Monoamine Oxidase (MAO-N) Biocatalyzed Synthesis of Indoles from Indolines Prepared via Photocatalytic Cyclization/Arylative Dearomatization

Article abstract of DOI:10.1021/acscatal.0c01351

The biocatalytic aromatization of indolines into indole derivatives exploiting monoamine oxidase (MAO-N) enzymes is presented. Indoline substrates were prepared via photocatalytic cyclization of arylaniline precursors or via arylative dearomatization of unsubstituted indoles and in turn chemoselectively aromatized by the MAO-N D11 whole cell biocatalyst. Computational docking studies of the indoline substrates in the MAO-N D11 catalytic site allowed for the rationalization of the biocatalytic mechanism and experimental results of the biotransformation. This methodology represents an efficient example of biocatalytic synthesis of indole derivatives and offers a facile approach to access these aromatic heterocycles under mild reaction conditions.

Full text of DOI:10.1021/acscatal.0c01351

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Article
Monoamine Oxidase (MAO-N) Biocatalyzed Synthesis of Indoles from
Indolines Prepared via Photocatalytic Cyclization/Arylative Dearomatization
Fei Zhao, Domiziana Masci, Salvatore Ferla, Carmine Varricchio, Andrea Brancale,
Serena Colonna, Gary W. Black, Nicholas J Turner, and Daniele Castagnolo
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c01351 • Publication Date (Web): 11 May 2020
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Monoamine Oxidase (MAO-N) Biocatalyzed
Synthesis of Indoles from Indolines Prepared via
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Photocatalytic
Cyclization/Arylative
Dearomatization
Fei Zhao,† Domiziana Masci,† Salvatore Ferla,‡ Carmine Varricchio,‡ Andrea Brancale,‡
Serena Colonna,† Gary W. Black,⊥ Nicholas J. Turner,§ Daniele Castagnolo†,*
†School of Cancer and Pharmaceutical Sciences, King's College London, London, SE1
‡
9NH, United Kingdom. School of Pharmacy and Pharmaceutical Sciences, Cardiff
⊥
University, King Edward VII Avenue, Cardiff, CF10 3XF, United Kingdom. Department
of Applied Sciences, Northumbria University, Ellison Place, NE1 8ST, Newcastle upon
§
Tyne, United Kingdom. School of Chemistry, Manchester Institute of Biotechnology,
University of Manchester, 131 Princess Street, M1 7DN, Manchester, United Kingdom.
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ABSTRACT. The biocatalytic aromatization of indolines into indole derivatives exploiting
monoamine oxidase (MAO-N) enzymes is presented. Indoline substrates were prepared
via photocatalytic cyclization of arylaniline precursors or via arylative dearomatization of
unsubstituted indoles and in turn chemoselectively aromatized by MAO-N D11 whole
cell biocatalyst. Computational docking studies of the indoline substrates in the MAO-N
D11 catalytic site allowed to rationalize the biocatalytic mechanism and experimental
results of the biotransformation. This methodology represents an efficient example of
biocatalytic synthesis of indole derivatives and offers a facile approach to access these
aromatic heterocycles under mild reaction conditions.
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KEYWORDS. Indoles, biocatalysis, MAO-N, aromatization, indolines.
INTRODUCTION.
The indole motif is considered a privileged scaffold in chemistry due to its large
presence in many natural products and pharmaceutical ingredients.1 Examples of
indole-containing natural products2 include tryptophan, 5-hydroxytryptamine, psilocin
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and vincamine, while examples of drugs having an indole nucleus are indomethacin,
sumatriptan and fluvastatin (Figure 1).3 The development of synthetic methods for the
construction of indoles has captured the attention of the scientific community over the
years and tremendous efforts have been made to synthesize this key heterocycle under
different reaction conditions. The Fischer synthesis of indoles4 is probably the best
known method to access indoles from phenylhydrazines. Other classical synthetic
approaches include the syntheses of Larock,5 Madelung,6 Nenitzescu7 and Schmid,8 or
the cyclization of nitro-arenes and anilines.9 The indole ring can also be constructed
from diverse functionalized starting materials in the presence of metal complexes,10 or
obtained through the oxidation of indoline precursors in the presence of various
oxidants,11 photoredox initiators,12 artificial macromolecules and materials13 or metals.14
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O
HO
N
H
OH
OH
N
N
NH2
NH2
O
N
H
N
OH
H
N
H
O
Tryptophan
5-Hydroxytryptamine
Psilocin
Vincamine
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Cl
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F
H
O
N
H
O
N
S
N
OH
O
N
O
OH
OH OH
O
N
O
Sumatriptan
Indomethacin
Fluvastatin
(a) Previous work: biocatalyzed synthesis of pyrroles and pyridines
R
R
R
N
R1
n
MAO-N D9
N
MAO-N D5
N
R1
1 
n = 1, R1 = H
n = 0, R
H
(b) This work: MAO-N biocatalyzed synthesis of indoles
R1
R
n
o
Hal
i
t
via photocatalysis
a
N
z
i
r
e
H
R
m
C
o
t
NR2
u
a
t
R1
O
R1
R1
hydrolysis
R
R
R
N
MAO-N
N
NH2
o
x
H
i
d
i
z
A
D
E
a
t
B
i
o
n
R
R1
NR2
via arylative
dearomatization
R
O
N
H
Figure 1. Representative bioactive molecules with the indole motif and previous and
current works on biocatalytic synthesis of aromatic nitrogen-containing heterocycles.
