Decoding the Consequences of Increasing the Size of Self-Assembling Tricarboxamides on Chiral Amplification

Article abstract of DOI:10.1021/jacs.9b02045

A complete series of experimental and theoretical investigations on the supramolecular polymerization of chiral (1 and 2) and achiral (3) oligo(phenylene ethynylene) tricarboxamides (OPE-TAs) is reported. The performance of seargents-and-soldiers (SaS) an

Full text of DOI:10.1021/jacs.9b02045

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Article
Decoding the Consequences of Increasing the Size of
Self-Assembling Tricarboxamides on Chiral Amplification
Elisa E. Greciano, Joaquín Calbo, Julia Buendia, Jesús
Cerdá, Juan Aragó, Enrique Ortí, and Luis Sánchez
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b02045 • Publication Date (Web): 15 Apr 2019
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Decoding the Consequences of Increasing the Size of Self-Assembling
Tricarboxamides on Chiral Amplification
Elisa E. Greciano,a,‡ Joaquín Calbo,b,‡ Julia Buendía,a, Jesús Cerdá,b Juan Aragó,b Enrique Ortí,*,b Luis
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Sánchez*,a
a Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040 Madrid,
Spain; e-mail: lusamar@quim.ucm.es.
bInstituto de Ciencia Molecular (ICMol), Universidad de Valencia, c/Catedrático José Beltrán, 2, 46980 Paterna, Spain; e-
mail: enrique.orti@uv.es.
ABSTRACT
A complete series of experimental and theoretical investigations on the supramolecular polymerization of chiral (1 and 2) and
achiral (3) oligo(phenylene ethynylene) tricarboxamides (OPE-TAs) is reported. The performance of seargents-and-soldiers (SaS)
and majority rules (MR) experiments has allowed deriving a full set of thermodynamic parameters, including the helix reversal penalty
(HRP) and the mismatch penalty (MMP). The results described illustrate the influence exerted by the number of stereogenic centers
per monomeric unit and the temperature on the chiral amplification phenomena. Whilst the HRP decreases upon decreasing the
number of chiral side chains, the MMP follows an opposite trend. The experimental trend observed in MR experiments contrasts with
that reported for benzenetricarboxamides (BTAs), for which the chiral amplification ability increases by lowering the number of
stereogenic centers or increasing the temperature. Theoretical calculations predict that the rotational angle between adjacent mono-
meric units in the stack (ca. 18°) gradually decreases when decreasing the number of branched chiral side chains, and leads to higher
MMP values in good accord with the experimental trend. The reduction of the rotational angle gives rise to less efficient H-bonding
interactions between the peripheral amide functional groups and is suggested to provoke a decrease of the HRP as experimentally
observed. In BTAs, increasing the number of stereogenic center per monomeric units results in a negligible change of the rotation
angle between adjacent units (ca. 65°) and, consequently, the steric bulk increases with the number of chiral side chains leading to
higher MMP values. The data presented herein contribute to shed light on the parameters controlling the transfer and amplification
of chirality processes in supramolecular polymers, highlighting the enormous influence exerted by the size of the self-assembling
unit on the final helical outcome.
the MR experiments, mixing unequal amounts of two enantio-
INTRODUCTION
mers makes the whole mixture to adopt the chiral sign dictated
The discovery of the spontaneous resolution in ammonium
sodium tartrate, made by Pasteur, initiated the challenging task
of deciphering the origin of asymmetry in Nature and, more spe-
cifically, the phenomenon of chirality and how chirality is trans-
ferred to the different levels of hierarchy.1 A large number of
scientific areas like asymmetric synthesis,2 enantioseparation,3
or molecular motors4 relies on chiral amplification at molecular
or supramolecular level. The use of amplification of chirality in
molecular reactions, especially for asymmetric catalysis, has
experienced an outstanding advance by the synergy of both ex-
perimental and theoretical data.5 However, the establishment of
clear rules and structure-property relationships for achieving an
accurate knowledge on the chiral amplification observed in self-
assembling systems is more challenging.6 Taking advantage of
the principles extracted from chiral covalent polymers, such as
polyisocyanates and polyacetylenes,7 the chiral amplification of
self-assembling systems has been investigated by following two
strategies known as sergeants-and-soldiers (SaS) and majority
rules (MR).6,8 In the SaS experiments, a minute number of chiral
units (the sergeants) command a large number of achiral units
(the soldiers) to yield enantiomerically enriched mixtures. In
by the chiral component added in excess.6,8
Supramolecular polymers,9 that is, macromolecular species in
which the monomeric units are joined together by non-covalent
forces, are an exceptional benchmark to perform chiral amplifi-
cation studies that contribute to shed light into the origin of ho-
mochirality.6 The rotated one-dimensional self-assembly of a
number of organic scaffolds affords helical columnar stacks that
are very valuable to investigate the processes of transfer and
amplification of chirality. Merocyanines,10 naphtalene bisi-
mides,11 perylene bisimides,12 p-conjugated systems,13 and C3-
symmetric tricarboxamides14 are some examples of organic
platforms utilized to investigate the chiral transmission and/or
amplification in supramolecular polymers.15
Despite the number of studies reporting the generation of chi-
ral supramolecular structures making use of axial chirality,16 in
the vast majority of the examples described, the construction of
helical supramolecular polymers is achieved by the peripheral
decoration of the self-assembling units with stereogenic cen-
ters.10-14 However, few studies report clear rules to understand
the requirements of a self-assembling unit to generate chiral su-
pramolecular ensembles. Only for the case of C3-symmetric
benzenetricarboxamides (BTAs)17 and oligo(phenylene
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ethynylene) tricarboxamides (OPE-TAs, compounds 1-3 in Fig-
Herein, we expand the studies on chiral amplification by in-
ure 1),18 a systematic investigation of the molecular structural
factors that lead to an efficient transfer of chirality has been car-
ried out.
