Aqueous solubility of organic compounds for flow battery applications: Symmetry and counter ion design to avoid low-solubility polymorphs

Article abstract of DOI:10.3390/molecules26051203

Flow batteries can play an important role as energy storage media in future electricity grids. Organic compounds, based on abundant elements, are appealing alternatives as redox couples for redox flow batteries. The straightforward scalability, the independence of material sources, and the potentially attractive price motivate researchers to investigate this technological area. Four different benzyl-morpholino hydroquinone derivatives were synthesized as potential redox active species. Compounds bearing central symmetry were shown to be about an order of magnitude less soluble in water than isomers without central symmetry. Counter ions also affected solubility. Perchlorate, chlorate, sulfate and phosphate anions were investigated as counter ions. The formations of different polymorphs was observed, showing that their solubility is not a function of their structure. The kinetics of the transformation can give misleading solubility values according to Ostwald’s rule. The unpredictability of both the kinetics and the thermodynamics of the formation of polymorphs is a danger for new organic compounds designed for flow battery applications.

Full text of DOI:10.3390/molecules26051203

molecules
Article
Aqueous Solubility of Organic Compounds for Flow Battery
Applications: Symmetry and Counter Ion Design to Avoid
Low-Solubility Polymorphs
Sergio Navarro Garcia 1, Xian Yang 2 , Laura Bereczki 1 and Dénes Kónya 1,
*
1
Central Research Institute of Natural Sciences, Magyar Tudósok körútja 2, 1117 Budapest, Hungary;
sergio.navarro@ttk.hu (S.N.G.); nagyne.bereczki.laura@ttk.mta.hu (L.B.)
JenaBatteries GmbH, Otto-Schott-Straße 15, 07745 Jena, Germany; xian.yang@jenabatteries.de
Correspondence: konya.denes@ttk.hu
2
*
Abstract: Flow batteries can play an important role as energy storage media in future electricity grids.
Organic compounds, based on abundant elements, are appealing alternatives as redox couples for
redox flow batteries. The straightforward scalability, the independence of material sources, and the
potentially attractive price motivate researchers to investigate this technological area. Four different
benzyl-morpholino hydroquinone derivatives were synthesized as potential redox active species.
Compounds bearing central symmetry were shown to be about an order of magnitude less soluble
in water than isomers without central symmetry. Counter ions also affected solubility. Perchlorate,
chlorate, sulfate and phosphate anions were investigated as counter ions. The formations of different
polymorphs was observed, showing that their solubility is not a function of their structure. The
kinetics of the transformation can give misleading solubility values according to Ostwald’s rule. The
unpredictability of both the kinetics and the thermodynamics of the formation of polymorphs is a
danger for new organic compounds designed for flow battery applications.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Citation: Garcia, S.N.; Yang, X.;
Bereczki, L.; Kónya, D. Aqueous
Solubility of Organic Compounds for
Flow Battery Applications: Symmetry
and Counter Ion Design to Avoid
Low-Solubility Polymorphs.
Molecules 2021, 26, 1203.
Keywords: organic redox flow battery; hydroquinone; solubility; solubility prediction; polymorph;
Ostwald’s rule
https://doi.org/10.3390/
molecules26051203
1. Introduction
Academic Editors: Joanna Krakowiak,
Petr Mazur and Peter Fischer
As renewable energy penetration increases, the importance of energy storage grows
accordingly to compensate its intermittency [1]. Redox flow batteries are one possible
Received: 28 January 2021
Accepted: 18 February 2021
Published: 24 February 2021
answer to the emerging need of storing energy. In these batteries, energy is stored in the
form of the chemical energy of two different chemical redox pairs. The greatest advantage
of flow batteries is that their rated power and stored energy/capacity can be adjusted
independently, which makes them the ideal candidate for grid applications.
