Spontaneous mirror-symmetry breaking coupled to top-bottom chirality transfer: From porphyrin self-assembly to scalemic Diels-Alder adducts

Article abstract of DOI:10.1039/c9cc05946f

This report shows how the net supramolecular chirality that emerged by spontaneous mirror-symmetry breaking (SMSB) at the mesoscale level can be transferred towards asymmetric solution chemistry. The J-aggregates obtained by self-assembly of an achiral porphyrin act as chiral counteranions in an iminium-promoted Diels-Alder reaction, leading to enantiomeric imbalances in the final adducts.

Full text of DOI:10.1039/c9cc05946f

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Spontaneous mirror-symmetry breaking coupled
to top-bottom chirality transfer: from porphyrin
self-assembly to scalemic Diels–Alder adducts†
Cite this: Chem. Commun., 2019,
55, 12219
Received 31st July 2019,
Accepted 16th September 2019
a
bc
Aitor Arlegui,
Josep M. Ribo,
Bernat Soler,a Alex Galindo,a Oriol Arteaga,bc Adolf Canillas,
ad
ad
Zoubir El-Hachemi,ad Joaquim Crusats
*
and
´
a
DOI: 10.1039/c9cc05946f
Albert Moyano
*
rsc.li/chemcomm
This report shows how the net supramolecular chirality that emerged on the control of the signs of racemic biases of anisotropic
by spontaneous mirror-symmetry breaking (SMSB) at the mesoscale supramolecular species11 such as liquid crystals, Langmuir
level can be transferred towards asymmetric solution chemistry. The films,12 Langmuir–Blodgett films,13 and supramolecular self-
J-aggregates obtained by self-assembly of an achiral porphyrin assembled systems14–16 by the effect of macroscopic shear
act as chiral counteranions in an iminium-promoted Diels–Alder forces.
reaction, leading to enantiomeric imbalances in the final adducts.
Asymmetric catalysis based on chiral supramolecular nano-
structures has been observed in a number of instances,17 but in
Biological macromolecules are almost without exception composed all of the systems studied to date the chirality of the catalyst has
of L-amino acids and D-carbohydrates. This phenomenon, not been generated by SMSB, and the asymmetric induction
customarily called ‘‘biological homochirality’’, has captured may originate from the molecular chirality elements (either
the attention of the scientific community since the seminal centers or axes) present in the discrete components of the
investigations of Pasteur.1 The prebiotic emergence of net macromolecular assembly. Therefore, if a chiral supramolecular
molecular chirality may be traced back to the phenomenon of system obtained in a nonracemic form by the action of SMSB in
spontaneous mirror-symmetry breaking (SMSB).2 The Soai the aggregation of achiral monomer species could be used as an
asymmetric autocatalytic addition of diisopropylzinc reagents3 enantioselective catalyst in a simple solution reaction, this would
remains to date the sole example of a chemical reaction that constitute a previously unknown way to generate net chirality
starting from achiral reagents can lead to chiral products with at the molecular level, which avoids the severe mechanistic
virtually complete enantiomeric purity in the nominal absence constraints for SMSB in chemical reactions taking place in
of any external chiral catalyst.4 With the possible exception of solution (i.e., highly specific non-linear reaction networks based
the aldol reaction between acetone and p-nitrobenzaldehyde,5,6 on enantioselective autocatalysis). In this approach, the chirality
the Soai reaction can be regarded as a unique demonstration of transfer would take place in a ‘‘top-bottom’’ fashion, without the
the existence of SMSB in a chemical transformation.7 Macro- need for the SMSB to take place in the reaction under study. This
scopically chiral chemical species (e.g., chiral solid surfaces) are would eventually prove that the macroscopic chirality of a
able to select the chiral signs of the products of the Soai hydrodynamic shear force can indeed be transferred to the local
reaction,8–10 probably as a result of tiny energetic imbalances molecular level, resulting in an enantiomeric excess of a chemical
which originated from the differential adsorption of enantio- reaction, by using the global chirality of the supramolecular
meric species. On the other hand, there are numerous reports structure as a relay at the mesoscale level.