vestigating the helical supramolecular polymerization of OPE-
TAs, both by SaS and MR experiments (Figure 1). We demon-
strate the influence exerted by molecular structural factors, i.e.,
the number of stereogenic centers at the peripheral side chains,
and also the influence of external factors, such as the tempera-
ture, on the ability of these systems to experience amplification
of chirality. A detailed energetic investigation has been per-
formed, and the HRP and MMP penalties have been derived for
these dynamic supramolecular polymers, showing important
differences with respect to previous studies reported for the
family of BTAs.17 In contrast to BTAs, decreasing the number
of stereogenic centers results in a negligible chiral amplifica-
tion, and increasing the temperature results in an increase of the
MMP, thus hindering the chiral amplification phenomenon.
Theoretical calculations have been utilized to confirm the pref-
erential handedness of OPE-TAs, and to rationalize the experi-
mental trends by invoking key structural parameters. The theo-
retical results indicate that the small rotational dihedral angle
between adjacent OPE-TAs along the helical stack, compared
to BTAs, stands as a crucial factor that conditions the chiral am-
plification in these and related supramolecular polymers. The
data presented in this work illustrate the enormous influence ex-
erted by the size of the self-assembling unit on the final helical
outcome, and allows establishing more clear rules on the struc-
ture/property relationship for chiral supramolecular polymers.
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The derivation of all the thermodynamic parameters associ-
ated to the polymerization mechanism, isodesmic or coopera-
tive,9 is required to obtain a detailed description of the chiral
amplification phenomena in supramolecular polymers. This
goal can be readily achieved by applying the equilibrium (EQ)
model, which considers the monomeric, oligomeric, and larger
supramolecular polymeric species present during the formation
of the corresponding supramolecular polymer.19 In addition, the
two-component version of the EQ model also allows deriving
the mismatch enthalpy DHmm. This parameter that quantifies the
mismatch penalty (MMP) due to the incorporation of a mono-
mer into an aggregate of its unpreferred helicity, has been esti-
mated in ~2 kJ·mol-1 for BTAs and OPE-TAs.18a,19 Together
with the MMP, it is important to consider the helix reversal pen-
alty (HRP) as an additional energy penalty for a chiral amplifi-
cation phenomenon. The HRP penalizes the creation of differ-
ent helical domains within a columnar stack and, to the best of
our knowledge, this parameter has only been calculated for the
supramolecular polymerization of BTAs.17 The balance be-
tween all these thermodynamic parameters, and especially the
MMP and the HRP, conditions the final outcome obtained from
SaS and MR experiments in the chiral amplification of supra-
molecular polymers.
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Figure 1. (a) Chemical structure of the symmetrically and asymmetrically substituted oligo(phenylene ethynylene) tricarboxamides
1-3. (b) Schematic illustration of the relationship between the point chirality embedded in the side chains of tricarboxamides 1-3 and
the helical outcome upon supramolecular polymerization. (c) Sergeants-and-soldiers experiments between chiral 1 or 2 and achiral
3. (d) Majority rules experiments for chiral 1 and 2 indicating the HRP and MMP effects.
In good analogy with BTAs, the supramolecular polymeriza-
RESULTS AND DISCUSSION
tion of OPE-TAs 1-3 proceeds through the formation of a triple
array of H-bonding interactions between the amide functional
groups and the consequent p-stacking of the aromatic moie-
ties.17 The synergy of these two non-covalent interactions yields
helical columnar stacks governed by a cooperative or nuclea-
tion-elongation mechanism. Theoretical calculations showed
that, in these columnar stacks, adjacent monomeric units are ro-
tated by ca. 18°. In addition, both experimental and theoretical
data demonstrated that the presence of stereogenic centers of
absolute configuration (S) at the side chains affords right-
handed P-type helices and those with an absolute configuration
Synthesis, supramolecular polymerization mechanism
and transfer of chirality. The synthesis of chiral tricarbox-
amides 1 and 2a as well as achiral tricarboxamide 3 has been
previously described by our research group.18a,18b Chiral tricar-
boxamides 2b and 2c, endowed with two or one stereogenic
centers, respectively, of absolute configuration (R), were pre-
pared by following a similar synthetic strategy to that described
for asymmetrically substituted 1b and 1c (Scheme S1). A full
spectroscopic characterization of all new compounds is in-
cluded in the Supporting Information.
