Flow electrochemistry: a safe tool for fluorine chemistry

Article abstract of DOI:10.1039/d1sc02123k

The heightened activity of compounds containing fluorine, especially in the field of pharmaceuticals, provides major impetus for the development of new fluorination procedures. A scalable, versatile, and safe electrochemical fluorination protocol is conferred. The strategy proceeds through a transient (difluoroiodo)arene, generated by anodic oxidation of an iodoarene mediator. Even the isolation of iodine(iii) difluorides was facile since electrolysis was performed in the absence of other reagents. A broad range of hypervalent iodine mediated reactions were achieved in high yields by coupling the electrolysis step with downstream reactions in flow, surpassing limitations of batch chemistry. (Difluoroiodo)arenes are toxic and suffer from chemical instability, so the uninterrupted generation and immediate use in flow is highly advantageous. High flow rates facilitated productivities of up to 834?mg h^?1with vastly reduced reaction times. Integration into a fully automated machine and in-line quenching was key in reducing the hazards surrounding the use of hydrofluoric acid.

Full text of DOI:10.1039/d1sc02123k

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Flow electrochemistry: a safe tool for fluorine
chemistry†
Cite this: Chem. Sci., 2021, 12, 9053
*
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Bethan Winterson, Tim Rennigholtz and Thomas Wirth
The heightened activity of compounds containing fluorine, especially in the field of pharmaceuticals,
provides major impetus for the development of new fluorination procedures. A scalable, versatile, and
safe electrochemical fluorination protocol is conferred. The strategy proceeds through a transient
(difluoroiodo)arene, generated by anodic oxidation of an iodoarene mediator. Even the isolation of
iodine(III) difluorides was facile since electrolysis was performed in the absence of other reagents. A
broad range of hypervalent iodine mediated reactions were achieved in high yields by coupling the
electrolysis step with downstream reactions in flow, surpassing limitations of batch chemistry.
(Difluoroiodo)arenes are toxic and suffer from chemical instability, so the uninterrupted generation and
immediate use in flow is highly advantageous. High flow rates facilitated productivities of up to 834 mg
hꢀ1 with vastly reduced reaction times. Integration into a fully automated machine and in-line quenching
was key in reducing the hazards surrounding the use of hydrofluoric acid.
Received 15th April 2021
Accepted 4th June 2021
DOI: 10.1039/d1sc02123k
rsc.li/chemical-science
cost as it is the uorine source for many organouorine
compounds such as uoropolymers and refrigerants. It is also
used as cleaning reagent in the semiconductor industry.8
Though, the utilization of HF, even on a laboratory scale, has
been hindered by its toxicity. Henceforth, despite the tremen-
dous progress in organouorine chemistry, safe and industri-
ally viable uorination protocols are still challenging.
Introduction
The construction of carbon–uorine bonds in organic mole-
cules is an upsurging eld in chemical synthesis, which still
presents ongoing difficulties for organic chemists. Fluorination
can enhance the lipophilicity, membrane permeability, metab-
olism, and therapeutic properties of drug molecules.1,2 In recent
years, uoropharmaceuticals have seen exponential growth in
the drug market, which provides major impetus for sustained
development. Almost one third of the top performing drugs in
the market contain a uorine atom in their structure.3 For
instance, lansoprazole (Prevacid), regulating stomach acid, and
uoxetine (Prozac), an anti-depressant, are considered among
the most successful uorine containing drugs. Broader incor-
poration is, nonetheless, largely limited by synthetic accessi-
bility. Naturally occurring organic uorine compounds are
relatively sparse and there are only a few biologically syn-
thesised organouorides.4 Thus, easy routes to C–F bond
formation cannot be derived from nature.
Hypervalent iodine reagents have emerged as powerful tools
for uorination chemistry.9 (Diuoroiodo)arenes are typically
prepared with HF and XeF2 for oxidations,10 ligand exchange of
(dichloroiodo)arenes in the presence of HgO,11 or the reaction
of iodosyl arenes with HF.12 Shreeve et al. disclosed a straight-
forward synthesis from arenes using Selectuor®, Et3N$3HF
and elemental iodine (Fig. 1).13 However, the requirement for
stoichiometric amounts of chemical oxidants in these reactions
is not sustainable.
