Symmetry breaking in the self-assembly of partially fluorinated benzene-1,3,5-tricarboxamides

Article abstract of DOI:10.1002/anie.201204727

The interplay of two subsequent aggregation processes results in a symmetry-breaking phenomenon in an achiral self-assembling system. Partially fluorinated benzene-1,3,5-tricarboxamide molecules self-assemble into a racemic mixture of one-dimensional P- and M-helical aggregates, followed by bundling into optically active higher-order aggregates or fibers (see picture). Copyright

Full text of DOI:10.1002/anie.201204727

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Chemie
DOI: 10.1002/anie.201204727
Chirality
Symmetry Breaking in the Self-Assembly of Partially Fluorinated
Benzene-1,3,5-tricarboxamides**
Patrick J. M. Stals, Peter A. Korevaar, Martijn A. J. Gillissen, Tom F. A. de Greef,
Carel F. C. Fitiꢀ, Rint P. Sijbesma,* Anja R. A. Palmans,* and E. W. Meijer*
In the early 1970s Young and co-workers described—hidden
in a report on stilbene derivates forming nematic liquid
crystals—a fascinating phenomenon: the formation of opti-
cally active phases out of racemic or achiral mixtures.[1] This
baffling phenomenon has since then been observed in various
liquid crystals ranging from banana-shaped[2] to columnar[3]
and nematic phases.[4] In solution, similar chiral symmetry-
breaking phenomena have been observed in various self-
assembling systems. DeRossi et al. reported one of the
earliest examples in their investigations on the self-assembly
of benzimidocyanines in solution,[5] while more recently
symmetry breaking was reported in self-assembling systems
driven by p–p interactions.[6,7] Self-assembling porphyrin-
based systems have been studied extensively in this respect,
usually when exposed to some kind of external stimulus.[7]
Recently, control of handedness of helical aggregates of
achiral porphyrin derivatives by applying a combination of
rotational and magnetic forces during the self-assembly
process gave detailed insights in the underlying mecha-
nisms.[7c] All of these experiments may help in answering
one of the most important questions still lingering in science:
why do homochiral compounds (l-amino acids and d-sugars)
prevail in nature?[8]
self-assembling supramolecular polymers and relies on
a subtle interplay of different types of noncovalent interac-
tions.[9] Typically, these chiral amplification effects are studied
for systems that are in thermodynamic equilibrium and the
excess of one enantiomer determines the supramolecular
chirality of the system. Benzene-1,3,5-tricarboxamides
(BTAs) comprising aliphatic side chains show thermodynami-
cally controlled self-assembly and one-dimensional helical
aggregates are formed in a cooperative fashion because of
hydrogen bonding.[10] The role of solvent, temperature,
concentration, and the position of the methyl substituent in
the alkyl side chain of BTAs on the self-assembly process has
been elucidated through extensive experimental and theoret-
ical studies.[11]
Symmetry breaking is never observed in homogeneous
systems that are racemic or achiral and under thermodynamic
equilibrium. When symmetry breaking in achiral molecules is
observed, the system is often not under thermodynamic
equilibrium. For example, Lehn and co-workers showed
a nonstatistical formation of helical handedness in the self-
assembly of foldamers,[6b] and in crystallization experiments
of amino acid derivatives a nonrandom distribution of the
final handedness was observed.[12] In these examples, the
systems display secondary nucleation phenomena—that is,
part of a preformed crystal or mother fiber initiates the
growth of another—in combination with an undetectable
amount of chiral impurity.[6b,12]
Here, we report on a class of achiral, partially fluorinated
benzene-1,3,5-tricarboxamides (BTAs, Figure 1 class A) that
show a unique, two-step self-assembly behavior. After self-
assembly into equal amounts of one-dimensional left- (M)
and right-handed (P) helical aggregates that do not show any
optical activity under thermodynamic equilibrium conditions,
a kinetically controlled secondary nucleation takes place in
which the one-dimensional helical aggregates bundle into
a higher order aggregate, or fiber, which is optically active.
