A stimuli responsive system of self-assembled anion-binding Fe₄L₆⁸⁺ cages

Abstract

A new cationic Fe₄L₆ cage molecule was synthesised from 4,4′-diaminobiphenyl, 2-formylpyridine and iron(II). The cage exists as a system of interconverting diastereomers in solution. The system adapts to the addition of anionic guest molecules, expressing a new combination of diastereomers that synergistically bind the guest molecules. Not only do the cage diastereomers interconvert, the volume of the individual cages adapts physically through the rotation of bonds, providing a tailored binding pocket for the guest lined with hydrogen-bond donors. A model for the resulting complex network of species was developed that allowed the system to be fully described. The anion binding constants and the kinetics of both diastereomer interconversion and guest exchange were measured.

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Introduction

Biological systems consist of mixtures of molecules that are organised into networks, collectively expressing functions which cannot be attributed to individual components acting in isolation.^1,2 These networks extend throughout living systems and perform roles essential for life, ranging from processes observable with the naked eye such as hemostasis (blood clotting) to those that occur on the molecular level, like the cascades of enzymes that recognise and transform specific substrates.¹ The study of synthetic chemical systems, in which mixtures of interacting molecules produce enhanced properties, is an attractive area as synthetic systems can be designed to be less complex than biological systems.³ Thus, the study of pattern formation,⁴ self-replication,⁵ dynamic combinatorial chemistry⁶ and self-sorting multi-component systems,⁷ which can be considered models for elaborate biological processes, have received significant recent attention. Ultimately, the key to unravelling the origin of life may come from studying the complex interactions of molecules.⁸

Adaptation is a feature displayed by living systems; biological processes and organisms change their behaviour in an environmentally dependent manner. For example, protein folding activates or deactivates enzymatic processes while organisms respond to climatic changes in order to survive.⁹ Chemical systems have also been demonstrated to adapt to external stimuli, either on the molecular level through physical changes,^10,11 or on the system-wide level with the expression of chemically distinct receptors after the addition of templating guest molecules; amplification in dynamic combinatorial systems^6,11 or allosteric binding¹² are two such examples. There are, however, very few examples of synthetic systems that produce multiple responses to stimuli at the same time, a feature of biological systems.^1,2,8 Here we present a new class of synthetic system, composed of interconverting diastereomers of a self-assembled cage molecule that adapts on the molecular and system-wide levels, to the presence of suitable guest molecules, producing synergistic anion binding.

Based on our experience^13–15 with the design and synthesis of self-assembled metallo-supramolecular capsules¹⁶ containing reversible metal–imine bonds,^17,18 we constructed a new anion-binding [Fe₄L₆]⁸⁺ cage that exists as a mixture of three diastereomers. Upon the addition of different anions, these cages adapt on the system-wide level, reorganising themselves to express a new combination of diastereomers to encapsulate the anionic guests; a higher proportion of guests are bound by the new mixture than would be possible with the original mixture, suggesting that the anion binding is a characteristic of the system rather than individual molecules. Not only do the cage diastereomers interconvert, the volume of the individual cages adapts physically through the rotation of bonds, providing a tailored binding pocket for the guest lined with hydrogen-bond donors.

Results and discussion

The reaction of six equivalents of 4,4′-diaminobiphenyl with twelve equivalents of 2-formylpyridine and four equivalents of iron(II) triflimide (Fe(NTf₂)₂) in acetonitrile afforded a deep purple microcrystalline powder in 90% yield. Microanalysis and mass spectrometry were consistent with the formation of a metallo-supramolecular [Fe^II₄L₆]⁸⁺ tetrahedron, [1]·8NTf₂ (Fig. 1). The ¹H NMR spectrum appeared complicated with eight signals observed for each proton environment in the ligand (Fig. 2). Two-dimensional (¹H–¹H COSY, NOESY) and DOSY NMR allowed the assignment of the peaks to a system of cages composed of three cage diastereomers, 1-T, 1-S₄ and 1-C₃ (ref. 15, 19, 20 and 21) (Fig. 1), in equilibrium. The ratio of these diastereomers was found to be 32 : 49 : 19, suggesting very small differences in total energy (1–3 kJ mol⁻¹) between each species.^21,25 The distribution of diastereomers was unaffected by concentration (0.1–50 mM) or variation in temperature (243–343 K). ¹⁹F NMR showed only one sharp peak corresponding to unencapsulated NTf₂⁻. A crystal structure of the product confirmed the formation of the [Fe^II₄L₆]⁸⁺ cage and showed that the triflimide anion was not encapsulated inside the cage (Fig. 1b) suggesting that a template was not required for the formation of 1.^14,22 [1]·8NTf₂ crystallised as the S₄ diastereomer, 1-S₄, which was observed to have the highest abundance in CD₃CN solution.