However, if considered in terms of greenness and sustainability, most of these
approaches suffer from some disadvantages, such as harsh reaction conditions, the use
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of rare metals or strong acids/bases, the use of stoichiometric amounts of oxidizing
agents or the requirement of prolonged heating, making them unappealing from an
environmental and industrial perspective. Surprisingly, despite the remarkable
achievements made in the field of indole synthesis, only few biocatalytic and chemo-
enzymatic methods for the synthesis of tryptophan and indoline derivatives have been
described in the literature.15 Although enzymes are widely used in the construction of
stereodefined chemical bonds, their use as sustainable biocatalysts in the synthesis of
aromatic heterocycles is still poorly explored so far. Our group, inspired by natural
metabolic transformations,16 first reported the biocatalytic synthesis of aromatic
heterocycles such as pyrroles, pyridines and furans disclosing the aromatizing
properties of MAO-N and laccase enzymes.17 As further extension of these studies and
with the aim to expand the scope of aromatic heterocycles accessible via biocatalysis,
herein we describe the aromatization of indolines A into indoles C exploiting MAO-N
whole cell biocatalysts (Figure 1). However, such biotransformation faces two main
challenges: the first challenge is to evaluate if MAO-N biocatalysts can oxidize the
indoline C-N bond to give the imine intermediate B, since the conjugation of the nitrogen
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atom in A with the benzene ring may affect the MAO-N oxidation;18 the second
challenge of this process is to achieve high levels of chemoselectivity to generate the
single indole product C from B by tautomerization, avoiding the hydrolysis or further
oxidization of B which may lead to the byproducts D or E. In this paper, a selective
enzymatic protocol for the efficient synthesis of indoles from indolines using MAO-N
D11 whole cell biocatalysts under mild conditions is reported. To the best of our
knowledge, this is the first example of biocatalytic aromatization of indolines into indole
derivatives described in the literature.
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RESULTS AND DISCUSSION
Freeze-dried whole cells containing MAO-N variants D5, D9, and D11 were selected
as the biocatalysts based on their known activity and selectivity toward structurally
related pyrrolidines and pyrrolines.17a,19-20 Initially, indoline 1a was treated with three
MAO-N variants in a NaPBS buffer (pH = 7.8, 1.0 M) at 37 °C in the presence of
isooctane co-solvent under air atmosphere for 24 h. The desired indole 2a was obtained
with 20% conversion when MAO-N D5 and D11 were used (entries 1 and 3, Table 1)
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while a lower conversion (entry 2) was observed with the variant D9. Since the co-
solvent used in enzymatic reactions may have a significant impact on the conversions,17
DMSO was then employed (entries 4-6) leading to an increase of the conversion (33%)
when MAO-N D11 was used as biocatalyst (entry 6). MAO-N D11 was thus employed
for further optimization. Pleasingly, extending the reaction time resulted in a remarkable
improvement of the conversion (83%) and good isolated yield (72%) (entry 8).
Increasing the loading of MAO-N D11 in the reaction mixture did not result in any
significant improvement of the conversion (entries 9-11). Similarly, the double addition
of the biocatalyst at different time did not influence the results (entries 12 and 13).
