Interrogation of 2,2′-Bipyrimidines as Low-Potential Two-Electron Electrolytes

Article abstract of DOI:10.1021/jacs.0c11267

As utilization of renewable energy sources continues to expand, the need for new grid energy storage technologies such as redox flow batteries (RFBs) will be vital. Ultimately, the energy density of a RFB will be dependent on the redox potentials of the respective electrolytes, their solubility, and the number of electrons stored per molecule. With prior literature reports demonstrating the propensity of nitrogen-containing heterocycles to undergo multielectron reduction at low potentials, we focused on the development of a novel electrolyte scaffold based upon a 2,2′-bipyrimidine skeleton. This scaffold is capable of storing two electrons per molecule while also exhibiting a low (～-2.0 V vs Fc/Fc+) reduction potential. A library of 24 potential bipyrimidine anolytes were synthesized and systematically evaluated to unveil structure-function relationships through computational evaluation. Through analysis of these relationships, it was unveiled that steric interactions disrupting the planarity of the system in the reduced state could be responsible for higher levels of degradation in certain anolytes. The major decomposition pathway was ultimately determined to be protonation of the dianion by solvent, which could be reversed by electrochemical or chemical oxidation. To validate the hypothesis of strain-induced decomposition, two new electrolytes with minimal steric encumbrance were synthesized, evaluated, and found to indeed exhibit higher stability than their sterically hindered counterparts.

Full text of DOI:10.1021/jacs.0c11267

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Article
Interrogation of 2,2′-Bipyrimidines as Low-Potential Two-Electron
Electrolytes
Jeremy D. Griffin, Adam R. Pancoast, and Matthew S. Sigman*
Cite This: J. Am. Chem. Soc. 2021, 143, 992−1004
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ABSTRACT: As utilization of renewable energy sources continues to expand, the need
for new grid energy storage technologies such as redox flow batteries (RFBs) will be
vital. Ultimately, the energy density of a RFB will be dependent on the redox potentials
of the respective electrolytes, their solubility, and the number of electrons stored per
molecule. With prior literature reports demonstrating the propensity of nitrogen-
containing heterocycles to undergo multielectron reduction at low potentials, we
focused on the development of a novel electrolyte scaffold based upon a 2,2′-
bipyrimidine skeleton. This scaffold is capable of storing two electrons per molecule
while also exhibiting a low (∼−2.0 V vs Fc/Fc+) reduction potential. A library of 24
potential bipyrimidine anolytes were synthesized and systematically evaluated to unveil
structure−function relationships through computational evaluation. Through analysis
of these relationships, it was unveiled that steric interactions disrupting the planarity of
the system in the reduced state could be responsible for higher levels of degradation in
certain anolytes. The major decomposition pathway was ultimately determined to be protonation of the dianion by solvent, which
could be reversed by electrochemical or chemical oxidation. To validate the hypothesis of strain-induced decomposition, two new
electrolytes with minimal steric encumbrance were synthesized, evaluated, and found to indeed exhibit higher stability than their
sterically hindered counterparts.
been developed. This could be in part due to the inherently
more reactive (from a thermodynamic perspective) nature of
electrolytes with extreme redox potentials. Specifically, redox
events at extreme potentials will produce low-lying unfilled
molecular orbitals (MOs) for catholytes or high-lying occupied
MOs for anolytes. Therefore, accomplishing the goal of
maximizing the voltage of nonaqueous RFBs will require
more systematic studies into the fundamental properties of
organic electrolytes that have both high chemical stability and
extreme redox potentials. Additionally, the energy density of
RFBs can be improved through the development of electro-
lytes that can access multiple charged states; this has been
accomplished in transition metal-based electrolytes20,21 but has
proven more difficult in organic systems.22−24 Commonly used
anolytes such as 9-fluorenone25 and alkylated phthalimide
derivatives18,26 are limited to the storage of a single electron in
the charged state. Other systems, including viologen
derivatives,22 4-benzoylpyridiniums,27 and anthraquinone
derivatives,23,28 have been shown to undergo two reductions,
INTRODUCTION
■
Renewable energy sources are expected to play an increasingly
important role in the global energy supply.1−3 However,
common renewable energy technologies, such as solar or wind
power, suffer from intermittent energy generation that could
cause grid stability issues.4−6 To overcome this limitation, large
scale energy storage systems need to be developed, including
redox flow batteries (RFBs).7−9 These systems store electrical
energy by flowing redox-active compounds (electrolytes) on
opposite sides of an electrochemical cell, simultaneously
reducing anolytes and oxidizing catholytes in the course of
charging. During discharge of the battery, the opposite redox
event is performed. RFBs have traditionally been dominated by
the use of aqueous vanadium systems due to their long
lifetimes and efficient cycling capabilities.10,11 However, from
environmental, sustainability, and economic perspectives, these
systems are not ideal.12−15
Organic electrolytes can hypothetically reach higher cell
voltages (and thus energy densities) because they are soluble
in nonaqueous and aqueous conditions,16 while simultaneously
addressing environmental and sustainability concerns. Non-
aqueous solvents such as acetonitrile (MeCN) offer a much
larger potential window (∼6 V) than that of H2O (1.23 V)17
and are capable of solubilizing organic electrolytes as well as
supporting electrolyte salts. While significant progress has been
reported,18,19 organic electrolytes with redox potentials at the
bounds of the electrochemical window of MeCN have not yet
Received: October 26, 2020
Published: January 7, 2021
https://dx.doi.org/10.1021/jacs.0c11267
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© 2021 American Chemical Society
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however, one or both of the reduction potentials occurs at
relatively moderate potentials (Figure 1).
investigated. Initial evaluation of several bis-heterocycle core
structures revealed that unsubstituted 2,2′-bipyrimidine was a
particularly promising redox-active subunit, which exhibited a
single reversible couple within the solvent window, at low
potential (E1/2red = −2.19 V vs Fc/Fc+). While a second redox
red
event was observed (Ep/2 = ∼−2.6 V), this couple was
irreversible and accessing it led to obvious decomposition on
the CV time scale (Figure 2A). It was hypothesized that
Figure 1. Comparison of the theoretical energy density of various
anolyte materials (half-cell) with 0.1 M active electrolyte. Green and
blue bars show the energy densities when using coordinating (green)
and noncoordinating (blue) supporting electrolytes. FL = 9-
fluorenone, Phth = N-alkyl phthalimide, MV = methyl viologen, Py
= 4-benzoylpyridinium, AQ = anthraquinone.
With this context in mind, our goal was to identify and study
electrolytes that could probe how one can simultaneously
optimize both the number of electrons stored per small
molecule and extreme redox potentials. To achieve this goal,
herein we present a combined experimental and computational
study of a new class of 2e−, low-potential anolytes derived from
a bipyrimidine core. A modular synthetic route was developed
that enabled the synthesis of a library of analogues, which were
evaluated for stability during electrochemical cycling. Struc-
ture−function relationships using a computational workflow
provided insights into what is required to achieve enhanced
cycling stability.
Figure 2. (A) Cyclic voltammograms of 2,2′-bipyrimidine (5 mM) in
0.1 M TBABF4/MeCN solution with switching potential at −2.6 and
−2.8 V, respectively. Glassy carbon working electrode (0.07 cm2).
Scan rate = 100 mV/s. (B) Designing a new anolyte that can store 2e−
at extreme redox potentials.
