Inducing Social Self-Sorting in Organic Cages To Tune The Shape of The Internal Cavity

Article abstract of DOI:10.1002/anie.202007571

Many interesting target guest molecules have low symmetry, yet most methods for synthesising hosts result in highly symmetrical capsules. Methods of generating lower symmetry pores are thus required to maximise the binding affinity in host–guest complexes. Herein, we use mixtures of tetraaldehyde building blocks with cyclohexanediamine to access low-symmetry imine cages. Whether a low-energy cage is isolated can be correctly predicted from the thermodynamic preference observed in computational models. The stability of the observed structures depends on the geometrical match of the aldehyde building blocks. One bent aldehyde stands out as unable to assemble into high-symmetry cages-and the same aldehyde generates low-symmetry socially self-sorted cages when combined with a linear aldehyde. We exploit this finding to synthesise a family of low-symmetry cages containing heteroatoms, illustrating that pores of varying geometries and surface chemistries may be reliably accessed through computational prediction and self-sorting.

Full text of DOI:10.1002/anie.202007571

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Inducing social self-sorting in organic cages to tune the shape of
the internal cavity
Authors: Valentina Abet, Filip T Szczypínski, Marc A Little, Valentina
Santolini, Christopher D Jones, Robert Evans, Craig Wilson,
Xiaofeng Wu, Michael F Thorne, Michael J Bennison, Peng
Cui, Andrew I Cooper, Kim E Jelfs, and Anna Grace Slater
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10.1002/anie.202007571
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Inducing social self-sorting in organic cages to tune the shape of the internal cavity
Valentina Abet,a,† Filip T. Szczypiński,b,† Marc A. Little,a Valentina Santolini,b Christopher D. Jones,a
Robert Evans,c Craig Wilson,a Xiaofeng Wu,a Michael F. Thorne,a Michael J. Bennison,a Peng Cui,a
Andrew I. Cooper,a Kim E. Jelfs,b and Anna G. Slatera,*
a Department of Chemistry and Materials Innovation Factory, University of Liverpool, Crown Street,
Liverpool L69 7ZD, United Kingdom; b Department of Chemistry, Imperial College London, Molecular
c
Sciences Research Hub, White City Campus, London W12 0BZ, United Kingdom; Aston Institute of
Materials Research, School of Engineering and Applied Science, Aston University, Birmingham B4 7ET,
United Kingdom.
† These authors contributed equally to this work.
* Email: anna.slater@liverpool.ac.uk.
ABSTRACT
Many interesting target guest molecules have low symmetry, yet most methods for synthesising hosts
result in highly symmetrical capsules. Methods of generating lower-symmetry pores are thus required
to maximise the binding affinity in host-guest complexes. Here, we use mixtures of tetraaldehyde
building blocks with cyclohexanediamine to access low-symmetry imine cages. Whether a low-energy
cage is isolated can be correctly predicted from the thermodynamic preference observed in
computational models. The stability of the observed structures depends on the geometrical match of
the aldehyde building blocks. One bent aldehyde stands out as unable to assemble into high-symmetry
cages—and the same aldehyde generates low-symmetry socially self-sorted cages when combined
with a linear aldehyde. We exploit this finding to synthesise a family of low-symmetry cages containing
heteroatoms, illustrating that pores of varying geometries and surface chemistries may be reliably
accessed through computational prediction and self-sorting.