Here we use the term secondary nucleation similar as is used
in amyloid aggregation literature, where it describes the
thickening of fibrils nucleated at the surface of the first-
formed one-dimensional stack to form a fiber.[13] This report is
the first on symmetry-breaking in a two-step self-assembling
system that relies on a hierarchical self-assembly process in
which hydrogen bonding dominates the formation of the
helical aggregates and dipole–dipole interactions dominate
the secondary nucleation with undetectable amounts of chiral
impurities. The first observation of this symmetry breaking
was by serendipity, but followed by an in-depth analysis of this
discovery with a series of molecules.
Some of these answers may be provided by the interesting
observations made in several synthetic, self-assembling sys-
tems in which a tiny amount of optically active material
suffices to induce a nonproportional response in the optical
activity of racemic or achiral systems. This supramolecular
analogue of chiral amplification occurs in several helically
[*] P. J. M. Stals, P. A. Korevaar, M. A. J. Gillissen, Dr. T. F. A. de Greef,
Dr. C. F. C. Fitiꢀ, Prof. Dr. R. P. Sijbesma, Dr. A. R. A. Palmans,
Prof. Dr. E. W. Meijer
Institute for Complex Molecular Systems and
Laboratory of Macromolecular and Organic Chemistry
Eindhoven University of Technology
P. O. Box 513, 5600 MB Eindhoven (The Netherlands)
E-mail: r.p.sijbesma@tue.nl
a.palmans@tue.nl
e.w.meijer@tue.nl
[**] This work was supported by the European Research Council (ERC
advanced grant number 246829). Charley Schaeffer is acknowl-
edged for assisting with measurements, the ICMS animation studio
(TU/e) is acknowledged for providing the artwork. Prof. Dr. Willi
Bannwarth (Freiburg University), Dr. Ilja Voets (Eindhoven Univer-
sity of Technology), and Prof. Dr. Jim Feast (Durham University) are
acknowledged for stimulating discussions.
Supporting information for this article, including detailed exper-
imental information, that is, synthetic procedures, equipment used,
and details on sample preparation, is available on the WWW under
http://dx.doi.org/10.1002/anie.201204727.
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which two regimes can be distinguished: a nucleation regime
in which all molecules are molecularly dissolved (indicated by
a constant UV signal) and an elongation regime in which the
aggregate rapidly grows (indicated by a decrease in UV
signal, corresponding to a blue-shift of the UV absorbance of
the aggregating BTAs).[10c] The two regimes are separated by
the (concentration-dependent) elongation temperature, Te.
For BTA-F9, at a concentration of 3 ꢀ 10ꢀ5 m, elongation
occurs at 334.8 K. As expected, no CD effect was observed for
the achiral compounds in class B, since self-assembly results
in equal amounts of P and M helical one-dimensional
aggregates.
The self-assembly of the partially fluorinated BTAs in
class A (for example, BTA-F8H, Figure 2B, full spectra shown
in Figure S2) is quite different from those of class B. In
addition to the characteristic transition that we ascribe to the
primary nucleation of one-dimensional helical aggregates,
there is a second transition, as observed by UV/Vis spectros-
copy, around room temperature. Intriguingly, this transition
coincides with the unexpected appearance of a CD effect,
indicative of a second transition into an optically active fiber.
This behavior was found for all batches of BTA-F8H,
prepared from different starting materials, and for BTA-
F12H (Figure S3). Linear dichroism, linear birefringence,
precipitation or other known artefacts were all excluded as
sources for the observed CD effect.[14]
Surprisingly, the shape of the Cotton effect measured for
BTA-F8H and BTA-F12H (Figure 2C) differs significantly
from that of previously observed alkyl-substituted BTAs, in
which either a single maximum at l = 223 nm or a maximum
peak at 216 nm and a shoulder at 242 nm were observed.[11a,c]
For BTA-F8H and BTA-F12H the maximum is significantly
red-shifted to around 253 nm. Also, the molar ellipticity, De,
Figure 1. Chemical structures of the partially fluorinated BTAs and
their schematic representation (the green part represents the fluori-
nated part, while the orange part represents the w-proton).