RESULTS AND DISCUSSION
■
Electrolyte Scaffold Selection and Synthesis. In 2015,
Sanford and co-workers disclosed the development of
pyridinium-based anolytes, which have subsequently been
studied to improve their stability and energy density by
employing both classical and modern physical organic
tools.29,30 Preliminary investigations by our team, as well as
previous reports from the Sanford lab,29 revealed that other
nitrogen-based heterocycles were capable of undergoing
reversible reduction at low potentials near the solvent window
(approaching −2.0 V vs Fc/Fc+). Of particular interest were
bis-heterocycles, such as bipyridines, as these molecules are
commonly employed in metal complexes as nonredox innocent
ligands.31−33 Additionally, these molecules present the
possibility of undergoing two consecutive reductions (in a
manner akin to viologen)22,34−36 at lower potentials. While
several substituted (particularly 5,5′-substituted) bipyridines
were found to have two reversible redox couples at low
potentials, ultimately bipyridines were not conducive to
systematic analysis, in part, due to the lack of a modular
route to their synthesis.
addition of electron-withdrawing groups onto the bipyrimidine
core could shift the second redox potential into the solvent
window; consequently, a synthetic route was designed to
access more electron-deficient ester-substituted bipyrimidines
(Figure 2B). The route was inspired by Buono and co-workers
in their synthesis of hydroxypyrimidines,37 which have been
demonstrated as important intermediates for the synthesis of
pharmaceuticals. An exciting aspect of the synthetic plan was
the use of a Biginelli condensation, which would theoretically
allow us to vary substitution at all three of the available
positions on the pyrimidine core due to the availability of a
wide variety of both aldehyde and ketoester starting materials.
This synthetic strategy afforded the opportunity to design a
subset of these molecules to study structure−function
relationships (vide infra). Typical Biginelli conditions (Figure
3, condition i) involved CuCl and H2SO4 in catalytic
quantities; however, in the case of aliphatic aldehydes, FeCl3·
6H2O was used as a superior alternative (condition ii).38 The
pyrimidinone products (1) following condensation can be
As a result, other nitrogen heterocycle-containing molecules,
which could may be more amenable to derivatization, were
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Figure 3. Synthetic route to substituted 2,2′-bipyrimidines: (i) 1 mol
% CuCl, 20 mol % H2SO4, R3OH, 70°C; (ii) 0.6 equiv of FeCl3·
6H2O, HCl, R3OH Δ; (iii) 1 mol % CuCl2, 20 mol % K2CO3, 2.0
equiv of tBuOOH, DCM, 40 °C; (iv) 1.2 equiv of K2S2O8, 3:2
MeCN:H2O, Δ; (v) 0.5 equiv of N,N-dimethylaniline, 8.5 equiv of
POCl3, 60−70 °C; (vi) 5.0 equiv of PPh3, 5.0 equiv of N-
chlorosuccinimide, dioxane, Δ; (vii) 5−10 mol % NiBr2, 10 mol %
2,2′-bipyridine, 2.0 equiv of Mn°, DMF 60 °C; (viii) electrochemical
conditions, see above.
Figure 4. Cyclic voltammograms of compound 4a with TBAPF6,
KPF6, NaPF6, and LiPF6 (0.5 M) as supporting electrolytes in MeCN.
Glassy carbon working electrode (0.07 cm2). Scan rate = 100 mV/s
scan rate.
Two-electron electrolytes can suffer loss of energy efficiency if
the redox couples of the individual electron transfers are very
different. If redox couples are sufficiently separated, a
significant amount of energy can be lost in the form of heat.27
Surprisingly, 2,2′-bipyrimidines containing esters at the 5,5′
positions were found to undergo two successive reduction
events at similar potentials (−1.83 and −2.00 V vs Fc/Fc+,
respectively); in some cases, the redox potential for both
couples are nearly identical (vide infra). The nature of the two
redox events is dependent, in part, on the identity of the
counterions associated with the reduced state (Figure 4). More
Lewis acidic counter cations lead to an anodic shift in
potential, a phenomenon also observed for the second
reduction of pyridinium-based electrolytes.27 This is rational-
ized by the stronger coordination of the countercation with the
anionic products of reduction. Interestingly, the use of KPF6 or
NaPF6 as the supporting electrolyte not only causes a shift in
redox potential of 4a (relative to TBAPF6) but also causes
both reduction waves to coalesce into a single discernible,
albeit broad (i.e., peak-to-peak separation ≠ 28.5 mV) redox
event. This indicates that the two couples are shifted closer
together but still thermodynamically inequivalent. LiPF6
resulted in the most dramatic shift in E1/2; however, both
redox events were again resolved into two distinct peaks. While
it is not clear why the relative difference in the two redox
couples are affected by the cation identity, it is possible this
arises from differences in how each countercation interacts
with the anion and dianion reduction products, respectively.44
To better understand the nature of both reduction products,
DFT calculations were undertaken. Using 4a as a model
system, geometry optimizations were carried out on the neutral
(4a), radical-anion (4a•−), and dianion (4a2−) charge states at
the M06-2X/6-31+G(d,p) level of theory45 with the
efficiently converted to the corresponding 2-hydroxypyrimi-
dines (2) via oxidation. In most cases, oxidation could be
achieved under the catalytic CuCl2 conditions described by
Buono and co-workers utilizing tBuOOH as a mild
stoichiometric oxidant (condition iii).37 In the case of ortho-
substituted aromatic groups (R1 = 2-aryl), oxidation proceeded
slowly under these conditions. Thus, oxidation of these
substrates could be achieved more efficiently using stoichio-
metric K2S2O8 (condition iv). Importantly, the first two steps
in the sequence have been reported to be highly scalable
(∼400 kg scale, conditions i and iii)37 without the need for
purification (products 1 and 2 could be obtained cleanly
through a simple filtration in most cases).
Converting 2-hydroxypyrimidines (2) to their respective 2-
chloropyrimidines (3) proceeded smoothly through the use of
POCl3 (condition v),39 with the exception of acid-sensitive
esters which required the use of Appel type conditions
(condition vi).40,41 Finally, a Ni-catalyzed homocoupling,
originally developed for the synthesis of bipyridines by Weix
and co-workers, could be adapted to the synthesis of the
desired bipyrimidine products (4).42 While these conditions
were not optimized for a particular substrate, it was discovered
that some minor changes could furnish the products with
higher efficiency (see SI for details). Additionally, the reductive
homocoupling can be carried out electrochemically to provide
4a in much higher yield relative to the Mn-mediated
conditions (Figure 3, see SI for details).43
Characterization of a Model Electrolyte. Cyclic
voltammetry (CV) experiments with compound 4a showed
that these substituted bipyrimidines undergo two reversible
redox events (Figure 4), initially confirmed via coulometry.
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Figure 5. (A) Rotational barriers of 4a, 4a•−, and 4a2− were computed by scanning θ1 and θ2 in 5° increments to find the highest energy structure,
which was used as the input geometry for transition state calculations. θ1 dihedral angle between the two pyrimidine rings. θ2 is the dihedral angle
between the ester and the pyrimidine ring (smallest angle). (B) Relevant molecular orbitals of 4a, 4a•−, and 4a2−. (C) Changes in NBO charge at
relevant atoms upon reduction from 4a → 4a•− and 4a•− → 4a2−. Mulliken spin density from 4a•−. All calculations were performed at the M06-
2X/6-31+G(d,p) level of theory with CPCM solvation in MeCN.
conductor-like polarizable continuum model (CPCM)46,47
solvation in acetonitrile. In the optimized geometry of 4a,
the two heterocycles do not adopt a planar conformation,
although the barrier to rotation around the bond is predicted
to be low (ΔΔG⧧θ1= ∼3 kcal/mol, Figure 5A).48 The LUMO
has symmetry similar to that of the SOMO of 4a•−, suggesting
a relatively small geometrical change following reduction
(Figure 5B). Because the barrier to rotation is low, adopting
the conformation necessary for the electron transfer to occur
should be facile. 4a•− takes on a planar geometry, with respect
to the two heterocycles, with the barrier to rotation increasing
to 13.5 kcal/mol, demonstrating the increase in bond order.