INTRODUCTION
Controlled host-guest recognition is of crucial importance to biological processes and artificial
supramolecular systems alike.[1,2] Cage-like compounds have been developed to exploit such host-
guest interactions to achieve pollutant remediation,[3] gas storage,[4] anion binding,[5] biomimetic guest
recognition,[6] molecular separations,[7] and nanoparticle templation.[8,9] Advantages of organic cage
hosts include their improved solubility over framework materials, making them excellent candidates
for both liquid- or solid-phase applications.[10–14] Furthermore, cages offer synthetic handles that can
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be used to finely tune their cavity shape and electronic properties, and hence potential interactions
with guest molecules.[7,15–19] However, the synthesis of molecular cages is often challenging,
particularly where multiple bonds must be formed selectively. To avoid this problem, many molecular
cage syntheses take advantage of dynamic covalent chemistry, in which reversible reactions provide
an error correction mechanism to ensure the thermodynamic cage product is obtained.[20–22] In the
case of imine-based cages, multiple amines and aldehydes must react to yield a single cage species
instead of oligomeric mixtures of imines.[23–26] Ideally, high-fidelity self-sorting biases the formation of
the cage product over the many other possible products, enabling selective isolation of the target
molecule.[27–29]
A limitation of self-sorting strategies is that they often result in the formation of highly symmetrical
products.[22,30,31] Reducing the symmetry of the host may induce anisotropy in the solid state, improve
the binding of low-symmetry guests, or enable more controlled and directional post-synthetic
modification.[32–35] For example, fine-tuning of the cavity of an organic cage has been shown to afford
precise control over the selectivity of the resultant solid-state material.[7] Stepwise syntheses
exploiting orthogonal reactivities can afford low-symmetry organic cages,[6,36,37] but this limits the
scalability of the resulting materials. Alternatively, low-symmetry architectures may be obtained by
purification of complex mixtures, but this is a laborious process and may be unachievable on a
preparative scale due to reconfiguration of the desired products.[38–41] A recent study showed that
low-symmetry cages can be formed using a lower-symmetry aldehyde precursor, but the presence of
multiple structural isomers precluded the unambiguous characterisation of the cage products.[42] We
sought to avoid these problems by designing an alternative single-step route to low-symmetry imine-
based cages. We used mixtures of multiple aldehyde precursors with different geometries to
investigate their self-sorting behaviour, screening for combinations that led to the selective formation
of low-symmetry cages.
We recently reported a series of Tet3Di6 tubular organic cages that were prepared through imine
formation between three pseudo-linear tetratopic aldehydes (“Tet”) and six ditopic amines (“Di”), and
selected the linear tetraaldehydes as a starting point for these studies.[43,44] Reacting a mixture of two
tetraaldehydes with a single diamine can produce three distinct sorting outcomes (see Figure 1(i)):
narcissistic self-sorting, in which only cages incorporating a single aldehyde precursor are observed;[45–
48]
social self-sorting, in which only cages incorporating both aldehyde precursors are observed;[27,49]
and scrambling, in which a mixture of different sorting outcomes are observed.[50] However, it is
extremely hard to predict – either intuitively or computationally – which outcome will be observed for
a given pair of aldehyde reactants. For simple cases, such as two linear aldehydes, one could expect
that narcissistic self-sorting is likely due to the mismatch in the aldehyde lengths and strain in the
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resultant cages.[48,51–53] It is much more difficult to predict the outcome when a linear aldehyde is
combined with a bent aldehyde, such as B1 (see Figure 1(ii)). We hypothesised that the greater
conformational degrees of freedom of non-linear aldehydes compared to linear aldehydes would aid
social self-sorting or scrambling by accommodating a wider range of options for the cage geometry.[54–
56]
Figure 1 (i) Illustration of narcissistically and socially self-sorted systems as opposed to non-sorted scrambled outcomes for
an imine-based organic cage forming reaction using linear (green) and bent (orange) aldehydes in presence of (1R,2R)-trans-
1,2-cyclohexanediamine (blue); (ii) structures of the bent (B1, B2) and (iii) linear (L1–4) tetraaldehydes used in this work.
To test our hypothesis, we studied imine-based cages formed from two bent tetratopic aldehydes B1–
2 and four linear aldehydes L1–4 of varying length (see Figure 1(iii)). First, we sought to confirm that
all the aldehydes individually form cages with (1R,2R)-trans-1,2-cyclohexanediamine (R,R-CHDA) in
the presence of trifluoroacetic acid catalyst. Each bent aldehyde was then reacted sequentially with
the series of linear aldehyde partners and R,R-CHDA to assess their cage-forming and self-sorting
behaviour. All reactions were characterised by ultra-performance liquid chromatography–mass
1
spectrometry (UPLC-MS) and H NMR spectroscopy. Where cage species could be isolated, crystal
structures were sought to confirm their identities and assess their stable conformations. The sizes of
isolable low-symmetry cages were further investigated in solution by diffusion-ordered spectroscopy
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(DOSY NMR) and ion-mobility spectrometry–mass spectrometry (IMS-MS). Aldehyde B1 was found to
induce social self-sorting in the studied cages, thus heteroatom-containing analogues of B1 were
synthesised and reacted using the same methods to test whether the self-sorting behaviour was
retained.