In order to foster a sustainable approach, the batch electro-
chemical synthesis of (diuoroiodo)arenes has been subject to
ongoing investigation (Fig. 1).14 For example, the electro-
chemical uorocyclisation of N-allylcarboxamides, uoro-
desulfurisation of dithioacetals and uorination of a-dicar-
bonyl compounds was the subject of elegant work by Waldvo-
gel14a and Fuchigami.14c,d While the selectivity and yields of the
products were generally high, the substrate types amenable
were limited because success was typically contingent on in-cell
applications. For instance, N-allylcarboxamides bearing nitro
functionalities, liable to cathodic reduction, did not give the
desired oxazoline in this manner.14a Applying an ex-cell
approach yielded the desired oxazoline, albeit in a low yield,
attributed to the chemical instability of the I(III)F2 mediator.14a
Even so, Lennox et al. demonstrated improved product diversity
The development of aza-uoro reagents such as
Selectuor®,5
N-uoropyridinium
salts,6
and
dieth-
ylaminosulfur triuoride7 was a major breakthrough, as they
are bench stable. Nevertheless, their high price, preparation
from uorine gas and signicantly poor atom economy means
there is limited potential for industrial application. Hydro-
uoric acid (HF) is commercially available and extremely low
School of Chemistry, Cardiff University, Park Place, Main Building, Cardiff, CF10 3AT,
Cymru/Wales, UK. E-mail: wirth@cf.ac.uk
† Electronic supplementary information (ESI) available. CCDC 2072599 (2c),
2043588 (5a) and 2043555 (8c). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/d1sc02123k
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active surface area of 12 cm2, applying galvanostatic conditions.
A PFTE recessed channel was tted in the ow cell giving
a 0.6 mL internal volume and a 0.5 mm interelectrode gap. N-
Allyl-4-methylbenzamide 1a served as a test substrate for the
elaboration of optimal electrolytic conditions for the synthesis
of iodine(III) diuoride reagents. The yield of the hypervalent
iodine reagent was inferred by the yield of 2a (using 19F NMR
spectroscopy with ethyl uoroacetate as internal standard,
Table 1), given the purication of (diuoroiodo)toluene is more
hazardous than 2a. Subsequently, the electrolysis was investi-
gated in detail through varying the electrode materials, solvent
system, ow rate, and current density. Initially, applying reac-
tion conditions similar to the literature14a with 4-iodotoluene
(0.1 M), an applied charge of 3 F, ow rate of 0.1 mL minꢀ1, and
stirring for 12 h post electrolysis in CH2Cl2/5HF$NEt3 (1 : 1 v/v),
the desired product 2a was observed in a moderate 51% yield
(Table 1, entry 1). Exchanging the expensive 5HF$NEt3 (ref. 18)
to 5.6HF$amine, made by diluting the cheaper and readily
available 9HF$Py (ref. 19) with 3HF$NEt3,20 led to no reduction
in yield (Table 1, entry 2). For the oxidation of iodine(I) to
iodine(III), a theoretical charge amount of 2 F is required.
Though, higher current densities promoted product formation
to higher yields but an increase from 5 F to 6 F led to no
additional increase (Table 1, entries 2–4). Further studies were
conducted by screening the solvent system.
Despite reasonable yields of 2a, the benzylic uorination of
3a was apparent. In contrast to the desired uorocyclisation,
benzylic uorination is non-mediated and results from the
direct anodic oxidation of 4-iodotoluene. Compound 4a itself is
a very poor mediator, thus the formation of this product had to
be minimised.14b Replacement of 5.6HF$amine by 3HF$NEt3 or
4.5HF$amine led to hampered or completely abolished uo-
rocyclisation (Table 1, entries 5 and 6). Aer electrolysis in
3HF$NEt3, the solution had a brown-violet colour consistent
with iodine liberation (see ESI†). When 4.5HF$amine was used,
benzylic uorination was highly selective (Table 1, entry 6).