Due to this relatively low barrier for rotation, in cases where
substituents on the heterocycle are not identical, an
equilibrium mixture of both conformers will likely be formed
following electron transfer. The HOMO of 4a2− demonstrates
symmetry similar to that of the SOMO of 4a•−, while the bond
order between the central heterocycles increases further as
demonstrated by an even higher barrier to rotation (30.3 kcal/
mol). This large barrier indicates that isomerization is not
likely occurring at room temperature in the dianionic state;
thus, the isomeric mixture obtained is likely dictated by the
distribution of 4a•−.
ester. After the first reduction, ΔG⧧
decreases because
(θ2)
coplanarity allows delocalization of the anionic charge (Figure
5A). In 4a2−, a coplanar conformation is adopted, however the
barrier to rotation remains accessible at room temperature
(ΔG⧧(θ2) = 9.2 kcal/mol). This implies a relatively small bond
order between the two groups, and that the anionic charge
primarily resides at the C5 position. The equilibrium
distribution between the ester conformers is likely controlled
by steric interactions of the ester with substituents at the 4 and
6 positions of the ring. The presence of multiple conformers/
isomers could have interesting implications for redox proper-
ties and solubility of the reduced species.
NBO calculations reveal that the largest increase of negative
charge is at the C2 and C5 carbons for 4a → 4a•− and 4a•−
→
4a2−, although there is significant increase in negative charge at
the heteroatoms as well (Figure 5C). Further, natural
population analysis also suggests a formal lone pair on the
C5 carbon with an occupancy of 1.32 electrons for 4a2−. MO
analysis shows that in the SOMO and HOMO of 4a•− and
4a2−, respectively, a relatively localized lobe at the C5 position
is present (Figure 5B). Similarly, the spin density in 4a•−
seems to be primarily localized at the C2 and C5 positions as
predicted by Mulliken population analysis. Thus, while the
ester group has an effect of stabilizing anionic charge in the
reduced states, a formal anionic charge is not observed on the
carbonyl oxygen as intuitively anticipated, but rather, due to
the distortion of the ester from planarity, lies more so on the
C5 positions. This result informed our later analysis of how the
reduced electrolytes decompose (vide infra).
As a result of steric repulsion with the substituents at the 4
and 6 positions, the ester does not achieve coplanarity with the
pyrimidine (4a, θ2 = 55°). The dihedral angle between each of
the heterocycles and the connected ester functionalities is
reduced in each subsequent electron transfer event, demon-
strating the importance of delocalization of the charge onto the
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Figure 6. Library of 2,2-bipyrimidines. Redox potentials referenced internally vs Fc/Fc+. %Fade = the overall capacity fade observed for each
compound. SOC = state of charge (highest reached). % Fade/h = overall capacity fade/total cycling time.
Evaluation of the Electrolyte Library for Cycling
Stability. After initial CV tests with 4a demonstrated that
both couples were reversible at low scan rates (ipa/ipc of 0.95 at
10 mV/s), illustrating stability on CV time scale, electro-
chemical cycling of 4a was carried out (see SI for details). The
anolyte was dissolved in MeCN, containing 0.5 M TBAPF6
supporting electrolyte and placed in one side of a divided H-
cell. Anolyte 4a was then reduced, first to 4a•− and then 4a2−
by application of a constant current (−5 mA), using a
reticulated vitreous carbon (RVC, 100 ppi) electrode. A
potential cutoff of −2.3 V was designated, at which point the
current was reversed (+5 mA), leading to regeneration of 4a.
To obtain information about stability from this data, this
cycle is repeated iteratively. Over the course of 50 cycles (18.3
h), a 17% loss of capacity was observed, corresponding to 1.1%
capacity fade/h, with Coulombic efficiency (CE) remaining
close to 100% over the course of the experiment. Overall %
fade in capacity is defined as the percent of capacity lost
relative to the highest overall capacity reached. Initial storage
stability tests of 4a were also carried out via bulk electrolysis,
controlling SOC to 80%. CV and NMR showed minimal
decomposition after 3 days in storage (see SI for details).
Because initial experiments demonstrated that 2,2′-bipyrimi-
dines were capable of undergoing two reversible reductions at
low potential, further exploration of these electrolytes was
undertaken. To evaluate potential structure−function trends, a
subset of substituted 2,2′-bipyrimidines was synthesized, with
24 compounds in total, utilizing the synthetic route described
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Figure 7. (A) Comparison of cyclic voltammograms of compounds 4f, 4a, 4j, and 4n, illustrating how structural changes led to differences in
relative shifts of E1/21 and E1/22. (B) DFT structures of the radical-anion and dianion of compounds 4f and 4n, respectively. Greater distortion of
the ester group from planarity leads to a cathodic shift in the first redox couple, while distortion of the pyrimidine ring leads to cathodic shift of the
second redox couple.
above (Figure 6). With the exception of 4i, which exhibited
poor solubility in MeCN and could not be electrochemically
characterized, all molecules synthesized were observed to have
reversible couples whose peak currents were linearly depend-
ent on the square-root of scan rate (see SI for details),
indicative of a diffusion-controlled electron transfer process.
Varying the identity of the ester was found to have subtle
effects on redox potentials (compounds 4a−e), while changes
to the substituents on the pyrimidine core led to larger
differences. As expected, electron-donating groups generally
lead to a negative shift in the redox potential for the two
couples, resulting in dialkyl-substituted 2,2′-bipyrimidines
(4r−x) having more extreme potentials. However, 4q
exhibited the least negative E1/2 values for both couples, due
to apparent stabilization afforded by the tethered ammonium
cation.
planarization of the carbonyl due to repulsive interactions (θ2
1
= 61°) and thus more extreme E1/2 values. A similar effect is
observed when comparing 4f2− (θ3 = 167°) and 4n2− (θ3 =
152°) where a greater degree of ring puckering is observed
when larger substituents are present adjacent to the ester. This
1
2
distortion effect seems to impact E1/2 more so than E1/2
,
leading to coalescence of the two redox potentials in more
hindered 2,2′-bipyrimidines.
H-cell cycling was carried out for each member of the
library, illuminating considerable differences in stability based
on structural changes, with overall % fade in capacity observed
ranging from 15% to 87% and the rate of fade (% fade/h)
ranging from 0.71% to 14.0% (Figure 6). Categorization of the
electrolytes based on % capacity fade/h during H-cell cycling,
which has been shown to be a more reliable metric for
analyzing cycling stability than overall capacity fade,16,49
illustrated several stability trends in the data (Figure 6, chart).
Empirically, it is evident that bipyrimidines bearing large
groups at the 4 and/or 6 positions have a pronounced decrease
in stability to electrochemical cycling, as illustrated by
compounds 4l−n as well as 4w (Figure 6, light red category).
