Thiosquaramide-Based Supramolecular Polymers: Aromaticity Gain in a Switched Mode of Self-Assembly

Article abstract of DOI:10.1021/jacs.0c02081

Despite a growing understanding of factors that drive monomer self-assembly to form supramolecular polymers, the effects of aromaticity gain have been largely ignored. Herein, we document the aromaticity gain in two different self-assembly modes of squara

Full text of DOI:10.1021/jacs.0c02081

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Article
Thiosquaramide-Based Supramolecular Polymers: Aromaticity Gain
in a Switched Mode of Self-Assembly
Victorio Saez Talens, Joyal Davis, Chia-Hua Wu, Zhili Wen, Francesca Lauria,
Karthick Babu Sai Sankar Gupta, Raisa Rudge, Mahsa Boraghi, Alexander Hagemeijer, Thuat T. Trinh,
Pablo Englebienne, Ilja K. Voets, Judy I. Wu,* and Roxanne E. Kieltyka*
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sı Supporting Information
ABSTRACT: Despite a growing understanding of factors that drive
monomer self-assembly to form supramolecular polymers, the effects
of aromaticity gain have been largely ignored. Herein, we document
the aromaticity gain in two different self-assembly modes of
squaramide-based bolaamphiphiles. Importantly, O → S substitution
in squaramide synthons resulted in supramolecular polymers with
increased fiber flexibility and lower degrees of polymerization.
Computations and spectroscopic experiments suggest that the oxo-
and thiosquaramide bolaamphiphiles self-assemble into “head-to-tail”
versus “stacked” arrangements, respectively. Computed energetic and
magnetic criteria of aromaticity reveal that both modes of self-
assembly increase the aromatic character of the squaramide synthons,
giving rise to stronger intermolecular interactions in the resultant
supramolecular polymer structures. These examples suggest that both hydrogen-bonding and stacking interactions can result in
increased aromaticity upon self-assembly, highlighting its relevance in monomer design.
INTRODUCTION
expected if they increase cyclic (4n + 2)π-electron delocaliza-
tion (i.e., increase aromaticity) in the hydrogen-bonded
heterocycles but are weaker if they reduce cyclic (4n + 2)π-
electron delocalization (decrease aromaticity) in hetero-
■
Supramolecular polymers are endowed with unique properties,
such as responsiveness and self-healing,
dynamic nature of the noncovalent interactions they are based
on, leading to numerous potential applications as biomedical
1
−3
due to the inherent
21,22,24
cycles.
Such effects are especially pronounced when
4
−6
hydrogen-bonded assemblies of cyclic π-conjugated motifs are
considered, as the effects of aromaticity gain in each of the
synthon rings can add up to an astonishing overall
materials, adhesives, inks, or personal care products7.
Noncovalent interactions, including hydrogen-bonding, −12
π-stacking, solvophobicity, and van der Waals, are responsible
for their self-assembly into hierarchical architectures through
stacking or molecular recognition of polymeric precur-
23
aromatization of the self-assembled system. Concurrently,
the Kieltyka group reported the self-assembly of a novel
squaramide-based bolaamphiphile that takes advantage of an
aromaticity gain to form robust supramolecular polymers in
1
3−20
sors.
Over the past years, the growing number of
synthesized monomers has contributed significantly to the
development of general design rules to facilitate monomer self-
assembly in organic solvents and water. However, to further
guide their rational design, it is necessary to understand factors
that influence the strengths of competing noncovalent
interactions either within a monomer or between them.
Here, we demonstrate the impact of the combination of
hydrogen bonding and stacking interactions with aromaticity
gain on the mode of monomer self-assembly in a supra-
molecular polymer.
25
26−29
water. Squaramides
are ditopic hydrogen-bonding
synthons that can self-associate through two hydrogen-bond
acceptors (CO groups) and two hydrogen-bond donors
(
N−H groups) directly opposite one another on a cyclo-
butenedione ring. Upon hydrogen bonding at both ends
simultaneously, the two CO π-bonds and the two N lone
pairs become polarized to give increased cyclic 2π-electron
Received: February 21, 2020
Recent works from Wu and Jackson and their co-workers
21−23
24
demonstrated computationally
and experimentally that
aromaticity gain can significantly influence the intermolecular
hydrogen-bonding abilities of heterocyclic, π-conjugated
monomers. Hydrogen-bonding interactions are stronger than
©
XXXX American Chemical Society
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A

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Figure 1. (a) Hydrogen bonding increases the aromatic character in oxosquaramide; the resonance form on the right shows increased cyclic 2π-
electron delocalization in the four-membered ring. (b) Carbonyls (CO) typically form hydrogen bonds with small deviations from the lone-pair
(
xy) plane, but thiocarbonyls (CS) can engage in hydrogen bonds with CS···H angles of close to 90°. As a result, CO- and CS-containing
synthons are expected to promote drastically different self-assembly modes. (c) Structures of the oxosquaramide (1a and 1b) and thiosquaramide
2a and 2b) bolaamphiphiles under study. Compounds 1a and 1b self-assemble into rigid fibers (top), while 2a and 2b self-assemble into short
(
flexible rodlike structures (bottom). This disparity is attributed to the “head-to-tail” self-assembly of the oxosquaramides 1′ versus the “stacked”
self-assembly of the thiosquaramides 2′.
delocalization (4n + 2, n = 0) in the four-membered ring
Figure 1a). Evidence based on experiment and computations
containing synthons may give rise to drastically different self-
assembled polymers compared to analogous CO-containing
synthons due to the oblique modes of contact they
(
revealed that the reciprocal effects of hydrogen bonding and
aromaticity intensify with the head-to-tail polymerization of
squaramide-based bolaamphiphiles, further reinforcing these
35−37
enable.
