Sterically demanding benzene-1,3,5-tricarboxamides: Tuning the mechanisms of supramolecular polymerization and chiral amplification

Article abstract of DOI:10.1039/c0sm00516a

Benzene-1,3,5-tricarboxamide (BTA) derivatives with one or three phenylalanine octyl ester (PheOct) moieties were synthesized and their supramolecular polymerization and chiral amplification behavior were investigated in mixing experiments between enantio

Full text of DOI:10.1039/c0sm00516a

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Sterically demanding benzene-1,3,5-tricarboxamides: tuning the mechanisms
of supramolecular polymerization and chiral amplification†
*
Martijn A. J. Veld, Daniel Haveman, Anja R. A. Palmans and E. W. Meijer*
€
Received 11th June 2010, Accepted 4th October 2010
DOI: 10.1039/c0sm00516a
Benzene-1,3,5-tricarboxamide (BTA) derivatives with one or three phenylalanine octyl ester (PheOct)
moieties were synthesized and their supramolecular polymerization and chiral amplification behavior
were investigated in mixing experiments between enantiomer pairs and in mixing with another, achiral
BTA component. The incorporation of PheOct moieties is shown to have a major impact on the
supramolecular self-assembly.
Because of the intrinsic helical nature of the hydrogen bond
Introduction
motif in the supramolecular polymer, a preferred helicity of the
aggregates is readily observed by circular dichroism (CD) spec-
troscopy when one or more stereocenters are present in the
substituents of non-racemic BTAs.8–10 Mechanistically, two types
of supramolecular polymerization processes can be distinguished
for the self-assembly of these supramolecular motifs.11 In the first
case of isodesmic self-assembly behavior, the association
constants for the first and subsequent association steps are equal
to one another. As a result, the fraction of aggregated monomer
displays a sigmoidal dependence on temperature. In the second
situation, the association constants for the first few monomer
additions are less favorable than all subsequent monomer addi-
tions. This type of behavior is known as the nucleation/elonga-
tion or cooperative self-assembly mechanism and is characterized
by a sudden change in the fraction of aggregated monomer as
a function of temperature or concentration. In BTA derivatives,
both types of supramolecular polymerization have been
described depending on the molecular structure. The N,N0,N00-
tris(alkyl) substitution pattern, for example, results in a highly
cooperative self-assembly process,12–14 whereas bipyridine or
dipeptide based substituents give rise to an isodesmic self-
assembly behavior.15,16 The exact reason for the observed
differences in the self-assembly process depending on the nature
of the side chains has not been fully elucidated, although the
ability to form strongly polarised intermolecular hydrogen bonds
in the aggregates appears to play an important role in the
cooperative self-assembly behavior.17
Benzene-1,3,5-tricarboxamide (BTA) based monomers (Fig. 1)
represent an appealing class of supramolecular polymers with
potential applications in nucleating agents for isotactic
polypropylene,1 non-covalent crosslinkers in thermoplastic
elastomers,2 nanostructured materials3 and organogelators.4,5
The self-assembly of these disc-shaped molecules results in
columnar structures as a result of strong, threefold intermolec-
ular hydrogen bonding and p–p interactions between consecu-
tive monomers.6 Moreover, both C3-symmetric BTAs and
desymmetrized BTAs with at least two different peripheral
substituents are synthetically well accessible via amide coupling
reactions of activated carboxylic acids with amine nucleophiles,
giving access to a wide variety of structurally diverse supramo-
lecular building blocks.2,7
The self-assembly behavior of BTAs can be fine-tuned by
adjusting the BTA periphery. The introduction of additional p–
p or hydrogen bonding interactions might result in an increased
strength of the intermolecular interactions, whereas sterically
demanding substituents will weaken these interactions. The large
structural diversity and common availability of amino acids
make those molecular fragments interesting candidates for
systematic studies on the relation between molecular structure
and BTA self-assembly behavior. The carboxylic acid group of
the amino acid is easily modified, and often both enantiomers of
the amino acids are commercially available, allowing for the
facile preparation of BTA enantiomer pairs and subsequent
chiral amplification studies. BTAs with amino acid derived
substituents have been described previously. At high concentra-
tions the formation of long, helical aggregates was shown by
Fig. 1 (a) Common molecular structure of benzene-1,3,5-tricarbox-
amides (BTAs) and (b) threefold intermolecular hydrogen bonding array
as observed in a BTA crystal structure.6
Laboratory for Macromolecular and Organic Chemistry, Department of
Chemical Engineering and Chemistry, Eindhoven University of
Technology, P.O. Box 513, 5600 MB Eindhoven, The Netherlands.
E-mail: A.Palmans@tue.nl; E.W.Meijer@tue.nl; Fax: +31 40 245 1036;
Tel: +31 40 247 3101
† Electronic supplementary information (ESI) available: Details
containing the synthetic procedures for the preparation of compound
1, additional CD and UV-vis spectra and information on the data
fitting procedures are available. See DOI: 10.1039/c0sm00516a
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transmission electron microscopy (TEM) studies for BTAs with
leucine methyl ester and valine methyl ester derived substitu-
ents.18 Additionally, the possibility to induce a preferential hel-
icity in aggregates of achiral BTAs by the introduction of chiral
BTA dopants was shown.18 More recently, a series of glycine
octyl ester (GlyOct), leucine octyl ester (LeuOct) and phenylal-
anine octyl ester (PheOct) based C3-symmetric BTAs were
prepared and investigated as potential organo-gelators.19 At high
concentrations, the (PheOct)3 BTAs showed the most promising
organogelation behavior, suggesting that large, interacting
aggregates can be formed. However, detailed studies on the
aggregation and chiral amplification behavior in dilute solution
were not reported.
pure (R)- or (S)-phenylalanine with 1-octanol according to
a literature procedure.19 The optically pure phenylalanine octyl
esters are subsequently reacted with either freshly prepared
bis(octylaminocarbonyl)benzoyl chloride (1)2 or with commer-
cially available benzene-1,3,5-tricarbonyl trichloride to give
target BTAs 2 and 4, respectively. All compounds were purified
by column chromatography and were obtained as white solids in
1
excellent purity according to H-NMR and elemental analysis.
