole; for details, see SI).4,11 Some examples
of denaturation titration curves are plotted in Figure 4, show-
ing that the stabilities of the nanoring complexes increase in
the order c-P6[e6]·T6* < c-P6[b5e]·T6 < c-P6[b6]·T6 <
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Figure 3. Partial 1H NMR spectra of c-P6[b6]·T6, c-P6[b5e]·T6, c-P6[be5]·T6*, and c-P6[e6]·T6* (700 MHz, CDCl3, 298 K).
c-P6[be5]·T6*. Nonlinear curve fitting of the titration data
gave the values of logKf listed in Table 2 (see SI for details).
The nanorings all bind the templates much more strongly than
the corresponding linear hexamers. Inserting two carbon atoms
into c-P6[e6] to give c-P6[be5] results in a colossal increase in
affinity for T6*; logKf increases from 29.0 to 38.5.
The level of chelate cooperativity12,13 in the porphyrin hex-
amer template complexes was evaluated by calculating the
effective molarities, ꢀꢁ, by comparing the stability of each
complex with that of a single-site reference interaction, using
equation (1):
!
!
!"#$
!
!
!
ꢀꢁ =
(1)
where ꢀꢁ is the geometric mean of the effective molarities for
five intramolecular interactions, Kchem is the statistically cor-
rected formation constant of the hexamer-template complex
(Kchem = Kf/768) and K1 is the statistically corrected binding
constant of a monovalent reference ligand for a zinc porphyrin
monomer. We use 4-phenylpyridine (K1 = 1.7 × 104 M–1) as a
reference for T6 and 4-phenylethynylpyridine (K1 = 3.2 × 103
M–1) as a reference for T6*. The values of logꢀꢁ listed in
Table 2 highlight the exceptionally high chelate cooperativity
of the c-P6[be5]·T6* complex; logꢀꢁ = 2.9 ± 0.1; ꢀꢁ = 830
± 190 M. This is among the highest effective molarities found
for any non-covalent supramolecular complex.13-15
Figure 4. Denaturation curves for titration of c-P6[b6]·T6, c-
P6[b5e]·T6, c-P6[be5]·T6*, and c-P6[e6]·T6* with N-methyl
imidazole. θ is the mole-fraction of nanoring bound to the tem-
plate, estimated as θ = (A – Af)/(Ai – Af), where A, Ai and Af are
absorption, initial absorption and final absorption, respectively.
Titrations were carried out in toluene at 298 K with a nanoring
concentration of ca. 1 µM.
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ratio reflects the position of thermodynamic equilibrium. At
1
2
equilibrium, the [c-P6[b6]·T6]/[c-P6[b5e]·T6] ratio is 1.23 ±
0.10, giving KC = 1.5 ± 0.2 (in CDCl3 at 298 K).
3
4
5
6
7
8
9
The strain energy in a porphyrin nanoring (ΔGstrain) can be
estimated from the difference in binding energy of the tem-
plate with the corresponding cyclic and linear oligomers, as
expressed by equations (3).4,16
Figure 5. The position of this equilibrium was probed by 1H
NMR spectroscopy to measure the relative affinities of c-P6[b6]
and c-P6[b5e] for T6.
The difference in formation constant between c-P6[b6]·T6
and c-P6[b5e]·T6 is surprisingly subtle. Presumably the weak-
er binding of c-P6[b5e] reflect its lack of D6h symmetry, be-
cause, according to our DFT calculations, its size-
complementarity is better than that of c-P6[b6] (Table 1). We
ΔGstrain = ΔGf (l-P6·template) – ΔGf (c-P6·template) (3)
The values of ΔGstrain calculated in this way for c-P6[be5], c-
P6[b5e] and c-P6[b6] (Table 2) are similar to the strain en-
thalpies from DFT (ΔHstrain, Table 1), indicating that the main
cause for the weaker binding of the linear oligomers is the
enthalpy cost of bending the linear oligomer into a cyclic con-
formation. This analysis assumes that there is no significant
change in conformation, or increase in strain, when the na-
noring binds the template, and that the strain in the bound lin-
ear oligomer is essentially the same as the strain in the na-
noring. Equation (3) does not provide a good estimate of the
strain if the template and/or nanoring undergo deformation on
complexation, as is the case when c-P6[e6] binds T6*; here the
low value of ΔGstrain reflects the poor shape complementarity
between the nanoring and the template.
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1
carried out a H NMR experiment to check the relative affini-
ties of c-P6[b6] and c-P6[b5e] for T6 in CDCl3. The competi-
tion equilibrium constant KC is defined as shown in Figure 5
and equation (2). The data from UV-vis-NIR denaturation
titrations (Table 2) indicate that logKC = 1.4 ± 0.4, in toluene
at 298 K.
c
-
-
-
P6[b e] c P6[b ]·T6
5 6
!
-
(c P6[b ]·T6)
6
!
ꢀ! =
=
! -
(c P6[b e]·T6)
5
!