Here, we show indeed that, upon O → S
exchange, monomers of 1 and 2 self-assemble into supra-
molecular polymers with surprisingly different morphologies as
a consequence of the self-assembly modes of the monomers:
oxosquaramides 1 self-assemble “head-to-tail”, while thiosquar-
amides 2 “stack” on top of each other due to the wider range of
angles permitted by sulfur to engage in CS···H interactions
2
5
interactions.
Inspired by these results, we performed an O → S exchange
of the carbonyl moieties to compare the effects of aromatic
gain in monomers on the self-assembly of oxosquaramide-
based bolaamphiphiles relative to their thiosquaramide
counterparts. Thiosquaramides, with their enhanced acidity
(
1
see the illustration of self-assembled N-methyloxosquaramides
30
′ and N-methylthiosquaramides 2′ in Figure 1c).
and lipophilicity compared to oxosquaramides, can poten-
tially self-assemble in very different ways due to the unique
supramolecular interactions enabled by their two thiocarbon-
yls. Thiocarbonyls are typically considered to be weaker
In this study, we report computations and experiments to
document the effects of aromaticity gain in the self-assembly of
oxo- and thiosquaramide bolaamphiphiles. Despite the differ-
ent three-dimensional arrangements of self-assembled oxo-
versus thiosquaramide synthons, computations suggest that
both modes of assembly enhance the aromatic character of the
respective squaramide monomers, leading to stronger inter-
molecular interactions between them and resulting in distinct
self-assemblies into their respective supramolecular polymers.
31
hydrogen-bond acceptors compared to carbonyls, but they
can engage in effective S···π interactions as well as less-
directional hydrogen-bond interactions due to the more
32,33
polarizable nature of the S lone pairs.
Studies based on a
survey of carbonyl- and thiocarbonyl-containing structures in
34
the Cambridge Structural Database (CSD), for example,
have shown that CO···H hydrogen bonds generally exhibit
small deviations (0° to 20°) from the lone-pair plane (i.e., the
plane defined by the two sets of O lone pairs; see the xy plane
in Figure 1b, top), while CS···H interactions can deviate
significantly from the lone-pair plane, displaying close to 90°
lone-pair plane···H angles (see Figure 1b, bottom) because of
the belt distribution of electrons on sulfur. Thus, CS-
RESULTS
■
Synthesis and Characterization of Squaramide-Based
Bolaamphiphiles. The molecular design of the squaramide-
based bolaamphiphiles 1 and 2 consists of two squaramide
synthons embedded within a hydrophobic core of alkyl chains,
surrounded by oligo(ethylene glycol)s to drive their nanophase
B
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segregation and one-dimensional self-assembly in water (see
25
Figure 1c). In the original design of 1a, activation of the
poly(ethylene glycol) by 1,1-carbonyldiimidazole was used to
couple to the hydrophobic spacer because of its synthetic
facility, but to eliminate any effects imparted by the formed
carbamate on the self-assembly, an identical molecule bearing
an ether between these domains was also synthesized and
compared. The oxo-derivative lacking the carbamate moieties
(1b) was prepared by an alternate synthetic protocol (Figure
S1 and Materials and Methods, Supporting Information (SI)],
resulting in moderate yields after reverse-phase column
chromatography. Subsequently, thio-analogues 2a and 2b
were prepared by reacting 1a and 1b, respectively, with a
∼
30-fold excess of pentathiodiphosphorus(V) acid-P,P′-bis-
(
pyridinium betaine) in acetonitrile at room temperature.
Liquid chromatography/mass spectrometry (LC−MS) was
used to determine the end point of the reaction, as extended
reaction times resulted in decomposition of the amphiphiles.
Notably, under these conditions selective thionation of the
carbonyl groups of the squaramide moieties (Figure S2, SI)
was achieved. This result is analogous to the selective
conversion of different types of carbonyls achieved with
38
Lawesson’s reagent at room temperature. Purification by
preparative high-performance reverse-phase column chroma-
tography (HPLC) required absence of acid in the mobile
phase due to sensitivity of the thiosquaramide moiety, giving
rise to the compounds in moderate yields (40% 2a, 47% 2b).
13
Carbon-13 nuclear magnetic resonance ( C-NMR) showed a
downfield shift of Δδ ≈ 20 ppm of the CS of the
thiosquaramide compared to the CO signal, and a Δδ ≈ 2−
4
ppm of the CC within the cyclobutenedione ring (Figure
S3, SI). The identity and purity of the synthesized compounds
were confirmed by a combination of several characterization
1
13
techniques, including H-NMR, C-NMR, LC−MS, HR-MS,
and ATR-FTIR (see the Supporting Information).
Monomer 2 Forms Shorter and More Flexible
Supramolecular Polymers Than 1 in Water. Cryogenic
transmission electron microscopy (cryo-TEM) and small-angle
X-ray scattering (SAXS) experiments probed the morphology
and internal structure of the squaramide-based supramolecular
polymers in water. These techniques revealed surprisingly
different aggregate morphologies, suggestive of a dissimilar
mode of self-assembly for oxosquaramides and thiosquar-
amides in their respective fibers. Both 1a and 1b resulted in
high-aspect-ratio fibers with lengths of 235 ± 118 and 246 ±
1
76 nm, respectively [Figures 2a,b and S4 and S5 (SI)]. In
contrast, the thionated 2a and 2b were 5−10 times shorter,
displaying rodlike structures with lengths of 41 ± 18 and 24 ±
2
7 nm, respectively [Figures 2a,b and S4 and S5 (SI)], but
showing a comparable critical aggregation concentration (1.41
−
5
39
×
10 M) (Figure S6, SI). The oxosquaramide supra-
molecular polymers (1a, 5.8 ± 1.2 nm; 1b, 5.7 ± 1.2 nm) were
Easyworm software provided values of 252 ± 116 nm for 1a
and 77 ± 17 nm for 2a (Figure 2d,e). Figure 2d displays the
2
also slightly thicker than the thiosquaramide derivatives (2a,
mean square end-to-end distance ⟨R ⟩ plots as a function of
the contour length for the fiber (1a) and rodlike (2a)
4
.8 ± 1.3 nm; 2b, 3.9 ± 1.1 nm) [Figures 2c and S5 (SI)].