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(R) gives rise to left-handed M-type helices.18 In good agree-
polymerization of 2a-c yields the same dichroic pattern and,
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ment with these preliminary data, new tricarboxamides 2b and
2c are also expected to form M-type helical structures, as indi-
cate the corresponding circular dichroism (CD) spectra. Figure
2 shows the CD spectra registered for chiral OPE-TAs 1 and 2
in methylcyclohexane (MCH) at a total concentration (cT) of 10
µM. Similarly to tricarboxamides 1, the supramolecular
consequently, the same helical outcome regardless the presence
of one (2c), two (2b) or three (2a) stereogenic centers at the side
chains. This implies that only one stereogenic center is suffi-
cient to bias the efficient transfer of chirality to the whole su-
pramolecular structure.18b
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Figure 2. (a-c) CD spectra of chiral tricarboxamides 1 and 2 in MCH, cT = 10 µM, 20 °C. SaS experiments for achiral 3 upon mixing
with chiral 2a (d), 2b (e), and 2c (f) (MCH, cT = 10 µM, 20 °C). The red curves in (d-f) correspond to a sigmoidal fitting to guide the
eye.
To confirm the preferential M–type helical handedness in our
novel tricarboxamide 2a-c derivatives decorated with chiral al-
iphatic chains with stereogenic centres with an absolute config-
uration R, theoretical calculations using the GFN2-xTB ap-
proach were performed (see the SI for computational details).20
The geometry of large supramolecular stacks of 20 monomeric
units was fully optimized, and the energy of right- and left-
handed helices was compared. Note that for derivatives 2b and
2c, two types of supramolecular arrangements can be obtained
by considering the relative disposition of the achiral and chiral
aliphatic chains in vicinal molecules along the stack (see Figure
3a-b for 2c and Figure S1 for 2b). In the eclipsed disposition,
achiral and chiral chains are placed in different arms of the he-
lix, whereas in the staggered disposition achiral and chiral
chains are intercalated along the growing direction of the helix.
Fully chiral 2a can only stack in an eclipsed configuration. The-
oretical calculations for 2a indicate that the energy difference
per monomeric unit between P and M helices is 6.3 kJ·mol–1 in
favor of the M helix. Similarly, the eclipsed left-handed stack-
ing of 2b is found 7.0 kJ·mol–1 per monomeric unit more stable
than the analogous right-handed column. Staggered stackings
of 2b lie in between in energy (Figure S2). Finally, the stag-
gered stackings of 2c are found more stable than the eclipsed
growth. For this derivative, the alternated M-type 20-mer is pre-
dicted 5.0 kJ·mol–1 per monomeric unit more stable than the
corresponding P-type aggregate. Minimum-energy geometries
for the most stable M-type stacks of 2a and 2c are displayed in
Figure 3c-d. Regardless of the number of chiral aliphatic chains,
GFN2-xTF calculations demonstrate that derivatives 2a-c ar-
range supramolecularly in a preferentially left-handed orienta-
tion. Considering that the stereogenic centres of 1a-c display
the opposite absolute configuration to that present in 2, the most
stable arrangements for 1a-c are right-handed helices (in good
accord with previous reports).18
By making use of the one-component version of the EQ model
and variable temperature (VT) UV-Vis experiments,19 a com-
plete set of thermodynamic parameters − nucleation enthalpy
(DHn), elongation enthalpy (DHe), elongation entropy (DS), nu-
cleation (Kn) and elongation (Ke) binding constants, and coop-
erativity factor (s) − have been derived for tricarboxamides 2
to complement those already reported for compounds 1 and 3
(Table 1). As expected, compounds 2 present very similar ther-
modynamic parameters to those obtained for chiral 1 and achi-
ral 3 and also for BTAs,17,19 thus confirming the cooperative
character of the supramolecular polymerization of these tricar-
boxamides.18
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chiral amplification ability by mixing chiral tricarboxamides 1
with achiral 3 has been previously reported.18b The data ex-
tracted from the corresponding SaS experiments, carried out by
adding increasing amounts of chiral tricarboxamides 1 to a so-
lution of achiral 3 and keeping the total concentration cT con-
stant, reveal that decreasing the number of stereogenic centers
at the side chains is accompanied with a drastic decrease on the
ability to amplify the chirality by the chiral self-assembling
unit.18b In good correlation, analogous results have been ob-
tained by mixing increasing amounts of chiral 2 and achiral 3.