Finally, to confirm that the aromatization of 1a was truly catalyzed by MAO-N D11 rather
than spontaneously promoted by the oxygen in the air, a set of control experiments
were carried out. When the MAO-N D11 biocatalyst was removed from the reaction
mixture, no desired product 2a was detected after 7 days (entry 14), suggesting the air
itself cannot promote this biotransformation at all. Likewise, the treatment of 1a with E.
coli BL21(DE3) cells harboring no MAO-N enzymes under the optimized conditions did
not lead to the formation of 2a (entry 15), confirming the crucial catalytic role of the
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enzyme MAO-N D11 in the aromatization of 1a. Since oxygen is required in MAO-N
catalyzed biotransformations to regenerate the FAD cofactor, H2O2 is normally
produced as side product and it might accelerate the further oxidation of the imine
intermediate into the byproduct indolin-2-one.21 However, neither the indolin-2-one
byproduct nor the hydrolysis byproduct 2-(2-aminophenyl)acetaldehyde (compounds D
and E in Figure 1) were detected in any reaction, clearly indicating the high
chemoselectivity and specifity of this biotransformation.
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Table 1. Optimization of the reaction conditions of the biocatalytic aromatization of
indoline 1a.
MAO-N
N
N
Buffer (pH 7.8)/co-solvent
(60/1), air, 37 oC, Time
H
H
1a
2a
Entry
MAO-Na
Co-solvent
Time (d)
Conv. (%)b
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4
5
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7
D5
D9
D11
D5
D9
D11
D11
isooctane
isooctane
isooctane
DMSO
DMSO
DMSO
1
1
1
1
1
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3
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D11
D11d
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
7
1
3
83 (72c)
54
77
83
81
76
0
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14
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D11 d
D11 d
D11d,e
D11 d,f
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4+3
2+1
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g
-
h
-
7
0
aReaction conditions: 1a (0.2 mmol), freeze-dried MAO-N whole cells (190 mg), buffer
(Na2HPO4/NaH2PO4, pH = 7.8, 1.0 M) (3.0 mL), co-solvent (50 μL), air, 37 °C, 1-7 days.
bConversion was determined by 1H NMR integration of the crude mixture. cIsolated yield.
d380 mg freeze-dried MAO-N D11 whole cells were used. e190 mg Freeze-dried MAO-N
D11 whole cells were added at the beginning of the reaction, and then another 190 mg
f
Freeze-dried MAO-N D11 whole cells were added at the fifth day of the reaction. 190
mg Freeze-dried MAO-N D11 whole cells were added at the beginning of the reaction,
and then another 190 mg Freeze-dried MAO-N D11 whole cells were added at the third
g
h
day of the reaction. No biocatalyst was added to the reaction mixture. E. coli
BL21(DE3) cells harboring no MAO-N enzymes were used.
Table 2. Biocatalytic aromatization of indolines 1a-1p.
R2
R2
MAO-D11
R3
R3
N
N
Buffer (pH 7.8)/DMSO
(60:1), air, 37 oC, 7 d
R1
R1
1
2
Entry Indole
R1
R2
R3
Conv. (%)a Yield (%)b
83 72
1
2a
H
H
H
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2b
2c
2d
2e
2f
H
H
H
H
H
H
H
H
H
H
H
H
H
5-F
4-Cl
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>99
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>99
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>99
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0
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H
5-Cl
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5
H
6-Cl
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H
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2g
2h
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6-I
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H
5-Me
5-OMe
6-OMe
5-CN
5-NO2
58
9
H
82
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2j
H
40
2k
2l
H
NAc
NAc
92
H
0
2m
2n
2o
2p
H
2-Me
3-Me
H
H
H
H
H
>99
>99
0
H
90
Me
Bn
NAc
NAc
H
0
Reaction conditions: 1 (0.2 mmol), freeze-dried MAO-N D11 whole cells (190 mg),
buffer (Na2HPO4/NaH2PO4, pH = 7.8, 1.0 M) (3.0 mL), DMSO (50 μL), air, 37 °C, 7
a
1
days. Conversion was determined by H NMR integration of the crude mixture.
bIsolated yields are reported. cNot available.
