Electrophilic bromination in flow: A safe and sustainable alternative to the use of molecular bromine in batch

Article abstract of DOI:10.3390/molecules24112116

Bromination reactions are crucial in today’s chemical industry since the versatility of the formed organobromides makes them suitable building blocks for numerous syntheses. However, the use of the toxic and highly reactive molecular bromine (Br₂) makes these brominations very challenging and hazardous. We describe here a safe and straightforward protocol for bromination in continuous flow. The hazardous Br₂ or KOBr is generated in situ by reacting an oxidant (NaOCl) with HBr or KBr, respectively, which is directly coupled to the bromination reaction and a quench of residual bromine. This protocol was demonstrated by polybrominating both alkenes and aromatic substrates in a wide variety of solvents, with yields ranging from 78% to 99%. The protocol can easily be adapted for the bromination of other substrates in an academic and industrial environment.

Full text of DOI:10.3390/molecules24112116

molecules
Article
Electrophilic Bromination in Flow: A Safe and
Sustainable Alternative to the Use of Molecular
Bromine in Batch
Reinout Van Kerrebroeck, Pieter Naert, Thomas S. A. Heugebaert, Matthias D’hooghe and
Christian V. Stevens *
SynBioC research Group, Department of Green Chemistry and Technology, Ghent University, Coupure Links
6
53, 9000 Ghent, Belgium; Reinout.vankerrebroeck@ugent.be (R.V.K.); Pieter.Naert@ugent.be (P.N.);
Thomas.heugebaert@ugent.be (T.S.A.H.); Matthias.Dhooghe@UGent.be (M.D.)
Correspondence: Chris.Stevens@UGent.be; Tel.: +32-9-264-5957; Fax: +32-9-264-6221
*
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editors: Maurizio Benaglia and Miquel A. Pericàs
Received: 30 April 2019; Accepted: 1 June 2019; Published: 4 June 2019
ꢀ
ꢁꢂꢃꢄꢅꢆ
Abstract: Bromination reactions are crucial in today’s chemical industry since the versatility of the
formed organobromides makes them suitable building blocks for numerous syntheses. However,
the use of the toxic and highly reactive molecular bromine (Br ) makes these brominations very
2
challenging and hazardous. We describe here a safe and straightforward protocol for bromination in
continuous flow. The hazardous Br or KOBr is generated in situ by reacting an oxidant (NaOCl)
2
with HBr or KBr, respectively, which is directly coupled to the bromination reaction and a quench of
residual bromine. This protocol was demonstrated by polybrominating both alkenes and aromatic
substrates in a wide variety of solvents, with yields ranging from 78% to 99%. The protocol can easily
be adapted for the bromination of other substrates in an academic and industrial environment.
Keywords: aromatic substitution; bromination; C–H activation; ionic liquids; microreactors
1
. Introduction
One of the major challenges in synthetic chemistry concerns the transformation of a relatively
inert C–H bond into a more active functional group. This can be done with transition metal catalysis in
the so-called C–H activation [ ]. An alternative option is direct bromination with molecular bromine
Br ), forming an organobromide. This is an optimal first step for most synthetic pathways since the
1
(
2
high reactivity of this formed organobromide allows for an easy subsequent conversion into a wide
variety of other functional groups [ ]. This reaction is, however, plagued by the use of toxic and
2–4
corrosive reagents [5] and a high risk of runaway reactions [6].
To circumvent these problems, brominations are often performed with alternative bromination
reagents, most commonly organic molecules containing a Br(I)-species. This bromine(I) can be bonded
to nitrogen (e.g., N-bromosuccinimide or tribromoisocyanuric acid [
7
–
9
]); iodine(III) [10]; carbon
−
(e.g., CBr4 [11]), or even three bromine atoms bonded together in Br3 , countered by an organic cation,
possibly forming an ionic liquid [12,13]. Although these alternatives provide a number of benefits,
especially for academic laboratories, they still are far from perfect—they are expensive, are often still
toxic and unsustainable, produce organic by-products, and most of them use molecular bromine in
their synthesis, thus not solving but only shifting the problem [9,14,15].