Self-assembly mechanism of PheOct derived BTAs
Whereas the self-assembly of N,N0,N00-tris(alkyl) BTAs is
strongly cooperative,14 the impact of bulky amino acid groups on
the mechanism of self-assembly in BTAs is not trivial to predict.
We studied the self-assembly mechanism of the PheOct BTA
derivatives by means of UV-vis and CD spectroscopy in dilute
solution. The spectral data of the PheOct BTA derivatives were
measured in methylcyclohexane (MCH), a solvent in which
BTAs aggregate, and in acetonitrile (MeCN), in which BTAs are
molecularly dissolved.14
In this paper, we report on our ongoing efforts to link the
molecular structure of BTAs to the nature of their self-assembly
mechanism and their effectiveness in the supramolecular ampli-
fication of chirality. We here evaluate the impact of one or three
phenylalanine octyl ester (PheOct) moieties on BTA self-
assembly behavior in dilute solution. We focused on this moiety
as the newly introduced phenyl ring might result in additional
and favorable p–p interactions, which are counterbalanced by
the increased steric demands. Additionally, the influence of the
PheOct moiety on the chiral amplification behavior is studied by
means of ‘‘majority rules’’ experiments.20,21 Finally, we mix the
newly synthesized compounds with N,N0,N00-tris(alkyl) BTAs to
evaluate their compatibility and to study how the BTA self-
assembly process in these mixtures is affected by the presence of
the (PheOct) BTAs.
The CD effect of ((S)-PheOct) (octyl)2 BTA ((S)-2) at
a concentration of 4.6 ꢀ 10ꢁ5 M in MCH consists of a single,
positive band in the wavelength region between 205 and 275 nm
(Fig. 2a, solid black line). The CD spectrum closely resembles the
spectrum of a chiral N,N0,N00-tris(alkyl) BTA, indicating a helical
organization of the benzene-1,3,5-tricarboxamide chromophore.14
Moreover, the size of the CD effect (D3 ¼ 30 L molꢁ1 cmꢁ1 at
220 nm, g ¼ 1.7 ꢀ 10ꢁ3) is similar to the value observed for chiral,
N,N0,N00-tris(alkyl) substituted BTAs (D3 ¼ 40 L molꢁ1 cmꢁ1 at
Results and discussion
Synthesis
The synthetic route to PheOct substituted benzene-1,3,5-tri-
carboxamides is depicted in Scheme 1. Both enantiomers of the
target BTAs were prepared to allow a detailed study of the self-
assembly and chiral amplification behavior. The synthesis of the
four target compounds starts with the esterification of optically
Fig. 2 (a) CD spectra for (PheOct) (octyl)2 BTAs (S)-2 (solid black line)
and (R)-2 (dashed black line). The molecularly dissolved state of (S)-2 in
MeCN is shown as well (solid gray line). (b) UV-vis spectra for (S)-2 in
MCH (black line) and MeCN (gray line) (all measurements: c ¼ 4.6 ꢀ
10ꢁ5 M).
Scheme 1 Synthesis of (PheOct) (octyl)2 BTA (2) and (PheOct)3 BTA
(4). (i) 2 mol eq. (R)- or (S)-phenylalanine octyl ester, 3 eq. Et3N, DCM,
overnight, rt; (ii) 3.2 mol eq. (R)- or (S)-phenylalanine octyl ester, 3.5 mol
eq. Et3N, DCM, 3 h, 0 ꢂC to rt.
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220 nm, g ¼ 1.6 ꢀ 10ꢁ3).13 As expected, a perfect mirror-image CD
spectrum was found for (R)-2 (Fig. 2a, dashed black line), whereas
the molecularly dissolved state of (S)-2 in MeCN displays a weakly
negativeCDeffectof3 mdeg atl ¼ 225 nm(Fig. 2a, grayline). This
small, residual CD effect most likely originates from the chiral
arrangement around the phenyl group of the amino acid. The UV-
vis spectrum of the aggregated state is blue shifted compared to the
molecularly dissolved state (Fig. 1b, black and gray line, respec-
tively), indicative of H-type aggregates.22
which is indicative of an isodesmic type of self-assembly
behavior.
The temperature-dependent cooling curves of (S)-2 were fitted
using an isodesmic self-assembly model to quantify the data
(details in ESI†) and three important parameters, Tm, the
temperature at which half of the monomer is aggregated, DHe,
the enthalpy of elongation and, the association constant K at
a certain temperature were extracted from the data (Table 1). The
Tm and DH values obtained from simultaneous UV-vis and CD
measurements are in good correspondence with one another.
The small differences in thermodynamic parameters as deter-
mined by these two techniques are most likely the result of
additional changes in the shape of the UV-vis spectra with
temperature, whereas in the CD spectra only the signal intensity
changes.