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
Traditionally, most flow batteries were based on the different oxidation states of
metals as electrolytes [
by the first all-organic one in 2014 [
been published [ ]. A redox flow battery must fulfil several criteria to be commercially
2]. The first semi-organic system was published in 2014 [
3], followed
4]. Since that time, several other chemistries have
5–7
successful; such as low cost, safe operation, and sustainable production scalability. When
water is used as a solvent, safe operation is guaranteed. The organic electrolyte makes
the scale up independent from locally available resources. However, to ensure a low
storage cost: cheaply executable synthesis routes, chemically stable and highly water-
soluble compounds are needed. The concentration of the electrolyte is important for
several reasons. In grid applications, energy density is not a critical issue as in the case of
electro-mobility, but a higher electrolyte concentration increases the final energy density
as well as the achievable current densities, leading to better usage of the reactor unit as a
whole and reducing capital and maintenance costs. Finally, high electrolyte concentration
increases the overall cycle efficiency by cycling less solvent (ballast) through the pumps.
Copyright:
© 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Molecules 2021, 26, 1203. https://doi.org/10.3390/molecules26051203
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Unfortunately, organic syntheses are not always straightforward. They are often the
result of many trial and error experiments conducted by synthetic chemists. Synthesizing a
target compound with the required analytical specifications is often a tedious and timely
process. Due to the difficulties in the syntheses and the importance of the solubility factor,
it would be desirable to be able to predict the solubility of the target compound before its
synthesis, so as to avoid all problems that can arise in synthesic procedures.
Pharma researchers have been predicting different physicochemical properties of
organic compounds for a long time. Although some properties like logP and logD values
can be predicted with acceptable accuracy [
8], solubility remains a difficult task. The
story of ritonavir [ ] andthe USD 250 million loss of Abbott on the issue in 1998 when it
9
was finally closed [10], highlighted how desperately the pharma industry needs a useful
prediction method for the aqueous solubility of organic compounds. A project titled
“The solubility challenge” was launched in 2008 by scientists from Cambridge University
and AstraZeneca [11], challenging theoretical chemists in their paper: “Can You predict
solubilities of 32 molecules using a Database of 100 Reliable Measurements?”. There were
99 researchers who participated in the challenge and sent their predictions. In 2009 the
results were analysed in the following paper: “Findings of the challenge to predict aqueous
solubility” [12]. Its conclusions were that no method could reliably predict the solubility of
many organic compounds. The partition coefficient and distribution coefficient are the ratio
of concentrations of a compound in a mixture of two immiscible solvents in equilibrium.
The partition coefficient describes the ratio of uncharged species, while the distribution
coefficient describes all species of the given compound. This explains why the latter is
often pH dependent. Their logarithmic values are logP and logD, which are commonly
used physicochemical parameters to express “greasiness” among pharma chemists. Their
calculated values, which are referred as clogP and clogD are quite predictable. Why is
it more difficult to predict solubility than the logP or logD values? The devil is in the
details, so it is necessary to investigate what energies occur during dissolution. Firstly, the
solute–solute and the solvent–solvent interactions should break up, and then the solute–
solvent interactions are formed. The solubility is determined by the sum of these three
energies. The latter two are reliably calculable, thus logP and logD values, which use
these two energies, are also predictable. However, the question remains as to what can be
said about the energies of solute–solute interactions. Fortunately, this area has also been
researched. Researchers of crystal structure predictions (CSPs) are continually challenging
themselves. The last CSP challenge in 2016 was the sixth, where five unpublished organic
compounds’ crystal structures were predicted. Although the computational methods and
capacities have advanced considerably, they were still not accurate and reliable enough
to give predictions about the energies in solid phase structures to serve as a basis for
solubility predictions. One of the most difficult tasks is to predict polymorphs. Polymorphs
are different crystal structures from the same given compound. Polymorph formation
can be influenced by the solvent, the rate of the crystal growth, temperature, pressure,
etc., indicating that the crystal structure is not only a function of a given compound, but
also depends on many other parameters. Ritonavir has two main polymorphs (the two
which caused the problem), but an additional three were found during the investigation
of the issue. Different polymorphs have different solubility values—five in the case of the
structure of ritonavir [13].