In these SaS experiments, a direct correlation between the num-
ber of stereogenic centers and the amplification of chirality is
observed. Thus, when mixing 2a, endowed with three stereo-
genic centers, and 3 in MCH at cT = 10 µM, a molar fraction of
around 0.2 is sufficient to bias the whole helicity of the mixture
(Figure 2d). This molar fraction increases to 0.4 for the mixture
of 2b, which contains two stereogenic centers, and achiral 3,
and is negligible for 2c (Figure 2e and 2f, respectively).
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We have checked the influence of temperature on the extent
of chiral amplification by performing the SaS experiments at
three different temperatures with the mixture of achiral 3 and
chiral 2a (Figure S3). As expected, and in good analogy with
BTAs,17a increasing the temperature results in the addition of a
higher fraction of chiral sergeant 2a to achieve a homochiral
system with a net helicity equal to unity. This effect confirms
that temperature weakens the strength of the non-covalent in-
teractions responsible for the supramolecular polymerization of
these tricarboxamides, and reduces the degree of aggregation
and the average stack length despite the cooperative character
of the mechanism.
Figure 3. Eclipsed (a) and staggered (b) disposition of chiral
chains along the helical stack of 2c. Minimum-energy geometry
calculated at the GFN2-xTB level for the most stable 20-mer
columnar M-helical stacks of 2a (c) and 2c (d).
To energetically quantify the effect that the number of stere-
ogenic centers in the chiral self-assembling unit exerts in ob-
taining a complete homochiral sytems in a SaS experiment, we
have used the mathematical model described for BTAs, in
which the two possible penalties for incorporating chiral units,
MMP, or chiral fragments, HRP, within a helical columnar
stack of unpreferred helicity is calculated.17a Considering that in
the cooperative supramolecular polymerization of achiral 3, a
racemic mixture of both the left-and right-handed helical struc-
tures are formed upon self-assembly, the MMP contribution can
be neglected. The chiral unit added to the racemic mixture will
be incorporated in the supramolecular polymer of its preferred
helicity since this situation prevents the system to be energeti-
cally penalized. Consequently, we have derived the HRP pa-
rameter for the six SaS experiments performed by mixing chiral
tricarboxamides 1a-c and 2a-c with achiral 3, at cT = 10 µM and
20 °C (Table 2). The value estimated for the HRP is maximum
Table 1. Thermodynamic parameters for tricarboxamides
1-3
c
sd
a
a
Seb
D
Hn
Compound
Kn
Kec
D
He
D
3.9
e+6
1a
52
1.3e-5
‒79.3 ‒140 ‒27.7
4.9
e+6
1b
1c
2a
2b
2c
3
‒76.9 ‒130 ‒24.3 265
5.4e-5
2.4e-5
1.1e-5
8.6e-5
7.9e-5
7.0e-5
7.5
e+6
184
761
‒83.9 ‒150 ‒26.3
‒80.6 ‒140 ‒22.5
2.9
e+6
−
1
(~13 kJ·mol ) for the mixtures of the tricarboxamides with
three stereogenic centers, 1a and 2a, with achiral 3, and de-
creases by decreasing the number of stereogenic centers in the
self-assembling unit (~11 kJ·mol−1 for 1b and 2b with 3, and ~8
4.8
e+6
‒76.8 ‒130 ‒23.1 417
9.5
e+6
−
1
750
‒78.5 ‒130 ‒17.7
kJ·mol for 1c and 2c with 3). Despite the error produced by
the model utilized for deriving the HRP parameter,17a the values
of the HRP are rather high and follow a clear tendency that pro-
vide a justification for the chiral amplification features experi-
mentally observed in the SaS experiments. The high HRP value
calculated for the mixtures of 1a and 2a with 3 hampers the for-
mation of domains with inversed helicity within a columnar
stack and, hence, favors the generation of homochiral supramo-
lecular polymers at relatively low excess of the fraction of the
chiral sergeant. However, decreasing the number of stereogenic
centers per monomeric unit results in a lower energy penalty for
those stacks with domains of inversed helicity, and yields a poor
0.2
e+6
‒78.0 ‒140 ‒26.9 15
−
−
1
1
a In kJ·mol‒1; b in J·K–1·mol ; c in L·mol ; d s = Kn/Ke. The
values of the two binding constants (Kn and Ke) and s were cal-
culated at 298 K. MCH as solvent.
Amplification of chirality. SaS experiments. The influence
of the number of stereogenic centers per monomeric unit on the
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and even a negligible ability for chiral amplification in the case
of tricarboxamides 1b-2b and 1c-2c, respectively.
1
Amplification of chirality. MR experiments. The above-de-
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scribed SaS experiments demonstrate that reducing the number
of stereogenic centers per monomeric unit decreases the ability
of these tricarboxamides to transfer the chiral information and,
consequently, the ability to achieve a fully amplified chiral
state. However, a further step is to determine the influence of
the number of stereogenic centers on the amplification of chi-
rality by performing MR experiments. In a MR experiment, mix-
ing unequal amounts of two enantiomers with invariable cT can
give rise to homochiral, fully amplified mixtures.