Solutions of BTAs (S,S,S)-4 and (R,R,R)-4 in MCH display
mirror-shaped CD spectra as expected for a pair of enantiomers
(Fig. 3a, solid and dashed black lines, respectively). Interestingly,
the CD spectrum of BTA 4 shows a bisignate Cotton effect
(Fig. 3a) in the wavelength region between 200 nm and 270 nm
and its shape is completely different from that of mono-PheOct
BTA 2 (overlay shown in Fig. S1†). In addition, the value of D3 at
l ¼ 225 nm (76 L molꢁ1 cmꢁ1; g ¼ 2.8 ꢀ 10ꢁ3) is around 2.5 times
higher than that of BTA 2. No significant CD effect is present for
the molecularly dissolved state in MeCN (Fig. 3a, gray line). The
UV-vis spectra of the aggregated state in MCH and the molec-
For BTA 4, the differences in the UV-vis spectra as a function
of temperature were too small to assess the degree of aggregation
as a function of temperature. Therefore, we monitored the
intensity of the CD effect at l ¼ 225 and 245 nm to obtain
temperature dependent spectral data. No evidence for a cooper-
ative aggregation process was observed for solutions of BTA
(S,S,S)-4 in MCH at concentrations between c ¼ 5 ꢀ 10ꢁ6 and 5
ꢀ 10ꢁ5 M. Instead, the temperature dependent CD measure-
ments showed a nearly linear variation of the signal intensity
with temperature (Fig. 4b and S3†). Interestingly, BTA 4 cannot
be fully aggregated or molecularly dissolved between 20 and
ularly dissolved state in MeCN at a concentration of 1 ꢀ 10ꢁ5
M
are very similar (Fig. 3a, black and gray line, respectively).
Temperature dependent UV-Vis and CD measurements
provide detailed information about the mechanism of supra-
molecular aggregation.23 The changes in intensity of the CD
effect and UV-vis absorption at l ¼ 225 nm were monitored
while cooling a solution of BTA (S)-2 in MCH from 90 ꢂC to 20
ꢂC at a rate of 2 ꢂC minꢁ1 (full spectra in Fig. S2†). Both the UV-
vis and CD data showed a sigmoidal dependence of the spectral
data with temperature after normalization of the data (Fig. 4),
ꢂ
90 C, making it impossible to determine the mechanism of the
self-assembly process from the temperature dependent cooling
curve. The changes in the shape of the CD spectra upon
Fig. 3 (a) CD spectra in MCH for (S,S,S)-4 (solid black line) and
(R,R,R)-4 (dashed black line). The molecularly dissolved state of (S,S,S)-
4 in MeCN is also shown (solid gray line). (b) UV-vis spectra for (S,S,S)-4
in MCH (black line) and MeCN (gray line) (all measurements: c ¼ 1 ꢀ
10ꢁ5 M, 20 ꢂC).
Fig. 4 (a) Normalized data for cooling curves of (S)-2 as determined by
UV-vis (black line) and CD spectroscopy (gray line) (c ¼ 4.6 ꢀ 10ꢁ5 M,
MCH) and (b) temperature dependence of the CD effect of (S,S,S)-4 (c ¼
5.0 ꢀ 10ꢁ5 M, MCH).
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5 ꢀ 10ꢁ5 M in MCH and the CD effect at l ¼ 225 nm was plotted
as a function of the ee (Fig. 8, black squares). Although the net
helicity (D3/D3max) shows a clear deviation from linearity (Fig. 6,
straight line), the majority rules effect is rather weak. Never-
theless, these results show that enantiomers of 2 can be incor-
porated into aggregates of their non-preferred helicity. As
a result of the isodesmic self-assembly behavior of BTA 2, only
small aggregates are present at c ¼ 5 ꢀ 10ꢁ5 M (DPN ¼ 2.9)
prohibiting quantification of the MR effect under these condi-
tions.26 In contrast, the sterically more demanding BTA 4 did not
show a majority rules effect (Fig. 6, white circles, full spectra in
Fig. S4b†).27
Table 1 Thermodynamic parameters characterizing the isodesmic self-
assembly behavior of BTA (S)-2 according to CD and UV-vis spectros-
copy (c ¼ 4.6 ꢀ 10ꢁ5 M, MCH)
Method
Tm/K
DHe/kJ molꢁ1
K (25 ꢂC)/Mꢁ1
UV-vis
CD
310.6
306.5
ꢁ98.8 ꢃ 0.4
ꢁ107.4 ꢃ 1.1
11.4 ꢃ 0.16 ꢀ 104
8.2 ꢃ 0.25 ꢀ 104
increasing the temperature (Fig. S3†) suggest that ill-defined
aggregates are formed.
