Aromatic Gain in a Supramolecular Polymer

Abstract

The synergy of aromatic gain and hydrogen bonding in a supramolecular polymer is explored. Partially aromatic bis(squaramide) bolaamphiphiles were designed to self-assemble through a combination of hydrophobic, hydrogen-bonding, and aromatic effects into stiff, high-aspect-ratio fibers. UV and IR spectroscopy show electron delocalization and geometric changes within the squaramide ring indicative of strong hydrogen bonding and aromatic gain of the monomer units. The aromatic contribution to the interaction energy was further supported computationally by nucleus-independent chemical shift (NICS) and harmonic oscillator model of aromaticity (HOMA) indices, demonstrating greater aromatic character upon polymerization: at least 30 % in a pentamer. The aromatic gain-hydrogen bonding synergy results in a significant increase in thermodynamic stability and a striking difference in aggregate morphology of the bis(squaramide) bolamphiphile compared to isosteres that cannot engage in this effect.
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Full text

German Edition:DOI:10.1002/ange.201503905
Non-Covalent Interactions International Edition:DOI:10.1002/anie.201503905
Aromatic Gain in aSupramolecular Polymer**
Victorio Saez Talens,Pablo Englebienne,Thuat T. Trinh, Willem E. M. Noteborn, Ilja K. Voets,
and Roxanne E. Kieltyka*
Abstract: The synergy of aromatic gain and hydrogen bonding
in asupramolecular polymer is explored. Partially aromatic
bis(squaramide) bolaamphiphiles were designed to self-assem-
ble through acombination of hydrophobic,hydrogen-bond-
ing, and aromatic effects into stiff,high-aspect-ratio fibers.UV
and IR spectroscopyshowelectron delocalization and geo-
metric changes within the squaramide ring indicative of strong
hydrogen bonding and aromatic gain of the monomer units.
The aromatic contribution to the interaction energy was further
supported computationally by nucleus-independent chemical
shift (NICS) and harmonic oscillator model of aromaticity
(HOMA) indices,demonstrating greater aromatic character
upon polymerization:atleast 30 %inapentamer.The
aromatic gain–hydrogen bonding synergy results in asignifi-
cant increase in thermodynamic stability and astriking differ-
ence in aggregate morphology of the bis(squaramide) bolam-
phiphile compared to isosteres that cannot engage in this effect.
Aromatic gain is considered to be athermodynamic driving
force in several organic reactions.Inaromatic substitutions,
Bergman cyclizations, aromatic Cope rearrangements,[1,5]H
sigmatropic shifts,and [4++2] cyclizations,among others,the
restoration of aromaticity helps to explain their exergonic
character and increased efficiency.[1] In supramolecular poly-
mers,[2] where monomers are held together by non-covalent
interactions resulting in higher-order aggregates with various
topologies,the concept of aromatic gain in the construction of
such systems is unexplored.
Aromaticity has captivated chemists since its introduction
as aconcept 150 years ago by Kekul¦.[3] In contrast to other
chemical concepts,such as chemical bonding,electronegativ-
ity and acidity/basicity,aromaticity is not adirect physical
observable and its exact definition is the subject of much
debate.[4] Classically,cyclic p-conjugated compounds are
aromatic when they show differences in geometric, energetic,
and magnetic criteria relative to their acyclic analogues.[5] In
recent years,computational methods such as nucleus-inde-
pendent chemical shift (NICS),[5c,6] harmonic oscillator model
of aromaticity (HOMA),[7] and aromatic stabilization ener-
gies (ASE),[5b] have grown in use to describe aromaticity.In
the case of NICS,excellent correlation has been reported with
experimental nuclear magnetic resonance data as well as
other descriptors of aromaticity,[4a] thus opening the door to
predict the aromaticity of new compounds and structures
apriori. Ve ry recently,NICS calculations demonstrated
reciprocal hydrogen-bonding–aromaticity relationships that
can have important consequences on the strength of hydro-
gen-bonding interactions.[8]
Squaramides,[9] which are composed of two NH hydrogen-
bond donors opposite two carbonyl hydrogen-bond acceptors
on aconformationally rigid cyclobutene ring, are predicted to
show partial aromatic character.[9] This character arises from
the delocalization of the nitrogen lone pair into the cyclo-
butenedione ring system (HîckelÏs rule:(4n+2) pelectrons,
n=0).[10] In the solid state,catemers of disecondary squar-
amides arranged in ahead-to-tail motif have been reported[11]
and they may benefit from strong resonance-assisted hydro-
gen bonding (RAHB) interactions similar to squaric acids.[12]
Applications of the squaramide unit have been found in
medicinal chemistry,catalysis,and anion recognition.[13] The
capacity of squaramides to form strong hydrogen bonds that
simultaneously influence their aromatic character is highly
appealing to guide the formation of increasingly stable
supramolecular polymers.Herein, we incorporate the squar-
amide synthon into abolaamphiphilic construct that self-
assembles into stiff fibers in water, and we explore the
coupling of hydrogen-bonding and aromatic gain using
experiment and computation.