We previously used density functional theory (DFT) formation energies to explain the
thermodynamically preferred cage topologies in the dynamic imine-based self-assembly
processes.[41,57–59] Comparing the thermodynamic stabilities of potential cage products can be a good
guide to selectivity, but the reaction outcome can also be affected by factors such as reaction
kinetics,[39,60–64] solvent effects,[65–68] and the solubilities of the species involved in the
equilibrium.[33,40,47] In parallel with the synthetic efforts, we used computational techniques to predict
the stability of the different homo- and heteroleptic structures originating from aldehydes B1–2 and
L1–4. The experimentally observed outcomes agreed with the relative gas-phase formation energies
of the possible Tet3Di6 products, showing the predictive power of the simple model for the self-sorting
behaviour of imine-based organic cages.
RESULTS AND DISCUSSION
Single aldehyde systems
Aldehydes B1–2 and L1–4 were synthesised via Pd-catalysed cross-coupling reactions (see ESI Section
S3 for the synthetic details). The reactions of L2 and L3 with R,R-CHDA have been reported to give
tubular covalent cages [3L2] and [3L3], respectively (see Figure 2 for the single crystal structures).[44]
The reaction of L1 with R,R-CHDA afforded a complex mixture of imine condensation products that
could be purified by recrystallisation to yield [3L1]. Reactions of L4 and B2 with R,R-CHDA both result
in single cage products [3L4] and [3B2], respectively. The single crystal structures of [3L1] and [3B2]
could be elucidated. Unlike for the other aldehydes, reaction products of B1 with either R,R- or S,S-
CHDA could not be identified and attempts to grow single crystals from such reaction mixtures were
unsuccessful. However, co-crystallisation of the opposite-handed reaction products led to re-
equilibration of the building blocks and provided a pseudo-C3h-symmetric [3B1-RS] cage. Investigation
of the crystal structure of [3B1-RS] revealed incorporation of equal amounts of each enantiomer of
CHDA into the cage structure, which is reminiscent of the CHDA self-sorting observed in a previously
reported organic cage CC3-RS.[69]
This result prompted us to computationally explore the thermodynamic preference for the formation
of pseudo-C3h cages incorporating both CHDA enantiomers against the corresponding enantiopure
Tet3Di6 cages (see ESI Section S2 for the computational details). Indeed, the DFT formation energy for
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[3B1-RS] was 20 kJ mol-1 lower than the formation energy for the enantiopure [3B1] at the M06-2X/6-
311G(3df,3pd) level of theory. B1 was the only studied aldehyde for which any preference was
observed. As the reaction of B1 with R,R-CHDA only formed the enantiopure [3B1] cage in trace
amounts, we postulated that more stable cages may result from the addition of linear tetraaldehydes,
enabling access to socially self-sorted lower-symmetry architectures. By contrast, cages including
linear aldehydes and B2 would compete with the favourable formation of [3B2], leading to narcissistic
self-sorting or statistical mixtures of all possibilities.
Figure 2 Side- and top-views of the solvated single crystal X-ray structures of the imine-based cages originating from the
reactions of tetraaldehydes L1–3 and B2 (grey) with R,R-CHDA (red). For B1, single crystals were only obtained for a pseudo-
C3h-symmetric structure incorporating both R,R- and S,S-CHDA (cyan). Hydrogen atoms and solvent molecules are omitted
for clarity, nitrogen atoms are in dark blue.
Mixed aldehyde systems
To explore self-sorting in the system, we combined aldehydes from the L and B families in single-pot
reactions with R,R-CHDA under cage-forming conditions. We expected the Tet3Di6 topology to be
favoured in all cases based on our previous work.[44] This assumption reduced the space of the possible
structures to a number that could be systematically explored by computational methods. As imine
formation is reversible under the reaction conditions used here, the observed product distributions
are expected to relate to the thermodynamic minima. Therefore, formation energies can be predictive
of the range of products seen. If all the possible cages have similar formation energies, we predict that
multiple cage products will be formed or that the self-sorted products will be selected by solvation
and entropic effects. Conversely, if one or more cages are much lower in energy than the other
possibilities, we predict that those structures will dominate the product distribution.