Additionally, even the kinetics of polymorph formation work against flow battery
researchers. According to Ostwald’s rule, it is often the polymorph with the higher solu-
bility (less-packed crystal structure) that is discovered sooner, and the polymorphs with
lower solubility (more ordered crystal structure) are discovered later [14]. This means
that a newly isolated compound’s solubility can change over time after its first isolation.
Unfortunately, this is most likely to happen in an unfavorable direction.
In this work, two pairs of hydroquinone derivatives were synthesized, whose chemical
structures were confirmed by the characterization of NMR and MS, followed by the
solubility measurement in four kinds of acids via gravimetric and NMR methods. We

Molecules 2021, 26, 1203
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show how the appearance of new polymorphs can cause unexpectedly huge changes in
solubility, what methods can be applied to avoid the formation of these densely packed
crystals that will lead to low solubility, and how to obtain structures with better solubility.
2. Results
Our research investigated different quinone derivatives as potential electroactive
compounds for all organic flow battery applications. The electrochemistry of these deriva-
tives will be discussed separately, in another article. Quinone is a good lead from an
electrochemistry perspective. Its redox potential is sufficiently high, its kinetics are fast,
and the quinone/hydroquinone reactant pair represents a two-electron reaction where all
participants are closed-shell compounds. However, neither its stability nor its solubility are
high enough for practical applications, making its derivatization inevitable. The Mannich
reaction is a straightforward option for its derivatization to build a C–C bond onto a phe-
nolic hydroxyl-containing aromatic ring. It is also important to protect the ortho position
of the phenolic hydroxyl as much as possible, due to its easily tautomerizable hydrogens
and its radical electron in the radical-ion formation during the electrode reaction.
Four hydroquinone derivatives were synthesised using the Mannich reaction
(Figure 1) [15]. DMHQ was originally reported in 1964 with only simple structural char-
acterizations and its chemical properties were not covered [16]. Its NMR spectrum was
acquired in deuterated chloroform in later research in our laboratory. The aqueous sol-
ubility of DMHQ in 1 M sulfuric acid was surprisingly good, reaching a concentration
of 1.7 M as measured by gravimetry. Unexpectedly, its solubility dropped below 0.1 M
one year later. It was supposed that the chemical structure of DMHQ had been changed.
Our supposition that the structure had changed was initially reinforced by the fact that
the stored compound was so poorly soluble that the spectrum was no longer measurable
in deuterated chloroform. However, the spectrum acquired in DMSO-d5 later showed
that the product had not been changed chemically. Instead, the compound’s chemical
integrity remained intact; the formation of a new polymorph led to its low solubility. The
hydrochloric acid salt of DMHQ was proven to be a good candidate for X-ray analysis,
resulting in a crystal structure where this polymorph was quite densely packed (Figure 2,
Table 1).
Figure 1.
Synthesized Mannich products. IUPAC names of the compounds: DMHQ:
MMHQ: 2,3-dimethyl-5-[(morpholin-4-
2,5-bis[(morpholin-4-yl)methyl]benzene-1,4-diol;
yl)methyl]benzene-1,4-diol; sym-DDHQ: 2,5-dimethyl-3,6-bis[(morpholin-4-yl)methyl]benzene-1,4-
diol; asym-DDHQ: 2,6-dimethyl-3,5-bis[(morpholin-4-yl)methyl]benzene-1,4-diol.

Molecules 2021, 26, 1203
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Figure 2. Crystal structure of the hydrochloric salt of DMHQ. Hydrogens are omitted for clarity. Green balls are chloride
ions, blue balls are water molecules, and the light green and blue spots show the space available for them in the crystal.
Table 1. Crystal data of the hydrochloric salt of DMDQ.