Overall, by comparison of the molecules with and without the
peripheral carbamates by cryo-TEM, these results suggest that
the squaramide synthons are largely responsible for the
observed self-assembled structures.
Statistical analyses of the cryo-TEM images with respect to
the shape fluctuations of the supramolecular polymer
structures suggest that 1a forms long, rigid, high-aspect ratio
fibers, while 2a forms short, semiflexible, rodlike structures.
Tracking of the contour lengths of the fibrillar assemblies using
structures, respectively. The persistence length (P ), which
l
quantifies the stiffness of a semiflexible polymer, was
2
determined from the ⟨R ⟩ value by applying the wormlike
39
chain model (WLC) (see the Supporting Information).
Supramolecular polymers of 1a displayed much larger P values
l
39
(581 ± 76 nm) compared to those of 2a (47 ± 4 nm),
indicating different mechanical properties for the oxo- versus
thiosquaramide analogues. From P , the bending rigidity of the
l
−
27
2
assembly of 1a [(2.4 ± 0.3) × 10 N m ] was determined to
C
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be around 10-fold greater relative to that of 2a [(1.9 ± 0.2) ×
philes within the cross-section as reported earlier by our
−
28
2
25
1
0
N m ].
group. Supramolecular polymers of 2a exhibit this character-
‑
1
Light-scattering experiments provided further insight into
istic I ∝ q scaling at small q values (Figure 3a, green line), but
they were better modeled with a form factor for semiflexible
homogeneous cylinders, resulting in an rcs (∼2.3 nm) on par
the aggregates of the oxo- versus thiosquaramide-based
monomers in solution. Static light scattering (SLS) measure-
ments of monomers 1a and 2a (Figure S7, SI) were performed
to compare their polymerization in water and their
depolymerization with the addition of a “good” solvent such
as CH CN to water, using a H O−CH CN (6:4) solution.
with cryo-TEM images. From the M of 2a, approximately 10−
L
1
4 bolaamphiphiles per nm (see Supporting Information) were
determined to be within the fiber cross-section. SAXS
‑
1
measurements of 1b (once again I ∝ q ) showed similar
scattering profiles to 1a with the carbamate moiety, whereas 2b
displayed a significantly reduced q-slope, indicating the
coexistence of fiberlike and spherical morphologies (Figures
S8 and S9, SI). Consequently, the morphological differences
and monomer packing found within the cross-section of 1
versus 2 clearly suggest that the mode of monomer self-
assembly is different for the oxo- and thiosquaramide
analogues.
3
2
3
Scattered light intensities of supramolecular polymers of 1a
and 2a indicated the presence of large objects in H O. When
2
1
a and 2a were dissolved in H O−CH CN (6:4), a large
2
3
decrease in scattering intensity was recorded, consistent with
the depolymerization of the squaramide-based supramolecular
polymers through solvation of the bolaamphiphiles; this effect
was less pronounced for 2a.
Small-angle X-ray scattering (SAXS) was performed to
Self-Assembled Monomers 1 and 2 Show Dissimilar
Spectroscopic Signatures in Water. Two absorption
maxima at 257 and 330 nm were recorded for 1a in water,
corresponding to its self-assembly into supramolecular
polymers (Figure 3b, solid blue line). When a good solvent
was added to 1a, the two maxima coalesce with an increase in
absorbance at 293 nm (Figure 3b, dotted blue line).
Conversely, the UV−vis spectrum of thiosquaramide analog
understand the morphology of the self-assembled aggregates.
‑
1
We previously found that self-assemblies of 1a display I ∝ q
scaling in the low-q regime (Figure 3a, blue line), which is
25
characteristic of fiberlike objects. The data were modeled
with a form factor for homogeneous cylinders, yielding a cross-
sectional radius (r ) of ∼3.4 nm. From this data, the cross-
cs
sectional mass per unit length (M ) of 1a was determined
L
(Table S1, SI), yielding a comparable number of bolaamphi-
2
a in water showed bands with maxima at 360 and 271 nm and
a small shoulder around 420 nm (Figure 3b, solid green line).
Moreover, irrespective of the concentration of 2a (c = 0.58−
58.0 μM), the spectral profile was retained in water (Figure
S10, SI). The effect of different solvents on the self-assembly of
a was also examined (Figure S11, SI). Upon the addition of a
2
good solvent, the band of 2a at 360 nm split into two, with a
peak at 384 nm and a shoulder at 356 nm, while the band at
2
71 nm shifted slightly to 273 nm (Figure 3b, green dotted
line). Similar trends were recorded in the UV−vis spectra of
b. Hence, stark differences in the absorbance profiles
2
observed for monomers 1a and 2a in the aggregated state
point to a difference in their organization within the polymers.
Time-dependent density functional theory (TD-DFT)
computations were performed to rationalize the spectral
differences of the oxo- versus thio-monomers in water and in
organic solvents. Two monomer models, N-methyloxosquar-
amide (1′) and N-methylthiosquaramide (2′), in both the
head-to-tail and stacked arrangements were examined. UV
absorption peaks for the isolated monomers and self-assembled
hexamers of 1′ and 2′ in both arrangements were simulated in
the 250 to 400 nm region and computed in implicit solvation
with a low dielectric constant (ε < 20; see the Supporting
Information) at the IEF-PCM-M06-2X/6-311+G(d,p) level, to
model 1 and 2 in their polymerized and depolymerized states
(
see Table 1).