Another option is to use Br , but to minimize the hazards by producing it in situ, by reacting
2
reduced bromide (in the form of hydrobromic acid or a bromide salt) with an oxidizing agent, e.g.,
hydrogen peroxide and other peroxides [16–18], Oxone [19], bromate [20,21], or even air or oxygen at
elevated temperatures or with a catalyst [22]. This approach solves the storage and transport problem,
Molecules 2019, 24, 2116; doi:10.3390/molecules24112116
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Molecules 2019, 24, 2116
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but the risk of a runaway reaction is still present. Selectivity can also be problematic due to the highly
reactive nature of the used reagents [23].
All these problems can be avoided by the development of a continuous flow process. The high
surface over volume ratio greatly diminishes the risk of a runaway reaction and ensures a good
parameter control, meaning optimal selectivities and conversions can be achieved with minimal
reagent or solvent [24]. This high selectivity and efficiency of continuous flow bromination has been
demonstrated in previous works [15
been done in batch, the hazards associated with transport and storage can be circumvented, and the
production rate can be tailored to the consumption rate. In situ generation of Br from HBr and H O
,25–28]. Additionally, by generating the bromine in situ, as has
2
2
2
resulted in a safe and efficient bromination protocol [29], and if the residual bromine is quenched
before leaving the reactor, the risk of accidental release of bromine drops to practically zero, since at
any given time there is not enough Br present in the reactor to harm either the environment or the
2
people performing the reaction in case of an accidental spill.
However, a comprehensive study of the versatility of this in situ-generated bromine in flow,
especially for electrophilic brominations, has not yet been performed. This paper provides a broadly
applicable protocol for electrophilic brominations, using in situ-generated bromine from bromide and
an oxidant.
2
. Results and Discussion
The protocol was devised with the main goal of reducing the risk of bromine exposure. This was
achieved by generating the bromine in situ (reactor 1), performing the reaction (reactor 2), and quenching
the unreacted bromine before it leaves the reactor (reactor 3), as depicted in Figure 1.
Figure 1. A general scheme for the bromination of organic compounds in flow. The exact parameters
used per substrate can be found in Table 1 and Section 3 Materials and Methods.
Preliminary experiments demonstrated that a combination of the first two steps (oxidation and
bromination) is not possible because of side product formation by oxidation and chlorination. A number
of oxidizing agents were considered: oxygen, hydrogen peroxide, sodium hypochlorite, and Oxone.
Sodium hypochlorite was selected because it is cheap, usable at any given pH, and does not need
elevated temperatures or metal catalysts. A minimal residence time of 48 s at room temperature was
found to be sufficient to complete the bromine oxidation in acidic environment (i.e., starting from
HBr), while in an alkaline environment (i.e., starting from KBr), the reaction proceeded more slowly,
although 5 min at room temperature was also sufficient:
(1)
Br and KOBr are brominating agents operating via the same mode of action. Both reagents
2
underwent a nucleophilic substitution on the bromine, expelling, respectively, a bromide group, a very

Molecules 2019, 24, 2116
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−
good leaving group, or potassium oxide (KO ), a very poor leaving group. This raises the idea that Br
2
will be a stronger brominating agent than KOBr. The bromination of (E,E,Z)-1,5,9-cyclododecatriene,
which went smoothly in the acidic medium (using Br ) but did not occur at all in alkaline medium
2
(
using KOBr), confirmed this hypothesis. Hence, bromination is strongly favourable in acidic media,
since both the kinetics and conversions are substantially higher. After bromination, the residual bromine
was quenched with Na SO , as this is cheap, water soluble, and does not produce any solid by-products.
2
3
A residence time of two minutes at room temperature was found to be sufficient to quench all of the
unreacted bromine, using two equivalents of Na SO per equivalent of formed bromine. In conclusion,
2
3
this approach (I) generates bromine in situ directly coupled to its consumption, (II) eliminates
exposure to bromine outside the reactor, and (III) avoids intensive downstream purification (i.e., flash
chromatography) due to the absence of organic side products caused by the use of purely inorganic
reagents in the bromination.
Table 1. Synthesis of four indicative organobromine compounds via in-situ Br2 generation
and bromination.