(2)
c
P6[b e]·T6
c
-
P6[b ]
5
6
A 1:1 mixture of c-P6[b6]·T6 and c-P6[b5e] was dissolved
in CDCl3 and N-methylimidazole was added to catalyze ex-
change of the template between the two nanorings. After equi-
librium had been established, the ratio of c-P6[b6]·T6 to c-
P6[b5e]·T6 was estimated by integration of the 1H NMR spec-
trum (see SI for details). Within experimental error, the same
mole ratio of complexes was formed by starting from a 1:1
mixture of c-P6[b6] and c-P6[b5e]·T6, confirming that this
Figure 6. Absorption (black lines) and fluorescence (dashed lines) spectra at 298 K of (left) c-P6[b6], c-P6[b5e], c-P6[be5], c-P6[e6] in
toluene containing 1% pyridine and (right) c-P6[b6]·T6, c-P6[b5e]·T6, c-P6[be5]·T6*, c-P6[e6]·T6* in toluene. Fluorescence quantum
yields (Φf) are given in %. The dip in the fluorescence spectra at around 1140 nm is due to absorption by the solvent.
5
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Journal of the American Chemical Society
binding constants can be tremendously sensitive to a geomet-
Page 6 of 7
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rical mismatch, particularly if the template is too big for the
cavity, as in c-P6[e6]·T6*. Even though T6* does not fit well
in the cavity of c-P6[e6], it is still an effective template for
directing the formation of this nanoring, probably because a
template needs to be complementary to the transition state for
cyclization, rather than complementary to the product.7 This
study also illustrates a new approach to estimating the strain in
macrocyclic receptors, by comparing their guest-affinities with
those of acyclic analogues. Strain free energies determined by
this method (ΔGstrain, Table 2) agree remarkably well with
strain enthalpies from DFT calculation of homodesmotic reac-
tions (ΔHstrain, Table 1), in every case except that of the c-
P6[e6]·T6* complex where there is poor shape complementa-
rity. This shows that the main barrier for bending a linear oli-
gomer into a circular conformation is enthalpic rather than
entropic.
Table 3. Fluorescence lifetimes, quantum yields and radia-
tive rates.a
compound
c-P6[e6]
krad (µs–1)
2.6
τf (ns)
0.49
0.28
0.44
0.51
0.22
0.32
0.34
1.43
Φf
0.0013
0.0026
0.010
0.018
0.0014
0.0039
0.0038
0.28
c-P6[be5]
9.4
c-P6[b5e]
23
c-P6[b6]
35
9
c-P6[be5]·T6*
c-P6[b5e]·T6
c-P6[b6]·T6
THS-l-P6[b5]-THS
6.3
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400
a All measurements were carried out in toluene (containing 1% by
volume of pyridine for the template-free nanorings to suppress
aggregation). Fluorescence lifetimes were measured using excita-
tion at 810 nm and detection at 1050 nm. Fluorescence quantum
yields were measured using THS-l-P6[b5]-THS as a standard.17
Radiative rates are calculated as krad = Φf/τf.
ASSOCIATED CONTENT
Supporting Information. Synthetic procedures and characteriza-
tion data; assignment of NMR spectra; UV-vis-NIR titrations;
NMR competition experiments; photophysical characterization;
computational chemistry and DFT calculations. This material is
available free of charge via the Internet at http://pubs.acs.org
Photophysical Behavior. The absorption and fluorescence
spectra of the nanorings and their template complexes are
compared in Figure 6. Fluorescence lifetimes, quantum yields
and radiative rates are listed in Table 3.17 The spectra of c-
P6[b6] and c-P6[b5e] are very similar (with and without bound
T6). There is more difference between the spectra of c-P6[e6]
and c-P6[be5], which probably reflects the greater strain in
these complexes and the severe dome-shaped distortions in c-
P6[e6]·T6* (Figure 2d). Data for a typical linear hexamer,
THS-l-P6[b5]-THS, are also included in Table 3, for compari-
son. Linear conjugated porphyrin oligomers of this type gen-
erally have high radiative rates and fluorescence quantum
yields.17,18 All the nanorings have much lower fluorescence
quantum yields and radiative rates than linear oligomers, as
would be expected for a forbidden S1-S0 transition in a sym-
metrical circular π-system.2,3,17 Comparison of the radiative
rates for c-P6[e6] and c-P6[be5] suggests that in this case, low-
ering the symmetry increases the oscillator strength, but in
general, the reduction in symmetry seems to be too subtle to
have a strong effect on the photophysical behavior.
AUTHOR INFORMATION
Corresponding Author
harry.anderson@chem.ox.ac.uk
Funding Sources
No competing financial interests have been declared.
ACKNOWLEDGMENT
We thank the ERC (grant 320969), EPSRC (EP/M016110/1), the
European Union’s Horizon 2020 research and innovation pro-
gramme (Marie Sklodowska-Curie grants MULTI-APP 642793
and SYNCHRONICS 643238) and the Swiss National Science
Foundation (P2BSP2_168919) for funding, the EPSRC UK Na-
tional Mass Spectrometry Facility at Swansea University for mass
spectra and the University of Oxford Advanced Research Compu-
ting Service (ARC) for support. M.J. thanks Oxford University for
a Scatcherd European Scholarship.
Conclusions
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