BTAs comprising two n-decyl chains and one partially
fluorinated chain (BTA-F5 to BTA-F12H, Figure 1) were
readily prepared by a multistep synthesis (see Scheme S1 in
the Supporting Information). Two types of partially fluori-
nated chains were employed, resulting in two classes of
fluorinated BTAs. In class A a hydrogen atom is present on
the w-position of the fluorinated chain. Two derivatives of this
class, differing in length of the fluorinated part were prepared
(BTA-F8H and BTA-F12H). The w-hydrogen atom is
electron-deficient as evidenced by the 1H NMR
spectrum of BTA-F8H (Figure S1). Three derivatives
were prepared in class B, in which the fluorinated
chains lack the electron-deficient hydrogen atom
(BTA-F5, BTA-F7, and BTA-F9). The purity of all
BTA compounds was confirmed by 1H, 13C, 19F NMR
spectroscopies, elemental analysis, and MALDI-
TOF-MS (see the Supporting Information for details).
To exclude the possibility that undetectable, non-
racemic impurities originating from the starting
materials influence the self-assembly process, we
synthesized BTA-F8H in four different batches using
different starting materials.
The self-assembly of the BTAs was investigated
using temperature-dependent circular dichroism
(CD) and ultraviolet (UV) spectroscopy in methyl-
cyclohexane (MCH, c = 3 ꢀ 10ꢀ5 m). The temperature
was decreased from 90 to 58C at a constant rate
(60 Khꢀ1) and the CD and UV intensity was moni-
tored at l = 223 nm, the maximum of the Cotton
effect usually observed for alkyl-substituted carbonyl-
centered BTAs.[10c,11a] The temperature-dependent
UV curves for the compounds in class B (as example,
BTA-F9, Figure 2A) are typical for a cooperative
Figure 2. Temperature-dependent UV (black) and CD measurements (gray) of
A) BTA-F9 and B) BTA-F8H (c=30 mm in MCH, probed at l=223 nm, l=1 cm).
C) CD effects for BTA-F8H (light gray) and BTA-F12H (dark gray; c=30 mm in
MCH, l=1 cm, T=293 K). D) CD effects observed for BTA-F8H in the absence of
additives (dark-gray triangle; normally observed negative CD effect and gray
star; rarely observed positive CD effect) and after the addition of S-pyroglutamic
acid (positive CD effect, light-gray circle) or of d-tartaric acid (negative CD
aggregation process involving primary nucleation in effect, black square).
2
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(BTA-F8H: De = ꢀ10.1 Lmolꢀ1 cmꢀ1 at 208C and BTA-F12H:
De = ꢀ7.0 Lmolꢀ1 cmꢀ1 at 208C) is substantially lower than
solutions of BTA-F8H at a concentration of 30 mm in MCH
showed the appearance of large aggregates below 308C with
a hydrodynamic radius (RH) of about 50 nm (Figure S6).[16]
The combined AFM and DLS results suggest that the
optically active aggregates have a larger diameter than that
of the one-dimensional BTA aggregates, implying that they
are formed by bundling of one-dimensional BTA aggregates.
The differences in self-assembly observed between the
BTAs of classes A and B indicate that the electron-deficient
hydrogen at the w-position of the partially fluorinated chain is
essential for the formation of optically active bundles. The
different behavior of -CF2-H and -CF3 end groups in the
that
of
enantiomerically
pure
BTAs
(j De j=
40 Lmolꢀ1 cmꢀ1).[10c,11a,c] Although the temperature-depen-
dent UV and CD cooling curves for BTA-F12H and BTA-
F8H show similar features (Figure 2B and Figure S3), the
second transition temperature (Tt) for BTA-F12H is higher
than that for BTA-F8H (310 and 299 K, respectively). The
lower j De j found for BTA-F12H in combination with a higher
Tt indicates that the longer fluorinated part results in a higher-
order aggregate or fiber that has a less pronounced preference
between the two possible forms than BTA-F8H but is more
readily formed.
The formation of optically active fibers from achiral BTA-
F8H and BTA-F12H is not limited to MCH as solvent, but is
also observed in other cyclic alkanes (cyclohexane and
decaline, see Figure S4). In linear alkanes (e.g. heptane and
dodecane), BTA-F8H and BTA-F12H were poorly soluble,
while they are molecularly dissolved in more polar solvents
such as chloroform.
In general, the CD effects for BTA-F8H and BTA-F12H
(Figure 2D, black curve) show a negative sign. In rare cases,
however, also positive CD effects were observed for BTA-
F8H (Figure 2D, dark-gray curve). This is a remarkable
observation since a stochastic process in the absence of chiral
information should result in an equal occurrence of positive
and negative CD effects. Noorduin et al. recently reported
enantiomerically enriched crystals obtained by abrasive
grinding and solution racemization. Deviations from a stat-
istical distribution of enriched crystals were attributed to
minute, enantiomerically enriched impurities.[12,15] Hence, we
investigated the effect of adding small amounts of insoluble,
chiral additives to 30 mm solutions of BTA-F8H in MCH.