−
Entry
Substrate
Product
Solvent
Eq. NaOCl Eq. Br
RT2
T2
Conversion Yield
◦
1
CHCl3
6
5
9
25 min
50
C
100%
100%
95%
83%
2
3
Et2O
7.5
150 s
rT
Cyclohexane/
DCM
◦
9
9
22.5
22.5
1 min
0
C
100%
100%
97%
78%
4
2-MeTHF/4
3 h
rT
The protocol was used to polybrominate different industrially relevant substrates as a proof
of concept. 2,4,6-Tribromophenol (Table 1, entry 1) is a biocide in wood and an intermediate
0
0
in the production of flame retardants [30]. 2,2 ,6,6 -Tetrabromobisphenol A (Table 1, entry 2)
and 1,2,5,6,9,10-hexabromocyclododecane (Table 1, entry 3) are important flame retardants, used,
respectively, in polycarbonate and epoxy resins and polystyrene [31].
Even though these retardants are less bio-persistent than other brominated flame retardants,
there is still cause for concern [32]. However, their production is necessary, since flame retardants
are very much needed for fire safety, and alternative flame retardants also cope with toxicity and
bio-persistence issues [32]. It is thus of vital importance that their synthesis is performed as efficiently
as possible, with maximal conversion and yield. Potential organic side products, through partial
bromination, are also bio-persistent organobromides and have to be avoided. To achieve this goal,
an excess of brominating agent was used to ensure full conversion and prevent organic side product
formation. This is both economically and environmentally viable due to the low cost and green nature
of the used brominating agent and its by-products (inorganic salts) compared to the organic substrate.
With this approach, full conversions and good to excellent yields (83–97%) were achieved. Solvent
choice was made purely based on solubility, since the solvent polarity had only a small effect on
the reaction rate. None of the tested solvents were found to be more prone to bromination than the
substrates. A suitable organic solvent for the bromination of cyclododecatriene (Table 1, entry 3) was
found through a screening of the common solvents and their mixtures by COSMOquick [33–35]. Since
phase transfer occurs quickly in microreactors and Br dissolves preferentially in an apolar solvent,
2
mixing was not a rate limiting factor in the obtained two-phase system [36]. Another big advantage
of reaching full conversion, mainly from an industrial point of view, is that thanks to the absence

Molecules 2019, 24, 2116
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of organic side or by-products, there was no need for any chromatographic purification. Simple
extraction(s) led to the pure end products.
Bromothymol blue is a pH indicator, and eosin Y (Table 1, entry 4) is mainly used as a histology
stain, for example in the H&E (Hematoxylin and Eosin) stain. Both, however, suffer from a poor
solubility in acidic water or organic solvents. (Bromo)thymol blue dissolves well in a homogeneous
alkaline water/ethanol mixture, and it was attempted to perform the reaction in a one-phase system.
Even though the inherently lower reactivity of KOBr compared to Br causes the need for longer
2
reaction times (4 h), the reaction seemed to work with 100% conversion. However, due to problems with
the work-up, it was not possible to confirm this by obtaining pure bromothymol blue, and caution has
to be taken in saying that switching from Br to KOBr is a possible solution to solve solubility problems.
2
It has been proven in literature, however, that KOBr is a valuable brominating agent, for example,
in cases where an alkaline environment is necessary to activate the substrate by deprotonating the
position that has to be brominated, in this case a methylsulfon(ate) [25].
While eosin Y could also be dissolved in alkaline water, the higher oxidation potential of KOBr
compared to Br caused the substrate to be degraded rather than brominated. The oxidation potential
2
of Br was low enough not to degrade eosin Y, so the bromination had to take place in an acidic
2
environment. Since a suitable water-immiscible solvent was not found, even when performing
screenings with COSMOquick [33
–35], the attention was turned to ionic liquids. Most ionic liquids
either did not dissolve fluorescein properly or were water-miscible. Trioctyl-(3-sulfopropyl)ammonium
perchlorate
perchlorate
4
4
, however, was found to be a suitable solvent. Trioctyl-(3-sulfopropyl)ammonium
is not commercially available so it was synthesized according to Scheme 1, based
on the literature protocol for the synthesis of trioctyl-(3-sulfopropyl)ammonium bistriflimide [37].
Perchlorate was chosen as anion, which is cheap, oxidative stable, and resistant to ion exchange [38].
This synthetic route involved N-alkylation of tertiary trioctylamine
furnish the zwitterionic sulfonate . Treatment of the latter with perchloric acid finally provided the
desired ionic liquid 4. A 1/9 mixture of this trioctyl-(3-sulfopropyl)ammonium perchlorate and
-methyltetrahydrofuran dissolved fluorescein and had an acceptable viscosity. This proves that
1 with 1,3-propane sultone 2 to
3
4
2
the presented protocol is not only viable in a wide range of conventional solvents, ranging from the
most bio-persistent, e.g., chlorinated solvents, to the most sustainable, e.g., 2-methyltetrahydrofuran,
but also in ionic liquids.