While the self-assembly of N,N0,N00-tris(alkyl) BTAs was
previously found to be strongly cooperative, the presence of one
PheOct moiety suffices to change the self-assembly mechanism
into an isodesmic behavior in (S)-2. The introduction of one
sterically demanding group clearly has a dramatic influence on
the nature of the self-assembly process. In other words, the
nucleation step as observed for tris(alkyl) BTAs, which is the
result of the formation of a macrodipole upon aggregation,17 is
possibly hampered by introduction of the PheOct moiety. Most
likely, the large steric demands of the PheOct moiety play an
important role, but the introduction of additional p–p interac-
tions and hydrogen bonding to the ester group may also have an
influence.19 The largely increased steric demands by introduction
of the PheOct moiety are immediately visible from the molecular
structure (Fig. 5). A direct result of the isodesmic aggregation
behavior is that only relatively small aggregates are present for
the PheOct derived BTAs in apolar organic solvents at concen-
trations of typically 5 ꢀ 10ꢁ5 M (DPN ¼ 2.9), whereas (octyl)3
BTA forms long, helical aggregates under otherwise identical
conditions (DPN $ 1000).14
For chiral tris(alkyl) substituted BTAs possessing methyl
groups at the chiral centre, strong majority rules effects are
generally found i.e. a large amount of monomers can be incor-
porated into aggregates of non-preferred helical sense. Upon
introduction of a PheOct substituent into a BTA, the ability to
incorporate monomers into an aggregate of non-preferred helical
sense is strongly reduced. For BTA 2, limited amounts of
monomers can be incorporated into aggregates of the wrong
helicity as shown by the small majority rules effect. The low
amount of chiral amplification is directly related to the isodesmic
self-assembly process of compound 2, which, on average, results
in relatively small aggregates under the given experimental
conditions.21 (PheOct)3 BTA 4 completely lacked a majority rules
effect, suggesting either a zero or very high energetic penalty for
incorporation of the non-preferred enantiomer in a chiral
Amplification of chirality in PheOct derived BTAs
In aggregates of chiral, tris(alkyl) substituted BTAs, a small
enantiomeric excess (ee) is sufficient to induce a preferred helicity
when enantiomers are mixed.24,25 This effect is known as the
‘‘majority rules’’ effect. The chiral nature of the PheOct moiety
and the formation of homochiral aggregates by optically pure
BTAs 2 and 4 triggered us to investigate the chiral amplification
behavior of these BTAs.
Fig. 6 D3 at l ¼ 225 nm as a function of ee as determined for BTA 2 (-,
c ¼ 5 ꢀ 10ꢁ5 M) and 4 (B, c ¼ 1 ꢀ 10ꢁ5 M). The solid lines represent
a situation without any amplification of chirality (all data: MCH, 20 ꢂC).
CD spectra of solutions of BTA 2 with varying ee values (full
spectra in Fig. S4a†) were measured at a total concentration of
Fig. 5 3D-space filling models showing the increasing steric demands by introduction of the PheOct moiety: (a) (octyl)3 BTA; (b) (PheOct) (octyl)2 BTA
(2) and (c) (PheOct)3 BTA (4).
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aggregate. The sterically demanding structure of BTA 4 (Fig. 5c)
hints towards the latter possibility and as a result separate
aggregates with opposite helicity are formed for both BTA
enantiomers. Therefore, the formation of aggregates with
opposite helicity for the two BTA enantiomers is a likely expla-
nation for the linear relationship between the ee and observed
CD effect.
BTA, showing that the chirality present in (S)-2 can be efficiently
transferred. Maximum amplification of chirality was observed at
a fraction of chiral BTA as low as 5 mol%.
We expect that the average size of the mixed aggregates
strongly depends on the composition of the sample due to the
different supramolecular self-assembly mechanisms of (octyl)3
BTA (cooperative) and 2 (isodesmic). To study this transition
from a highly cooperative to an isodesmic type of self-assembly
behavior in more detail, temperature dependent UV-vis
measurements were performed on a sample with x(S)-2 ¼ 20 mol%
(Fig. 7b and full spectra in Fig. S6†) and compared to those of
pure (octyl)3 BTA and pure (S)-2. Since (octyl)3 BTA is achiral,
only UV temperature dependent measurements allow for
comparison between the three samples. A similar UV cooling
curve was obtained for the sample with 20 mol% (S)-2 and for
a sample containing pure (octyl)3 BTA. In both cases cooperative
self-assembly behavior is present (Fig. 7b) as can be seen from
a sudden change in the degree of aggregation with a decrease in
temperature. The thermodynamic parameters (Te, he, and Ka)
that describe the cooperative self-assembly process (Table 2)
were extracted from the data.14 These parameters are the
temperature of elongation (Te) at which the self-assembly process
starts, the enthalpy gain upon aggregation after the nucleation
step (he) and the association constant of the nucleation step (Ka).
The latter parameter is a measure for the degree of cooperativity
shown by the supramolecular system and the smaller its value is,
the more cooperative the aggregation process.
Mixed aggregates of PheOct derived BTAs and (octyl)3 BTA
Both PheOct substituted BTAs and (octyl)3 BTAs form
columnar aggregates in dilute MCH solutions with the difference
that self-assembly in PheOct substituted BTAs is isodesmic while
in (octyl)3 BTAs self-assembly occurs in a cooperative way.
Therefore, it is interesting to investigate whether PheOct
substituted BTAs and (octyl)3 BTAs form mixed aggregates and
if so, which type of self-assembly behavior will dominate in the
mixed aggregates.
Mixtures of chiral BTA (S)-2 with achiral (octyl)3 BTA in
MCH were studied first. The D3 of samples of varying compo-
sition was measured at l ¼ 225 nm at a total BTA concentration
of 5 ꢀ 10ꢁ5 M (Fig. 7a, full spectra in Fig. S5†). A remarkable
and very steep increase in the magnitude of the CD effect was
observed upon addition of the initial 5 mol% of (S)-2, while the
D3 values leveled off after 10 mol% (S)-2 and finally reached the
value observed for pure (S)-2. BTA (S)-2 is thus able to induce
a preferential helicity in aggregates mainly consisting of (octyl)3
Comparing the thermodynamic parameters for the sample
x(S)-2 ¼ 0.20 and pure (octyl)3 BTA shows only minor differences.
The higher temperature at which the self-assembly process starts
in the pure (octyl)3 sample (Table 2, entry 1) can be explained by
the 20% lower (octyl)3 concentration in the mixed sample.