A systematic increase in % fade/h is observed when increasing
the size of the 4-substituent as seen in the series of compounds,
4a (Me), 4j (Et), 4l (iPr), and 4n (tBu). Aryl substitution
seems to have a generally stabilizing effect, as the majority of
the best performing compounds are aryl substituted, although
compounds 4o and 4p, bearing only methyl groups on the
pyrimidine rings, also exhibited comparatively good stability.
As observed in previous studies,30 redox potential was not
found to be a reliable predictor of stability (Figure 8), although
the most stable compounds generally were observed to have
less extreme average redox potentials.
Interestingly, the identity of the functionality at the 4 and 6
1
positions of the bipyrimidine seemed to not only affect E1/2
2
and E1/2 values but also their relative position to each other
(Figure 7A). DFT analysis highlighted that due to the steric
congestion about the ester functionality at the 5 position, two
distinct types of geometrical distortion can occur in the
radical−anion (4•−) and dianions (42−) following reduction.
As discussed above, the carbonyl group in 4•− is distorted from
the expected planarity with the aromatic ring. However, in 42−
the pyrimidine ring itself is puckered to achieve resonance
delocalization of the anionic charge present at the C5 position,
which becomes more impactful in the dianionic charge state
(Figure 7B).
Substituents on either side of the ester lead to a systematic
effect on the first redox couple, with groups that facilitate a
1
relatively large degree of planarity, leading to less extreme E1/2
values. For example, 4f •− bears a 2-tolyl group, which allows a
greater degree of planarity of the carbonyl (θ2 = 28°) due to
the orthogonal positioning of the aromatic ring relative to 4a•−.
Larger groups, such as the tBu substituent in 4n•−, lead to less
Investigation into the Origin of Electrolyte Decom-
position. While it was initially surprising that increased steric
hindrance increased the rate of decomposition, these general
observations led us to consider that geometric distortion of the
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However, independent experiments revealed that these
features likely arise from crossover of reactive species from
the counter-side of the H-cell and thus are not indicative of the
inherent stability of the molecules to electrochemical cycling
(see SI for details).
Because a single major decomposition pathway seemed to be
responsible for the majority of the observed capacity loss
during cycling, further investigation of this decomposition
product was undertaken. Due to the rapid decomposition of
compound 4n in the respective charge states, this compound
was selected as a model to study the relevant decomposition
pathway. Bulk electrolysis of a solution of 4n was undertaken
at −2.4 V (vs Ag/AgNO3) to achieve ∼100% SOC,
subsequently generating the unknown decomposition product,
which could be characterized by 2D NMR analysis (Figure 10,
see SI for experimental details and characterization). Chemical
derivatization of the decomposition product was undertaken
by treating the compound with 4-bromobenzyl bromide,
allowing for analysis of the resulting products by mass
spectrometry. The composition of the resulting compound is
consistent with the structure depicted as 6n (Figure 10), and
thus, via inference, the decomposition is assigned as 5n, which
is formed through protonation of 4n2−. To explore how 5n was
formed, a separate electrolysis was carried out in d3-MeCN.
Figure 8. %Fade/h versus the average redox potential for each 2,2′-
bipyrimidine.
bipyrimidine could be a contributing factor to decomposition
during H-cell cycling. To validate this hypothesis, we
endeavored to identify products of decomposition. After each
H-cell cycling experiment, a CV was taken to detect any
changes (Figure 9).
While several decomposition products were observed
throughout the course of the library evaluation, one major
distinctive feature was detected in the majority of H-cell
cycling experiments (see SI for CVs of all library members). As
depicted in Figure 9, when comparing the most and least stable
compounds from the initial data set (4f and 4n), an irreversible
oxidative feature is observed with an Ep/2 ∼ −1.0 V vs Fc/Fc+
after 50 charge/discharge cycles. This feature was accompanied
by the appearance of a sharp reductive feature with Ep/2 ∼ −2.7
V vs Fc/Fc+. The appearance of these features correlated with
the degree of decomposition of the active electrolyte. Other
decomposition products were commonly observed by CV as
well, which generally appeared below −2.5 V vs Fc/Fc+.
1
Upon H NMR analysis of the resulting reduced material, the
diagnostic methine signal was absent while other signals
remained unchanged, suggestive of deuteration. Deuterium
incorporation was verified via alkylation with 4-bromobenzyl
bromide and analysis by mass spectrometry. Taken together,
the decomposition pathway is proposed to occur via
protonation of the dianion with the solvent.
While other minor decomposition products were present as
well, identifying a major pathway of decomposition provided
key insight into how more stable electrolytes could be
developed. DFT analysis of 5n shows that significant strain is
Figure 9. (A) Formation of decomposition product after H-cell cycling experiments (50 cycles). (B) CV before and after H-cell cycling of
compound 4f highlighting minimal decomposition. (C) CV after the H-cell cycling of 4n, showing a large degree of decomposition. Bulk
electrolysis of the decomposition product at −0.4 V led to the regeneration of 4n. (D) Normalized discharge capacity of 4n vs cycle number. Large
decrease in capacity was observed after 50 cycles. After electrolysis of 5n, some capacity was regenerated.
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remained relatively low throughout the remaining nine cycles.
This suggests a more rapid decomposition of 4n, and following
these 10 cycles, 5n is once again generated. The conversion of
5n back to 4n can be undertaken multiple times. The low CE
observed, and rapid conversion back to 5n, is suggestive of
buildup of a stronger acid source following the bulk
electrolysis. This is likely a consequence of the formation of
a cationic intermediate following two-electron oxidation of 5n;
however, the acid source has not yet been identified.
To investigate this potential avenue for regeneration of
decomposed material further, compound 4l was chemically
reduced via potassium naphthalenide in THF, followed by a
salt exchange with TBACl in MeCN (Figure 11). After 24 h,
Figure 10. Identification of the major decomposition product via a
combination of NMR and chemical derivation analysis.
relieved from 4n2− upon protonation to render the C5 carbon
sp3 hybridized and allowing the ester to position itself away
from the congested pyrimidine ring. Ring puckering in the
remaining reduced pyrimidine ring is also relieved, because the
remaining anionic charge can be adequately stabilized via
delocalization in the ring system. This is consistent with the
hypothesis that geometric strain induced by reduction to the
dianionic charge state is primarily responsible for the instability
of certain electrolytes.
In considering the decomposition process results from a
simple protonation event, a unique avenue for regeneration of
redox active material was envisioned, similar to the process of
anthraquinone regeneration reported by Aziz and co-work-
ers.28 This was inspired by the observation of 5n (∼−1.0 V vs
Fc/Fc+) undergoing two-electron oxidation upon exposure to
ambient air to ultimately regenerate the neutral 2,2′-
Figure 11. Chemical reduction and decomposition of compound 4l
followed by regeneration of the neutral molecule after addition of a
hydride scavenger.
1
bipyrimidine 4n via deprotonation as evidenced by H NMR
(see SI for details). It was also discovered that 5n could be
electrolyzed to partially reform 4n by performing bulk
electrolysis at −0.4 V as evidenced by CV (Figure 9C). After
50 electrochemical cycles of 4n, nearly all of the redox active
material had been depleted, with only ∼10% of the theoretical
capacity remaining after 50 cycles. However, upon electrolysis
of 5n, a renewal of capacity was observed after 10 additional
cycles were carried out, reaching a maximum of ∼30% of the
theoretical capacity, providing further evidence for the
reappearance of 4n (Figure 9D).
significant decomposition to the protonated species was
observed by analysis of an aliquot of the solution by CV
(∼70% of the material was lost based on the CV peak heights).