Fig. 1 Self-assembly of the tetrahedral [Fe₄L₆]⁸⁺ cage complex, 1. (a) Six equivalents of 4,4′-diaminobiphenyl react with twelve equivalents of 2-formylpyridine and four equivalents of an iron(II) salt in acetonitrile at 50 °C overnight to produce 1. Suitable iron(II) salts include Fe(NTf₂)₂, Fe(OTf)₂, Fe(ClO₄)₂·6H₂O, Fe(PF₆)₂·6MeCN and Fe(BF₄)₂·6H₂O producing [1]·8NTf₂, [1]·8OTf·7H₂O, [1]·8ClO₄·12H₂O, [1]·8PF₆·3H₂O and [1]·8BF₄·3MeCN respectively in 80–90% yields after precipitation with diethyl ether and chromatography as appropriate. (b) Schematic view of the X-ray crystal structure of [1]·8NTf₂·5MeCN·2H₂O·Et₂O. The complex crystallises as the S₄ diastereomer (1-S₄) with two Λ and two Δ metal centres. Average Fe–Fe distances are 12.5 Å and the calculated void volume is 65 ų. (c) Schematic representation of the three diastereomers of 1. Purple and blue metal centres are of opposite stereochemical configuration, green lines represent anti-linkages between homochiral metal centres and red lines represent syn-linkages between heterochiral metal centers. 1-T has one magnetically equivalent environment per atom labelled in (a); 1-C₃ has four such environments; 1-S₄ has three such environments.

Fig. 2 ¹H NMR spectra (400 MHz, CD₃CN, 298 K) of 1 with different anions. For clarity, only peaks corresponding to T-symmetric diastereomers are labelled in red (see Fig. 1 for labelling scheme), blue dots indicate peaks corresponding to 1-S₄, green dots indicate peaks corresponding to 1-C₃. Where small peaks are unlabelled they correspond to less than 1% relative abundance and are within the error of the measurements. (a) [1]·8NTf₂; 1-T, 1-S₄ and 1-C₃ are observed in a 32 : 49 : 19 ratio. (b) [1]·8OTf; 1-T, 1-S₄ and 1-C₃ are observed in a 32 : 49 : 19 ratio. (c) [PF₆⊂1]·7PF₆; 1-T, 1-S₄ and 1-C₃ are observed in a 59 : 29 : 15 ratio. (d) [ClO₄⊂1]·7ClO₄; 1-T, 1-S₄ and 1-C₃ are observed in a 68 : 8 : 24 ratio. (e) [BF₄⊂1-T]·7BF₄; only 1-T is observed. (f) [NO₃⊂1-T]·7NTf₂ formed from the addition of one equivalent of tetrabutylammonium nitrate to [1]·8NTf₂. (g) [Br⊂1-T]·7NTf₂ formed from the addition of one equivalent of tetrabutylammonium bromide to [1]·8NTf₂. (h) [I⊂1-T]·7NTf₂ formed from the addition of one equivalent of tetrabutylammonium iodide to [1]·8NTf₂.

The synthesis of the tetrahedral cage 1 was also possible when other iron(II) salts were employed. Thus, [1]·8OTf, [1]·8ClO₄, [1]·8PF₆ and [1]·8BF₄ could be prepared from the corresponding iron(II) salts in similar yields to that of [1]·8NTf₂. The ¹H NMR spectra of [1]·8OTf, [1]·8ClO₄ and [1]·8PF₆ again displayed the presence of diastereomers, while within the limits of detection, [1]·8BF₄ gave exclusively peaks corresponding to the T-symmetric diastereomer, 1-T (Fig. 2). In [1]·8OTf, the T : S₄ : C₃ ratio was 32 : 49 : 19, the same as observed for [1]·8NTf₂, however, for the perchlorate analogue the ratio was 64 : 8 : 28 and in [1]·8PF₆ it was 59 : 26 : 15, suggesting that the system of cage molecules was adapting to the presence of different anions.