In order to test experimentally this concept, we selected as the
supramolecular catalytic species for top-bottom chirality transfer
a
´
the J-aggregates18 of meso-tetrakis(4-sulfonatophenyl)porphyrin
(zw-TPPS4, Scheme 1), which belongs to a family of achiral
amphiphilic porphyrins yielding stable supramolecular chiral
J-aggregates with well-defined structures in aqueous acidic
media. For this type of aggregate, the chirality signs of permanent
racemic biases may be selected by hydrodynamic stirring forces of
clock- or anticlock vortex stirring when these forces are exerted
during their preparation.14–16 zw-TPPS4 is readily available in
relatively large amounts, and the intrinsically chiral sheet of its
Department of Inorganic and Organic Chemistry, Universitat de Barcelona, Martı i
`
Franques 1, E-08028 Barcelona, Catalonia, Spain. E-mail: j.crusats@ub.edu,
amoyano@ub.edu
b
´
`
Department of Applied Physics, Universitat de Barcelona, Martı i Franques 1,
E-08028 Barcelona, Catalonia, Spain
c FEMAN Group, Institute of Nanoscience and Nanotechnology (IN2UB), University
´
`
of Barcelona, Martı i Franques 1, 08028 Barcelona, Catalonia, Spain
d
´
`
Institute of Cosmos Science (IEEC-ICC), University of Barcelona, Martı i Franques
1, 08028 Barcelona, Catalonia, Spain
† Electronic supplementary information (ESI) available: Synthetic and analytical
procedures. See DOI: 10.1039/c9cc05946f
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Scheme 2 Aqueous Diels–Alder reaction between cyclopentadiene and
(E)-cinnamaldehyde using the zw-TPPS4Á(isoindoline)2 heteroaggregates
as catalysts.
Scheme 1 Structures of zw-TPPS4 depending on its concentration in
water.
J-aggregate single-walled open nanotubes shows surfaces occupied
by anionic sulfonate groups.16,19
In the absence of metal cations and other counteranions,
the porphyrin-based J-aggregates derived from the achiral
diprotonated monomer of zw-TPPS4 can be regarded as zwitter-
ionic chiral supramolecular sulfonic acids. We reasoned that if
the porphyrin aggregate could act as a catalyst for a suitable
reaction, its chirality at the mesoscale level could in principle
be transferred down to the molecular level. A viable mechanism
for this chirality transfer would be provided by the capacity of
the anionic aggregate of acting as a supramolecular chiral
counteranion of an achiral a,b-unsaturated iminium cation
(which due both to electrostatic and hydrophobic interactions
should be in close contact at the electrical double layer with the
peripheral phenylsulfonate anions of the aggregate), in the
spirit of List’s asymmetric counteranion directed catalysis
(ACDC).20 A suitable benchmark reaction, besides being capable
Scheme 3 Schematic representation of the catalytic cycle.
of promotion by this activation mode, should take place in ammonium salt heteroaggregate (see the ESI†). Following chromato-
aqueous media (since these porphyrin J-aggregates are not stable graphic purification, the diastereomeric mixture of racemic alde-
in non-aqueous solutions), and should not involve anionic hydes was reduced to the corresponding alcohols by NaBH4 in
nucleophiles in order to ensure that it takes place on the surface MeOH, and the two pairs of enantiomers were separated by chiral
of the aggregate. Taking into account these requirements, we HPLC (see the ESI† for the details). The retention time for each
selected for our study the Diels–Alder cycloaddition between an stereoisomer was unambiguously assigned by comparison with the
a,b-unsaturated aldehyde (cinnamaldehyde) and cyclopentadiene, HPLC trace of the enantioenriched alcohol mixture resulting from
as a prototypical iminium-promoted aqueous reaction that can be reduction of the same Diels–Alder adducts obtained by catalysis of
run in the absence of any organic co-solvent (Scheme 2).21 We the reaction by the HClO4 salt of (S)-bis(3,5-trifluoromethyl-
envisaged that the chiral heteroaggregate obtained by treating the phenyl)prolinol trimethylsilyl ether (5 mol%, water, rt, 7 h), accord-
zwitterionic aggregate with two molar equivalents of an achiral ing to Hayashi and co-workers.21 This allowed us to establish a
cyclic secondary amine (isoindoline) could act as an heterogeneous detection limit of Æ0.6% ee for this method of analysis, corres-
catalyst for the aqueous Diels–Alder reaction, and that the chiral ponding to the maximum % ee recorded for the nominally racemic
environment provided by the J-aggregate could result in the samples in several independent control experiments. Before running
formation of scalemic cycloadducts (Scheme 3).
the chirality transfer experiments with our porphyrin J-aggregate-
After some experimentation, we found that in order to get based catalytic systems, and taking into account the acceleration of
reasonable reaction rates, we had to use relatively concentrated Diels–Alder reactions both ‘‘in water’’23 and ‘‘on water’’24 conditions,
solutions of the reagents (0.25 M in cinnamaldehyde), 3 molar we performed the reaction in the absence of any catalyst, and we
equivalents of cyclopentadiene, and a 30 mol% of the secondary found a maximum 2% conversion after 3 days at rt.
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In order to obtain chiral porphyrin J-aggregates in water aggregate is formed, addition of the opposite enantiomer of the
without the need for acidification – so as not to add additional chiral selector does not change the bisignate CD signal of the
achiral counteranions that could compete with the ACDC sample, as determined by Mueller matrix polarimetry (see the
mechanism – we prepared zw-TPPS4 by direct sulfonation of ESI†).