Compound
DMDQ.2HCl
Empirical formula
Formula weight
C16 H30 Cl2 N2 O6
417.32
Temperature
140(2)
Radiation and wavelength
Crystal system
Cu-Kα, λ = 1.54187 Å
monoclinic
Space group
P 21/c
Unit cell dimensions
a = 9.2629(2) Å
b = 15.4919(3) Å
c = 7.4246(2) Å
◦
α = 90
◦
β = 110.973(8)
◦
γ = 90
994.84(6) Å3
2
Volume
Z
Density (calculated)
Absorption coefficient, µ
F(000)
1.393 Mg/m3
−1
3.238 mm
444
colorless
Crystal color
Crystal description
Crystal size
Absorption correction
Max. and min. transmission
θ−range for data collection
Index ranges
Reflections collected
Completeness to 2θ
Independent reflections
Reflections I > 2σ(I)
Refinement method
prism
0.72 × 0.48 × 0.38 (mm)
numerical
0.5390.766
◦
5.114 ≤ θ ≤ 68.172
−11 ≤ h ≤ 10; −18 ≤ k ≤ 18; −8 ≤ l ≤ 7
17,903
0.972
1763 [R(int) = 0.0332]
1733
full-matrix least-squares on F2

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Table 1. Cont.
Compound
DMDQ.2HCl
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2σ(I)]
R indices (all data)
Max. and mean shift/esd
Largest diff. peak and hole
1763/0/134
1.184
R1 = 0.0308, wR2 = 0.0787
R1 = 0.0317, wR2 = 0.0793
0.000; 0.000
−3
0.249; −0.244 e.Å
Figure 3 illustrates the two methods used to determine solubility. The first method
was gravimetry which required a higher amount of analyte to reduce any error arising
from possible co-crystalized compounds. This method is easy to realize without the need
for high-tech equipment, and its result is also a reference for the other method performed
by NMR spectroscopy. The NMR method required only a small quantity of the analyte
and was more accurate as no co-crystalized compounds were counted in its homogeneous
solution phase.
Figure 3. Flow chart of the gravimetric and NMR methods used for determining solubility.
The NMR spectra used to determine the solubility were recorded with a known
amount of imidazole as the internal standard. After processing the NMR spectra, the
solubility results of the four hydroquinone derivatives are summarized in Table 2.
Table 2. Solubilities of different quinone derivatives in 1 M acids.
−
−
2−
3−
Compound
Cl
ClO4
SO4
PO3
0.07 1
MMHQ
DMHQ
sym-DDHQ
asym-DDHQ
1
0.02
0.01
-
-
0.48
0.48
0.03 1
0.08 2
0.06 3
0.44
0.53
0.40
0.55
-
-
2
Notes: These two compounds’ gravimetric analysis was used to validate the NMR method; First isolated
polymorph showed 1.7 M solubility by the gravimetry method; 3 First polymorph showed 0.24 M solubility by
the NMR method.
As supposed from the X-ray structure, anions with different charge and space needs
could alter the crystal structure and therefore its solubility. Chloride and perchlorate, which
are commonly used anions in organic salt crystals, were poorly soluble, whereas the final
solubility of sulfate crystals was strongly dependent on the structure of the cation pair.

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Phosphate had good solubility in all cases. This demonstrates that sulfuric acid is a better
choice for an organic flow battery application because of its higher conductivity, better
availability, and cheaper price. As seen in Table 2, central symmetry had a detrimental
effect on solubility in sulfuric acid in the cases of DMHQ and sym-DDHQ. This is based on
the supposition that these compounds create better packed solids which results in higher
lattice energy, the energy of the solute–solute interactions, which means lower solubility.
However, when the central symmetry was broken and crystal formation was hindered,
higher solubility was found (MMHQ, asym-DDHQ).
3. Discussion
The results of this study clearly indicate that organic compounds at higher concentra-
tions can behave unexpectedly in aqueous conditions. Similar experiences have been found
by researchers working in the field of organic flow batteries. Anthraquinone disulfonic
acid (AQDS) is a popular choice due to its chemical stability, which comes from the fact
that both the oxidized form (2
×
6 electrons) and the reduced form (1
×
14 electron) fulfil
the 4n+2 conjugated ring electron in Hückel’s rule, so both are aromatics (Figure 4). It can
be seen that the anthraquinone/dihydro-anthraquinone pairs were the smallest system
with this characteristic (together with its same molecular weight isomer: the phenantrene-
9,10-dione).