Table 2. Helix Reversal Penalty (HRP) determined from fit-
ting the SaS data
Mixturea 3 + 1a 3 + 1b 3 + 1c 3 + 2a 3 + 2b 3 + 2c
b
HRP
13.2
11.6
7.7
12.4
10.2
7.7
a cT = 10 µM; 20 °C; b in kJ·mol−
1
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Figure 4. Changes in CD intensity (red circles: l = 280 nm, black squares: l = 303 m) as a function of ee upon adding (S)-1 to a
solution of (R)-2 (MCH, cT = 10 µM) at 20 °C (a-c), 30 °C (d-f), and 40 °C (g-i) . ee = 1.0 corresponds to pure (S)-1 and ee = -1.0
corresponds to pure (R)-2. The red curves correspond to a sigmoidal fitting to guide the eye.
around ~2 kJ·mol−1 was derived. This value is very similar to
Our previous studies indicate that mixing solutions at cT =
that derived for BTAs with three stereogenic centers (~2.1
−
1
kJ·mol ).17 As in the previous section, we have investigated
the influence of the number of stereogenic centers per mono-
meric unit in the ability to yield a fully homochiral mixture.
Thus, we have performed MR experiments at cT = 10 µM and
at temperature of 20 °C by mixing tricarboxamides 1b and 2b,
10 µM of tricarboxamides 1a and 2a, both endowed with three
stereogenic centers, results in a non-linear variation of the di-
chroic response indicative of an efficient chiral amplification
at a 48 % of enantiomeric excess (ee).18c Applying the two-
component version of the EQ model,19 a MMP value of
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with two (S) and two (R) stereogenic centers, respectively, and
discotics, a full homochirality is afforded more easily by in-
creasing the temperature, and the MMP range from ~2
1
2
3
4
5
6
7
8
also by mixing tricarboxamides 1c and 2c, with only one (S)
and one (R) stereogenic center, respectively (Figure S4). The
experimental results show that reducing the chiral information
per monomeric unit is accompanied by a reduced ability of the
system to achieve a complete amplified state. Thus, whilst a
48 % of ee is required for the mixture 1a+2a to provide a ho-
mochiral mixture, higher values of ee (57 % for 1b+2b and
>80 % for 1c+2c) are necessary to get a complete chiral re-
sponse (Figure 4). These experimental data are in good ac-
cordance with that inferred from the SaS experiments, but are
in clear contrast to that described for BTAs, for which reduc-
ing the number of stereogenic centers per monomeric unit
yields a more efficient chiral amplification.17
To justify the experimental findings, we have calculated the
MMP factor.19 The high HRP value derived from the SaS ex-
periments suggests that reversing the handedness of a helical
columnar stack is highly unfavorable; thus, the incorporation
of a chiral unit into a columnar helical stack of its unpreferred
helicity is energetically more favorable. Consequently, in the
MR experiments, the HRP factor can be neglected and, from
an energetic point of view, only the MMP factor has to be con-
sidered. Thus, we have determined the MMP (Figure S5 and
Table 3) by applying the two-component version of the EQ
model19 and the thermodynamic data extracted from the vari-
able-temperature experiments.
−
1
−
1
kJ·mol at room temperature to ~1 kJ·mol at 50 °C.17To
achieve a better knowledge of the effect exerted by tempera-
ture on the chiral amplification phenomenon experienced by
the reported tricarboxamides, we have also performed VT-CD
experiments for different ee values. These VT-CD measure-
ments were done only for mixtures of compounds 1a+2a and
1b+2b because the mixture of tricarboxamides 1c+2c experi-
ences a weak chiral amplification that decreases, becoming
negligible, by raising the temperature. The comparison of the
cooling curves obtained for the 1a+2a mixture and the enan-
tiopure tricarboxamides 1a and 2a allows the determination of
the influence exerted by temperature to bias the degree of chi-
ral amplification. As in the previous CD experiments, the VT-
CD measurements were accomplished in MCH as solvent and
at cT = 10 µM, by using a cooling rate of 1 K·min-1 and tem-
perature ranging from 90 to 20 °C.
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In the case of the pure enantiomers 1a and 2a, a gradual de-
crease of the dichroic response is observed upon heating the
solution. The reduction of the intensity of the dichroic signal
is rapid at intermediate temperatures (~33 °C), and it is can-
celled at the temperature of elongation Te = 67 °C (Figure 5).
Similar curves are obtained for pure 1b and 2b (Figure S6).
The non-sigmoidal shape of the cooling curves is characteris-
tic of the cooperative supramolecular polymerization mecha-
nism that governs the formation of the helical, columnar
stacks for these chiral tricarboxamides.