Scheme 1. The synthesis of the ionic liquid, trioctyl-(3-sulfopropyl)ammonium perchlorate 4.
3
. Materials and Methods
3
.1. General Procedure
The reactor was constructed according to the scheme presented in Figure 1. All connections were
poly(ethylene-co-tetrafluoroethylene) (ETFE) T-mixers and Luer lock adapters, as polyether ether
ketone (PEEK) gets easily degraded by Br . All tubing was polytetrafluoroethylene (PTFE) and had,
2
unless stated otherwise, an internal diameter (ID) of 1 mm.
Hydrobromic acid was bought in a 48 w% solution in water from Acros Organics, and sodium
hypochlorite in a 13% active chlorine solution in water from Fisher Scientific (Hampton, NH, USA),

Molecules 2019, 24, 2116
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but both were titrated (acid-base and iodometric), since the exact concentration can differ from the
labeled one, especially for NaOCl. This concentration also diminishes over time, even when refrigerated.
Anhydrous Na SO was bought from Fisher Scientific and a stock solution was made in water (200 g/L).
2
3
3
.2. 2,4,6-Tribromophenol (Table 1, Entry 1)
Phenol was purchased from Acros Organics and used without any purification. The reactor was
built as depicted in Figure 1. Both reactor 1 and 3 had an ID of 1 mm and a volume of 3 mL, but reactor
◦
2
had an ID of 2.4 mm and a volume of 50 mL. Reactor 2 was placed in a 50 C water bath. The HBr
and NaOCl were titrated to find a concentration of 8.89 M for HBr and 1.45 M for NaOCl. A phenol
solution of 0.194 M in CHCl was made, as well as a solution of 200 g/L Na SO in H O. The latter
3
2
3
2
three solutions were pumped by the peristaltic pumps of the Vapourtec E-series (VapourTec Ltd, Bury
Saint Edmunds, UK), while the HBr was loaded in a syringe and placed on a Chemyx Fusion 100
syringe pump (Chemyx Inc, Stafford, TX, USA). The flow rates were 0.196 mL/min for HBr (9 eq.),
0
.804 mL/min for NaOCl (6 eq.), 1 mL/min for phenol (1 eq.), and 1.468 mL/min for Na SO (12 eq.).
2 3
This resulted in a residence time of 25 min in reactor 2, the bromination reactor. After running the
reaction for three complete residence times, the outlet was collected for 30 min.
The two phases were separated, and the water phase was extracted with 3
×
50 mL CHCl3.
All organic phases were combined, dried with MgSO , filtrated, and evaporated in vacuo. Drying
4
under a high vacuum yielded 1.83 g of pure 2,4,6-tribromophenol (yield = 95%). Purity was confirmed
by liquid chromatography-mass spectrometry (LC–MS) (Agilent Technologies, Santa Clara, CA, USA)
1
13
and nuclear magnetic resonance spectroscopy (NMR), both H-NMR and C-NMR (Bruker, Billerica,
MA, USA). These spectra can be found in the Supporting Information.
0
0
3
.3. 2,2 ,6,6 -Tetrabromobisphenol A (Table 1, Entry 2)
Bisphenol A was purchased from Sigma-Aldrich (St. Louis, MO, USA) and used without any
purification. The reactor was built as depicted in Figure 1. All tubing had an internal diameter of 1 mm,
and the three reactors had volumes of 2, 10, and 3 mL respectively. The HBr and NaOCl were titrated
to find a concentration of 8.89 M for HBr and 1.45 M for NaOCl. A bisphenol A solution of 0.233 M
in Et O was made, as well as a solution of 200 g/L Na SO in H O. The latter three solutions were
2
2
3
2
pumped by the peristaltic pumps of the Vapourtec E-series, while the HBr was loaded in a syringe and
placed on a Chemyx Fusion 100 syringe pump. The flow rates were 0.393 mL/min for HBr (7.5 eq.),
1
.61 mL/min for NaOCl (5 eq.), 2 mL/min for bisphenol A (1 eq.), and 2.94 mL/min for Na SO (10 eq.).
2 3
This resulted in a residence time of 2 min and 30 s in reactor 2, the bromination reactor. After running
the reaction for three complete residence times, the outlet was collected for 10 min.