Upon addition of triphenylcarbenium tetrafluoroborate
(Ph3C+BF4 ) as a formal hydride scavenger, regeneration of
−
4l was observed by CV (∼90% of the decomposed material
regenerated) and 1H NMR, along with the formation of
triphenylmethane. It is not clear if the regeneration occurs via a
concerted hydride abstraction or via stepwise electron transfer
50
(Ph3C+BF4 , E1/2 = −0.11 V in MeCN vs Fc/Fc+)
−
red
Overall, a low Coulombic efficiency (CE) of only 40% was
observed for the first cycle following electrolysis, and CE
followed by H atom abstraction. This method of regenerating
bipyrimidines seems to be more efficient than direct
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Figure 12. (A) Truncation model for 42− which drastically decreased the number of conformers that needed to be computed. (B) Multivariate
linear regression model relating % capacity fade/h with structural features of the electrolytes. (C) Parameters contained in the model.
Boltz
NBO(C4/C6)
is the average, Boltzmann weighted, NBO charge at the C4 and C6 positions on the truncation model. Max. DistortionBoltz is the
maximum of the two possible modes of distortion from planarity.
electrolysis, likely because it eliminates acid buildup. With the
degradation and regeneration pathways unveiled, future
investigations into second-generation bipyrimidine anolytes
will be carried out in due course.
conformer. These were subjected to DFT optimization at the
M06-2X/6-31+G(d,p) level of theory with CPCM solvation in
MeCN. Various features (see SI for details) were then
collected from the DFT optimized structures, including
Boltzmann weighted parameters. The original 24 library
members were split into training (16 electrolytes, black
squares) and validation sets (8 electrolytes, green squares)
using a pseudorandom automated process.53 MLR analysis was
performed using a forward stepwise linear regression
algorithm,53 to identify important features that correlate to
the experimentally obtained % fade/h data. A statistical model
containing two terms was identified (Figure 12B) with an R2
value of 0.86 indicating a good correlation. Internal (Q2 = 0.80
and K-fold = 0.78) and external (R2val = 0.81) validations were
carried out to evaluate the robustness of the model. The two
terms found in the model are the average of the NBO charges
at the C4 and C6 positions and the maximum distortion from
planarity of the truncation model system. Both parameters are
derived from Boltzmann weighting of conformers (Figure
12C).
The average NBO charge at the C4 and C6 positions is
proposed to generally describe the overall stabilizing effect that
aromatic groups have at these positions. The positive
coefficient associated with this parameter presumably indicates
that electron donating alkyl groups lead to a higher degree of
polarization of the CN double bond. Interestingly, this
parameter was found to be the most important descriptor of
stability in the model as evidenced by the magnitude of the
coefficient, indicating that electron-donating alkyl groups lead
to a less stable electrolyte. The distortion from planarity was
found to be an important parameter as well, validating our
hypothesis that torsional strain built up in the electrolyte upon
reduction could lead to more rapid decomposition. Two
different modes of distortion were identified during evaluation
of the library, underscoring that the identity of the substituents
at the C4 and C6 position can change the manner in which 42−
Identifying Structure−Activity Trends and Designing
Improved Electrolytes. Having identified a decomposition
pathway for compound 4n, we set out to globally test the
hypothesis that strain relief plays a significant role in
decomposition for the library of compounds evaluated. To
probe this, we elected to undertake the development of
multivariate linear regression (MLR) models, as it is clear from
the empirical data that multiple factors are responsible for the
observable changes in decomposition rate. These tools have
been commonly used by our lab to relate various experimental
outcomes to computationally derived physical properties of
chemical compounds.51−53 To initiate the analysis, we selected
the dianionic species (42−) to perform feature selection, as this
species was experimentally determined to be responsible for
the primary decomposition processes (vide supra).
Because conformational flexibility of the substituents at the
C4 and C6 positions was likely to have a significant impact on
the strain induced in the ring system, we reasoned that
conformational analysis was likely to be a key factor in
developing effective statistical models.54−56 However, con-
formational searching of the 24 members in the 2,2′-
bipyrimidine library revealed that many structures led to an
extensive number of conformers and isomers (e.g., conforma-
tional searching of 4m2− revealed >400 relevant conformers).
Therefore, due to the symmetrical nature of the molecules,
truncation of 42− to represent only one-half the molecule
(4trunc2−) was undertaken (Figure 12A). This strategy has been
used successfully in previous efforts57−59 and was found to
reduce the number of conformers and isomers drastically.
Using this workflow, conformational searching was per-
formed using the OPLS3 force field60 to identify conformers
within a 5 kcal/mol energy window of the most stable
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Figure 13. (A) Additional compounds synthesized based on virtual screening. Redox potentials referenced internally vs the Fc/Fc+. % Fade = the
overall capacity fade observed for each compound. SOC = state of charge. % Fade/h = overall capacity fade/total cycling time. (B) CV before and
after electrochemical cycling of 4z highlighting that no decomposition occurring from protonation of the electrolyte was observed. (C) Storage
stability test of 4z (40 mM) at 75% SOC (i.e., 50% 4z•− and 50% 4z2−). CV of an aliquot was taken after 3 days (∼5 mM), highlighting that no
visible decomposition was present.
is distorted. As noted previously, large alkyl substituents such
as tBu can force puckering of the pyrimidine ring to maintain
conjugation with the ester. However, it was also found that
interactions between the ester substituent and longer
substituents at the C4 and C6 sites can also force the carbonyl
out of planarity, even in the dianionic charge state. The most
severe of these two modes of distortion was found to correlate
to the rate of decomposition.
External validations from the initial data set provided
evidence that the model had relatively good predictive
capabilities, as demonstrated by the extrapolation of the
worst performing electrolyte 4n. We were interested in
examining whether this improved understanding of the
underlying features of electrolyte stability could be leveraged
to design more robust electrolytes. Simultaneously with
statistical modeling efforts, virtual screening of several new
bipyrimidine structures (focusing on aromatic substituted
compounds) revealed that 4y2− and 4z2− should be only
modestly distorted from planarity (Figure 13A). Further, after
obtaining parameters from the truncated structures, the MLR
model predicts that these compounds should be two of the
most stable electrolytes (Figure 12B, red squares).
Synthesis of these compounds using the route described
above revealed that they experienced low % capacity fade per
hour during electrochemical cycling and were indeed two of
the most stable compounds, albeit 4y performed equally to the
previous best compound 4f. Interestingly, while the prediction
for 4y is very close to the experimentally observed value, 4z is
predicted by the model to have a negative % fade/h. Due to
the physical constraints of the experimental output, linear
extrapolation beyond 0% fade/h does not make physical sense
but implies that 4z is likely to be a very stable electrolyte. CVs
taken of compounds 4y and 4z following H-cell cycling
showed no apparent decomposition to the protonated species
(Figure 13B, see SI for 4y); however, a decomposition product
is apparent at ∼−2.5 V vs Fc/Fc+. This product was
hypothesized to arise from crossover of reactive species from
the counter side of the electrochemical cell (see SI for details).
We posited that due to some reactivity with reactive counter
side material, reading out inherent stability of these molecules
at the limits of the H-cell cycling assay (close to 0.6% fade/h)
could be inaccurate.
