Assembly-driven synthesis of hybrid molecular capsules controlled by chiral sorting

Article abstract of DOI:10.1039/c3cc41515e

Chiral capsules with polar interiors (reversed capsules) undergo heterochiral sorting and exhibit positive mutalism-both hemispheres mutually benefit from the association. This feature can be coupled with partial reversibility of the formation reaction an

Full text of DOI:10.1039/c3cc41515e

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COMMUNICATION
Assembly-driven synthesis of hybrid molecular
capsules controlled by chiral sorting†
Cite this: Chem. Commun., 2013,
49, 3860
Michał Wierzbicki and Agnieszka Szumna*
Received 27th February 2013,
Accepted 19th March 2013
DOI: 10.1039/c3cc41515e
www.rsc.org/chemcomm
Chiral capsules with polar interiors (reversed capsules) undergo
heterochiral sorting and exhibit positive mutalism – both hemi-
spheres mutually benefit from the association. This feature can be
coupled with partial reversibility of the formation reaction and
utilized to amplify synthesis of hybrid capsules made of hemi-
spheres that cannot be formed independently.
Non-covalent assembly can contribute considerably to the overall
stability of systems, and therefore it can be used as a directing force
for numerous chemical processes. Nature often uses molecular
recognition to drive the selectivity of its crucial chemical reactions.
Chemists have also shown that molecular recognition can be
employed to direct synthesis of complex molecular architectures
that are not achievable by simple chemoselective synthesis
(rotaxanes, knots, etc.,).1,2 Dynamical combinatorial chemistry
couples stability gained from recognition with reversibility of the
chemical reaction. In this way the most stable assemblies have a
chance to be amplified.3–6 In the current communication we show
that the stability gained from non-covalent assembly of capsular
dimers can be used to control their own chemical synthesis.
Additionally, we show that chiral sorting plays a crucial role
in the selectivity of this process. We and others have pre-
viously demonstrated that sorting7–12 and chiral sorting, in parti- Scheme 1 Synthesis and structure of ‘‘reversed’’ capsules.
cular,13–17 can effectively control assembly of capsules. However, it
has not been previously shown that that chiral sorting can also
mutually influence the chemical synthesis of hemispheres.
polar molecules.18,19 Since the binding motif of the dimer (inter-
Recently we reported the synthesis of L-2a, which is composed actions by two belts of salt bridges) involves only amino acid
of a rigid resorcin[4]arene scaffold and flexible L-phenylalanine backbones, it can be expected that similar capsules should be
arms (Scheme 1).17 The product dimerizes quantitatively in the formed with other amino acids having hydrophobic side chains.
reaction mixture and it is isolated as capsules (L-2a)2 in a high However, we have currently found that using even chemically
overall yield (70%). The self-complementary dimers (L-2a)2 have similar amino acids leads to dramatic changes: not only in the
two unique features: they are chiral and have polar interiors, association and complexation properties but also in the outcome
which makes them very efficient in chiral recognition of small of the chemical synthesis. We have found that the assembly
process and successful formation of the product by the Mannich
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52,
reaction are inextricably connected.
We have tested the Mannich reaction with various hydro-
phobic amino acids: Ala 1b, Leu 1c, Val 1d and Ile 1e. In the case
01-224 Warsaw, Poland. E-mail: agnieszka.szumna@icho.edu.pl;
Fax: +48 22 6326681; Tel: +48 22 343 2101
† Electronic supplementary information (ESI) available: Synthetic and isolation pro-
of L-1b, the dimeric homochiral capsule (L-2b)2 was formed in the
reaction medium and isolated in 50% yield (ESI†). However, for
cedures. NMR spectra of all new capsules synthesized. CCDC 918981. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c3cc41515e
c
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L-1c, an amino acid with a longer and more flexible alkyl chain,
the obtained product had a very complicated NMR spectrum with
pronounced upfield shifted signals of methyl groups (ESI†).