Table 3. Mismatch Penalty (MMP) determined from fit-
ting the MR dataa
1a+2a
2.0 ± 0.2
1b+2b
2.5 ± 0.1
1c+2c
b
MMP 20 ºC
5.4 ± 0.4
b
MMP 30 ºC
2.5 ± 0.1
3.3 ± 0.2
2.9 ± 0.2
3.7 ± 0.2
8.6 ± 1.2
b
MMP 40 ºC
12.0 ± 0.2
a All the experiments performed in MCH at cT = 10 µM; b in
kJ·mol‒1.
The values derived for the MMP clearly show that this pen-
alty notably increases by decreasing the number of stereo-
genic centers. Especially interesting is the case of the mixture
of tricarboxamides 1c + 2c, endowed with only one stereo-
−
1
genic center, for which the calculated MMP is 5.4 kJ·mol .
This value is comparable to that obtained for the HRP from
the SaS experiments by using the mixtures of 3 + 1c and 3 +
2c (Table 2). The similarity between the MMP and the HRP
in the chiral amplification processes involving tricarbox-
amides 1c and 2c indicate that it is energetically possible to
have helical reversals within a stack.
Figure 5. Cooling curves of mixtures of tricarboxamides 1a
and 2a with variable values of the ee (MCH, cT = 10 µM, cool-
−
1
ing rate 1 K·min ). The red lines depict the fitting to the one-
component EQ model.
To complement all the studies related with the chiral ampli-
fication properties of these tricarboxamides, we have also in-
vestigated the influence of temperature on the MR experi-
ments (Figure 4). Increasing the temperature to 30 and 40 °C
hinders the formation of the helical aggregates and, conse-
quently, a less intense dichroic response for the enantiopure
samples and for the mixture of both tricarboxamides is ob-
served. The values calculated for the MMP (Table 3) clearly
show that the larger the number of stereogenic centers, the
higher the amplification of chirality, and that temperature de-
creases the ability of the tricarboxamides for the amplification
of chirality. These data are in clear contrast with those re-
ported for BTAs, in which the effect is the opposite. In BTA
The cooling curves of 1a+2a and 1b+2b at ee of 55 % and
80 % present a different shape (Figure 5 and S6). In these mix-
tures, heating the solution produces a rapid reduction of the
dichroic response. This effect is especially remarkable for
those mixtures at ee = 55 %, in which the cooling curves can
be visualized as two straight lines that intersect at the Te. Fur-
thermore, the destabilizing effect exerted by the minor enan-
tiomer on the stability of the columnar stacks is demonstrated
by the lower Te values of the mixtures compared with that ob-
served for the pure enantiomers (Table 4). The decrease in the
dichroic response upon raising the temperature is a direct con-
sequence of the increase of the MMP with temperature, and a
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Journal of the American Chemical Society
typical feature of cooperative processes. In the case of mix- comprise the rotation angle between adjacent monomeric
1
2
3
4
5
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7
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tures of the reported tricarboxamides, the increasing value of
the MMP, together with the disassembly effect exerted by
temperature, provokes a more rapid disassembly of the chiral
supramolecular polymer into the constitutive monomers.
units along the growing axis (q), the intermolecular distance
between central benzene centroids (dI), and the H-bond dis-
tance (dH) between adjacent amide groups (Figure 6a). Mini-
mum-energy geometries obtained at the GFN2-xTB level of
theory indicate that intermolecular distances dI are scarcely
affected by the number of chiral chains in our OPE-TAs, with
average values of 3.25 Å and 3.26 Å for eclipsed 2a and 2b,
respectively. As the minimum-energy stack of 2c presents an
alternated disposition of the chiral chains, the intermolecular
distance between vicinal discotics in the stack is computed
slightly shorter for this derivative (dI = 3.20 Å). H-bond dis-
tances vary in the range of 1.73 to 1.95 Å, with average values
of 1.81, 1.79 and 1.79 Å for 2a, 2b and 2c, respectively.22
The optimized geometries, however, indicate that the stack-
ing rotation per monomeric unit (q) systematically decreases
upon reducing the number of chiral chains in the discotic tri-
carboxamide, going from an average value of 18.51° in 2a to
18.38° in 2b and to 18.31° in 2c. This leads to a small but no-
ticeable 1.1% reduction of q in passing from three-chiral-
chains 2a to one-chiral-chain 2c. Larger values of the stacking
rotation imply smaller steric hindrance between neighboring
chains (Figure 6b), and thus smaller MMP values. To estimate
the MMP, we computed the energy penalty of introducing a
“wrong” chiral OPE-TA into a columnar 20-mer stack of its
unpreferred handedness (see the Supporting Information for
details). Theoretical calculations predict that this penalty in-
creases upon decreasing q, with MMP values of 1.40, 2.01,
and 3.10 kJ·mol–1 per monomeric unit and per “wrong” chiral
discotic for 2a, 2b, and 2c, respectively, which nicely agree
with the MR experimental results.