Increasing the proportion of HF above 5.6HF$amine resulted in
increased yields of 2a and decreased yields of 4a (Table 1,
entries 7 and 8). Aer electrolysis, the solutions were pale yellow
which is indicative of iodine(III) formation (see ESI†). The
anodic oxidation of 4-iodotoluene proceeded with full conver-
sion and a quantitative yield using 7HF$amine. To obtain an
insight into the differences between the explored HF solutions,
cyclic voltammetry studies were performed in various HF$a-
mine dilutions (Fig. 2). For the electrochemical preparation of
TolIF2, hydrouoric acid provides the ligands, is the electrolyte,
and contributes the balancing cathodic reaction. Due to the
relatively high oxidation potentials of aryl iodides, the electro-
chemical stability of the solvent can be critical.21 The stability of
the solvents against anodic oxidation was contrasted using the
arbitrary stability criterion dened as jlim ¼ 20 mA cmꢀ2. The
anodic stability of the nHF$amine solvents increased with
increasing values of n. For example, the 7HF$amine solvent is
about 0.64 V (Elim ¼ 2.48 V, jlim ¼ 20 mA cmꢀ2) more stable to
oxidation compared to 3HF$NEt3 (Elim ¼ 1.84 V, jlim ¼ 20 mA
Fig. 1 Methods for the preparation and use of (difluoroiodo)arenes.
by successfully using ex-cell methodology, which avoids
competitive substrate oxidation or un-selective uorination.14b
While these examples represent a signicant advancement
in electrochemical uorinations, the low productivity of batch
procedures and hazards surrounding the handling of large
volumes of HF have yet to be addressed. Flow chemistry can be
particularly advantageous. With respect to safety, ow systems
can be superior when in-line quenching is realised which
minimises the HF exposure risk to the experimentalist. Flow
chemistry can even be combined with automated platforms so
that unsafe reagents can be completely remotely managed.15,16
Especially, when considering the larger volumes of HF neces-
sary for gram-decagram synthesis, remote management of un-
safe reagents becomes particularly benecial. Industrial appli-
cations are inherently biased towards synthetic strategies that
are safe and reduce constraints in resources. It is, therefore,
manifest that a ow procedure would be of signicant value.
Herein, we disclose our efforts into the development of a safe,
scalable, and versatile uorination protocol for organic
molecules.
Results and discussion
The electrolysis was performed in an undivided, commercially cmꢀ2). Although, these solvents should all be sufficiently stable
available ow cell17 bearing two platinum electrodes with an to facilitate the desired iodine(III) formation. Indeed, these
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Table 1 Optimization of the anodic oxidation of 4-iodotoluene under flow conditionsa
Entry
Charge (F)
Flow rate (mL minꢀ1
)
nHF$amine
Co-solvent
Yield 2a (%)b
Yield 4a (%)b
1
2
3
4
5
6
7
8
3
3
5
6
5
5
5
5
5
5
5
5
5
5
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.25
0.5
1
5HF$NEt3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2 : HFIP (3 : 1)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
51
50
76
75
0
<5
76
>95
82
0
50
12
12
12
<5
87
12
<5
0
0
0
<5
<5
<5
5.6HF$amine
5.6HF$amine
5.6HF$amine
3HF$NEt3
4.5HF$amine
5.6HF$amine
7HF$amine
7HF$amine
7HF$amine
7HF$amine
7HF$amine
7HF$amine
7HF$amine
9
10c
11d
12
13
14
0
>95
87
75
CH2Cl2
a
Standard reaction conditions: undivided ow cell, Pt electrodes (active surface area: 12 cm2), interelectrode distance: 0.5 mm, 1a (1 equiv.), 4-
iodotoluene (1 equiv.), CH2Cl2: nHF$amine (1 : 1 v/v). HFIP: 1,1,1,3,3,3-hexauoro-2-propanol. Yield determined by 19F NMR using ethyl
b
uoroacetate as internal standard. c Glassy carbon anode. d Panasonic carbon anode.
Subsequently, the inuence of co-solvent was examined. We
reasoned that the addition of HFIP could be benecial for the
transformation as it could act as a radical-stabilizing co-solvent,
provide a more facile cathodic reaction, and even improve
selectivity towards iodine(III) formation. Yet, despite the complete
suppression of benzylic uorination, a signicant reduction in
the yield of 2a was observed (Table 1, entry 9). Also, reduction in
the HF dilution was investigated to minimize by-product
formation and increase the percentage recovery of the medi-
ator. However, any dilution resulted in decreased yields. None-
theless, the HF acid requirement (50% v/v) is signicantly lower
than previous publications (75% v/v).14b Varying the anodic
material gave no improvement to the electrochemical procedure.