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Once the reaction conditions were optimized, the substrate scope was explored. A
series of commercially available indolines bearing different substituents on the
heterocyclic nucleus was treated with MAO-N D11 under the optimal conditions. The
results are reported in Table 2. The indolines 1b-g bearing a halogen substituent on the
benzene ring were converted into the corresponding indoles 2b-g with good to excellent
conversion and yields (Table 2, entries 2-7). Good to excellent conversions were also
obtained with indolines 1h-j bearing electron-donating groups on the aromatic ring
(Table 2, entries 8-10) while no conversion was observed for 1k-l bearing the electron-
withdrawing substituents -NO2 and -CN (Table 2, entries 11-12). In order to better
explain the different reactivity of indolines 1 and their interaction with the catalytic site of
MAO-N D11, docking studies were performed (Figure 2).19
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Figure 2. Proposed binding modes for compounds 1i (A), 1l (B), 1p (C) in the MAO-N
D11 catalytic site (PDB ID: 3ZDN).19 The nitrogen atom of 1i and 1l is oriented toward
the FAD nitrogen and carbon atom (represented as black atom)) involved in the
mechanism of reaction, whereas substituent on the nitrogen forces compound 1p in a
different orientation. Carbon atoms of compound 1i are shown in turquoise, compound
1l in orange, compound 1p in gold. The binding area of the catalytic site is represented
as a transparent surface. FAD is represented as ball-and-stick. Nitrogens of 1i, 1l,1p
and FAD are shown in blue.
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All the substrates 1a-n bearing a substituent R3 on the benzene ring occupy the MAO-N
catalytic site in a similar manner with the methylene group at the α position of the
indoline nitrogen correctly oriented toward the FAD cofactor. However, no differences
in binding were observed in the case of substrates 1i and 1l (Figures 2A and 2B)
despite their opposite reactivity. It was thus assumed that electronic rather than steric
factors could be responsible for the different conversions observed in the biocatalytic
transformation. Hence, a different computational approach was exploited to calculate
the electrostatic potential surface (EPS) using Gaussian.22 The EPS illustrates the
charge distributions of molecules three dimensionally, giving an indication on the
abundance of electrons around different atoms. According to the proposed MAO-N
biocatalytic mechanism,18c-e the aromatization reaction occurs through the abstraction of
a hydride from the -methylene of indolines 1 by the FAD cofactor of the enzyme as
shown in Figure 3. The following flavin deprotonation of the indoline-FAD adduct,
favored by two active-site molecules of water, leads to indole products and FADH2,
which is in turn re-converted into FAD by O2. The analysis of the EPS of the electron-
rich indoline 1i clearly shows a higher electron density localized on its nitrogen atom as
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well as the -methylene group (Figure 3A), thus favoring the hydride abstraction step by
the FAD cofactor. On the contrary, the presence of the NO2 substituent in 1l significantly
withdraws the electrons form the -methylene group of the indoline, considerably
reducing its electron density and the ability of FAD to abstract a hydride to promote the
following aromatization. Finally, indolines 1m-n, bearing a methyl substituent on the 5-
memebered ring, were fully converted into indoles 2m-n which were isolated in excellent
yields (Table 2, entries 13-14). Even if substrates 1m-n carry a stereocenter, no
enantiopreference of MAO-N D11 towards one or the other enantiomer was observed.
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R
H
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O
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O
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H
H2O2
HN
H
N
FAD
7
O2
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9
R
N
R
N
H
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O
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O
O
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HN
HN
N
N
H
H
O
N
H
FADH2
H
O
H
H
N
R
N
O
N
H
H
H
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HN
N
H
H
H
N
O
H
N
Figure 3. Plausible mechanism of the MAO-N biocatalytic aromatization of indolines (up)
and electrostatic potential surface (EPS) for 1i (A-down) and 1l (B-down).
Despite MAO-N enzymes are able to oxidize a number of tertiary amines, when
indolines 1o-p bearing a methyl or a benzyl group on the nitrogen were treated with
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MAO D11, no conversion into indoles 2o-p was detected (Table 2, entries 15-16).
Computational studies clearly show that the presence of a substituent on the indoline
nitrogen (i.e. in 1p) does not allow the correct orientation of the molecule (Figure 2C) in
the MAO-N binding site, in turn affecting the ability of the FAD cofactor to abstract the -
hydride.
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Table 3. Photo-biocatalytic sequence for the synthesis of indoles 2n, 5a-5f.