Storage Stability Tests. To get a more accurate
assessment of the inherent stability of the molecules, we
conducted storage stability tests for several different classes of
compounds, including compounds 4m, 4r, 4y, and 4z. These
compounds were selected for storage stability tests to represent
a wide range of stability in H-cell cycling but also based on
their solubilities in the charged states. Storage stability tests
were carried out via bulk electrolysis in a divided cell at four
different SOC for each molecule (25%, 50%, 75%, and
∼100%). The reduced compounds were then transferred to a
separate vessel, and their stability was monitored by acquiring
CV over a period of several days. This would allow us to
determine the relative stabilities of 4•−, 42−, and mixtures of
each. Generally, compounds that were unstable in H-cell
cycling were also found to be unstable in storage stability (i.e.,
4m and 4r). Unsurprisingly, the rate of decomposition for
these compounds increased as the SOC was increased and they
were found to be decomposed after 1−2 days in high SOC
(see SI for details). Alternatively, compound 4y was found to
•−
be relatively stable when only accessing 4y (25% and 50%
2−
SOC), but gradual decomposition was observed when 4y
was accessed. Finally, as suggested by MLR models, 4z was
found to be stable in high SOC even after 3 days in storage
(Figure 13C). Additionally, none of the decomposition
products observed during H-cell cycling were formed during
the storage stability test, confirming that some degree of
decomposition arises from crossover of reactive intermediates
during H-cell cycling. This work represents a fundamental
investigation into the properties of low potential, two-electron
anolytes. These types of anolytes have so far been relatively
incompatible with redox flow battery conditions; therefore, a
more basic understanding of their properties is necessary to
employ anolytes with extreme potentials in a flow battery
setting. It is envisioned that further elaboration of the
bipyrimidine scaffold could yield a potential anolyte for
deployment in a redox flow battery.
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included in this report were recorded at the David M. Grant
NMR Center, a University of Utah Core Facility. Funds for
construction of the Center and the helium recovery system
were obtained from the University of Utah and the National
Institutes of Health awards 1C06RR017539-01A1 and
3R01GM063540-17W1, respectively. NMR instruments were
purchased with support of the University of Utah and the
National Institutes of Health award 1S10OD25241-01.We
acknowledge Prof. Shelley Minteer for helpful discussions.
CONCLUSIONS
■
In summary, we have designed a new class of organic anolytes
that are capable of storing two electrons at very negative
potentials. An initial library of 24 electrolytes was designed and
evaluated electrochemically. A large disparity in the stability of
these molecules upon electrochemical cycling allowed us to
utilize a combination of experimental and computational
techniques to identify key structure−function relationships. By
characterization of a major decomposition pathway, an avenue
for regeneration of the active electrolyte was uncovered, which
could have implications for future electrolyte design.
Identification of this decomposition product also informed
the development of a MLR model that supports the hypothesis
of geometrical strain-induced decomposition of 2,2′-bipyr-
imidines. This allowed us to design an additional anolyte that
possessed a higher degree of stability in both electrochemical
cycling and multiday storage. Future work in this area will
focus on how other properties of these molecules can be
improved, particularly solubility.61 Additionally, continued
development of strategies to regenerate decomposed electro-
lytes in a flow-battery setting is ongoing.
REFERENCES
■
(1) World Energy Model; International Energy Agency: Paris, 2020.
(2) Annual Energy Outlook 2020; U.S. Energy Information
Administration, Office of Energy Analysis, U.S. Department of
Energy: Washington, DC, 2020.
(3) Abdmouleh, Z.; Alammari, R. A. M.; Gastli, A. Review of Policies
Encouraging Renewable Energy Integration & Best Practices.
Renewable Sustainable Energy Rev. 2015, 45, 249−262.
(4) Yang, Z.; Zhang, J.; Kintner-Meyer, M. C. W.; Lu, X.; Choi, D.;
Lemmon, J. P.; Liu, J. Electrochemical Energy Storage for Green Grid.
Chem. Rev. 2011, 111 (5), 3577−3613.
(5) Johnson, S. C.; Rhodes, J. D.; Webber, M. E. Understanding the
Impact of Non-Synchronous Wind and Solar Generation on Grid
Stability and Identifying Mitigation Pathways. Appl. Energy 2020, 262,
114492.
(6) Liu, W.; Lund, H.; Mathiesen, B. V. Large-Scale Integration of
Wind Power into the Existing Chinese Energy System. Energy 2011,
36 (8), 4753−4760.
(7) Dunn, B.; Kamath, H.; Tarascon, J.-M. Electrical Energy Storage
for the Grid: A Battery of Choices. Science 2011, 334 (6058), 928−
935.
(8) Rugolo, J.; Aziz, M. J. Electricity Storage for Intermittent
Renewable Sources. Energy Environ. Sci. 2012, 5 (5), 7151.
(9) Soloveichik, G. L. Flow Batteries: Current Status and Trends.
Chem. Rev. 2015, 115 (20), 11533−11558.
(10) Kear, G.; Shah, A. A.; Walsh, F. C. Development of the All-
Vanadium Redox Flow Battery for Energy Storage: A Review of
Technological, Financial and Policy Aspects. Int. J. Energy Res. 2012,
36 (11), 1105−1120.
(11) Luo, J.; Hu, B.; Hu, M.; Zhao, Y.; Liu, T. L. Status and
Prospects of Organic Redox Flow Batteries toward Sustainable Energy
Storage. ACS Energy Lett. 2019, 4 (9), 2220−2240.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11267.
■
sı
Experimental procedures for all reactions, spectroscopic
characterization data for all new compounds, detailed
computational methods, copies of H and 13C NMR
1
spectra, and Cartesian coordinates (PDF)
AUTHOR INFORMATION
Corresponding Author
Matthew S. Sigman − Department of Chemistry, University of
Utah, Salt Lake City, Utah 84112, United States; Joint
Center for Energy Storage Research, Argonne, Illinois 60439,
United States; orcid.org/0000-0002-5746-8830;
Email: sigman@chem.utah.edu
■
Authors
(12) Viswanathan, V.; Crawford, A.; Stephenson, D.; Kim, S.; Wang,
W.; Li, B.; Coffey, G.; Thomsen, E.; Graff, G.; Balducci, P.; Kintner-
Meyer, M.; Sprenkle, V. Cost and Performance Model for Redox Flow
Batteries. J. Power Sources 2014, 247, 1040−1051.
(13) Winsberg, J.; Hagemann, T.; Janoschka, T.; Hager, M. D.;
Schubert, U. S. Redox-Flow Batteries: From Metals to Organic
Redox-Active Materials. Angew. Chem., Int. Ed. 2017, 56 (3), 686−
711.
Jeremy D. Griffin − Department of Chemistry, University of
Utah, Salt Lake City, Utah 84112, United States; Joint
Center for Energy Storage Research, Argonne, Illinois 60439,
United States; orcid.org/0000-0001-9866-8129
Adam R. Pancoast − Department of Chemistry, University of
Utah, Salt Lake City, Utah 84112, United States; Joint
Center for Energy Storage Research, Argonne, Illinois 60439,
United States
(14) Weber, S.; Peters, J. F.; Baumann, M.; Weil, M. Life Cycle
Assessment of a Vanadium Redox Flow Battery. Environ. Sci. Technol.
2018, 52 (18), 10864−10873.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c11267
́
(15) Fernandez-Marchante, C. M.; Millan, M.; Medina-Santos, J. I.;
Lobato, J. Environmental and Preliminary Cost Assessments of Redox
Flow Batteries for Renewable Energy Storage. Energy Technol. 2020, 8
(11), 1900914.
Notes
The authors declare no competing financial interest.
(16) Kwabi, D. G.; Ji, Y.; Aziz, M. J. Electrolyte Lifetime in Aqueous
Organic Redox Flow Batteries: A Critical Review. Chem. Rev. 2020,
120 (14), 6467−6489.