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For each reaction studied, we manually constructed the Tet3Di6 cages in all possible stoichiometries
of the linear and bent aldehydes. We then applied a workflow consisting of high-temperature
molecular dynamics simulations with OPLS3e force field,[70] followed by further geometry
optimisations at the PBE-GD3/TZVP-MOLOPT-GTH level of theory[71–78] to find the expected gas-phase
conformations of the resulting cages (see ESI Section 3 for more details). Single point energies were
calculated for the modelled structures at the M06-2X/6-311G(3df, 3dp) level of theory and the
resulting formation energies are summarised in Table 1 (for B1) and Table 2 (for B2). These calculations
are performed on isolated molecules in the gas phase, which does not consider solvent effects, and
hence large energetic differences are needed to predict solution-phase structures with confidence.
In parallel, we attempted to address the problem synthetically by targeting the cage stoichiometry of
[L + 2B] (+ 6 R,R-CHDA omitted for clarity). A deuterated variant of aldehyde L3 was available from a
previous study and used in reactions with B1 to allow discrimination of the resultant cages by mass in
the UPLC-MS.[79] No such deuterated analogue was available for the mixture of L4 and B2, and the
1
reaction was characterised primarily by H NMR chemical shifts and UPLC retention times. Tables 1
and 2 summarise which structures were experimentally observed.
Reactions of B1 with aldehydes L1–4 and R,R-CHDA all resulted in cage compounds corresponding to
entries marked with asterisks in Table 1 (see ESI Section S3.4 for screening details and raw spectra).
For the shortest linear aldehyde L1, the major cage product was a pseudo-D3 low-symmetry [L1 + 2B1]
cage, which was readily isolated via recrystallisation. The structure of this compound was elucidated
by single crystal X-ray diffraction (see Figure 4) and was the lowest energy structure predicted for that
system. When the elongated L2 was used instead, the two major products observed by UPLC-MS were
a low-symmetry [2L2 + B1] cage and the previously described homoleptic [3L2], which again were the
two lowest-energy predicted structures. For the even longer aldehyde L3-d, a complex mixture was
observed by UPLC-MS (see ESI Figures S16-S21 and Tables S3-S4). The major product was identified as
the [3L3-d] cage, in agreement with the computational models. Lower-mass peaks corresponding to
[2L3-d + B1] and [L3-d + 2B1] could also be detected, both structures being of comparable DFT
formation energies. The relative proportions of the products could not be determined due to
insufficient chromatographic separations. For the longest aldehyde trialled, L4, the major product was
the symmetrical tubular [3L4] cage, which was of significantly lower DFT energy than any competing
structure in this system. In all cases, other species could be detected by mass spectrometry as trace
products, including the chiral cage [3B1], but could not be isolated. The distribution of the products is
affected by the length of the linear aldehydes L1–4 in a seemingly unpredictable way, but the observed
structures agree with predicted trends in the DFT formation energies. The length of L1 appears to be
suitable to relieve strain in a cage containing two B1 moieties; L2 is of suitable length to relieve strain
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in a cage containing one B1 moiety, but L3 and L4 seem to be too long and do not form stable mixed
Tet3Di6 cages with B1.
Reactions involving aldehyde B2 and aldehydes L1–4 also all resulted in the formation of cage
compounds (see Table 2 and ESI Section S3.4). For aldehydes L2 and L3, the outcomes of the reactions
were scrambled and all possible Tet3Di6 cages were observed, which were all of comparable DFT
formation energies. For L1 and L4, we observed narcissistic self-sorting. In the case of L4, signals
1
corresponding to [3B2] and [3L4] can be seen by H NMR and two clear peaks with retention times
corresponding to [3B2] and [3L4] can be seen in the chromatogram (see ESI Figures S22-S26 and Table
S5). However, as all products in this system have the same mass, it was not possible to unambiguously
characterise the self-sorting behaviour with mass spectrometry. While formation energies of [3L1]
and [L1 + 2B2] are comparable, and the formation energy of [3L4] is higher than that of the socially-
sorted cages [nL4 + mB2], we propose that the clean narcissistic self-sorting in those cases is a result
of antagonistic coupling between the homoleptic and the heteroleptic cages in these libraries.[80]
Formation of the stable [3B2] cage removes free B2 from solution, thus favouring the formation of
[3L1] over [L1 + 2B2]. Similarly, formation of the significantly more stable [3L2] cage removes free L2
from the system, thus shifting the equilibrium towards clean formation of [3B2] over the [nL4 + mB2]
structures.