Figure 4. Aromaticity of the anthraquinone/dihydro-anthraquinone redox pair according to
Hückel’s rule.
The solubility differences between different isomers of AQDS is well known [17].
The 9,10-dioxo-9,10-dihydroanthracene-2,6-disulfonic acid disodium salt (2,6-AQDSNa2)
is poorly soluble in water, with an aqueous solubility below 0.1 M. The same is true
for 9,10-dioxo-9,10-dihydroanthracene-1,5-disulfonic acid disodium salt (1,5-AQDSNa2),
which also has central symmetry. It has an aqueous solubility of 0.07 M. The asymmetric
analogue of 2,6-AQDS and 1,5-AQDS without central symmetry is the 9,10-dioxo-9,10-
dihydroanthracene-2,7-disulfonic acid (2,7-AQDS). Its disodium salt’s solubility is 0.58
M/0.74 M; the difference is about an order of magnitude higher compared to those of the
2,6- and 1,5-AQDS disodium salts (Figure 5).

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Figure 5. Solubility difference between 1,5-, 2,6-, and 2,7-AQDS disodium salts. The 1,5- and 2,6-
AQDS derivatives have central symmetry while the 2,7-AQDS does not. Their difference in solubility
is about an order of magnitude. The solubility of 2,6-AQDS disodium salt was determined using the
NMR method with imidazole as the internal standard.
Analogous to the 1,5- and 2,6- vs. 2,7-AQDS derivatives, the solubility results of the
four compounds presented in this work show a similar phenomenon regarding the effect
of the molecular symmetry and the applied counter ion on the corresponding aqueous
solubility, as listed in Table 2. The example in Figure 6 further demonstrates the importance
of taking into consideration the molecular symmetry when designing novel redox-active
organic molecules targeting high solubility. The aqueous solubility of MMHQ in 1 M
sulfuric acid was 0.48 M. When replacing the apolar methyl group with the polar tertiary
amine group, enhanced solubility is expected in acidic conditions. However, the solubility
of sym-DDHQ decreased by an order of magnitude to 0.06 M. Even though the freshly
obtained product had a solubility of 0.24 M in 1 M sulfuric acid, a more stable polymorph
formed about a year after the first measurement showed the lower 0.06 M value. In this
case, the molecular symmetry apparently dominated the impact on the aqueous solubility.
As a comparison, the asym-DDHQ without central symmetry had a solubility of 0.44 M in
1 M sulfuric acid (Table 1).
Therefore, it can be concluded that structural asymmetry can have a positive effect
on molecular solubility, even by an order of magnitude. On the other hand, it is clear that
counter ions have an important role in solubility as well. This is because the charge and
size of the counter ion in the crystal determine the solubility by influencing the lattice
energies of the different crystal structures.
Practically, the AQDS derivatives used as negolytes in flow battery applications will
probably be a mixture of isomers because the sulfonation of anthraquinone cannot be
directed to give only one product. Separation of these isomers on an industrial scale is
impractical due to the time and resources required to find totally new synthetic approaches
which could create too many risks.
Consequently, targeting quinone derivatives without molecular central symmetry
is encouraged in order to achieve the best solubility. If there is any doubt over whether
the intrinsic solubility can be found, then the potentiometric cycling for the polymorph
creation ([PC]2) method is a useful tool to find the corresponding polymorph in their order

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of formation [18]. It is highly recommended that [PC]2 experiments are run before upscaling
a potential candidate to avoid possible surprises with lower-solubility polymorphs.
Figure 6. This virtual reaction shows how strongly the molecular symmetry can influence the solubility.