(17) Gong, K.; Fang, Q.; Gu, S.; Li, S. F. Y.; Yan, Y. Nonaqueous
Redox-Flow Batteries: Organic Solvents, Supporting Electrolytes, and
Redox Pairs. Energy Environ. Sci. 2015, 8 (12), 3515−3530.
(18) Yan, Y.; Robinson, S. G.; Sigman, M. S.; Sanford, M. S.
Mechanism-Based Design of a High-Potential Catholyte Enables a 3.2
V All-Organic Nonaqueous Redox Flow Battery. J. Am. Chem. Soc.
2019, 141 (38), 15301−15306.
ACKNOWLEDGMENTS
■
This research was supported by the Joint Center for Energy
Storage Research (JCESR), a U.S. Department of Energy,
Energy Innovation Hub. J.D.G. thanks the National Institute of
Health for financial support through a F32 Ruth L. Kirschtein
NRSA fellowship (F32 GM129980). Computational resources
were provided from the Center for High Performance
Computing (CHPC) at the University of Utah. NMR results
1002
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J. Am. Chem. Soc. 2021, 143, 992−1004

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Article
(19) Yan, Y.; Vaid, T. P.; Sanford, M. S. Bis(Diisopropylamino)-
Cyclopropenium-Arene Cations as High Oxidation Potential and
High Stability Catholytes for Non-Aqueous Redox Flow Batteries. J.
Am. Chem. Soc. 2020, 142 (41), 17564−17571.
(20) Cabrera, P. J.; Yang, X.; Suttil, J. A.; Brooner, R. E. M.;
Thompson, L. T.; Sanford, M. S. Evaluation of Tris-Bipyridine
Chromium Complexes for Flow Battery Applications: Impact of
Bipyridine Ligand Structure on Solubility and Electrochemistry. Inorg.
Chem. 2015, 54 (21), 10214−10223.
(21) Sevov, C. S.; Fisher, S. L.; Thompson, L. T.; Sanford, M. S.
Mechanism-Based Development of a Low-Potential, Soluble, and
Cyclable Multielectron Anolyte for Nonaqueous Redox Flow
Batteries. J. Am. Chem. Soc. 2016, 138 (47), 15378−15384.
(22) Hu, B.; Liu, T. L. Two Electron Utilization of Methyl Viologen
Anolyte in Nonaqueous Organic Redox Flow Battery. J. Energy Chem.
2018, 27 (5), 1326−1332.
(23) Huang, J.; Yang, Z.; Vijayakumar, M.; Duan, W.; Hollas, A.;
Pan, B.; Wang, W.; Wei, X.; Zhang, L. A Two-Electron Storage
Nonaqueous Organic Redox Flow Battery. Adv. Sustain. Syst. 2018, 2
(3), 1700131.
(24) Attanayake, N. H.; Kowalski, J. A.; Greco, K. V.; Casselman, M.
D.; Milshtein, J. D.; Chapman, S. J.; Parkin, S. R.; Brushett, F. R.;
Odom, S. A. Tailoring Two-Electron-Donating Phenothiazines To
Enable High-Concentration Redox Electrolytes for Use in Non-
aqueous Redox Flow Batteries. Chem. Mater. 2019, 31 (12), 4353−
4363.
(25) Wei, X.; Xu, W.; Huang, J.; Zhang, L.; Walter, E.; Lawrence, C.;
Vijayakumar, M.; Henderson, W. A.; Liu, T.; Cosimbescu, L.; Li, B.;
Sprenkle, V.; Wang, W. Radical Compatibility with Nonaqueous
Electrolytes and Its Impact on an All-Organic Redox Flow Battery.
Angew. Chem., Int. Ed. 2015, 54 (30), 8684−8687.
(26) Wei, X.; Duan, W.; Huang, J.; Zhang, L.; Li, B.; Reed, D.; Xu,
W.; Sprenkle, V.; Wang, W. A High-Current, Stable Nonaqueous
Organic Redox Flow Battery. ACS Energy Lett. 2016, 1 (4), 705−711.
(27) Hendriks, K. H.; Sevov, C. S.; Cook, M. E.; Sanford, M. S.
Multielectron Cycling of a Low-Potential Anolyte in Alkali Metal
Electrolytes for Nonaqueous Redox Flow Batteries. ACS Energy Lett.
2017, 2 (10), 2430−2435.
Novel Dual Redox Shuttle for Supercapacitors. J. Mater. Chem. A
2016, 4 (12), 4562−4569.
(35) DeBruler, C.; Hu, B.; Moss, J.; Liu, X.; Luo, J.; Sun, Y.; Liu, T.
L. Designer Two-Electron Storage Viologen Anolyte Materials for
Neutral Aqueous Organic Redox Flow Batteries. Chem. 2017, 3 (6),
961−978.
(36) Liu, W.; Liu, Y.; Zhang, H.; Xie, C.; Shi, L.; Zhou, Y.-G.; Li, X.
A Highly Stable Neutral Viologen/Bromine Aqueous Flow Battery
with High Energy and Power Density. Chem. Commun. 2019, 55 (33),
4801−4804.
(37) Yamamoto, K.; Chen, Y. G.; Buono, F. G. Oxidative
Dehydrogenation of Dihydropyrimidinones and Dihydropyrimidines.
Org. Lett. 2005, 7 (21), 4673−4676.
(38) Lu, J.; Ma, H. Iron(III)-Catalyzed Synthesis of Dihydropyr-
imidinones. Improved Conditions for the Biginelli Reaction. Synlett
2000, 2000 (01), 63−64. .
(39) Zhou, Y.; Lin, C.; Xing, Y.; Chen, L.; Yan, X. Efficient
Construction of the Nucleus of Rosuvastatin Calcium. J. Heterocycl.
Chem. 2017, 54 (3), 1898−1903.
(40) Sugimoto, O.; Mori, M.; Tanji, K. A Facile Halogenation of
Some Hydroxyheterocycles Using Triphenylphosphine and N-
Halosuccinimide. Tetrahedron Lett. 1999, 40 (42), 7477−7478.
(41) Sugimoto, O.; Mori, M.; Moriya, K.; Tanji, K. Application of
Phosphonium Salts to the Reactions of Various Kinds of Amides.
Helv. Chim. Acta 2001, 84 (5), 1112−1118.
(42) Buonomo, J. A.; Everson, D. A.; Weix, D. J. Substituted 2,2′-
Bipyridines by Nickel Catalysis: 4,4′-Di-Tert-Butyl-2,2′-Bipyridine.
Synthesis 2013, 45 (22), 3099−3102.
(43) It should be noted that efforts to expand the scope of the
electrochemical homocoupling beyond 3a gave yields comparable to
that of the traditional method; this could be a reflection of anolyte
instability in the charged state because, under the reaction conditions,
the bipyrimidine product is likely reduced.
(44) Zhao, Y.; Yu, Z.; Robertson, L. A.; Zhang, J.; Shi, Z.;
Bheemireddy, S. R.; Shkrob, I. A.; Y Z; Li, T.; Zhang, Z.; Cheng, L.;
Zhang, L. Unexpected Electrochemical Behavior of an Anolyte
Redoxmer in Flow Battery Electrolytes: Solvating Cations Help to
Fight against the Thermodynamic−Kinetic Dilemma. J. Mater. Chem.
A 2020, 8 (27), 13470−13479.