Contrary to B1, aldehyde B2 has more degrees of freedom and forms a stable [3B2] cage as well as
scrambled mixtures of heteroleptic cages with other aldehydes. Chromatographic separations of the
mixtures containing heteroleptic cages [2L2 + B1], [nL2 + mB2], and [nL3 + mB2] are currently under
investigation. The reaction of L1 and B1 with R,R-CHDA stands out as the only combination which
produces a low-symmetry heteroleptic organic cage as the only product detected by NMR.
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Table 1 Side- and top-views of the DFT-optimised structures (PBE-GD3/TZVP-MOLOPT-GTH) of the possible Tet3Di6 outcomes
for the reactions using mixtures of B1 and L1-4 under cage forming conditions. Underneath are the single point formation
energies (M06-2X/6-311G(3df, 3dp)) in kJ mol-1. Entries marked with asterisks are the experimentally observed outcomes.
Building blocks are coloured according to Figure 1, nitrogen atoms are dark blue, hydrogen atoms are omitted.
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Table 2 Side- and top-views of the DFT-optimised structures (PBE-GD3/TZVP-MOLOPT-GTH) of the possible Tet3Di6 outcomes
for the reactions using mixtures of B2 and L1-4 under cage forming conditions. Underneath are the single point formation
energies (M06-2X/6-311G(3df, 3dp)) in kJ mol-1. Entries marked with asterisks are the experimentally observed outcomes.
Building blocks are coloured according to Figure 1, nitrogen atoms are dark blue, hydrogen atoms are omitted.
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Heteroatom-containing [L1 + 2B1X] systems
To investigate whether social self-sorting would also be observed with analogues of B1 we synthesised
thiophene (B1S) and pyridyl (B1N) derivatives that have structurally related geometries (see Figure 3
for the chemical structures and ESI Section S3.2 for the synthetic details). Due to the incorporation of
heteroatoms and differently sized rings in their cores, these aldehydes were expected to produce
cages with different pore geometries and electronic properties.[48,81,82]
Figure 3 Chemical structures of heteroatom-containing aldehydes B1N and B1S.
Figure 4 Side- and top-views of the single crystal X-ray structures of the socially-sorted [L1 + 2B1X] cages originating from
the reactions of mixtures of tetraaldehydes (grey) L1 and B1 (left) or B1S (right) with R,R-CHDA (red).
In both cases, the reactions of B1S and B1N with L1 and R,R-CHDA gave analogues of [L1 + 2B1] as the
major product, accompanied by significant formation of the corresponding homoleptic [3B1X] cages
(see ESI S3.5 for the synthetic details). Computational modelling predicts comparable formation
energies for [L1 + 2B1X] and [3B1X] in both cases, with a slight preference for the heteroleptic
structures (see ESI Section S2 for the computational details). Inspection of the computational models
suggests that [L1 + 2B1] and its analogues exhibit similar shapes and sizes. It was possible to obtain a
single crystal X-ray structure of [L1 + 2B1S] (see Figure 4) and comparison of this structure to that of
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[L1 + 2B1] supports this hypothesis. Unfortunately, however, crystallisation experiments of [L1 +
2B1N] were unsuccessful. Thus, we investigated the size of the cages in solution by DOSY NMR
experiments, which demonstrated the hydrodynamic radii are similar for all three structures (see ESI
Section S4). Further evidence was obtained from IMS-MS experiments, which indicated that the drift
times for the three cages are similar (see ESI Section S5), supporting the conclusion that the subtle
differences in the linker structures have little effect on the overall molecular size in these systems.[83,84]
We performed analysis of the shapes and electronic structures of the internal cage cavities to probe
the effect of using different aldehydes. Cage geometries were optimised as described previously.