Exchanging a platinum anode to a carbon based anode could be
benecial due to their reduced cost and lower overpotential
(Table 1, entries 10 and 11). Albeit, both glassy carbon and
panasonic carbon did not facilitate the desired reaction.
To evaluate the potential of coupling the electrochemical
Fig.
3HF$NEt3
nHF$amine : CH2Cl2 (1 : 15 v/v), Pt disk (immersed surface area: 3
mm2), Pt wire counter electrode, Ag/0.01 M AgCl reference, 10 mV sꢀ1
2
Cyclic voltammetry (CV) studies of HF$amine dilutions;
generation of (diuoroiodo)toluene with a second reaction in
ow, the stability of the electrolysis step over time was investi-
gated. Using the optimal conditions (Table 1, entry 12), the
electrolysis was run for 3.5 h and analysed every 30 min by 19F
NMR spectroscopy. Pleasingly, no change in yield or voltage,
which would be indicative of passivation, was observed. Iden-
tication of the mediator was conrmed via anodic oxidation of
only 4-iodotoluene 3a in ow. (Diuoroiodo)toluene 4b was
isolated as a pure product in 82% yield. A range of other
iodoarenes could also be oxidised in acceptable to excellent
yields. Whilst the electron rich arenes 4b and 4f could be syn-
thesised in excellent yields, the electron poor arenes 4e and 4g
(orange), 7HF$amine (red). CV conditions:
.
solvents have previously been utilised in the electrochemical
generation of (diuoroiodo)arenes.14 On the other hand, the
cathodic potentials gave more insight. A higher cathodic
potential was observed with decreasing values of n, i.e.
5.6HF$amine Ep ¼ ꢀ1.21 V, and 7HF$amine Ep ¼ ꢀ0.95 V.
Hence, the increased yields in the higher acidity solutions can
be, in part, attributed to their more facile reduction potential.
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were formed in lower yields due to their higher oxidation
potential. For 4d, the un-expected low yield is attributed to
decomposition of the starting material during electrolysis. Even
though a 4-tBuPhI mediator could effectively prevent benzylic
uorination, its high price (5 g ¼ £168)22 as opposed to 3a (25 g
¼ £19.5)23 would not be economical. The electrochemical
generation of iodine(III) diuorides is still respectable given the
higher yields and/or drastically reduced reaction times
compared to chemical oxidants (Fig. 3).13,24
To demonstrate the efficiency of the ow electrochemical
generation of 4b, several hypervalent iodine mediated trans-
formations were demonstrated in a coupled manner. Given the
relatively high oxidation potentials of iodoarenes, efficient ex-
Fig.
3 Electrochemically generated (difluoroiodo)arenes. Yields
determined by 19F NMR spectroscopy using ethyl fluoroacetate as an
internal standard. The NMR yields are based on the yield of the oxa-
zoline 2a (given the 1 : 1 stoichiometry). Yields in parenthesis are iso-
lated yields of the corresponding (difluoroiodo)arenes.
Fig. 4 Fluorinations using flow electrolysis. Yields refer to the isolated products, or NMR yields in parentheses. Batch electrolysis is performed in
an undivided cell, Pt (anode, active surface area 1.2 cm2) and Pt (cathode), 3 F, 50 mA cmꢀ2, 5.6HF$amine : CH2Cl2 (1 : 1 v/v). Flow electrolysis is
performed in an undivided cell, Pt (anode, active surface area 12 cm2) and Pt (cathode), 5 F, 16.75 cm2, 7HF$amine : CH2Cl2 (1 : 1 v/v), 0.25
mL minꢀ1. Blue refers to in-cell procedures, green refers to ex-cell procedures.30
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cell protocols are important to prevent possible oxidation/
reduction of the substrate. Since the instability of 4b can
make ex-cell procedures inefficient in batch,14a we summarized
the immediate generation and use in ow (2.4 min) compared
to batch (7.2 h)14b could be hugely benecial as it allows little
time for mediator degradation. More importantly, the long
reaction times in batch could be circumvented by a ow
approach, which drastically improves the productivity and
industrial viability of these processes. For safety and exposure
purposes, a simple in-line quenching process was established
by injecting aqueous Na2CO3 or NaOH using a third pump aer
the desired reaction time and mixing in a third ow reactor,
followed by phase separation (see ESI†).