Secondly, the enthalpy of elongation (he) shows a more negative
value for pure (octyl)3 BTA than for the mixed aggregates. This
means that the formation of mixed aggregates is energetically
a slightly less favorable from an enthalpic point of view. Third of
all, the difference in nucleation constant (Ka) between the two
measurements is relatively small, showing that the nucleation step
is not strongly affected by the presence of (S)-2. Apparently, the
incorporation of (S)-2 into mixed aggregates is the energetically
most favorable situation, although a small enthalpic penaltyneeds
to be paid by the formation of less-stable aggregates.
The sterically demandingPheOctyl moiety present in BTA(S)-2
effectively induces a preferential helicity in mixed aggregates with
(octyl)3 BTA. To see whether a further enhancement is possible by
introduction of three PheOct moieties, mixing experiments
between (S,S,S)-4 and (octyl)3 BTA were performed at a total
concentration of 1 ꢀ 10ꢁ5 M. Full CD spectra of various
compositions were measured directly after mixing of the two
components.29 A clear interaction between the two BTAs was
observed although no amplification of chirality was found
Fig. 7 (a) Mixing experiment of (S)-2 and (octyl)3 BTA showing
a maximum CD effect at x(S)-2 ¼ 0.05. The data are normalized to the
maximum CD effect at l ¼ 225 nm, ctotal ¼ 5 ꢀ 10ꢁ5 M, MCH, 20 ꢂC. The
solid line represents the situation where only dilution effects are opera-
tive. (b) Normalized temperature-dependent UV-vis absorbance of
(octyl)3 BTA (filled black squares), a mixture of (octyl)3 BTA and (S)-2
(open squares; x(S)-2 ¼ 0.20), and (S)-2 BTA (filled grey squares) (l ¼
225 nm, data normalized to absorbance values at 90 ꢂC and 10 ꢂC).
Table 2 Thermodynamic parameters for the self-assembly process of
pure (octyl)3 BTA and a mixture with 20 mol% (S)-2 (l ¼ 225 nm, ctotal
¼
5 ꢀ 10ꢁ5 M, MCH)
Entry
x(S)-2 (mol%)
Te/K
he/kJ molꢁ1
Ka (—)
1
2
0
20
347.9
344.1
ꢁ71.6 ꢃ 0.3
ꢁ64.6 ꢃ 0.3
1.9 ꢀ 10ꢁ4
5.4 ꢀ 10ꢁ4
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(Fig. 8a). Surprisingly, two different regimes are observed,
depending on which of the two BTAs is present in excess (Fig. 8c).
with 1 : 1 stoichiometry between BTAs (S,S,S)-4 and (octyl)3
BTA until all (PheOct)3 BTA has been consumed.
The regime in which (octyl)3 BTA is in excess (0 # x(S,S,S)-4
<
The second part of the titration curve with excess (S,S,S)-4
(0.5 < x(S,S,S)-4 # 1.0) displays a gradual change of the CD spec-
trum from the 1 : 1 complex into that of pure (S,S,S)-4 (full
spectra in Fig. S7b†). The numerically average of the spectra from
the 1 : 1 complex and a solution of pure (S,S,S)-4 was identical to
the experimentally determined spectrumof a sample with 75mol%
(S,S,S)-4. This suggests that for all compositions in this range, the
1 : 1 complex is formed until all (octyl)3 BTA has been consumed,
while the excess (S,S,S)-4 is present in separate aggregates.
To substantiate the formation of a stable heterocomplex with
1 : 1 stoichiometry between (S,S,S)-4 and (octyl)3 BTA further,
temperature dependent measurements were performed for solu-
tions containing 25, 50 and 75 mol% of (S,S,S)-4 and a total
concentration of 1 ꢀ 10ꢁ5 M (cooling curves and full spectra in
Fig. S8†). Interestingly, the UV cooling curves of solutions
containing 0 or 25 mol% chiral BTA 4 are similar and show
a cooperative self-assembly behavior. The sample containing 25
mol% (S,S,S)-4 displayed changes in the UV spectra similar to
those observed for a pure (octyl)3 BTA solution at c ¼ 5 ꢀ 10ꢁ6
M. The shape of the cooling curve for this sample and the
temperature of elongation (Te ¼ 316 K) were nearly identical to
the results found for a 5 ꢀ 10ꢁ6 M solution of pure (octyl)3 BTA
(Te ¼ 317 K). These observations are indicative for the inde-
pendent formation of separate aggregates of (octyl)3 BTA. In
contrast, the UV cooling curve of solutions containing 50 or
75 mol% chiral BTA 4 is similar to that of pure (S,S,S)-4 and
clearly shows an isodesmic behavior. These observations are
a strong indication towards the preferential formation of a heter-
ocomplex with 1 : 1 stoichiometry next to aggregates of the BTA
that are present in excess, as is schematically shown in Fig. 9.30
0.50) shows a linear relationship between the amount of (S,S,S)-4
and the intensity of the CD spectrum, while the shape of the CD
spectrum is independent on the composition (full spectra in
Fig. S7a†). Interestingly, the shape and magnitude of the CD
spectrum with x(S,S,S)-4 ¼ 0.50 (Fig. 8b, black line) are different
from that of a sample of pure (S,S,S)-4 at half of the original
concentration (Fig. 8b, gray line). In the mixed sample two
additional bands are observed around l ¼ 245 nm and 260 nm
(Fig. 8b, black line), showing that this spectrum must be attrib-
uted to a different species than an aggregate of pure (S,S,S)-4.