Computed UV spectra of the monomer, head-to-tail
hexamer, and stacked hexamer of 1′ suggest that oxosquar-
amide synthons self-assemble through a head-to-tail mode in
water and depolymerize in low-dielectric solvents. The
computed UV spectrum of the head-to-tail 1′ hexamer shows
two largely separated peaks at 258.2 and 278.9 nm,
corresponding to the HOMO → LUMO+1 and HOMO →
LUMO transitions of neighboring monomers. In the computed
spectrum of the monomer, these peaks coalesce and appear at
−
1
Figure 3. (a) Experimental SAXS profiles of 1a and 2a (5 mg mL ).
The curves are modeled with a form factor for homogeneous and
flexible homogeneous cylinders for 1a and 2a, respectively. The blue
curve is shifted vertically by multiplying by a factor of 10 to enable
comparison of the two profiles. (b) UV−vis spectra of 1a and 2a (c =
2
63.3 and 263.1 nm, respectively. In sharp contrast, the
computed UV spectra of the monomer, head-to-tail hexamer,
3
0 μM) in H O (solid line) and H O−CH CN (6:4) (dotted line).
and stacked hexamer of 2′ suggest that thiosquaramide
2
2
3
D
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Table 1. Computed UV−Vis Absorptions (λmax, in nm) for
the Monomers, Head-to-Tail Hexamers, and Stacked
Hexamers of 1′ and 2′ in Implicit Solvation in a Low-
consistent with the in-line and parallel alignment of the
transition dipole moments within the squaramide units, giving
rise to the concomitant formation of H- and J-bands. In the
case of 2′ and 2a, supramolecular polymerization results in a
blue-shift of the monomer absorbance spectra that can be
ascribed to the formation of an H-type aggregate with a parallel
arrangement of transition dipole moments, suggesting a
cofacial orientation of the thiosquaramide units. Moreover,
the weak red-shifted shoulder observed experimentally at 420
nm is consistent with other supramolecular polymers involving
stacked chromophores that exhibit a rotational offset in the
a
Dielectric Solvent at IEF-PCM-M06-2X/6-311+G(d,p)
1
′ (oxo)
2′ (thio)
2
2
2
2
2
2
63.3 (0.53)
63.1 (0.36)
78.9 (3.05)
58.2 (2.47)
58.0 (1.16)
51.5 (1.43)
350.4 (0.45)
339.1 (0.36)
351.9 (3.42)
337.8 (1.96)
344.6 (0.94)
342.3 (0.98)
monomer
head-to-tail (n = 6)
stacked (n = 6)
41
aggregated state.
a
Only transitions with oscillator strengths >0.35 are listed (actual
An alternative explanation for the observed shifts in the
absorbance spectra results from analyzing the symmetry of the
π-orbitals involved in the UV transitions. In the head-to-tail
hexamer of 1′, the HOMO and LUMO orbitals of neighboring
monomers are out-of-phase, and thus, disrupting this
disfavored interaction leads to a red-shifted HOMO →
LUMO transition (the peak at 258.2 nm shifts to 263.3 nm)
upon disassembly. The HOMO and LUMO+1 orbitals of
neighboring monomers are in-phase, and thus, disrupting this
bonding interaction leads to a blue-shifted HOMO → LUMO
value in parentheses).
synthons self-assemble in water through a stacked mode. The
computed UV spectrum of the stacked hexamer shows two
closely separated peaks at 342.3 and 344.6 nm, corresponding
to the HOMO → LUMO+1 and HOMO → LUMO
transitions of neighboring monomers. In the computed
spectrum of the monomer, these peaks respectively split to
3
39.1 and 350.4 nm. These computed results are consistent
+
1 transition (the peak at 278.9 nm shifts to 263.1 nm) upon
with the experimentally obtained UV−vis spectra for 1a and 2a
in water and H O−CH CN (6:4) (Figure 3b). For
disassembly (Figure 4a). Overall, the net effect is the
coalescing of two peaks upon depolymerization of an oxo-
polymer.
2
3
comparison, the computed UV results of the alternate self-
assembly modes, i.e., stacked for 1′ and head-to-tail for 2′, did
not correlate with the experimentally observed trends (see the
data in Table 1). Hence, the distinct UV−vis spectra recorded
experimentally for 1a and 2a correlate well with head-to-tail
and stacked modes, respectively, as computed by TD-DFT.
The observed spectral shifts of 1a and 2a in the polymerized
and depolymerized forms can be further rationalized by the
In the stacked hexamer of 2′, the HOMO and LUMO
orbitals of neighboring monomers are out-of-phase, and thus,
disrupting this disfavored interaction leads to a dominant red-
shifted HOMO → LUMO transition (the peak at 344.6 nm
shifts to 350.3 nm) on disassembly. The HOMO and LUMO
+
1 orbitals of neighboring monomers have mixed in-phase and
40
out-of-phase interactions, so the absorption shows a negligible
shift upon disassembly (the peak at 342.3 nm shifts to 339.1
nm) (Figure 4b). Overall, the net effect is the splitting of two
coalescing peaks upon depolymerization of the thio-polymer.
To unravel the supramolecular polymerization mechanism, a
cosolvent approach was taken to denature the self-assemblies
of 1a and 2a. Changes in the absorption spectra of 1a and 2a (c
exciton theory of Kasha et al. Computed transition dipole
moments for the HOMO−LUMO and HOMO−LUMO+1
transitions in 1′ and 2′ revealed one to be parallel and the
other perpendicular to the C2 symmetry axis of the
(
thio)squaramide ring (Figure 4). In the computed (1′) and
experimental (1a) UV−vis spectra, the simultaneous blue- and
red-shifting of the squaramide bands upon its polymerization is
=
15−40 μM) (Figures 5, S12) in water were monitored by
titrating the respective monomers at the same concentration in
CH CN. The degree of aggregation (α ) was plotted as a
3
agg
function of the solvent volume fraction for each monomer to
determine thermodynamic parameters when fit with the
solvent denaturation model as reported by de Greef, Meijer
42
and co-workers. The depolymerization of 1a and 2a was
observed at different solvent compositions: while the
disappearance of the band at 330 nm for 1a required less
CH CN (24.5 vol %), the appearance of the band at 384 nm
3
for 2a required more (33.3 vol %).