5,10,15,20-tetraphenylporphyrin (TPP), followed by centrifuga-
The experimental results obtained for the isoindolinium-
tion of the solid zwitterionic aggregate and removal of excess mediated aqueous Diels–Alder reaction following this approach
sulfuric acid by repeated washing with water until constant are presented in Table 1. The measured ee values in three
pH was achieved. Then, simply by addition of two molar different pairs of experiments (entries 2–4) did consistently
equivalents of isoindoline used as a co-catalyst to an aqueous show the same correlation, so that the J-aggregates showing a
suspension of zw-TPPS4, the ionic chiral TPPS4Á(isoindoline)2 bisignated (+/À) CD spectrum (entries 2a, 3a and 4a) lead to the
heteroaggregates used as catalysts were straightforwardly preferential formation of (2R,3R)-exo/(2S,3S)-endo pairs,
obtained. Mueller matrix polarimetry (see the ESI†) shows that whereas those showing a bisignated (À/+) CD spectrum (entries
the addition of isoindoline, in spite of changing somehow the 2b, 3b and 4b) lead to the preferential formation of (2S,3S)-exo/
structure of the aggregate as inferred from the increase in (2R,3R)-endo pairs; note that when the reaction was carried out
linear dichroism, does not change the circular dichroism of with the substitution of the zw-TPPS4 aggregate by two equiva-
the sample originating from the supramolecular structure of lents of p-toluenesulfonic acid (entries 1a and 1b), only racemic
zw-TPPS4. It should be noted that, under these conditions, the (ee o 0.6%) mixtures of diastereomers were obtained. This
chiral bias sign of the porphyrin aggregate used as an organo- blank experiment proves that the chiral quaternary ammonium
catalyst (determined by polarimetry, see the ESI† for further cation by itself has no effect whatsoever on the enantio-
details) is not affected by stirring since it has already been set in selectivity of the organocatalyzed reaction in the absence of
when SMSB takes place during the uncontrolled self-assembly the supramolecular scaffold.‡ Altogether, these results lead to
process.25 Preliminary results using zw-TPPS4 as obtained the conclusion that the enantioselectivity of the reaction can
following this synthetic procedure – without any contact with solely be attributed to the supramolecular handedness of the
chiral substances – show that the adducts are in most cases catalytic heteroaggregates.
obtained in a nonracemic form, albeit with very low ee values
In conclusion, we have demonstrated that the purely
(see the ESI† for a representative example). Unambiguous proof supramolecular chirality of amphiphilic porphyrin J-aggregates
of the existence of chirality transfer from the catalyst to the (generated by SMSB during the aggregation process) can be
reaction adducts would require the observation of an unequi- transferred down to the molecular level, leading to small but
vocal correlation between the supramolecular chirality sign of measurable deviations from the racemic composition in the
the heteroaggregates and the absolute configurations of the chiral products arising from the Diels–Alder cycloaddition
major enantiomers of the Diels–Alder adducts under mirrored between cyclopentadiene and (E)-cinnamaldehyde (ee’s up to
experimental conditions. However, at the high zw-TPPS4 concentra- 5.5%). The sense of the asymmetric induction in this reaction
tions needed for the organocatalyzed Diels–Alder reactions can be unambiguously correlated with the supramolecular
(ca. 4 Â 10À2 M) the chiral outcome of the porphyrin SMSB chirality sign of the catalytic heteroaggregates, as measured by
self-assembling process is known to be unavoidably biased the CD signals of the bisignated exciton coupling absorption
always to the same chiral sign.21
bands. Since the kinetic conditions for SMSB (highly enantio-
After considerable experimentation we were pleased to find selective autocatalysis and nonlinearity) are much more easily
that in the presence of small amounts of either enantiomer of a met in nucleation and in self-assembly processes than in reac-
chiral quaternary ammonium salt derived from 1-phenylethylamine, tions taking place in molecular solutions,26 the present results can
(R)/(S)-Q (Scheme 4), the supramolecular handedness of the be considered as a proof of principle for a hitherto unregarded
zw-TPPS4 homoaggregates obtained by concentration of a mechanism for the emergence of net chirality in molecular
dilute aqueous solution of monomeric zw-TPPS4 could be systems, in which the SMSB takes place in the formation
selected at will while preserving the ACDC conditions required of chiral supramolecular dissipative structures with catalytic
for the enantioselectivity of the reaction, and that this handedness properties, leading to asymmetric imbalances in their compositions
was indeed maintained after the addition of 2 molar equivalents of that are subsequently transferred to a standard enantioselective
isoindoline to furnish the final zw-TPPS4Á(isoindoline)2 hetero- reaction (absolute asymmetric catalysis). Through this mechanism
aggregate, as evinced by the signs of the bisignate CD spectra a macroscopic polarization force, based on e.g. hydrodynamic
(ESI†). Chiral selectors (R)-Q and (S)-Q only play their role at the vortices, can be converted into a microscopic one in the form of
onset of the aggregation process of the porphyrin. Once the tiny ee’s which can then in turn tip other SMBS processes in
primordial chemical networks. This ‘‘top-bottom’’ chirality transfer
could, on the other hand, be relevant for the emergence of biological
homochirality in connection with the scenario recently proposed by
Liu and co-workers,26 in which chiral supramolecular aggregates of
achiral prebiotic molecules arise by the action of hydrodynamic
torques in the chiral microvortices created in the rock micropores
near to deep-sea hydrothermal vents on prebiotic Earth.