Table 4. Te values extracted from the cooling curves of the
pure (S) enantiomers 1a and 1b and the mixtures of 1a+2a
and 1b+2b at ee = 55 and 80 %.a
9
1a 1b 1a+2a 1a+2a 1b+2b 1b+2b
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(55%) (80%) (55%) (80%)
b
Te
67 65
61
64
61
64
a MCH, cT = 10 µM; b in °C
These experimental findings strongly contrast to those pre-
viously described for BTAs. In BTAs, increasing the temper-
ature allows reducing the energetic cost of incorporating a
monomeric unit into a columnar stack of its unpreferred helic-
ity. As a consequence, the consecution of a homochiral stack
is favored at relatively high temperatures depending on the
enantiomeric excess. The relaxation of the N‒H···O=C H-
bonding interactions between vicinal amide functional
groups, upon increasing the temperature, has been considered
to explain this trend.17 A similar behavior could be expected
for the described OPE-TAs 1-3 since the supramolecular
polymerization of these tricarboxamides proceeds, as for
BTAs, through the formation of a triple array of H-bonding
interactions between the amide groups and, concomitantly, by
the π-stacking of the aromatic units.18 However, there is a
clear geometrical difference between BTAs and tricarbox-
amides 1−3. In the formation of the columnar stacks between
BTAs, the rotation angle between the monomeric units is of
ca. 60° to optimize the N‒H···O=C bonds (2.1 Å) and the π-
stacking of the benzene rings (ca. 3.5 Å).21 This rotation angle
between the stacked monomeric units produces a possible but
weak interaction between the side chains on adjacent mole-
cules. Raising the temperature weakens both the H-bonding
interactions and the π-stacking of the benzene rings, and in-
creases the distance between the BTA monomeric units. This
reduces the interaction between the side chains, and especially
of the stereogenic centers present in these chains, and favors
the incorporation of monomeric units into columnar stacks of
unpreferred helicity to yield fully homochiral aggregates. The
larger size of the tricarboxamide discotics 1−3 drastically re-
duces the rotation angle between the monomeric units in the
stack to ca. 18°.18a As discussed below, with this rotation angle
the side chains are spatially close which originates van der
Waals steric interactions. Increasing the temperature relaxes
the distances between the aromatic units and the H-bonding
interactions, but does not alleviate the hindrance between the
side chains. Therefore, the incorporation of a monomeric unit
of chiral tricarboxamides 1 or 2 into a stack of its unpreferred
helicity would increase the steric interaction between the
branched side chains, thus increasing the MMP and, conse-
quently, the difficulty to achieve fully homochiral aggregates.
In order to provide a structural/energetic explanation of the
chiral amplification trends in OPE-TAs, which differ from
those reported for BTAs, we analyzed the minimum-energy
geometry of the most stable supramolecular 20-mer stacks of
2a-c (Figure 3c-d). Intermolecular parameters scrutinized
Figure 6. a) Inter- and intramolecular structural parameters
characterizing the OPE-TA supramolecular helices: rotational
angle between adjacent molecules along the stack (q), twisting
angle of the amide groups (f), intermolecular discotic-discotic
distance (dI) and H-bond distance (dH). Schematic illustration
of the steric hindrance effect exerted by the chiral, aliphatic
chains of vicinal units in OPE-TA 2a (b) and the analogous
BTA (c).
The occurrence of larger stacking rotations upon increasing
the number of chiral chains could also explain the differences
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found experimentally in the HRP. This penalty refers to the conditioned by the steric hindrance between the peripheral
1
2
3
4
5
6
7
8
interaction along the growing axis between two helices of dif-
ferent handedness and, as already reported, can be related with
the efficiency of H-bond interactions.17 For larger stacking ro-
tations (e.g. in 2a), H-bond interactions become more direc-
tional (more handed oriented), and thus the penalty when two
columns of different handedness interact is increased. The av-
erage twisting angle adopted by the amide groups (f in Figure
6a) to form the intermolecular H-bonds is predicted to be 36.0°
for 2a.23 In contrast, by reducing the rotating angle q (e.g., in
2c), H-bond interactions are less directed to a particular hand-
edness (f of 39.1° for 2c), and thus the HRP is expected to be
smaller. These trends follow the experimental behavior in-
ferred from the SaS data.
side chains, larger values being found for larger number of
chiral side chains. Larger stacking rotation angles imply
smaller steric hindrance between neighboring chains and lead
to smaller MMP values, thus explaining the experimental
trends found for the MMP and HRP parameters. In contrast,
the large rotational angle predicted for columnar stacks of
BTAs (ca. 65°) gives rise to weak interactions between the
side chains, and remains mostly unchanged with the number
of stereogenic centers. Thus, increasing the number of chiral
side chains in BTAs increases the steric hindrance, which re-
sults in larger MMP values whereas the HRP remains unal-
tered. The experimental consequence is that in BTAs the
smaller the number of stereogenic centers per monomeric unit
the larger the chiral amplification ability.