After heating and cooling these solutions, the addition of, for
example, S-pyroglutamic acid resulted in a larger,
positive CD effect (Figure 2D), whereas addition
of S-(ꢀ)-phenylglycine, d-tartaric acid or l-tarta-
ric acid resulted in negative CD effects (Fig-
ure 2D). Similar effects were observed for BTA-
F12H (Figure S5). These results suggest that sur-
face-assisted secondary nucleation may play a role
in the formation of the optically active fibers and
that minute chiral impurities present in the
environment influence the sign and magnitude of
the observed CD effect.
hierarchical self-assembly is rationalized by the high polar-
[17]
ꢀ
ꢀ
ization of the C F bond. This causes polarization of the C
ꢀ
H bond on the same carbon resulting in the formation of CF2
H···F CFH interactions between two or more BTA stacks.
ꢀ
Although the interaction between an electron-deficient
hydrogen and fluorine is weak,[18] C H···F interactions are
ꢀ
stabilizing as shown by several examples in supramolecular
chemistry and crystal engineering.[19] However, because of the
weak character of these fluorine–hydrogen interactions,
multiple interactions are required to bundle one-dimensional
BTA aggregates. Previously, we showed that small energy
differences between left- and right-handed helicity in one-
dimensional helical BTA aggregates can be amplified by the
cooperative character of the self-assembly process.[20] Hence,
we propose that—prior to bundling—the fluorinated chains at
the periphery of a one-dimensional helical BTA aggregate
form a ribbon, resulting in a fluorine-enriched patch on the
periphery of the one-dimensional aggregates (Figure 3D). As
a result of this one-dimensional microphase separation, the
fluorine-enriched ribbons facilitate the hierarchical bundling
or surface-assisted secondary nucleation of one-dimensional
aggregates into optically active fibers.
We further investigated the fibers formed by
BTA-F8H with atomic force microscopy (AFM)
and dynamic light scattering (DLS) measure-
ments. Solutions of BTA-F8H in dichloroethane
(0.8 mgmLꢀ1) were placed in a chamber filled
with MCH. After five days, 5 mL of this solution
was dropcasted on mica, allowed to dry and
subsequently measured with AFM. Figure 3A
shows a representative amplitude image of the
resulting fibers. Fibers with a diameter of 60 nm
were observed, significantly larger than the diam-
Figure 3. Panel A: AFM amplitude micrograph for dropcasted solutions of BTA-F8H
on mica (scale bar=0.5 mm). Panels B and C: Results of stopped-flow experiments
for solutions of BTA-F8H. Panel D: Proposed self-assembly mechanism for partially
eter of a one-dimensional BTA aggregate, which
would have diameter of approximately
a
1.6 nm.[11a] DLS measurements conducted on fluorinated BTAs of class A.
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To unravel the mechanism involved in the formation of
the optically active bundles for BTA-F8H, we studied the
temperature-dependent aggregation using a combination of
UV/Vis and CD spectroscopy at different concentrations. The
sharp transitions observed in the UV/Vis absorption at
223 nm at the elongation temperature (Te) and in the CD
effect at the critical bundling temperature (Tt) reveal that
nucleation phenomena are involved both in the formation of
the optically silent one-dimensional aggregates as well as in
the subsequent bundling into optically active fibers (Fig-
ure S7).[21] The temperature Te as derived from UV/Vis
spectroscopy follows a concentration dependence in agree-
ment with the nucleated formation of one-dimensional helical
aggregates: the Vanꢁt Hoff plot (logarithm of concentration
vs. 1/Te, Figure S8) results in an enthalpy of elongation (DHe)
of ꢀ63 kJmolꢀ1, which is close to previously reported values
for nonfluorinated BTA systems.[10c,11a,c] Whereas the temper-
ature-dependent assembly of one-dimensional helical aggre-
gates occurs under thermodynamic control,[10c] significant
hysteresis was observed in the formation and disappearance
of the CD effect upon subsequent cooling and heating
(Figure S9). The slow dynamics in the formation of the
optically active fibers is in sharp contrast to the formation of
one-dimensional aggregates consisting of BTAs substituted
with aliphatic side-chains in which case the self-assembly is
close to being diffusion-controlled and hence is practically
always under thermodynamic control.[10c]
The results clearly indicate that the formation of optically
active fibers of fluorinated BTA moieties comprises two
steps: 1) the cooperative, hydrogen-bond-driven aggregation
into one-dimensional helical aggregates consisting of equal
amounts of P and M helices under thermodynamic control,
and 2) the formation of optically active fibers with a fluori-
nated core in which one of the two helical one-dimensional
aggregates dominates (Figure 3D). Although we expect
a stochastic process in the formation of the optically active
fiber, the involvement of chiral impurities results in a prefer-
ence towards one helicity, even when different compounds
and synthetic batches are considered.