Furthermore, titrations of 1a revealed a cooperative process
cooperativity parameter σ = 0.013) with a nonsigmoidal
(
profile, whereas a greater than an order of magnitude larger
cooperativity parameter (σ = 0.610) was determined for 2a,
indicating a substantially less cooperative supramolecular
polymerization (Table S2, SI). In line with the relative
amounts of CH CN to denature the assemblies, a more-
3
−
1
negative ΔG° was obtained for 2a (−57.9 kJ mol ) in
−
1
comparison to 1a (−40.2 kJ mol ). Hence, the supra-
molecular polymers formed from 2a are more stable than those
of 1a, likely due to their increased hydrophobicity and π-
stacking tendency; however, the lesser degree of cooperativity
of their polymerization points to a difference in the
Figure 4. Orbital interactions of neighboring monomers in HOMO−
LUMO and HOMO−LUMO+1 transitions for (a) head-to-tail (for
1
′) and (b) stacked (for 2′) arrangements. The direction and
magnitude of the computed transition dipole moments for each
transition are indicated.
E
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Figure 6. IR spectrum recorded in the N−H region (inset) and amide
I and amide II regions in D O for both 1a and 2a (5.8 mM).
2
−1
wavenumbers (3166 cm ), consistent with a decrease in
hydrogen bonding between the monomers (Figure S13, SI). In
D O, 2a showed a CO stretch for the carbamate moiety
2
−
1
−1
(
(
1687 cm ) and an intense ring breathing band (1727 cm )
Figure 6, green). Additionally, the N−H stretch of 2a was red-
−
1
shifted (3140 cm ) and higher in intensity in comparison to
that of 1a, congruent with hydrogen bonding of the N−H
groups of thiosquaramide. When 2a was dissolved in D O−
2
CD CN (6:4), the CO band of the carbamate group shifted
3
−
1
to a higher wavenumber (1698 cm ), whereas the intense ring
breathing band appeared at a lower wavenumber (1720 cm )
−
1
than in the D O spectra. The N−H stretch moved to a lower
2
−
1
wavenumber (3136 cm ) and the intensity of the peak
intensity was maintained (Figure S14, SI).
These results suggest that hydrogen bonds are retained with
the addition of a good solvent and is consistent with LS data
showing less depolymerization of 2a compared to 1a. Similar
trends were also observed for 1b and 2b (as well as 1a and 2a)
in the solid state (Figures S15 and S16, SI), with removal of
the carbamate moiety resulting in the loss of the NH stretch in
the range of 3300 cm for both monomers. Notably, the
relatively narrow N−H stretch band of 2a would suggest the
symmetrical participation of both thiosquaramide NH groups
in hydrogen bond interactions on self-assembly. Collectively,
the solution-phase IR results suggest that both 1 and 2 engage
in hydrogen bond interactions upon self-assembly through the
squaramide moiety.
Figure 5. The degree of aggregation (αagg) plotted as a function of the
volume fraction of CH CN as determined from UV−vis denaturation
3
experiments for 1a (a) at λ = 330 nm and 2a (b) at λ = 384 nm. Data
for the various monomer concentrations (c = 15−40 μM) were fit
with the equilibrium model. Spectral data can be found in the
Supporting Information.
−
1
noncovalent interactions responsible for their formation. The
less-directional and weaker hydrogen-bonding interaction
afforded by the thiosquaramide and its π-stacking preference
promote the self-assembly of 2a in a less cooperative manner,
forming shorter fibers with a decreased persistence length. This
result is in contrast to 1a, for which head-to-tail hydrogen
bonding is key to its cooperative aggregation that enables the
formation of long and rigid fibers.
Solid-State NMR Studies Support a Distinct Packing
Mode of Monomers 1 and 2 in Their Aggregated
States. To provide a more comprehensive molecular picture
of the self-assembly of both monomers 1a and 2a, solid-state
NMR experiments in their aggregated and depolymerized
Fourier transform infrared (FTIR) spectra were obtained for
1
a and 2a in D O and D O−CD CN (6:4) to probe the role
2
2
3
of hydrogen-bonding interactions in the self-assembly of the
states were performed. Monomers dried from H O were used
2
oxo- and thiosquaramide monomers. In D O, 1a showed C
to probe their aggregated structures, whereas samples dried
2
−
1
O stretches from the squaramide (1645 cm ) and carbamate
from H O−CH CN (6:4) were used to examine the
2
3
−
1
(
1693 cm ) moieties, a small broad ring breathing band
depolymerized state as in the aforementioned experiments.
−
1
13
(
1799 cm ), and an N−H stretch from the squaramide (3158
1D C−CPMAS experiments of 1a in both states showed
−
1
cm ) (Figure 6, blue). When 1a was dissolved in D O−
CD CN (6:4), the CO bands were shifted to lower (1641
nearly the same set of NMR peaks (Figures S17 and S18, SI),
with the quaternary carbons of the CO bond of squaramide
at 181 ppm, the CC bond of the squaramide at 166 ppm,
and the CO of the carbamate at 157 ppm. Signals between
70 and 75 ppm were ascribed to the carbons within the
2
3
−
1
−1
cm ) and higher (1698 cm ) wavenumbers, respectively,
while the ring breathing band appeared at a lower wavenumber
−
1
(
1794 cm ). The N−H stretch was shifted to higher
F
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1
13
Figure 7. H− C HETCOR experiments performed at a contact time of 2048 μs on 1a (a) and 2a (b) in their polymerized (H O) form.