The two phases were separated, and the water phase was extracted with 3
×
50 mL Et O. All organic
2
phases were combined, dried with MgSO , filtrated, and evaporated in vacuo. Drying under a high
4
0
0
vacuum yielded 2.10 g of pure 2,2 ,6,6 -tetrabromobisphenol A (yield = 83%). A perfect selectivity was
obtained, while incorrect parameters resulted in the degradation of the carbon skeleton and production
1
13
of tribromophenol (
δ = 7.64). Purity was confirmed by LC–MS, H-NMR.and C-NMR. These spectra
can be found in the Supporting Information.
3
.4. 1,2,5,6,9,10-Hexabromocyclododecane (Table 1, Entry 3)
E,E,Z)-1,5,9-cyclododecatriene was bought from Fisher Scientific and used without any
(
purification. The reactor was built as depicted in Figure 1. All tubing had an internal diameter
of 1 mm, and the three reactors had volumes of 0.4, 1, and 1 mL respectively. Reactor 2 was cooled
by an ice/water bath to prevent overbromination forming hepta- and octabromocyclododecane.
The HBr and NaOCl were titrated to find a concentration of 9.16 M for HBr and 1.31 M for
NaOCl. An (E,E,Z)-1,5,9-cyclododecatriene solution of 0.107 M in a 1/2 mixture of cyclohexane
and dichloromethane was made, as well as a solution of 200 g/L Na SO in H O. All reagents were
2
3
2
loaded in syringes, but while the HBr, NaOCl and Na SO were pumped by Chemyx Fusion 100
2
3

Molecules 2019, 24, 2116
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syringe pumps, the cyclododecatriene was pumped by a Harvard PhD 22/2000 pump. The flow rates
were 0.132 mL/min for HBr (22.5 eq.), 1.313 mL/min for NaOCl (9 eq.), 0.5 mL/min for cyclododecatriene
(
1 eq.) and 0.609 mL/min for Na SO (18 eq.). This resulted in a residence time of 1 min in reactor 2,
2 3
the bromination reactor. After running the reaction for three complete residence times, the outlet was
collected for 15 min.
The two phases were separated, and the organic phase was dried with MgSO4,
filtrated and evaporated in vacuo. Drying under a high vacuum yielded 502 mg of pure
1,2,5,6,9,10-hexabromocyclododecane (yield = 97%). Purity was confirmed by LC–MS. This spectrum
can be found in the Supporting Information.
3
.5. Eosin Y (Table 1, entry 4)
Fluorescein was purchased from Acros Organics and used without purification. The reactor was
built as depicted in Figure 1. All tubing had an internal diameter of 1 mm, and the three reactors had
volumes of 0.4, 7, and 1 mL respectively. The HBr and NaOCl were titrated to find a concentration of
9
.16 M for HBr and 1.29 M for NaOCl. A solution of 200 g/L Na SO in H O was made. Fluorescein
2 3 2
(704.6 mg) was dissolved in 40 mL of a 1/9 volumetric mixture of trioctyl-(3-sulfopropyl)ammonium
perchlorate and 2-methyltetrahydrofuran. A few drops of hydrobromic acid were added to improve
the dissolution. This mixture was stirred until properly dissolved, exemplified by a clear deep red color.
All reagents were loaded in syringes, but while the HBr, NaOCl and Na SO were pumped by Chemyx
2
3
Fusion 100 syringe pumps, the fluorescein was pumped by a Harvard PhD 22/2000 pump. The flow
rates were 0.00338 mL/min for HBr (22.5 eq.), 0.00959 mL/min for NaOCl (9 eq.), 0.0259 mL/min for
fluorescein (1 eq.), and 0.01559 mL/min for Na SO (18 eq.). This resulted in a residence time of 3 h
2
3
in reactor 2, the bromination reactor. After running the reaction for three complete residence times,
the outlet was collected for 15 h.
The two phases were separated, and the water phase was discarded. A 50 mL value of isobutanol
was added to the organic phase, and concentrated NaOH was added until the color changed from
orange to dark red with a green shade. This mixture was extracted with 3
×
50 mL of water, during
which the pH was held high enough to keep the color from changing back to orange. Since the
end product is brightly coloured, this extraction can easily be followed up. It was noted that it was
impossible to perform the extraction with full efficiency, resulting in a lower yield than expected.