This gradual change suggests the formation of a heterocomplex
Conclusions
The introduction of a phenylalanine octyl ester (PheOct) moiety
in BTAs has a distinct influence on the supramolecular self-
assembly behavior. In contrast to tris(alkyl) substituted BTAs no
cooperative type of self-assembly behavior is observed and an
isodesmic self-assembly mechanism is found instead. As a result,
this class of compounds is less suitable for application as low
molecular weight organogelators, since relatively high concen-
trations are required to reach sufficiently large, interacting
aggregates that finally result in the gel state. The influence of the
steric demands of the PheOct moiety becomes clearly visible in
mixing experiments with achiral N,N0,N00-tris(octyl) BTA and in
mixing experiments between the PheOct BTA enantiomers. The
mixing experiments with (octyl)3 BTA reveal a strong interaction
between both PheOct BTAs and the tris(alkyl) achiral BTA. For
BTA 2 a strong amplification of chirality was observed, whereas
(PheOct)3 BTA 4 showed the preferential formation of a 1 : 1
heterocomplex with (octyl)3 BTA, without the induction of
a preferred helicity in aggregates consisting of mainly (octyl)3
BTA. A weak majority rules effect is observed for 2, which is the
result of the relatively small average aggregate size due to the
isodesmic self-assembly process. Therefore only limited amounts
of monomers can be incorporated into aggregates of non-
preferred helicity. Moreover, the increased steric requirements
for the PheOct moiety might further limit the incorporation of
Fig. 8 (a) Full CD spectra at 10 mol% increments for a mixing experi-
ment between (S,S,S)-4 and (octyl)3 BTA (ctotal ¼ 1 ꢀ 10ꢁ5 M, MCH,
20 ꢂC). The solid black line in the middle shows the sample containing
50% (S,S,S)-4. (b) Comparison of CD spectra of a mixture of (S,S,S)-4
and (octyl)3 BTA (x(S,S,S)-4 ¼ 0.50) at ctotal ¼ 1 ꢀ 10ꢁ5 M (black line) and
a solution of pure (S,S,S)-4 at c ¼ 5 ꢀ 10ꢁ6 M (gray line). (c) Mixing
experiment between (S,S,S)-4 and (octyl)3 BTA showing the existence of
two different regimes depending on the BTA present in excess (data
shown for: l ¼ 225 nm, ctotal ¼ 1 ꢀ 10ꢁ5 M, MCH, 20 ꢂC).28
This journal is ª The Royal Society of Chemistry 2011
Soft Matter, 2011, 7, 524–531 | 529

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Synthetic procedures
The preparation of monoacid chloride 1 according to a modified
literature procedure2 is described in the ESI†. Both enantiomers
of optically pure phenylalanine octyl ester were synthesized
according to a literature procedure.19 Since phenylalanine octyl
ester turned out to be unstable upon storage, a double amount of
this partially degraded compound was used in the amide
coupling for the syntheses of 2 and 4.
N0,N00-Dioctyl-N-[(S)-(benzyl)octyloxycarbonylmethyl]benzene-1,
3,5-tricarboxamide ((S)-2). Under an argon atmosphere, a solution
of 3,5-bis(N-octylaminocarbonyl)benzoyl chloride (1) (170 mg,
0.31 mmol) in dry DCM (2 mL) was prepared. A solution of L-
phenylalanine octyl ester (182 mg, 0.65 mmol, 2.1 eq.) and Et3N
(140 mL, 1.0 mmol, 3.3 eq.) in dry DCM (4 mL) was added by
syringe over a 10 min interval while stirring at rt. Stirring was
continued overnight, after which the reaction mixture was diluted
with DCM (10 mL) and washed with 1 M HCl (2 ꢀ 15 mL).
During extraction, 2-propanol (4 mL) was added to improve phase
separation. The organic layer was dried over Na2SO4, filtered and
concentrated in vacuo to give the crude product, which was purified
by manual column chromatography over normal silica gel
(heptane/EtOAc 2 : 1, Rf ¼ 0.15). BTA (S)-2 was isolated as
a sticky white solid (108 mg, 0.15 mmol, 50%). 1H-NMR (CDCl3):
8.24 (s, 1H, ArH (core)), 8.16 (s, 2H, –ArH (core)), 7.34–7.18 (m,
5H, –Ph (Phe)), 7.16 (d, 1H, J ¼ 7.7 Hz, –CONH–(Phe)), 6.55 (t,
2H, J ¼ 5.3 Hz, –CONH–(octyl)), 5.02 (ddd, 1H, J ¼ 7.7, 6.7, 6.0
Hz, –CONHCHRR0–), 4.16–4.10 (m, 2H, –COOCH2–), 3.44 (dt,
4H, J ¼ 5.3, 5.2 Hz, –CONHCH2–), 3.28 (dd, 1H, J ¼ 13.7, 6.0 Hz,
Ha–CH2Ph), 3.22 (dd, 1H, J ¼ 13.7, 6.7 Hz, Hb–CH2Ph), 1.71–
1.53 (m, 6H, –COOCH2CH2– + –CONHCH2CH2–), 1.44–1.19 (m,
30H, –CH2–), 0.88 (t, 9H, J ¼ 5.5 Hz, –CH3) ppm. 13C-NMR
(CDCl3) d: 171.7, 165.7, 165.5, 135.9, 135.6, 134.6, 129.4, 128.8,
128.5, 128.0, 127.4, 77.4, 66.1, 54.2, 40.5, 38.1, 31.9, 31.9, 29.7, 29.4,
29.3, 29.3, 29.2, 28.6, 27.1, 25.9, 22.7, 14.2 ppm. (Signals missing
due to overlapping peaks.) FT-IR: n ¼ 3234, 3064, 2956, 2924,
2855, 1746, 1636, 1556, 1498, 1466, 1456, 1440, 1366, 1303, 1198,
1171, 739, 723, 699 cmꢁ1. MALDI-TOF-MS: calculated M ¼
691.49 g molꢁ1, observed m/z ¼ 714.41 [M + Na]+, 692.38 [M + H]+
g molꢁ1. Elemental analysis: C42H65N3O5 (691.98). Calcd: C: 72.90,
H: 9.47, N: 6.07; obs: C: 73.19, H: 9.57, N: 5.96%.