2
Highlighted areas are described in the text.
oligo(ethylene glycol) chain, and those between 29 and 69
ppm were assigned to the aliphatic chains on both sides of the
squaramide. In the case of 2a, similar 1D spectra were obtained
for the two states. Signals for oligo(ethylene glycols), aliphatic
chains, and carbamate CO were found at similar chemical
shift ranges; however, distinct signals were observed for
carbons in the thiosquaramide ring (Figures S19 and S20, SI).
The CC bond of squaramide was assigned to the peak at
polymer morphology, as observed by cryo-EM and scattering
methods.
Computational Studies of Head-to-Tail versus
Stacked Arrangements of Self-Assembled Oxo- and
Thiosquaramides. Density functional theory (DFT) compu-
tations of the head-to-tail and stacked hexamers of 1′ and 2′
were carried out to examine the competition between the
different self-assembly modes. Single-point energy calculations
at the IEF-PCM-M06-2X/6-311+G(d,p) level (see Materials
and Methods, SI) reveal a more-negative averaged interaction
1
70 ppm, and a broad signal was found for the CS bonds at
1
99 ppm, significantly deshielded in comparison to that of the
energy (ΔE ) for the head-to-tail 1′ hexamer (−37.5 kJ/mol)
CO bond on squaramide.
int
compared to that of the stacked 1′ hexamer (−32.5 kJ/mol),
To further deconvolute the self-assembly modes of 1a and
1
13
indicating that the head-to-tail mode is favored for 1′.
2
a, 2D H− C heteronuclear correlation (HETCOR) experi-
Conversely, the computed averaged ΔE for the head-to-tail
ments were collected in both states [Figures 7 and S21 (SI)].
Contact times between 250 μs and 5 ms (Figures S21 and S22,
SI) were examined to probe the magnetization transfer intra-
and intermolecularly. At longer contact times, above 2 ms,
signals from the carbons of the squaramide and carbamate
became apparent. Extensive aggregation of 1a in the solid state
resulted in several cross-peaks between the squaramide carbons
and flanking protons on the nearby aliphatic chains not
observed in the depolymerized sample [Figure 7a, boxed areas,
and Figure S21a (SI)] or at shorter contact times (250 μs),
pointing to interactions between monomers. Importantly, a
cross-peak was observed between the NH protons and CO
and CC carbons, confirming the head-to-tail hydrogen-
bonding mode between oxosquaramide monomers (Figure 7a,
red and blue circles). In sharp contrast, for 2a with the same
contact time (2 ms), CS carbon and NH proton cross-peaks
were absent for polymers in both conditions (Figure 7b), and
cross-peaks with protons flanking squaramide were not
detected. The lack of the CS and NH cross-peaks is in
contrast to FTIR data that suggest a hydrogen bond
interaction in the thiosquaramide moiety; however, such
interactions were previously undetected by the HETCOR
int
2
′ hexamer (−32.0 kJ/mol) was significantly lower relative to
that of the stacked 2′ hexamer (−47.6 kJ/mol), suggesting a
dominant stacking mode for 2′. Computed interaction energies
in the gas phase corrected for basis set superimposition error
(
(
BSSE) show the same trend and are included in Table S3
SI).
Accordingly, computed electron density difference (EDD)
maps for the head-to-tail vs stacked dimers of 1′ and 2′ show
that CO’s form effective hydrogen-bonding interactions with
N−H’s in the O lone-pair plane, but CS’s form stronger
interactions with the N−H’s at roughly 90° angles to the S
lone-pair plane. As shown in Figure 8a (top), EDD maps for
the head-to-tail 1′ and 2′ dimers show increased electron
density at the O/S’s (indicated in red, electron density gain)
and decreased electron density at the amine H’s (indicated in
blue, electron density loss); as expected by the stronger
hydrogen-bond-acceptor ability of CO, the head-to-tail 1′
dimer displays greater electron density change. In Figure 8a
(
bottom), EDD maps of the stacked 1′ and 2′ dimers also
show increased electron density at the O/S’s (in red) and
decreased electron density at the general N−H region (in
blue), suggestive of attractive noncovalent interactions
between the stacks. The much greater electron density change
for the stacked 2′ dimer is consistent with the ability of CS
43
technique in hydrogen-bonded thiobarbituric acids. More-
over, the absence of cross-peaks of the CC carbons of
thiosquaramide with other parts of the monomer as observed
for oxosquaramide can also point to a less regular aggregate
structure. This interpretation would be in line with the low
persistence length of the fibers of 2a and the lesser degree of
cooperativity in their supramolecular polymerization, as
determined from solvent denaturation experiments. Cumu-
32,33
to engage in less directional hydrogen bond interactions.
These findings further support that differences in the physical
properties and spectroscopic features of the supramolecular
polymers of oxosquaramide versus thiosquaramide bolaamphi-
philes likely arise from their preferred self-assembly modes.
Even though monomers of thiosquaramides can also
assemble through a head-to-tail mode, the stacked mode is
much preferred, because the electron distribution on the S
atom is anisotropic. As shown in Figure 8b, the computed
1
13
latively, the differences in the 2D H− C HETCOR solid-
state NMR spectra point to a distinctive internal organization
of the monomers within the fibers having an impact on the
G
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Figure 9. Computed geometries in implicit solvation for the isolated
monomers of 1′ and 2′ (bond distances in angstroms, values in bold
font), the head-to-tail hexamer of 1′ (left, averaged bond distances for
each of the monomeric units, values in italic font), and the stacked
hexamer of 2′ (right, averaged bond distances for each of the
monomeric units, values in italic font).
shorten (by 0.004 Å) and the ring CC bond lengthens (by
0
.004 Å), but the C−C and CS bonds exhibit little to no
change (a 0−0.003 Å change).