Further experiments showed that the product existed in a
dimeric form (L-2c)2 but one of the leucine side chains was self-
encapsulated, thus preventing guest complexation. This was in
contrast to (L-2a)2, which in some solvents could also exist in self-
encapsulated form but remained fully effective in guest binding.
The most surprising behaviour was observed for L-1d. In this case
we did not obtain a capsule (L-2d)2. Moreover, despite numerous
attempts, the secondary amine L-2d could not be obtained even in
its monomeric form, using this reaction.
Fig. 2 Top view of X-ray structures of: (a) homochiral dimer (L-2a)2 (Refcode
HOWHAD); (b) heterochiral dimer (L-2a)(D-2a).
denotes steric crowding
between phenylalanine side chains (highly disordered CH2Cl2 and CH3NO2
molecules were removed by SQUEEZE).
In order to gain insight into possible reasons for such
differences we examined the course of the Mannich reaction positions (Fig. 1e). Attempts to force the reaction by heating,
between resorcin[4]arene, formaldehyde and various amino prolonged reaction times, addition of acidic catalyst (AcOH,
acids by NMR (Scheme 1 and Fig. 1). We chose the two 10%) or addition of methanol (5–50%) to disassemble aggregates
borderline cases: L-1a and L-1d. In both cases the reaction also failed. These results indicate that the formation of benzox-
initially led to the formation of variously substituted benzox- azines 3 is reversible (as also proved by others)20 and assembly
azines 3 (Fig. 1a and e). The existence of benzoxazine inter- of a dimeric capsule (L-2a)2 moves the equilibrium towards
mediates was confirmed using HSQC and DOSY spectra (ESI†). secondary amines. Apparently, for L-1d this driving force is
For L-1a the signals of benzoxazine species gradually dis- missing, and therefore the reversible step of the Mannich
appeared during the progress of the reaction and finally, after reaction does not lead to secondary amine L-2d.
5 days, the main product was L-2a, which assembled into
The possible reason why a capsular dimer fails to form can
capsules (L-2a)2 (Fig. 1b and c). However, for L-1d the reaction be deduced from the X-ray structure. In homochiral dimer
did not equilibrate to yield the final four-substituted secondary (L-2a)2 the amino acid side chains are grouped pairwise
amine product L-2d. Instead, very broad peaks were obtained, (Scheme 1 and Fig. 2).17 This can create potential sterical
indicative of non-specific aggregation (Fig. 1d). After addition conflicts between amino acid side chains, especially branched
of methanol to disassemble the aggregates, the spectrum at the position next to the stereogenic center (like L-Val).
revealed a complicated mixture of randomly substituted ben- However, the steric hindrance can be considerably diminished
zoxazines 3 and secondary amines 2 with unreacted aromatic in a dimer composed of hemispheres of opposite chirality. The
X-ray structure of (L-2a)(D-2a) shows that in a heterochiral
capsule the amino acid side chains form a pinwheel type of
structure that is devoid of steric clashes (Fig. 2b).‡ This results
in the formation of a more stable dimer. Indeed, we have
previously proven that, in solution, a heterochiral capsule is
thermodynamically more stable than a homochiral one.17
Based on this structural information we have predicted that,
even though we cannot obtain a homochiral capsule (L-2d)2 for
steric reasons, the formation of a heterochiral capsule (L-2d)(D-2d)
should be possible and can therefore possibly drive the reversible
step of the Mannich reaction. This observation prompted us to
develop a strategy for obtaining hybrid capsules21–24 that are not
accessible through a traditional sequence: chemical reaction -
isolation of homochiral capsules - association of heterochiral
capsules. We took advantage of the reversibility of benzoxazine
formation and the higher thermodynamic stability of heterochiral
arrangement. Therefore, we tested the effectiveness of assembly-
driven synthesis at the different levels (Fig. 3) and under various
reaction conditions.§ First we used a pre-formed homochiral
capsule (L-2a)2 as a template for formation of a heterochiral
hybrid capsule with a D-1d partner (Fig. 3a). The product
(L-2a)(D-2d) was isolated in 45% yield. This result finally proves
that the assembly can drive the synthesis and also eliminates the
possibility that inherent reactivity of valine is responsible for the
negative outcome of the Mannich reaction. We then investigated
Fig. 1 1H NMR spectra (600 MHz) of reaction mixtures: (a) after 1 day from
substrate L-1a (CDCl3); (b) after 5 days from substrate L-1a (CDCl3); (c) final
isolated product from substrate L-1a (CDCl3); (d) after 5 days from substrate L-1d
(CDCl3); (e) after 5 days from substrate L-1d (CDCl3 : CD3OD 1 : 1); (f) isolated
whether we could obtain a hybrid capsule without a pre-formed
template. In the first approach the reactions were carried out so
product (L-2d)(D-2d) (CDCl3); s – solvent, b – benzoxazine, r – unreacted aromatic
positions from resorcinarene.