Fig. 9 Schematic representation of the mixing experiments with (S,S,S)-
4 and (octyl)3 BTA showing the preferential formation of a 1 : 1 heter-
ocomplex and separate aggregates for the BTA present in excess. (The
cartoon only indicates the formation of mixed aggregates and does not
state anything about the relative size of the various aggregates).
monomers with a non-preferred configuration at the stereo-
centre. The latter effect was even more pronounced for BTA 4,
which did not show a majority rules effect at all. The self-
assembly and chiral amplification studies on the PheOct derived
BTAs show a highly interesting and sometimes surprising self-
assembly behavior. Clearly, the class of amino acid ester
substituted BTAs is attractive enough to be examined in more
detail in the future to get a better insight into the supramolecular
behavior of these BTA aggregates.
Experimental section
Materials and equipment
Detailed information on the origin of the used chemicals and used
equipment for analysis of the synthesized compounds can be
found in the ESI†. UV-vis and CD measurements were performed
on a Jasco J-815 spectropolarimeter using spectrograde MCH as
solvent. The sensitivity, time constant and scan rate were chosen
appropriately. Temperature-dependent measurements were per-
formed with a PFD-425S/15 Peltier-type temperature controller
and an adjustable temperature slope. Unless stated otherwise,
a temperature gradient of 2 ꢂC minꢁ1 was used. In all other
measurements, the temperature was set at 20 ꢂC.
N0,N00-Dioctyl-N-[(R)-(benzyl)octyloxycarbonylmethyl]benzene-1,
3,5-tricarboxamide ((R)-2). BTA (R)-2 was synthesized according
to the procedure for the enantiomer using equal amounts of reac-
tants. Pure BTA (R)-2 was isolated as a sticky white solid (128 mg,
Procedure for UV-vis and CD measurements
The desired amount of compound was weighed out and dissolved
in the appropriate amount of solvent to directly reach the desired
concentration, unless otherwise stated. The solutions were care-
fully heated, allowed to cool to rt and sonicated for at least 10
min, heated again and cooled to rt. The heating and sonication
procedure was performed each time an earlier prepared solution
was used. In the mixing experiments, at least 2500 mL of solution
containing the first component were put into a 1 cm cuvette.
Appropriate amounts of solutions with the second component
were added using a microlitre syringe, after which the cuvette was
closed and mixed well by shaking. The sample was put back into
the spectrometer which was kept at the desired temperature
(20 ꢂC) and equilibrated for at least 1 min, after which the
spectrum was recorded.
1
0.18 mmol, 60%). H-NMR (CDCl3): 8.22 (s, 1H, –ArH (core)),
8.14 (s, 2H, –ArH (core)), 7.34–7.20 (m, 5H, –Ph (Phe)), 6.63 (t, 2H,
J ¼ 5.2 Hz, –CONH–(octyl)), 5.02 (ddd, 1H, J ¼ 7.2, 6.7, 6.0 Hz,
–CONHCHRR0–), 4.16–4.10 (m, 2H, –COOCH2–), 3.62 (d, 1H,
J ¼ 7.4 Hz, –CONH–(Phe)) 3.48–3.39 (dt, 4H, J ¼ 5.3, 5.2 Hz,
–CONHCH2–), 3.28 (dd, 1H, J ¼ 13.7, 6.0 Hz, Ha–CH2Ph), 3.22
(dd, 1H, J ¼ 13.7, 6.7 Hz, Hb–CH2Ph), 1.71–1.53 (m, 6H,
–COOCH2CH2– + –CONHCH2CH2–), 1.44–1.19 (m, 30H, –CH2–),
0.88 (t, 9H, J ¼ 5.5 Hz, –CH3) ppm. 13C-NMR (CDCl3) d: 171.6,
165.6, 165.5, 135.9, 135.6, 134.6, 129.4, 128.8, 128.5, 128.0, 127.4,
77.4, 66.1, 54.2, 40.5, 38.2, 31.9, 31.9, 29.7, 29.4, 29.3, 29.3, 29.2,
28.6, 27.1, 25.9, 22.7, 14.2 ppm. (Signals missing due to overlapping
530 | Soft Matter, 2011, 7, 524–531
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ꢁ
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peaks.) FT-IR: n ¼ 3231, 3064, 2956, 2924, 2855, 1746, 1636, 1556,
1498, 1466, 1456, 1440, 1366, 1301, 1198, 1170, 739, 723, 699 cmꢁ1.
MALDI-TOF-MS: calculated M ¼ 691.49 g molꢁ1, observed m/z ¼
714.36 [M + Na]+, 692.36 [M + H]+ g molꢁ1. Elemental analysis:
C42H65N3O5 (691.98). Calcd: C: 72.90, H: 9.47, N: 6.07; obs: C:
72.65, H: 9.38, N: 5.97%.