1) Ir-photoinitiator,
R2
I
DIPEA, MeCN, blue light
r.t., 24 h
R1
R1
N
R2
N
H
2) MeOH, 6 N HCl,
80 oC, 12 h
Ac
3
4a-f, 1n
R2
MAO-D11
R1
N
Buffer (pH 7.8)/DMSO
(60:1), air, 37 oC, 7 d
H
5a-f, 2n
Entry
Indole
5a
R1
R2
Me
Ph
H
Conv. (%)a
Yield (%)b
1
2
3
4
5
H
H
>99
>99
>99
>99
50
94
88
91
92
41
5b
5c
5-Me
5-OMe
6-F
5d
H
5e
H
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5f
6-Cl
H
H
H
>99
>99
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90
2n
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8
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Reaction conditions: 1) photocatalysis: 3 (0.4 mmol), [Ir(dtbbpy)(ppy)2]PF6 or
(Ir[dF(CF3)ppy]2(dtbpy))PF6 (3 mol%), DIPEA (4.0 mmol), MeCN (4.0 mL), 5 W blue
LED, r.t., 24 h; 2) hydrolysis: N-acetyl indoline (0.3 mmol), MeOH (1.0 mL), 6 N HCl (4.0
mL), 80 °C, 12 h; 3) biocatalysis: 1n or 4 (0.2 mmol), freeze-dried MAO-N D11 whole
cells (190 mg), buffer (Na2HPO4/NaH2PO4, pH = 7.8, 1.0 M) (3.0 mL), DMSO (50 μL),
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a
1
air, 37 °C, 7 days. Conversion was determined by H NMR integration of the crude
mixture. bIsolated yield.
The aromatization of indolines bearing different substituents (aliphatic and aromatic) on
the 5-membered ring, was then explored (Tables 3 and 4). A photocatalytic strategy
was adopted to synthesize the 3-alkyl-susbtituted indolines 4,23 with the aim to combine
photo- and biocatalysis in a synthetic sequence. Various iodo-anilines 3 were treated
with the appropriate Ir-photoinitiator ([Ir(dtbbpy)(ppy)2]PF6 for indolines 4b-f and 1n or
(Ir[dF(CF3)ppy]2(dtbpy))PF6 for indoline 4a) under blue light (LED) to afford the cyclized
acetyl-indolines S424 which were then deprotected in HCl to give indolines 4a-f. The
latter were suspended in buffer/DMSO media and treated with MAO-N D11 to afford
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indoles 5a-f with excellent conversions and yields (Table 3, entries 1-6). Again, indole
2n was prepared with an excellent conversion and yield through the same photo-
biocatalytic sequence (Table 3, entry 7). In order to rationalize these experimental data,
additional computational studies were carried out. In particular, at first glance, it was
unclear why indoline 4b bearing a stereocenter at C3 was fully converted into indole 5b
and no enantiopreference in MAO-N D11 oxidation was observed. Computational
analysis clearly shows that both enantiomers of 4b bind the catalytic site of MAO-N D11
in a slightly different way but with the α-methylene group still correctly orientated toward
the FAD cofactor (Figure 4A and 4B). Thus, it is reasonable to think that both
enantiomers of 4b are oxidized by MAO-N D11, explaining the observed full conversion
into 5b.
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Figure 4. Proposed binding modes for compounds (R)-4b (A) and (S)-4b (B) in the
MAO-N D11 catalytic site (PDB ID: 3ZDN). Both enantiomers of 4b are able to orientate
the -methylene group toward the FAD, nearby the nitrogen next to the carbon atom
(represented as black atom) as proposed for the mechanism of reaction. Carbon atoms
of compound (R)-4b are shown in dark green, compound (S)-4b in light green. The
binding area of the catalytic site is represented as a transparent surface. FAD
is represented as ball-and-stick. Nitrogens of 1i, 1l,1p and FAD are shown in blue.
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Since indolines 7a-e bearing an aryl group on the 5-membered ring could not be
accessed through the same photocatalytic synthetic pathway, an alternative
dearomatizing/re-aromatizing strategy was developed. Indoles 6a-c, unsubstituted at
positions C2 and C3, were treated with appropriate benzene derivatives in the presence
25
of AlCl3
and converted, after acetyl deprotection,24 into the corresponding
dearomatized aryl-indolines 7a-e in good yields. Interestingly, the benzene derivatives
attack the indoles 6a-c at the positions C2 or C3 depending on the nature of the
substituents. Toluene attacked indole 6a preferentially at position C2 while benzene
attacked 6a at position C3 affording respectively 7a and 7b after deprotection. Indolines
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7c and 7d bearing a phenyl ring at positions C2 and C3 respectively, were obtained as
the main products from substituted indoles 6b-c. Finally, the attack of the bulky m-
xylene occurred preferentially at position C3 of 6a to give the indoline 7e after
deprotection. Indolines 7a-e were then treated with MAO-N D11. Results are reported in
Table 4. The 2-aryl indolines 7a and 7c were aromatized into the indoles 8a and 8c with
excellent conversions and yields (entries 1 and 3), while lower conversions were
observed for the 3-susbtituted indolines 7b and 7d (entries 2 and 4), plausibly due to
steric factors. Indoline 7b was recovered as a racemate from the reaction mixture. No
improvements in the conversion of 7b into 8b were observed when the
biotransformation was carried out for 10 days. Finally, a low conversion (<8%) was
observed for the 3-m-xylyl indoline 7e (entry 5). Interestingly, compound 7e docked the
catalytic site of MAO-N in an orientation similar to other indoline compounds, potentially
suggesting a good conversion. However, the bulkier 3-m-xylyl group could represent a
steric hindrance making it difficult for 7e to enter the narrow active site of the enzyme
D11.19
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Table 4. Arylative dearomatization-biocatalytic aromatization sequence for the synthesis
of indoles 8a-e.