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A similar geometry analysis was performed for 20-mer co-
lumnar stacks of BTAs analogous to 2a-c that were also fully
optimized at the GFN2-xTB level (see the Supporting Infor-
mation for details). Calculations show that the number of chi-
ral chains barely impacts on the stacking rotation of BTAs,
with a 0.3% increase of q in going from the three-chiral-chains
derivative to the one-chiral-chain discotic. The negligible ef-
fect of the number of chiral chains for q can be rationalized by
the absolute stacking rotation, which is computed of ca. 65°
(Figure 6c). This large monomer rotation along the growing
axis is due to the fact that the amide groups in BTAs are di-
rectly linked to the central benzene ring, and leads to a stack-
ing arrangement where chiral chains of neighboring discotics
do not interact as they are spatially distant (Figure 6c). As q
remains practically constant in BTAs, increasing the number
of chiral centers inevitably increases the steric bulk in the col-
umn, and thus the MMP is meant to increase. Moreover, HRP
is reported to be independent of the number of chiral chains
for BTAs,17b in good accord with the stacking rotation invari-
ance.
The data presented herein contribute to shed light on the pa-
rameters controlling the transfer and amplification of chirality
processes in supramolecular polymers, highlighting the enor-
mous influence exerted by the size of the self-assembling unit
on the final helical outcome, and help to establish more clear
rules on the structure/property relationships for the supramo-
lecular polymerization of chiral self-assembling systems.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Full experimental details, additional CD measurements, and the-
oretical calculations, including Figures S1-S6, Tables S1-S14
(PDF)
AUTHOR INFORMATION
Corresponding Author
* lusamar@quim.ucm.es
* enrique.orti@uv.es
CONCLUSIONS
We have described a complete series of experimental and
theoretical investigations on the supramolecular polymeriza-
tion of oligo(phenylene ethynylene) tricarboxamides (OPE-
TAs, compounds 1-3). We have expanded previous studies on
transfer and amplification of chirality to demonstrate the in-
fluence exerted by the number of stereogenic centers per mon-
omeric unit and the temperature on the chiral amplification
phenomena by carrying out SaS and MR experiments. We
have derived a full set of thermodynamic parameters includ-
ing the helix reversal penalty (HRP) and the mismatch penalty
(MMP). The values derived for the former demonstrate that
the larger the number of chiral side chains, the higher the
HRP, leading to a more efficient amplification of chirality.
Otherwise, increasing the number of stereogenic centers per
monomeric unit results in a lower MMP, enhancing the chiral
amplification phenomenon. Decreasing the temperature also
leads to a more efficient chiral amplification. These experi-
mental data sharply contrast with those reported for BTAs, for
which the chiral amplification ability in MR experiments in-
creases by lowering the number of stereogenic centers or in-
creasing the temperature.
ORCID
Luis Sánchez: 0000-0001-7867-8522
Enrique Ortí: 0000-0001-9544-8286
Juan Aragó: 0000-0002-0415-9946
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manu-
script.
‡ These authors contributed equally.
ACKNOWLEDGMENT
Financial support by the MINECO of Spain (CTQ2017-82706-P,
CTQ2015-71154-P and Unidad de Excelencia María de Maeztu
MDM-2015-0538),
the
Generalitat
Valenciana
(PROMETEO/2016/135 and SEJI/2018/035), the Comunidad de
Madrid (NanoBIOCARGO, P2018/NMT-4389), and European
Feder funds (CTQ2015-71154-P) is acknowledged. E. E. G. and
J. B. are grateful to Universidad Complutense de Madrid for her
predoctoral fellowship. J.C. acknowledges the Generalitat Valen-
ciana for a I+d+i postdoctoral fellowship (APOSTD/2017/081).
To gain insight for this behavior, we performed theoretical
calculations by utilizing the GFN2-xTB approach. Calcula-
tions first confirm that (R)-stereogenic centers favor the for-
mation of M-type helical structures, the opposite being found
for (S)-stereogenic centers. Second, they show that the rota-
tional angle between neighboring OPE-TA units (ca. 18°) is
ABBREVIATIONS
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Journal of the American Chemical Society
(8) (a) Wang, Y.; Fang,H.; Tranca, H.; Qu, H.; Wang, X.;
BTAs, 1,3,5-benzenetricarboxamides; OPE-TAs, oligo(phe-
Markvoort, A. J.; Tian, Z.; Cao, X. Elucidation of the origin
of chiral amplification in discrete molecular polyhedral. Nat.
Comm. 2018, 9, 488-495. (b) Dressel, C.; Reppe, T.; Prehm,
M.; Brautzsch, M.; Tschierske, C. Chiral self-sorting and am-
plification in isotropic liquids of achiral molecules. Nat.
Chem. 2014, 6, 971–977.
1
2
3
4
5
6
7
8
nylene ethynylene)-tricarboxamides; SaS, sergeants-and-sol-
diers; MR, majority rules; HRP, helix reversal penalty; MMP,
mismatch penalty.
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