Concluding, we have analyzed the symmetry breaking in
the self-assembly of a new class of achiral and partially
fluorinated BTAs, which show a unique two-step self-
assembly. A crucial element in the symmetry breaking is the
presence of weak interactions between fluorine atoms and
electron-deficient (CF2-H) hydrogen atoms on the periphery
of the fluorinated BTA stacks. These fluorine–hydrogen
interactions result in bundling of one-dimensional BTA
aggregates by secondary nucleation, in which the influence
of a minute chiral impurity is strongly amplified. We believe
that the observations discussed and rationalized here will
provide new insights in understanding serendipitously found
symmetry-breaking processes.
Received: June 16, 2012
Revised: August 8, 2012
The slow dynamics in the formation of the optically active
BTA-F8H fibers prompted us to study the aggregation
kinetics in detail using stopped-flow CD spectroscopy. The
kinetic profiles were obtained by injection of a solution of
BTA-F8H from dichloroethane (a good solvent) into an
excess of MCH, thereby initiating the hierarchical self-
assembly of BTA-F8H. The subsequent formation of optically
active bundles was probed by following the CD effect at l =
223 nm as a function of time at 108C and at concentrations of
20, 30, 40, 48, and 50 mm (Figure 3B and Figure S11). A lag
phase was observed in the initial stages of the aggregation
process, as expected for nucleated aggregation.[22] However,
in contrast to kinetic studies on the aggregation of porphyrin,
oligo-(p-phenylene vinylene) derivatives, and proteins,[23]
both the lag phase as well as the time at which the conversion
equalled 50% (t-50) was concentration independent (Fig-
ure 3C). This t-50 concentration independence excludes
a mechanism whereby formation of optically active bundles
occurs through a homogeneously nucleated mechanism.
However, the rate limiting step in the appearance of optically
active bundles might be the formation of fluorine ribbons
along the periphery of one-dimensional helical BTA aggre-
gates, or the conversion from a racemic mixture of P and M
one-dimensional aggregates within the optically active fibers
to a nonracemic ratio between P and M one-dimensional
aggregates. Alternatively, formation of optically active fibers
can occur by surface-assisted secondary nucleation of free
monomers along the fluorine ribbon of a one-dimensional
BTA aggregate, resulting in a concentration-independent t-50
value as well. For a full analysis of all considered mechanisms,
the reader is referred to the Supporting Information.
Published online: && &&, &&&&
Keywords: aggregation · circular dichroism · helical structures ·
.
self-assembly · symmetry breaking
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[13] We refer to the term secondary nucleation as is common in
amyloid aggregation literature; see for example: V. Foderà, F.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Chirality
The interplay of two subsequent aggre-
gation processes results in a symmetry-
breaking phenomenon in an achiral self-
assembling system. Partially fluorinated
benzene-1,3,5-tricarboxamide molecules
self-assemble into a racemic mixture of
one-dimensional P- and M-helical aggre-
gates, followed by bundling into optically
active higher order aggregates or fibers
(see picture).
P. J. M. Stals, P. A. Korevaar,
M. A. J. Gillissen, T. F. A. de Greef,
C. F. C. Fitiꢁ, R. P. Sijbesma,*
A. R. A. Palmans,*
E. W. Meijer*
&&&& — &&&&
Symmetry Breaking in the Self-Assembly
of Partially Fluorinated Benzene-1,3,5-
tricarboxamides
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!