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R2
1)
R2
AlCl3, DCM,
r.t., 1 h
R1
R1
N
Ac
N
2) MeOH, 6 N HCl,
80 oC, 12 h
H
6a-c
7a-e
R2
MAO-D11
R1
N
H
Buffer (pH 7.8)/DMSO
(60:1), air, 37 oC, 7 d
8a-e
Entry Indole
R1
R2
Conv. (%)a Yield (%)b
1
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3
4
5
8a
8b
8c
8d
8e
H
H
2-p-Tolyl
3-Ph
>99
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>99
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83
48
98
40
-
5-OMe
6-Cl
H
2-Ph
3-Ph
3-(3,5-di-Me-Ph)
Reaction conditions: (1) arylative dearomatization: 6a-c (1.25 mmol), arene (1.87
mmol), AlCl3 (4.37 mmol), DCM (4.0 mL) r.t., 1 h; (2) hydrolysis: N-acetyl indoline (0.43
mmol), MeOH (1.0 mL), 6 N HCl (4.0 mL), 80 °C, 12 h; (3) biocatalysis: 7a-e (0.2 mmol),
freeze-dried MAO-N D11 whole cells (190 mg), buffer Na2HPO4/NaH2PO4 (pH = 7.8, 1.0
M, 3.0 mL), DMSO (50 μL), air, 37 °C, 7 days. aConversion was determined by 1H NMR
integration of the crude mixture. bIsolated yield.
CONCLUSIONS
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In conclusion, the aromatizing biocatalytic activity of MAO-N enzymes on indoline
substrates has been demonstrated for the first time. The variant biocatalyst D11 proved
to be the best enzyme for such biotransformation. A variety of indoline derivatives 1, 4
and 7, in turn prepared via photocatalytic cyclization of allyl-anilines or via arylative
dearomatization of indoles, have been converted into aromatic indoles 2, 5 and 8 with
good to excellent yields under mild reaction conditions. Computational studies revealed
that the biocatalytic aromatization of indolines into indoles is mainly affected by two
factors, namely the distribution of electrons around the indoline nitrogen and the α-
methylene group, and the ability of the substrates to align to the FAD cofactor with the
correct orientation in the catalytic site of the enzyme. Even if the approaches used for
the synthesis of the substituted indoline substrates still show some limits in terms of
greenness and sustainability due to harsh conditions, the present methodology
highlights the enormous potentiality of MAO-N enzymes to be exploited not only as
deracemizing but also as aromatizing biocatalysts and widens the horizons of
biocatalysis in the synthesis of non-chiral aromatic molecules.
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ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
*E-mail: daniele.castagnolo@kcl.ac.uk
Author Contributions
The manuscript was written through contributions of all authors. All authors have given
approval to the final version of the manuscript.
Funding Sources
K. C. Wong Foundation
Mobility Projects Call for Research Doctorates (n. 2682)
Sêr Cymru II programme
Notes
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The authors declare no competing financial interest.
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Supporting Information. Experimental details, procedures, and copies of spectra (PDF).
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This information is available free of charge on the ACS Publications website.
ACKNOWLEDGMENT
We gratefully acknowledge the K. C. Wong Foundation for financial support and the
Fellowship to FZ. DM and DC acknowledge the University of Roma “La Sapienza” for
Mobility Projects Call for Research Doctorates (n. 2682). SF is supported by the Sêr
Cymru II programme which is part-funded by Cardiff University and the European
Regional Development Fund through the Welsh Government.
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