4. Materials and Methods
4.1. Nuclear Magnetic Resonance Spectroscopy (NMR)
1H NMR spectra were recorded in DMSO-d6 or CDCl3 solution at room temperature,
on a Varian Unity Inova 500 spectrometer (Bruker Corp. Oxford, UK) (500 and 125 MHz
for 1H NMR and APT-NMR spectra, respectively), with the residual solvent signal as the
lock and imidazole as the internal standard (only for solubility determination). Chemical
shifts (δ) and coupling constants (J) are given in ppm and Hz, respectively.
4.2. Liquid Chromatography-Mass Spectroscopy (LC-MS)
HPLC-MS measurements were performed using a Shimadzu LCMS-2020 (Shimadzu
Corp. Kyoto, Japan) device equipped with a Reprospher (Altmann Analytik Corp. München,
Germany) 100 C18 (5
µ
m; 100 mm
×
3 mm) column and a positive/negative double ion
source (DUIS) with a quadrupole MS analyzer in the range of 50–1000 m/z. The samples
were eluted with gradient elutions, using eluent A (0.1% formic acid in water) and eluent B
(0.1% formic acid in acetonitrile). The flow rate was set to 1.5 mL/min. The initial condition
was 5% eluent B, followed by a linear gradient to 100% eluent B by 1.5 min; from 1.5 to 4.0
min, 100% eluent B was retained; and from 4 to 4.5 min, it returned by a linear gradient to
5% eluent B, which was retained from 4.5 to 5 min. The column temperature was kept at
room temperature, and the injection volume was 1–10 µL. The purity of the compounds
was assessed by HPLC with UV detection at 215 and 254 nm; all starting compounds were
known, purchased, or synthetically feasible, and >95% pure.
4.3. X-ray Crystallography
A colorless single crystal of DMHQ.HCl was mounted on a loop with paratone oil.
Intensity data were collected on a Raxis Rapid II diffractometer (graphite monochromator;
Cu-Kα radiation, λ = 1.54178 Å) at 140 K. The structures were solved by charge-flipping
methods (and subsequent difference syntheses) and then anisotropic full-matrix least-
squares refinement on F2 for all non-hydrogen atoms was performed. The hydrogen atomic
positions could be located on difference Fourier maps. Hydrogen atomic positions were
calculated from assumed geometries. Hydrogen atoms were included in the structure
factor calculations, but they were not refined. The isotropic displacement parameters of the

Molecules 2021, 26, 1203
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hydrogen atoms were approximated from the U(eq) value of the atom they were bonded
to. Molecular graphics were made by the Mercury software.
CCDC 2058624 contains the Supplementary Crystallographic Data for this paper.
4.4. Synthesis
All hydroquinone derivatives were synthesized via a one-step Mannich type conden-
sation from the corresponding hydroquinone.
General method for the Mannich reaction (DMHQ, MMHQ, sym-DDHQ): To a homo-
geneous solution of morpholine (3 eq.) and paraformaldehyde (3 eq.) in 20 mL of isopropyl
alcohol, a solution of the corresponding hydroquinone (10 g, 1 eq.) in 50 mL of isopropyl
alcohol was added. The mixed solution was refluxed for 1.5 h and then concentrated to
give a white crystalline raw product. The product was washed with two 50 mL portions of
diethyl-ether and dried naturally.
In the case of asym-DDHQ, a different procedure was used: a homogeneous solution
of morpholine (19 mL, 4 eq.) and paraformaldehyde (6.5 g, 4 eq.) in 50 mL of toluene and
50 mL of 2-(2-ethoxyethoxy) ethanol was heated at 110 ◦C and the distillate was removed.
Then 2,6-dimethylbenzoquinone (10 g, 1 eq.) was slowly added. The mixed solution was
heated for 20 h at 145 ◦C and then concentrated. Remaining solvents were distilled and
the crude product was purified by filtering through a pad of silica gel using hexane/ethyl
acetate (v/v = 3:7) with two drops of triethylamine as eluent.