The ¹⁹F NMR spectrum of [1]·8OTf showed only one sharp peak consistent with unencapsulated OTf⁻, while [1]·8BF₄ gave two peaks in a 1 : 7 ratio suggesting that a tetrafluoroborate anion had been encapsulated inside 1. Similarly, [1]·8PF₆ produced peaks for both free and bound PF₆⁻. The bound PF₆⁻ gave three signals, corresponding to hexafluorophosphate anions encapsulated in each of 1-T, 1-S₄ and 1-C₃ which were present in the same ratio observed in the ¹H NMR. ¹H–¹⁹F HOESY of [1]·8BF₄ and [1]·8PF₆ (see ESI†) and crystal structures of the perchlorate, tetrafluoroborate and hexafluorophosphate species (Fig. 3) confirmed encapsulation of these anionic guests within the tetrahedral host.

Fig. 3 X-ray crystal structures of host–guest complexes. The approximately T-symmetric host structures are shown as schematic representations and the encapsulated guests as space-filling representations. The ΔΔΔΔ-enantiomer of each cage is shown; both enantiomers are present in each crystal structure. (a) [BF₄⊂1-T]·7BF₄·5.25MeCN·0.25Et₂O, average Fe–Fe separation 12.6 Å and calculated volume 69 ų. (b) [ClO₄⊂1-T]·4ClO₄·3OTf·4MeCN·2Et₂O, average Fe–Fe separation 12.6 Å and calculated volume 74 ų. (c) [PF₆⊂1-T]·7PF₆·9MeCN·3Et₂O, average Fe–Fe separation 12.7 Å and calculated volume 87 ų. (d) [I⊂1-T]·3I·3.5OTf·0.5NTf₂·2MeCN·Et₂O, average Fe–Fe separation 12.6 Å and calculated volume 66 ų.

The addition of either PF₆⁻, BF₄⁻ or ClO₄⁻ to a solution of either of the empty cages ([1]·8NTf₂ or [1]·8OTf) produced new peaks and/or changes in the diastereomer ratios present in the ¹H NMR (see Table 1), indicating a system-wide response to their presence. Further anionic and neutral guests were also screened for potential binding in CD₃CN (see ESI†). Nitrate, iodide, bromide, chloride and hexafluoroarsenate were observed to bind inside 1, and each induced changes in the corresponding diastereomer ratios (Fig. 2); the addition of small organic guests and larger anions did not induce changes in 1's ¹H NMR spectrum. Other anions including sulfate and phosphate resulted in a colour change and precipitation, suggesting decomposition of the cage.

Table 1 Diastereomer ratios, binding constants (K_a) and calculated volumes for a number of anions and their encapsulation by 1

Anion	Anion volume (Å^3)	Ka (M^−1)			Diastereomer ratio (T : S4 : C3)
		K^TG	K^SG	K^CG
a Determined by ^19F NMR.b Binding not observed.c Determined by competitive titration with the PF6^− adduct.d Addition of more than two equivalents of guest resulted in cage decomposition.e Determined by competitive titration with the Br^− adduct.
NTf2^−	156	0	0	0	32 : 49 : 19
OTf^−	85	0	0	0	32 : 49 : 19
SbF6^−	85	0	0	0	32 : 49 : 19
AsF6^−	80	1.5^a	^b	^b	32 : 49 : 19
PF6^−	75	1.00(5) × 10^3	0.29(2) × 10^3	0.43(4) × 10^3	59 : 26 : 15
Cl^−^d^,^e	24	2.5(6) × 10^5	^b	^b	100 : 0 : 0
Br^−^c^,^a	28	5.6(11) × 10^5	^b	^b	100 : 0 : 0
ClO4^−^e	55	1.1(3) × 10^6	0.18(2) × 10^6	0.81(4) × 10^6	64 : 8 : 28
NO3^−^d^,^e	41	1.2(4) × 10^6	^b	^b	100 : 0 : 0
BF4^−^e	53	2.2(5) × 10^6	^b	^b	100 : 0 : 0
I^−^e	35	1.7(4) × 10^7	^b	^b	100 : 0 : 0

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Not only are the empty diastereomers of 1 (1-T, 1-S₄ and 1-C₃) in equilibrium in solution, each may also bind an anionic guest (G), with the corresponding host–guest complexes ([G⊂1-T], [G⊂1-S₄] and [G⊂1-C₃]) also in equilibrium with each other. The resulting network of equilibria in a solution of 1 is represented schematically in Fig. 4a. The equilibrium constants and diastereomer ratios could be determined from NMR experiments and are given in Table 1 (see the ESI† for the derivation of the binding model).