Compound 1consists of two oligo(ethylene glycol) methyl
ether chains opposite acentral hydrophobic core with two
embedded squaramide units (Figure 1). 1HNMR spectra of
1in D2Owere suggestive of strong aggregation that is
resistant to thermal denaturation up to 6588C. Only 1HNMR
spectra recorded in CDCl3or [D2]HFIP were well-resolved
and suggestive of various degrees of depolymerization.
Theeffect of the squaramide synthon on the self-assembly
of 1in water was evaluated by cryo-transmission electron
[*] V. Saez Talens, W. E. M. Noteborn, Dr.R.E.Kieltyka
Department of Supramolecular and Biomaterials Chemistry
Leiden Institute of Chemistry,Leiden University
P.O. Box 9502, 2300 RA Leiden (The Netherlands)
E-mail:r.e.kieltyka@chem.leidenuniv.nl
Dr.P.Englebienne
Process &Energy Laboratory
Delft University of Technology
Leeghwaterstraat 39, 2628 CB Delft (The Netherlands)
Dr.T.T.Trinh
Department of Chemistry
NorwegianUniversity of Science and Te chnology
7491 Trondheim (Norway)
Dr.I.K.Voets
Department of Chemical Engineering and Chemistryand
Institute for Complex Molecular Systems
Eindhoven University of Technology
P.O. Box 513, 5600 MB Eindhoven (The Netherlands)
[**] We thank R.I. Koning (TEM), B. Koster (TEM), F. Galli (AFM), M.
Rabe (IR), A. J. M. Sweere (CULGI), R. Matadeen (TEM, NeCEN), K.
Pieterse (ICMS Animation Studio), and A. Kros for essential
discussions. This work is funded by aVENI grant (to R.E.K.) from
NWO.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201503905.
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microscopy (cryo-TEM) and atomic force microscopy
(AFM). Cryo-TEM images of 1(1 wt%) displayed stiff,
micrometer-long fibrils with auniform diameter. Short, rod-
like structures on the order of 12.6 2.4 nm in length were
found upon sonication (Figure 2a)and slowly progressed into
micrometer-long fibers.Fibers of 1were 6.4 1.2 nm in
diameter, on par with the length of the hydrophobic region of
the bolaamphiphile (Figure 2b). By small-angle X-ray scat-
tering measurements (SAXS,Figure 2c), across-sectional
radius (rcs)of3.5 nm and across-sectional mass per unit
length (ML)of2.5 ×10
20–6.0 ×10
20 gnm¢1was determined for
fibers of 1,indicating that approximately 10–30 squaramide
bolaamphiphiles per nm can be found along the fiber axis.
These results suggest that hydrogen bonds parallel to the fiber
axis drive the formation of highly anisotropic fibers,mean-
while the combination of hydrophobic and p-interactions
between squaramide moieties facilitate the assembly of
several bolaamphiphiles in the lateral direction (Figure 1).
To better understand the consequence of self-assembly on
the squaramide synthon, spectroscopy at the molecular level
was pursued. UV spectroscopy of 1in water showed maxima
at 255 and 329 nm, and ashoulder around 310 nm (Figure 3a).
Disruption of the polymerized state was achieved using both
temperature and various solvents.More specifically,hexa-
fluoroisopropanol (HFIP), apotent hydrogen bond disruptor,
promoted depolymerization resulting in the gradual loss of
the red-shifted hydrogen-bonded squaramide N¢Hproton-
donor p–p*bands (329 nm) and the blue-shifted C=Oproton-
acceptor n–p*bands (255 nm), concomitant with the growth
of the non-hydrogen bonded monomer band (310 nm).[14]
These experimental trends are in agreement with TD-DFT
calculations,where two superimposed absorption bands of
similar intensity corresponding to the HOMO–LUMO and
HOMO–(LUMO +1) transitions are predicted for the mo-
nomer;inoligomers,the high wavelength band is progres-
sively red-shifted while the other appears blue-shifted. Self-
assembly of 1through strong hydrogen bonding interactions
results in increased orbital overlap between squaramide units
and further electron delocalization within the individual
squaramide rings,enabling aromatic gain to occur.
Geometric changes to the squaramides upon self-assem-
bly were examined by IR spectroscopy.Solutions of
1(2 wt%) in D2Owere measured at room temperature.
Above the amide Iregion, asmall broad band at 1796 cm¢1,
consistent with squaramide ring breathing, was found exper-
imentally and confirmed by modeling (Figure 3b). In the
amide Iregion, asymmetric and symmetric C=Ostretches
(1687, 1676, and 1642 cm¢1)ofthe squaramide and carbamate
moieties were recorded. Strong hydrogen bonding of the
squaramide units was observed through the N¢Hstretch at
3162 cm¢1(inset in Figure 3b). In [D2]HFIP,the blue-shifting
of several bands such as the ring breathing (13 cm¢1)and
symmetric C=Ostretch (14 cm¢1)modes were observed and
suggestive of depolymerization. Owing to lack of transpar-
encyof[D
2]HFIP in the N¢Hregion, an approximation for
free N¢Hstretch (3452 cm¢1)was made for 1in CDCl3.The
experimental data correlated well with ab initio calculations.