(45) Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals
for Main Group Thermochemistry, Thermochemical Kinetics,
Noncovalent Interactions, Excited States, and Transition Elements:
Two New Functionals and Systematic Testing of Four M06-Class
Functionals and 12 Other Functionals. Theor. Chem. Acc. 2008, 120
(1), 215−241.
(46) Barone, V.; Cossi, M. Quantum Calculation of Molecular
Energies and Energy Gradients in Solution by a Conductor Solvent
Model. J. Phys. Chem. A 1998, 102 (11), 1995−2001.
(47) Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. Energies,
Structures, and Electronic Properties of Molecules in Solution with
the C-PCM Solvation Model. J. Comput. Chem. 2003, 24 (6), 669−
681.
(48) DFT calculations were performed without inclusion of counter-
cations, which is likely to affect the absolute magnitude of rotational
barriers.
(28) Goulet, M.-A.; Tong, L.; Pollack, D. A.; Tabor, D. P.; Odom, S.
A.; Aspuru-Guzik, A.; Kwan, E. E.; Gordon, R. G.; Aziz, M. J.
Extending the Lifetime of Organic Flow Batteries via Redox State
Management. J. Am. Chem. Soc. 2019, 141 (20), 8014−8019.
́
(29) Sevov, C. S.; Brooner, R. E. M.; Chenard, E.; Assary, R. S.;
́
Moore, J. S.; Rodríguez-Lopez, J.; Sanford, M. S. Evolutionary Design
of Low Molecular Weight Organic Anolyte Materials for Applications
in Nonaqueous Redox Flow Batteries. J. Am. Chem. Soc. 2015, 137
(45), 14465−14472.
(30) Sevov, C. S.; Hickey, D. P.; Cook, M. E.; Robinson, S. G.;
Barnett, S.; Minteer, S. D.; Sigman, M. S.; Sanford, M. S. Physical
Organic Approach to Persistent, Cyclable, Low-Potential Electrolytes
for Flow Battery Applications. J. Am. Chem. Soc. 2017, 139 (8), 2924−
2927.
(31) Kober, E. M.; Sullivan, B. P.; Meyer, T. J. Solvent Dependence
of Metal-to-Ligand Charge-Transfer Transitions. Evidence for Initial
Electron Localization in MLCT Excited States of 2,2’-Bipyridine
Complexes of Ruthenium(II) and Osmium(II). Inorg. Chem. 1984, 23
(14), 2098−2104.
(49) Kowalski, J. A.; Neyhouse, B. J.; Brushett, F. R. The Impact of
Bulk Electrolysis Cycling Conditions on the Perceived Stability of
Redox Active Materials. Electrochem. Commun. 2020, 111, 106625.
(50) Connelly, N. G.; Geiger, W. E. Chemical Redox Agents for
Organometallic Chemistry. Chem. Rev. 1996, 96 (2), 877−910.
(51) Sigman, M. S.; Harper, K. C.; Bess, E. N.; Milo, A. The
Development of Multidimensional Analysis Tools for Asymmetric
Catalysis and Beyond. Acc. Chem. Res. 2016, 49 (6), 1292−1301.
(52) Guo, J.-Y.; Minko, Y.; Santiago, C. B.; Sigman, M. S.
Developing Comprehensive Computational Parameter Sets To
Describe the Performance of Pyridine-Oxazoline and Related Ligands.
ACS Catal. 2017, 7 (6), 4144−4151.
(32) Lumpkin, R. S.; Kober, E. M.; Worl, L. A.; Murtaza, Z.; Meyer,
T. J. Metal-to-Ligand Charge-Transfer (MLCT) Photochemistry:
Experimental Evidence for the Participation of a Higher Lying MLCT
State in Polypyridyl Complexes of Ruthenium(II) and Osmium(II). J.
Phys. Chem. 1990, 94 (1), 239−243.
(33) England, J.; Scarborough, C. C.; Weyhermuller, T.; Sproules, S.;
̈
Wieghardt, K. Electronic Structures of the Electron Transfer Series
[M(Bpy)3]n, [M(Tpy)2]n, and [Fe(Tbpy)3]n (M = Fe, Ru; n = 3+,
̈
2+, 1+, 0, 1−): A Mossbauer Spectroscopic and DFT Study. Eur. J.
Inorg. Chem. 2012, 2012 (29), 4605−4621.
(34) Sathyamoorthi, S.; Kanagaraj, M.; Kathiresan, M.;
Suryanarayanan, V.; Velayutham, D. Ethyl Viologen Dibromide as a
1003
https://dx.doi.org/10.1021/jacs.0c11267
J. Am. Chem. Soc. 2021, 143, 992−1004

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(53) Santiago, C. B.; Guo, J.-Y.; Sigman, M. S. Predictive and
Mechanistic Multivariate Linear Regression Models for Reaction
Development. Chem. Sci. 2018, 9 (9), 2398−2412.
(54) Robinson, S. G.; Yan, Y.; Hendriks, K. H.; Sanford, M. S.;
Sigman, M. S. Developing a Predictive Solubility Model for
Monomeric and Oligomeric Cyclopropenium-Based Flow Battery
Catholytes. J. Am. Chem. Soc. 2019, 141 (26), 10171−10176.
́
(55) Miro, J.; Gensch, T.; Ellwart, M.; Han, S.-J.; Lin, H.-H.;
Sigman, M. S.; Toste, F. D. Enantioselective Allenoate-Claisen
Rearrangement Using Chiral Phosphate Catalysts. J. Am. Chem. Soc.
2020, 142 (13), 6390−6399.
(56) Werth, J.; Sigman, M. S. Connecting and Analyzing
Enantioselective Bifunctional Hydrogen Bond Donor Catalysis
Using Data Science Tools. J. Am. Chem. Soc. 2020, 142 (38),
16382−16391.
(57) Yamamoto, E.; Hilton, M. J.; Orlandi, M.; Saini, V.; Toste, F.
D.; Sigman, M. S. Development and Analysis of a Pd(0)-Catalyzed
Enantioselective 1,1-Diarylation of Acrylates Enabled by Chiral Anion
Phase Transfer. J. Am. Chem. Soc. 2016, 138 (49), 15877−15880.
(58) Crawford, J. M.; Stone, E. A.; Metrano, A. J.; Miller, S. J.;
Sigman, M. S. Parameterization and Analysis of Peptide-Based
Catalysts for the Atroposelective Bromination of 3-Arylquinazolin-
4(3H)-ones. J. Am. Chem. Soc. 2018, 140 (3), 868−871.
(59) Crawford, J. M.; Sigman, M. S. Conformational Dynamics in
Asymmetric Catalysis: Is Catalyst Flexibility a Design Element?
Synthesis 2019, 51 (5), 1021−1036.
(60) Harder, E.; Damm, W.; Maple, J.; Wu, C.; Reboul, M.; Xiang, J.
Y.; Wang, L.; Lupyan, D.; Dahlgren, M. K.; Knight, J. L.; Kaus, J. W.;
Cerutti, D. S.; Krilov, G.; Jorgensen, W. L.; Abel, R.; Friesner, R. A.
OPLS3: A Force Field Providing Broad Coverage of Drug-like Small
Molecules and Proteins. J. Chem. Theory Comput. 2016, 12 (1), 281−
296.
(61) Preliminary efforts to measure solubility show that compound
4z has only a moderate solubility in MeCN (0.1 M), while the
dianionic charge state (4z2−) seems to be a miscible oil when TBA+
counterions are utilized.
1004
https://dx.doi.org/10.1021/jacs.0c11267
J. Am. Chem. Soc. 2021, 143, 992−1004