c
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compound, but not a functional material. Since the self-assembly
process is very slow, the real value of the newly synthesized
compound can be easily overlooked.
In conclusion, we have shown that the chemical synthesis of
capsules with reversed polarity is driven by their self-assembly. The
hemispheres can mutually promote their own formation. There-
fore, it is possible to obtain a capsule made of two different
hemispheres even if none of them can be synthesized separately.
Both formation by chemical reaction and successful isolation are
inextricably connected with formation of dimers. If the capsules are
not formed either due to steric requirements or due to denatura-
tion, the products cannot be obtained, even as monomers. Higher
thermodynamic stability of heterochiral dimers can be employed to
drive the chemical reaction of their formation. The new hybrid
dimers obtained by this approach exhibit positive mutalism – they
stabilise their own formation and cannot exist separately.
We acknowledge the financial support from the National
Science Centre (Grant No. N204 187839).
Fig. 3 Sorting experiments in the synthesis of hybrid capsules.
Notes and references
that the first step took place separately for opposite enantiomers.
Then the reaction mixtures were combined and the mixture was
allowed to assemble and equilibrate (Fig. 3b). In this way the test
capsule (L-2a)(D-2d) was obtained in 51% yield. The strategy has
proven to be effective for the synthesis of new capsules made of
two monomers, of which none was obtained as a single compo-
nent, for example (L-2e)(D-2d) (62%) and (L-2d)(D-2d) (49%).
Finally, a totally one pot procedure using racemic amino acids
was tested. However, the limitation of this approach is the first
reaction step (attachment to the resorcinarene skeleton) which,
under mild conditions (required for effective assembly), has
limited (or no) reversibility. Therefore, the one-pot procedure
proved to be ineffective.
‡ Crystallographic data for (L-2a)(D-2a) Â 6 CH2Cl2 Â 6 CH3NO2:
C180H230Cl12N14O44 M = 3719.18, 0.63 Â 0.76 Â 0.93 mm3, mono-
clinic, space group P21/n (no. 14), a = 17.9860(7), b = 32.4038(14), c =
32.9781(14) Å, b = 90.406(2)1, V = 19219.6(14) Å3, Z = 4, Dc = 1.285 g cmÀ3
,
F000 = 7856, CuKa radiation, l = 1.54184 Å, T = 173(2) K, 2ymax = 136.11,
415 267 reflections collected, 34 285 unique (Rint = 0.0690). Final GooF =
1.035, R1 = 0.0700, wR2 = 0.1917, R indices based on 28 496 reflections with
I > 2s(I) (refinement on F2), 1860 parameters, 0 restraints. Lp and absorption
corrections applied, m = 2.227 mmÀ1. Squeeze procedure has been applied
to remove highly disordered solvent molecules. CCDC 918981.
§ See ESI† for details.
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