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N,N0,N00-Tris[(S)-(benzyl)octyloxycarbonylmethyl]benzene-
1,3,5-tricarboxamide ((S,S,S)-4). BTA (S,S,S)-4 was prepared
according to a literature procedure19 using freshly prepared (S)-
phenylalanine octyl ester and commercially available benzene-
1,3,5-tricarbonyl trichloride to give the product in 70% yield.
1H-NMR (DMSO-d6) d: 9.13 (d, 3H, J ¼ 7.6 Hz, –CONH–), 8.40
(s, 3H, –ArH (core)), 7.32–7.22 (m, 12H, –Ph (Phe)), 7.22–7.16
(m, 3H, –Ph (Phe)), 4.68 (ddd, H, J ¼ 7.6, 6.0, 6.0 Hz, –CON-
HCHRR0–), 4.02 (t, 6H, J ¼ 6.4 Hz, –COOCH2–), 3.16–3.10 (m,
6H, –CH2Ph), 1.55–1.42 (m, 6H, –COOCH2CH2–), 1.28–1.10
(m, 30H,–CH2–), 0.82 (t, 9H, J ¼ 6.7 Hz, –CH3) ppm. 13C-NMR
(DMSO-d6) d: 171.4, 165.4, 137.5, 134.1, 129.2, 128.9, 128.2,
126.4, 64.5, 54.5, 39.5, 36.2, 31.1, 28.5, 28.5, 28.0, 25.2, 22.0, 13.9
ppm. FT-IR: n ¼ 3231, 3063, 3030, 2954, 2926, 2856, 1742, 1638,
ꢁ
ꢁ
13 P. J. M. Stals, M. M. J. Smulders, R. Martın-Rapun, A. R. A. Palmans
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1558, 1497, 1456, 1363, 1325, 1197, 1168, 1109, 739, 698 cmꢁ1
.
MALDI-TOF-MS: calculated M ¼ 987.60 g molꢁ1, observed m/
z ¼ 1010.55 [M + Na]+, 988.55 [M + H]+ g molꢁ1. Elemental
analysis: C60H81N3O9 (988.30). Calcd: C: 72.92, H: 8.26, N: 4.25;
obs: C: 72.68, H: 8.35, N: 4.17%.
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27 To exclude slow kinetics upon mixing, a solution with 58% ee was
annealed for 3 h at 90 ꢂC and cooled again to 20 ꢂC. No differences
in the magnitude or shape of the CD effect were observed before
and after annealing of the solution.
28 Depending on the wavelength at which the CD effect is monitored, the
shape of the titration curves can vary. This is a direct result of the
different shape of the CD spectra.
N,N0,N00-Tris[(R)-(benzyl)octyloxycarbonylmethyl]benzene-
1,3,5-tricarboxamide ((R,R,R)-4). BTA (R,R,R)-4 was synthe-
sized according to the procedure for the enantiomer using equal
amounts of reactants. Pure BTA (R,R,R)-4 was obtained as
a sticky white solid (1.80 g, 83%). 1H-NMR (DMSO-d6) d: 9.13 (d,
3H, J ¼ 7.7 Hz, –CONH–), 8.40 (s, 3H, –ArH (core)), 7.32–7.22
(m, 12H, –Ph (Phe)), 7.22–7.14 (m, 3H, –Ph (Phe)), 4.68 (ddd, H,
J ¼ 7.6, 6.0, 6.0 Hz, –CONHCHRR0–), 4.02 (t, 6H, J ¼ 6.4 Hz,
–COOCH2–), 3.19–3.08 (m, 6H, –CH2Ph), 1.55–1.42 (m, 6H,
–COOCH2CH2–), 1.30–1.11 (m, 30H, –CH2–), 0.82 (t, 9H, J ¼ 6.8
Hz, –CH3) ppm. 13C-NMR (DMSO-d6) d: 171.4, 165.4, 137.5,
134.1, 129.2, 128.9, 128.2, 126.4, 64.5, 54.5, 36.2, 31.1, 28.5, 28.5,
27.9, 25.2, 22.0, 13.9 ppm. FT-IR: n ¼ 3231, 3063, 3030, 2954,
2926, 2856, 1742, 1639, 1558, 1497, 1456, 1364, 1326, 1197, 1168,
1109, 739, 699 cmꢁ1. MALDI-TOF-MS: calculated M ¼ 987.60 g
molꢁ1, observed m/z ¼ 1010.49 [M + Na]+, 988.49 [M + H]+
g
molꢁ1. Elemental analysis: C60H81N3O9 (988.30). Calcd: C: 72.92,
H: 8.26, N: 4.25; obs: C: 72.74, H: 8.19, N: 4.05%.
Acknowledgements
M.V. and A.P. thank Council for the Chemical Sciences of the
Netherlands Organization for Scientific Research (CW-NWO)
for financial support.
References and notes
29 Annealing of a sample containing 55% (S,S,S)-4 for 2 h at 90 ꢂC did
not show any difference in either the size or shape of the observed CD-
spectra compared to the non-annealed sample, thereby showing the
instantaneous spectral changes upon mixing.
1 M. Kristiansen, P. Smith, H. Chanzy, C. Baerlocher, V. Gramlich,
L. McCuskcr, T. Weber, P. Pattison, M. Blomenhofer and
H. W. Schmidt, Cryst. Growth Des., 2009, 9, 2556–2558.
30 The exact structure of the 1 : 1 heterocomplex formed between
(S,S,S)-4 and (octyl)3 BTA is unknown.
ꢀ
2 J. Roosma, T. Mes, P. Leclere, A. R. A. Palmans and E. W. Meijer,
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Soft Matter, 2011, 7, 524–531 | 531