Fig. 5 Reaction scheme for iodofluorinations.
unsuccessful. Adding molecular iodine followed by allylbenzene
in an ex-cell manner did not yield 12ca, and only the diuori-
nated product 12cb was obtained in 39% yield. Since previous
methods are performed in the absence of a HF$amine solvent,31
we thought that removal of excess amounts of nucleophilic
uoride maybe necessary to yield the desired product. Although
aqueous-organic extraction to remove the HF$amine solvent
was not reasonable in batch, the addition of an in-line liquid–
liquid extractor32 in ow was simple. Injecting water and
applying an in-ow liquid–liquid extractor aer the electro-
chemical reactor facilitated removal of hydrouoric acid
(Fig. 5). Combining the organic solvent stream with a stream of
molecular iodine and the alkene/alkyne yielded the iodo-
uorinated products 12a, 12b and 12ca in excellent yields. Since
the diuorinated product was not observed in the absence of
HF, we reasoned that the issues experienced in batch are
unlikely due to a competitive reaction between the TolIF2 and
the alkene,31 but likely due to substitution of iodide, in the
product, by nucleophilic uoride. This, in turn, is promoted by
excess amounts of the nucleophilic uoride source, HF$a-
mine.33 Indeed, treating the iodouorinated product 12ca with
TolIF2 and 5.6HF$amine yielded the diuorinated product
12cb. The pharmaceutically relevant compounds 12d and 13a
were also synthesised in good yields, 12d through the iodo-
uorination of the alkene and 13a by the electrochemical uo-
rination of the corresponding thioacetal. Overall, the yields of
the nal products are generally high, and the system could be
easily manipulated to accompany the different reaction condi-
tions required for each product.
We then investigated the versatility of this uorination
procedure (Fig. 4). First, the uorocyclisation of N-allylcarbox-
amides was targeted. Despite only moderately increased yields
compared to batch, a dramatic increase in productivity was
observed due to the shortened reaction times, from 1–6 mg hꢀ1
in batch, to 100–311 mg hꢀ1 in ow. Unsurprisingly, the ex-cell
synthesis of 2c in batch (25%) was much lower yielding than the
ow procedure (52%). This is attributed to the chemical insta-
bility of (diuoroiodo)toluene, indicating the immediate use in
ow is much more effective. Of particular note, electrochemical
methods have so far been uniquely limited to aromatic
substituents in the a-position to the carbonyl.14a Indeed, the
uorocyclisation of 1h, 1i, 1j, 1k and 1m did not proceed in
batch. The substrates bearing saturated N-heterocycles 2j, 2k
and 2m were particularly problematic in batch. Their preference
for Shono-type uorination (Ep ¼ 1.6 V for 1m) as oppose to
iodoarene oxidation (Ep ¼ 1.7 V), meant in-cell applications
were not possible. In fact, applying an in-cell procedure for
compound 1m gave no desired uorocyclisation, but small
quantities of Shono-type uorination 2mb (7%) (detected by
HRMS and 19F NMR spectroscopy). No remaining starting
material could be observed due to decomposition. Given their
preference for Shono-type uorination when exposed to elec-
tricity, we rationalized that an ex-cell approach was more viable.
But, even the ex-cell approach in batch did not lead to product
formation, although no decomposition of the starting material
was observed. Since extending the reaction time from 15 h to
24 h (electrolysis time + stirring time) gave trace amounts of the
products, we concluded that a ow approach may be more
successful. With this approach, the non-aromatic oxazolines
could be synthesised in good yields in ow, apart from 2h. It
was even possible to generate an aliphatic 2-oxazoline (2l) in
a modest 54% isolated yield. Given the efficiency of the ex-cell
application in ow, the scope of readily oxidised or reduced
substrates was extended. A versatile set of reactions including
vic/gem diuorinations, monouorinations, a-uorinations of
ketones, ring contractions, and uorocyclizations of alcohols
and carboxylic acids could all be performed in modest to
excellent yields. In all cases, the productivities were increased
from 4–9 mg hꢀ1 quantities in batch, to 100–300 mg hꢀ1 in ow.