The water phases were combined, extracted once with 50 mL of petroleum ether to remove the residual
◦
organic solvents or ionic liquid, cooled to 0 C and carefully acidified with concentrated H SO .
2
4
The precipitated eosin Y was filtered off as an orange paste and was dried under a high vacuum.
An 612.2 mg amount of pure eosin Y (yield = 78%) was obtained as an orange powder. Purity was
1
13
checked by LC–MS, H-NMR.and C-NMR. These spectra can be found in the Supporting Information.
3
.6. Synthesis of Trioctyl-(3-sulfopropyl)ammonium Perchlorate 4
In a 250 mL flame-dried flask the following were loaded: 1,3-propane sultone
2 (0.20 mol, 24.4 g),
trioctylamine
heated under reflux under an inert Ar-atmosphere. After 72 h, the solvent was evaporated in vacuo,
and the residual brown waxy residue was thoroughly washed with Et O until white and dried under a
1 (0.15 mol, 53.1 g), dry toluene (100 mL), and a stirring bar. The reaction mixture was
2
high vacuum. The zwitterion
3
(Scheme 1) was obtained as a powder in quantitative yield, its purity
1
was confirmed by H-NMR. 50% HClO in H O was added (22.5 mol, 45.2 g), and the mixture was
4
2
◦
heated to 50 C for 5 h, after which two phases had formed. A 50 mL amount of deionized water was
added, and the mixture was extracted with 3 50 mL Et O. Every piece of glassware that came into
×
2
contact with the ionic liquid was rinsed with Et O to minimize the losses and maximize the yield of
2
the viscous ionic liquid. The combined organic phases were evaporated in vacuo and dried under a
high vacuum until 81.32 g (94.1% overall yield). Pure trioctyl-(3-sulfopropyl)ammonium perchlorate
4
1
(
Figure 2) was obtained as a very viscous brown liquid, and its purity was confirmed by H-NMR and
1
3
C-NMR. These spectra can be found in the Supporting Information.

Molecules 2019, 24, 2116
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Figure 2. Trioctyl-(3-sulfopropyl)ammonium perchlorate.
1H-NMR (400 MHz, acetone-d6):
δ
= 0.84 (t, J = 7 Hz, 9H; C11H3), 1.25–1.35 (m, 30H; C6-10H2), 1.77 (br.
s, 6H, C5H2), 2.22 (br. s, 2H, C2H2), 3.14 (t, J = 7 Hz, 2H; C3H2, 3.58 (br. t, J = 8 Hz, 6H; C4H2), 3.35 (m,
2
2
H; C1H2), 10.26 (br. s, D O-exch. SO3H); 13C-NMR (100 MHz, acetone-d ), 13.7 (
1.5 (C ), 22.4 (C ), 26.0 (C ), 28.7 (C ), 28.9 (C ), 31.6 (C ), 47.9 (C ), 56.7 (C ), 58.7 (C ).
C
11), 17.6 (C2),
2
6
6
5
10
7
8
9
3
1
4
4
. Conclusions
A safe and sustainable protocol for the generation, in situ use, and subsequent quench of
bromine was described. The versatility of this protocol was shown by the polybromination of a
variety of substrates in different solvents and even ionic liquids. By performing the reaction in flow,
an inherently difficult and dangerous reaction was made safe and straightforward. The high conversion,
easy work-up, and minimal waste generation due to the superior reaction parameter control in the
microreactor are especially important in reactions like brominations, since potential organobromide
side products are problematic due to their bio-persistence. By avoiding these, a very unsustainable,
but nevertheless very important and necessary, reaction can be made considerably greener and safer.
Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/24/11/2116/s1:
Spectra of all synthesized compounds.
Author Contributions: Conceptualization, R.V.K. and C.V.S.; methodology, R.V.K.; investigation, R.V.K.; resources,
P.N.; writing—original draft preparation, R.V.K.; writing—review and editing, R.V.K., P.N., T.S.A.H., M.D. and
C.V.S.; funding acquisition, R.V.K., T.S.A.H. and C.V.S.
Funding: Financial support for this research from the Fund for Scientific Research Flanders (FWO Vlaanderen) is
gratefully acknowledged.
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the
study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to
publish the results.
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Sample Availability: Samples of the compound trioctyl-(3-sulfopropyl)ammonium perchlorate 4 are available
from the authors.
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