Harmonic oscillator model of electron delocalization
44
(
HOMED) analyses confirm these observations, showing
increased HOMED values when 1′ (0.329, HOMED value for
isolated monomer) self-assembles into the head-to-tail 1′
hexamer (0.383, averaged HOMED values for six monomer
units), while those of 2′ (0.447, isolated monomer) and the
stacked 2′ hexamer (0.445, average for six monomer units)
stay close. HOMED values range from 0 (nonaromatic) to 1
(
fully aromatic compounds) and measure the degree of ring
bond equalization in molecules as a criterion for aromaticity
see Tables S4 and S5, SI). These computed parameters
Figure 8. (a) Computed electron density difference (EDD) maps for
the head-to-tail 1′ and 2′ dimers (note the larger lobes on 1′), as well
as stacked 1′ and 2′ dimers (note the larger lobes on 2′). (b)
Electrostatic potential maps (MEP) of 1′ and 2′ monomers (blue
indicates electron density loss and positively charged; red indicates
electron density gain and negatively charged).
(
suggest that the geometries of oxo- and thiosquaramides
change in distinct ways upon monomer self-assembly.
Computations based on the magnetic and energetic criteria
of aromaticity revealed a significant aromaticity gain in both
the head-to-tail self-assembled monomers of 1′ and the stacked
monomers of 2′. Isotropic nucleus independent chemical shifts
electrostatic potential map (MEP) of the 2′ monomer reveals
positively charged regions at the back end of the two C−S
bonds, indicating the presence of a σ-hole (note the electron-
rich periphery above and below the σ-hole). For this reason, a
bonding interaction at a near 90° angle to the C−S bond is
preferred, supporting a dominant stacked arrangement of self-
assembled thiosquaramides. Moreover, computed NBO
E2PERT analyses at the B3LYP-D3/6-31+G(d) level reveal
minimal S lp (lone pair) → NH σ* (0.25 kJ/mol) and N lp →
CS σ* (0.29 kJ/mol) interaction energies, suggesting
negligible orbital interactions between the N−H and CS
groups of neighboring stacked thiosquaramides. These results,
along with the computed MEP map for the stacked
thiosquaramide dimer, suggest that the stacking interactions
between thiosquaramide monomers are mostly electrostatic
45,46
(NICS)
were computed at 0.6 Å above each of the head-
to-tail 1′ ring centers and at 0.8 Å above each of the stacked 2′
ring centers (due to the more diffuse orbitals of the S atoms)
to quantify the magnetic effects of the aromaticity gain. As
shown in the Table S6 (SI), the computed isotropic NICS for
both 1′ [NICS(0.6) = −7.0 ppm] and 2′ [NICS(0.8) = −3.7
ppm] become more negative in the head-to-tail 1′ hexamer
[NICS(0.6) = −6.7 to −7.3 ppm] and stacked 2′ hexamer
[NICS(0.8) = −3.2 to −4.6 ppm], documenting the
aromaticity gain in both monomers upon self-assembly.
47
Block-localized wave function (BLW) analyses quantified
the energetic effects of the aromaticity gain in the head-to-tail
hexamer of 1′ and the stacked hexamer of 2′ (see Table S7,
SI). The BLW method, the simplest variant of valence bond
calculations, measures π-electron delocalization energies (DEπ)
in molecules by comparing the energy of the fully delocalized
wave function (Ψdeloc) of a molecule to that of its hypothetical
(
i.e., between the positively charged H’s of the N−H groups
and the negative region of the S atoms).
Computational Studies of Aromaticity Gain in Oxo-
and Thiosquaramide Supramolecular Polymers. Com-
puted geometries for the monomers and hexamers of 1′ and 2′
at the IEF-PCM-B3LYP-D3/6-31+G(d) level (Figures S23−
S26 and Table S8, SI) show that the ring bonds of 1′ [Figures
π-electron localized wave function (Ψ ) in which all π-
loc
electron delocalization effects are “turned off”: DE = Ψ
−
π
deloc
Ψ
(i.e., a more negative DE value indicates more π-electron
loc
π
9
and S23, left, values in bold font (SI)] become more bond
delocalization in a molecule). The computed DE difference
π
length equalized (i.e., increased aromatic character) upon self-
assembly in the head-to-tail 1′ hexamer (values in italic font);
all of the single bonds shorten (by 0.005−0.018 Å) and the
double bonds lengthen (by 0.009−0.013 Å). In contrast, the
ring bonds of 2′ [Figures 9 and S23, right, values in bold font
between the isolated monomers (e.g., 1′ and 2′) versus head-
to-tail or stacked monomers provides a measure of the extra
gain in π-electron delocalization in monomers upon self-
assembly; ΔDE = DE (head-to-tail or stacked monomer) −
π
π
DE (monomer) (i.e., a more negative ΔDE value indicates
π
π
(
SI)] are altered to a lesser degree upon self-assembly in the
more π-conjugation gain upon head-to-tail or stacked assembly
of the monomer). Large negative ΔDEπ values suggest
stacked 2′ hexamer (values in italic font); the two C−N bonds
H
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Article
enhanced aromatic character in the self-assembled monomer
AUTHOR INFORMATION
■
(
see the Supporting Information).