Thereaer, we focused our attention on the di-
functionalization of unsaturated compounds by two different
atoms, such as the iodouorination of alkenes/alkynes.
Finally, in an effort to further increase the safety and scal-
ability prospects, a fully automated approach was developed
(Fig. 6). The pumps and potentiostat were computer controlled
and the product was collected automatically using a fraction
collector. Using this approach, the rapid exercise of multiple
Intriguingly, our initial baseline reactions in batch were Fig. 6 Fluorinations using automated electrolysis.
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experiments and completely remote handling of hydrouoric
acid mixtures was possible. The larger volumes of HF$amine
necessary for scale-up procedures could be handled in a safer
manner, since no human interaction was needed. In this
procedure, a ow rate of 1.0 mL minꢀ1 (Table 1, entry 14),
a substrate concentration of 0.07 M, and a 4-iodotoluene
concentration of 0.1 M was used. The scalability of the method
was initially demonstrated by preparing gram-scale quantities
of 5a (1.25 g, 834 mg hꢀ1), 7a (1.24 g, 824 mg hꢀ1) and 7b (1.22 g,
812 mg hꢀ1). By this method, the productivity of 7a was
increased from 287 mg hꢀ1 at a ow rate of 0.25 mL minꢀ1, to
824 mg hꢀ1 at 1.0 mL minꢀ1 and each 6.3 mmol reaction could
be performed in just 1.5 h. Also, the diuorinated product 14a,
derived from the unactivated alkene, could even be produced on
an 8 g scale in just 10.5 h. Pleasingly, upon scaling up from a 1 g
to 8 g scale for compound 14a, no decrease in yield was
observed. Inspection of the electrodes following all large scale
reactions revealed no passivation and a steady voltage was
observed throughout the experiments. Since all scale up reac-
tions could be performed with no detrimental effect on the yield
of the products, the above results demonstrate the reliability of
the ow electrochemical uorination procedure.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
We thank the School of Chemistry, Cardiff University and
EPSRC (PhD studentship to B. W.), for nancial support.
Support for the research stay (T. R.) by the University of Leipzig,
Germany, is gratefully acknowledged.
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Conclusions
In summary, a scalable, reliable, and safe uorination procedure
using hypervalent iodine mediators has been developed.
(Diuoroiodo)arenes are toxic, suffer from chemical instability
and are prone to hydrolysis, so the uninterrupted generation and
immediate use in ow exceeds limitations in batch. Since air and
moisture can be effectively excluded, the yields of ex-cell appli-
cations in ow are oen signicantly higher yielding. Effectively
decoupling iodine(III) formation with the desired reaction
removed any functional group bias of batch procedures. A versa-
tile scope of hypervalent iodine mediated uorinations such as
uorocyclisations, diuorinations, monouorinations and ring
contractions were achieved in good to excellent yields. The system
could be effortlessly manipulated to facilitate a broad range of
reactions by changing the residence time, solvent, or temperature
of the reaction coil. Most notably, the electrochemical approach
for the di-functionalisation of alkenes/alkynes by non-identical
atoms could only be envisioned in ow. Integration into an
automated electrolysis machine and a simple in-line quenching
process facilitated completely remote handling of toxic hydro-
uoric acid. Given the emerging importance of organic uorina-
tion procedures for the pharmaceutical industry, and their bias
towards procedures that are safe, scalable, and reduce constraints
in resources, a ow procedure is invaluable.
Data availability
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All available data are included in the supporting information.
¨
3287; (b) T. Noel, Y. Cao and G. Laudadio, Acc. Chem. Res.,
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2019, 52, 2858; (c) N. Kockmann, P. Thenee, C. Fleischer-
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Author contributions
2, 258; (d) M. Elsherbini, B. Winterson, H. Alharbi,
´
Experiments: BW and TR, manuscript: BW and TW.
A. A. Folgueiras-Amador, C. Genot and T. Wirth, Angew.
9058 | Chem. Sci., 2021, 12, 9053–9059
© 2021 The Author(s). Published by the Royal Society of Chemistry

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