These results revealed that bond lengths in the squaramide
are systematically altered as afunction of oligomer length
(Figure 4a): double bonds become longer, whereas single
bonds shorten, resulting in aring with less bond length
alternation. With these bond lengths,wecomputed HOMA
values of ¢0.015 and 0.516 for the isolated monomer and the
central monomer in apentamer,respectively,while avalue of
Figure 1. a) Structure of the squaramide-based bolaamphiphile 1.b)Self-assembly of 1into fibrillar structures, and depolymerization by
hexafluoroisopropanol(HFIP). Within the fibrillar structure, hydrogen bonds are proposed to occur parallel to the fiber axis while p-interactions
between squaramidebolaamphphiles occur in the lateral direction, as depicted. c) Proposed hydrogen-bonding interactions between squaramide
monomers.
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one is defined for aromatic compounds.Experiments point to
strong hydrogen bonding and computed geometric consid-
erations demonstrate an increase in aromatic character within
the squaramide unit due to supramolecular polymerization.
NICS-scan profiles,[15] ameasurement of the magnetic
shielding above and at the center of the ring, were computed
on an axis passing though the center of the squaramide ring
for monomers to pentamers to quantify the aromatic charac-
ter upon oligomerization. Theprofiles for the individual
squaramide units were negative overall and exhibited amini-
mum around 0.6 è, consistent with an aromatic ring. Upon
increasing oligomer length, the NICS values became more
negative without achange in the shape of the curves,
suggestive of increased aromaticity.Inparticular,the change
in NICS at 0.6 èfrom the ring plane (Figure 4b)when going
from amonomer (¢6.8) to the central monomer of apentamer
(¢8.4), is in line with previous reports.[16] Additionally,the
aromatic stabilization energy accounts for at least 30 %ofthe
total interaction energy in asquaramide pentamer
(¢85.6 kJmol¢1out of ¢271.7 kJmol¢1including BSSE cor-
rection) using aheterodimer of vinylogous amides that cannot
exhibit aromaticity as areference.
We further investigated the thermodynamic consequence
of aromatic gain experimentally by measuring the critical
aggregation concentration (CAC)using static light scattering
(SLS). An order of magnitude lower CAC, corresponding to
afree energy difference DDGagg =¢5.25 kJmol¢1,was
obtained for molecule 1(7.94 ×10
¢6m)incomparison to
urea-based analogue 5(7.41 ×10
¢5m;see the Supporting
Information) (Figure 5). These results are further supported
Figure 2. Cryo-TEM images of 1in aqueoussolution (1 wt %) after
sonication: a) t=0, and b) t=2weeks. Inset :Histogramsoflength (a)
and width (b). Scale bar :a)50nm ;b)100 nm. c) Small-angleX-ray
scattering profiles of squaramidefibers collected at aconcentration of
4and 5mgmL¢1.
Figure 3. a) UV/Vis spectrum of 1in water (0.005 wt %) as afunction
of HFIP concentration. b) IR spectrum recorded in the amide Iregion
and amide II in D2Oand [D2]HFIP. Inset:N
¢Hand C¢Hstretch
region.
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by DFT calculations,where the interaction energy computed
per hydrogen bond of urea oligomers was found to be smaller
(¢23.9 vs. ¢35.6 kJmol¢1for pentamers) and does not
increase as steeply with oligomer length (+18%vs.
+30%). Intriguingly,astriking difference in the fiber
morphology was found above the CACofboth molecules.
Whereas 1consistently formed long and stiff micron-sized
fibers,short worm-like or spherical aggregates were obtained
for 5.Given the similarity of the hydrophilic and hydrophobic
blocks,these results suggest that the coupling of aromatic gain
and hydrogen-bonding in addition to the structural rigidity of
the squaramide units act collectively to lower the critical
aggregation concentration, and propagate the formation of
high-aspect-ratio fibers in water.
We find that the capacity of squaramides to couple
hydrogen bonding and aromaticity facilitates the formation of
robust supramolecular polymers.The gain in aromatic
character upon assembly is demonstrated through bond
length equalization, decreased NICS values,high aromatic
stabilization (ASE) values,and increased thermodynamic
stability of the resultant aggregates.These changes are in
accordance with the geometric,magnetic,and energetic
criteria used to describe aromaticity.Moreover,the aromatic
gain is asignificant component of the total interaction energy
of squaramide-based supramolecular polymers,explaining
the observed increase in thermodynamic stability relative to
the monomers and to their urea counterparts.Insummary,
this self-tuning behavior between hydrogen bonding and
aromaticity within the squaramide ring system cannot be
achieved by other simple ditopic synthons,such as ureas or
amides,commonly used to construct supramolecular poly-
mers.Therefore,weanticipate that the information gained
here can enrich the palette of hydrogen-bonding monomers
used for supramolecular polymer assembly by implementing
aromaticity as adesign consideration.
Keywords: aromaticity ·non-covalent interactions ·
self-assembly ·squaramides ·supramolecular polymers
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Received:April 28, 2015
Published online: July 14, 2015
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