Sym-DDHQ needed a previous hydrogenation step to synthesize the correspond-
ing hydroquinone derivative (2,5-dimethylhydroquinone), since its starting material is
available commercially only in the quinone form (p-xyloquinone): To a solution of p-
xyloquinone (10 g, 1 eq.) in 100 mL of methanol, 5% Pd/C (0.1 eq.) was added in an
autoclave and the autoclave was closed. The mixture was kept at 40 ◦C and three charges
of 7.5 bar of H2 were introduced. After the total consumption of H2, the mixture was
filtered through a pad of celite to remove Pd/C residues and the filtrate was concentrated.
Recrystallization of the filtrate in methanol gave 2,5-dimethylhydroquinone.
1H nuclear magnetic resonance (NMR), high-performance liquid chromatography
(HPLC), and mass spectroscopy (MS) were performed to confirm the structure of targeted
molecules:
DMHQ (2,5-bis[(morpholin-4-yl)methyl]benzene-1,4-diol): 1H NMR (500 MHz, CDCl3):
1
δ
6.49 (2H, s), 3.74 (8H, s), 3.65 (4H, s), 2.56 (8H, s); H NMR (500 MHz, DMSO):
δ
9.33
(2H, s), 6.53 (2H, s) 3.58 (8H, t, J = 5 Hz), 3.47 (4H, s), 2.40 (8H, s); HPLC rt = 0.985 min;
MS (m/z) = 309.
MMHQ (2,3-dimethyl-5-[(morpholin-4-yl)methyl]benzene-1,4-diol): 1H NMR (500 MHz,
CDCl3):
sym-DDHQ (2,5-dimethyl-3,6-bis[(morpholin-4-yl)methyl]benzene-1,4-diol): 1H NMR
(500 MHz, DMSO): 10.5 (2H, s), 3.63(4 H, s), 3.59 (8H, t, J = 5 Hz), 2.45 (8H, s), 2.04 (6H, s);
δ 3.74 (4H, s), 3.70 (2H, s), 2.56 (4H, s), 2.16 (9H, s); HPLC rt = 1.468 min; MS (m/z) = 252.
δ
HPLC rt = 0.994 min; MS (m/z) = 337.
asym-DDHQ (2,6-dimethyl-3,5-bis[(morpholin-4-yl)methyl]benzene-1,4-diol): 1H NMR
(500 MHz, CDCl3):
δ 3.74 (8H, t, J = 5 Hz), 3.70 (4 H, s), 2.59 (8H, s), 2.24 (6H, s); HPLC rt =
0.919 min; MS (m/z) = 337.
5. Conclusions
This article shows that polymorph formation is a real danger in compound design
for organic flow batteries, as it can drastically reduce the aqueous solubility of the target
compound by forming a more densely packed crystal. The biggest issue is that the precise
and reliable prediction of aqueous solubility is still not possible regardless of polymorph
formation. The timescale of the appearance of the polymorph with lower solubility is
unpredictable as well. In the case of forming salts, changing the counter ion is a possible
option if other conditions permit. Our general advice is that it is better to avoid the central
symmetry of the targeted molecules in order to decrease the probability of the formation of

Molecules 2021, 26, 1203
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a stable polymorph that will undesirably lower the solubility. This statement is true for
AQDS derivatives as well—another important compound group in flow battery chemistry.
Supplementary Materials: The following are available online, crystallographic data.
Author Contributions: Investigation: L.B. and S.N.G. Methodology: X.Y. Supervision: D.K. Writing—
review and editing: X.Y. Writing—original draft preparation: D.K. All authors have read and agreed
to the published version of the manuscript.
Funding: The research of X.Y. and S.N.G. has received funding from the European Union’s Horizon
2020 research and innovation programme under the Marie Skłodowska-Curie Grant Agreement No.
765289. The work of L.B was supported by the National Research, Development and Innovation
Office-NKFIH through OTKA grants KH129588 and K124544. The contribution of D.K. was financed
by VEKOP-2.3.2-16-2017-00013 grant.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: During the research Marvin was used for drawing, displaying, and characterizing.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Research samples of hydroquinone derivatives are available by e-mailing to
Denes Konya (konya.denes@ttk.mta.hu).
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