Remarkably, the computed ΔDE values for each of the
Corresponding Authors
π
Judy I. Wu − Department of Chemistry, University of Houston,
Houston, Texas 77204, United States; orcid.org/0000-
monomers in the head-to-tail 1′ hexamer (averaged ΔDE =
π
−
=
115.0 kJ/mol) and the stacked 2′ hexamer (averaged ΔDE
π
0003-0590-5290; Email: jiwu@central.uh.edu
−86.2 kJ/mol) are large and negative, suggesting significant
Roxanne E. Kieltyka − Supramolecular and Biomaterials
Chemistry, Leiden Institute of Chemistry, Leiden University,
aromaticity gain upon self-assembly (see Table S3 of the SI for
more details). These computations suggest that in low-
dielectric environments, such as in the hydrophobic core of a
supramolecular polymer, the aromaticity gain can be
considered as an important driving force when combined
with noncovalent bonding to direct the self-assembly of
supramolecular polymers.
2
9
300 RA Leiden, The Netherlands; orcid.org/0000-0001-
152-1810; Email: r.e.kieltyka@chem.leidenuniv.nl
Authors
Victorio Saez Talens − Supramolecular and Biomaterials
Chemistry, Leiden Institute of Chemistry, Leiden University,
300 RA Leiden, The Netherlands
2
DISCUSSION AND CONCLUSION
Joyal Davis − Supramolecular and Biomaterials Chemistry,
Leiden Institute of Chemistry, Leiden University, 2300 RA
Leiden, The Netherlands
Chia-Hua Wu − Department of Chemistry, University of
Houston, Houston, Texas 77204, United States
Zhili Wen − Department of Chemistry, University of Houston,
Houston, Texas 77204, United States; orcid.org/0000-
■
In this report, we demonstrate that oxosquaramide and
thiosquaramide monomers self-assemble into surprisingly
different fibrillar morphologies in water: oxosquaramide-
based bolaamphiphiles form long, rigid, fibrillar architectures,
while the thio-analogues form short, flexible, rodlike structures.
Evidence based on spectroscopic measurements and computa-
tional analyses revealed that oxosquaramides self-assemble into
a head-to-tail arrangement by aligning their hydrogen-bond
donors (N−H’s) and acceptors (CO’s) along the squar-
amide ring plane. On the other hand, thiosquaramides prefer
antiparallel stacked configurations, in which the N−H’s of each
unit are stacked above and below the CS’s of adjacent layers,
resulting in interactions at a CS···H angle close to 90°. The
head-to-tail hydrogen bonding in oxosquaramides facilitates
supramolecular polymerization by a cooperative mechanism to
form long and rigid polymers, while the stacked interaction of
the thiosquaramides results in a decrease of the length and
stiffness of the aggregates, on par with their polymerization in a
less cooperative fashion. IR measurements of the self-
assembled oxo- and thiosquaramides show peaks consistent
with the hydrogen bonding of the squaramide moieties, with
the head-to-tail hydrogen-bonding mode being supported by
solid-state NMR studies for oxosquaramide. Moreover,
computations revealed that polarization of monomers in both
the head-to-tail and stacked self-assembly modes can increase
the aromatic character of squaramide synthons. These findings
further suggest that changes in the aromatic characters of
0001-5678-0163
Francesca Lauria − Supramolecular and Biomaterials
Chemistry, Leiden Institute of Chemistry, Leiden University,
2300 RA Leiden, The Netherlands
Karthick Babu Sai Sankar Gupta − Supramolecular and
Biomaterials Chemistry, Leiden Institute of Chemistry, Leiden
University, 2300 RA Leiden, The Netherlands; orcid.org/
0000-0002-3528-2912
Raisa Rudge − Supramolecular and Biomaterials Chemistry,
Leiden Institute of Chemistry, Leiden University, 2300 RA
Leiden, The Netherlands
Mahsa Boraghi − Department of Chemistry, University of
Houston, Houston, Texas 77204, United States
Alexander Hagemeijer − Supramolecular and Biomaterials
Chemistry, Leiden Institute of Chemistry, Leiden University,
2300 RA Leiden, The Netherlands
Thuat T. Trinh − Department of Chemistry, Norwegian
University of Science and Technology, 7491 Trondheim,
Norway; orcid.org/0000-0002-1721-6786
Pablo Englebienne − Process & Energy Laboratory, Delft
University of Technology, 2628 CB Delft, The Netherlands
Ilja K. Voets − Laboratory of Self-Organizing Soft Matter and
Institute for Complex Molecular Systems, Eindhoven
University of Technology, 5600 MD Eindhoven, The
Netherlands; orcid.org/0000-0003-3543-4821
2
2
synthons can be used to “fine-tune” the intermolecular
interactions between monomers, with potent effects on their
mode of supramolecular polymerization. We emphasize that,
beside the often-used checklist for controlling noncovalent
interactions relevant for self-assembly, aromaticity gain should
also be considered in the molecular design of monomers, as
well as more broadly in supramolecular chemistry.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c02081
Notes
ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available free of charge at
The authors declare no competing financial interest.
■
*
ACKNOWLEDGMENTS
■
https://pubs.acs.org/doi/10.1021/jacs.0c02081.
We would like to thank T. Sharp, R. I. Koning, and B. Koster
for assistance with cryo-TEM experiments; L. C. Gascoigne for
Materials and Methods, synthetic procedures, solution
and solid-state NMR spectra, cryoTEM imaging, light
scattering experiments, UV-Vis spectroscopy, solution
and solid-state IR spectroscopy, DFT-computed geo-
metries, NICS analysis, BLW computation, Cartesian
coordinates of optimized geometries (Figures S1−S26
and Tables S1−S8) (PDF)
SLS measurements; G. Fernandez, K. Kartha, W. E. M.
́
Noteborn, and A. Kros for fruitful discussions; and R. Das for
computing the electron density difference maps. I.K.V. (NWO
ECHO-STIP Grant 717.013.005, NWO VIDI Grant
7
7
23.014.006) and R.E.K. (NWO-ECHO-STIP Grant
17.014.005, NWO-VENI Grant 722.012.011) acknowledge
The Netherlands Organization for Scientific Research (NWO)
I
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Article
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