Scheme 4 Structures of the chiral selectors used to polarize the zw-
TPPS4 spontaneous mirror symmetry breaking (SMSB).
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Table 1 Correlation between the absolute configurations of the major enantiomers of the reaction products obtained in the isoindolinium-promoted
aqueous Diels–Alder reactions between cyclopentadiene and (E)-cinnamaldehyde, and the supramolecular chirality of the zw-TPPS4Á(isoindoline)2
heteroaggregates used as organocatalysts (Scheme 2)
Chiral sign
selectord
ee (exo) Æ 0.6%g
ee (endo) Æ 0.6%g
b
Entrya
zw-TPPS4
Catalyst CD signale
Conv.f (%)
exo : endo f
(configuration)h
(configuration)h
1a
1b
2a
2b
3a
3b
4a
4b
2 Â p-TsOHc
2 Â p-TsOHc
Batch I
Batch II
Batch II
Batch I
Batch III
Batch III
(R)-Q
(S)-Q
(R)-Q
(S)-Q
(R)-Q
(S)-Q
(R)-Q
(S)-Q
Ø
Ø
32
19
27
36
24
28
25
33
60 : 40
54 : 46
59 : 41
60 : 40
58 : 42
55 : 45
57 : 43
56 : 44
B0
B0
B0
B0
Bisignated (+/À)
Bisignated (À/+)
Bisignated (+/À)
Bisignated (À/+)
Bisignated (+/À)
Bisignated (À/+)
5.5 (2R,3R)
1.1 (2S,3S)
3.7 (2R,3R)
4.8 (2S,3S)
1.0 (2R,3R)
2.6 (2S,3S)
2.7 (2S,3S)
2.1 (2R,3R)
1.1 (2S,3S)
1.6 (2R,3R)
2.8 (2S,3S)
2.2 (2R,3R)
a
b
All experiments were simultaneously carried out in pairs under carefully controlled comparable conditions. Owing to the stochastic nature of
the aggregation process of the porphyrin, together with its sensitive dependence on uncontrollable imponderables including the presence of traces
of unidentified contaminants,22 different synthetic batches of zw-TPPS4 were used for the experiments reported in the table; note also that in
c
entries 2 and 3 the porphyrin samples were swapped in relation to the enantiomer used as a chiral selector. Blank experiments were performed by
substituting zw-TPPS4 by two equivalents of p-toluenesufonic acid for the sake of making the experimental conditions between reactions as similar
as possible, except for the presence of the supramolecular chiral array (note that in the structure of the self-assembled heteroaggregate two
opposite meso-4-sulfonato groups are involved in the stabilization of the supramolecular structure, while the other two in the periphery can interact
d
with two isoindolinium/iminium cations). A 1 : 10 molar ratio of one of the enantiomers of compound Q and zw-TPPS4 was used to select the
chiral outcome of the SMSB process that takes place during the formation of the supramolecular organocatalyst; see the ESI for a detailed
e
description of the whole chiral selection procedure. CD-signals of the bisignated exciton coupling bands at 489 nm corresponding to the
J-aggregate of zw-TPPS4 in the zw-TPPS4Á(isoindoline)2 heteroaggregates; the signs are reported from longer to shorter wavelengths (see the ESI).
f
g
Determined from the integration of the aldehyde proton signals in the 1H-NMR spectra of the reaction crudes. Determined by HPLC on a chiral
stationary phase, after reduction of the aldehyde adduct mixture to the corresponding alcohols (NaBH4/MeOH). A detection limit of Æ0.6% ee was
h
established from the largest ee values measured in expected racemic samples without using chiral catalysts. Absolute configuration, see
Scheme 2 and ref. 21.
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vacion y Universidades, Agencia Estatal de Investigacion,
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‡ Even in the presence of the porphyrin heteroaggregates, any catalytic
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the fact that further addition of any amount of the opposite enantiomer
of the chiral selector does not revert the sense of the chiral induction.
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