These structures were used to calculate the total electron density and the electrostatic potential at
the M06-2X/6-311+G(d,p) level of theory. We found the 0.0004 a.u. density isosurface and selected a
subsurface approximating the internal cavity of each cage (see ESI Section S2.5 for the algorithm and
the implementation). Figure 5 shows the mapping of the electrostatic potential onto the cavity
surface. The potential around the main window between the two non-linear aldehydes is most
affected by the neighbouring heteroatoms, while the entire cavity surface becomes narrower and
elongated in the case of the more expanded thiophene linker in [L1 + 2B1S]. The heteroatoms
themselves have little effect on the shape of the void, but do affect its electronic properties, providing
a subtle yet important distinction that may have consequences for guest binding and selectivity.
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Figure 5 Side-, window-, and top-views of the electrostatic potential inside the cavities of the socially-sorted [L1 + 2B1X]
cages, mapped onto the 0.0004 a.u. total electron density isosurface calculated at the M06-2X/6-311+G(d,p) level of theory.
CONCLUSIONS
Four new tetraaldehydes, two linear (L1, L4) and two non-linear (B1, B2), were synthesised and
reacted with R,R-CHDA to form three new Tet3Di6 organic cages: [3L1], [3L4], and [3B2]. Aldehyde B1
did not form the expected cage [3B1] when reacted with R,R-CHDA or S,S-CHDA. However, upon co-
crystallisation of reaction mixtures containing B1 and both enantiomers of CHDA, the formation of the
pseudo-C3h-symmetric cage [3B1-RS] was observed. We exploited the lack of a stable homochiral cage
[3B1] to form low symmetry cage compounds containing mixtures of B1 and linear aldehydes L1–4 of
varying lengths. Computationally obtained formation energies of the resultant cages were able to
rationalise the experimentally observed resultant cages. In particular, the heteroleptic cage [L1 + 2B1]
was predicted to be more stable than the corresponding homoleptic cages [3L1] and [3B1], and was
indeed preferentially formed. Two heteroatom-containing analogues of [L1 + 2B1] were formed using
this strategy, demonstrating the generality of the social self-sorting approach to synthesis of organic
cages of low-symmetry. The slight change in the aldehyde geometry and the incorporation of
heteroatoms did not affect the overall size of the cage molecules, while allowing for tuning of the
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shape and electronic properties of the internal cavity. We hope that these results will aid the design
of more anisotropic organic cages for challenging separations and the selective encapsulation of
biologically relevant low-symmetry guests.
ACKNOWLEDGEMENTS
We thank the Royal Society and the Engineering and Physical Sciences Research Council (EPSRC) for a
Royal Society-EPSRC Dorothy Hodgkin Fellowship (A.G.S) and a Royal Society University Research
Fellowship (K.E.J.). A.G.S., V.A., and C.D.J. thank the EPSRC for funding (EP/R005931/1). K.E.J. and F.T.S.
thank the Leverhulme Trust for a Leverhulme Trust Research Project Grant. C.W. and A.G.S. thank the
EPSRC for a Summer Vacation Bursary. Via our membership of the UK's HEC Materials Chemistry
Consortium, which is funded by EPSRC (EP/L000202, EP/R029431), this work used the ARCHER UK
National Supercomputing Service (http://www.archer.ac.uk). A.I.C. and M.A.L. thank the EPSRC for
funding (EP/N004884/1). This work made use of shared equipment located at the Materials Innovation
Factory (MIF); created as part of the UK Research Partnership Innovation Fund (Research England) and
co-funded by the Sir Henry Royce Institute. Mass spectrometry data was acquired in the MIF, at the
EPSRC UK National Mass Spectrometry Facility at Swansea University, and on our own equipment.
M.B. and A.G.S. thank the University of Liverpool for a Returners Fund. We thank Diamond Light
Source for access to beamlines I19 (CY21726) and Dr Sarah A. Barnett for support during the remote
access beamtime session.
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Table of Contents summary
A combined experimental-computational approach provided a platform for the synthesis of low-
symmetry imine cages from mixtures of tetraaldehyde building blocks. This social self-sorting
approach was applied to obtain a family of new cages containing heteroatoms, illustrating that pores
of varying geometries and surface chemistries may be reliably accessed.
Keywords
Cage compounds, molecular design, molecular materials, multi-component self-assembly, self-
sorting, supramolecular chemistry
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