Fig. 4 The network of species present in 1 after the addition of an anionic guest and calculated responses of the system. (a) Each of the three diastereomers of 1 (1-T, 1-S₄ and 1-C₃) are in equilibrium with each other; these relationships are governed by the equilibrium constants K_TC, K_TS and K_SC. Encapsulating an anionic guest, G, by 1-C₃ produces [G⊂1-C₃], encapsulation of G by 1-T produces [G⊂1-T] and encapsulation of G by 1-S₄ produces [G⊂1-S₄]. These equilibria are governed by the equilibrium constants K^C_G, K^T_G and K^S_G, respectively. The host–guest complex diastereomers are also in equilibrium with each other with the relationships governed by the equilibrium constants K^′_TC, K^′_TS and K^′_SC. (b) Calculated (see the ESI†) change in the total fraction of each diastereomer upon addition of PF₆⁻. 1-C₃ stays almost constant, and 1-T increases at the expense of 1-S₄. (c) Calculated (see the ESI†) change in the total fraction of each diastereomer upon addition of ClO₄⁻. 1-C₃ and 1-T increase at the expense of 1-S₄. (d) Calculated (see the ESI†) change in the total fraction of each diastereomer upon addition of BF₄⁻. 1-T increases at the expense of both 1-S₄ and 1-C₃.

The information obtained from these experiments can be used with the model of equilibria (Fig. 4a) to produce a full description of the network of 1 and the way it responds to the influence of different external stimuli (anions). This description allows for speciation curves to be derived, which describe the relationships between each component of the system at varying guest concentrations. The diastereomeric adaptation of the system (measured as fractions of the total concentration of 1) upon the addition of various anions are given in Fig. 4b, 4c and 4d. In each case a different response to each anion is observed. The addition of PF₆⁻ to 1 (Fig. 4b) produced little change in the fraction of 1-C₃, while 1-T increased at the expense of 1-S₄. In contrast, upon the addition of ClO₄⁻ (Fig. 4c), both 1-T and 1-C₃ increased and 1-S₄ was disfavoured. Adding BF₄⁻ instead resulted in the exclusive formation of 1-T (Fig. 4d). The system is thus capable of responding in various ways depending on the size and shape of the added guest.

The largest anion to be encapsulated within 1 was hexafluoroarsenate which has a volume of 80 ų, but was only weakly bound (K_a = 1.5 M⁻¹). The larger hexafluoroantimonate (85 ų) was not encapsulated. The binding constants obtained for the smaller anions were substantially higher (all greater than 10³ M⁻¹ affinity). In general, guests that have symmetry elements that match those of the T-symmetric host were bound more strongly.

The halides were found to bind in size order, with iodide producing the highest binding constant (1.7(4) × 10⁷ M⁻¹) of the guests explored; 1 is 30 times more selective for iodide than the other halides. Cage 1 represents the strongest 1 : 1 iodide binding host of which we are aware in either synthetic²³ or natural systems.²⁴ Indeed, this represents the strongest 1 : 1 host–guest binding for a metal–organic host that can be isolated in the absence of a guest.^14,25

The combination of strong binding and adaptive diastereomeric response upon the addition of a guest leads to a significant enhancement of anion binding. In each of the cases where 1-T was expressed exclusively upon guest addition (BF₄⁻, NO₃⁻ and halides), the quantity of guest encapsulated is amplified by more than 200% compared to the hypothetical guest binding of the system if the ratio of diastereomers remained at the pre-addition values of 32 : 49 : 19. The system of cages responds as a network to the addition of certain anionic guests, reconfiguring to synergistically bind anions in a manner that would not be possible without such a response.

The crystal structures of the host–guest complexes (Fig. 3) suggest that, in addition to electrostatics, the ability of 1 to bind anions originates from non-classical hydrogen bonding.²⁶ In [BF₄⊂1-T] and [ClO₄⊂1-T] the tetrahedral guests are arranged such that each of their fluorine and oxygen atoms, respectively, point towards the faces of the cage to take advantage of three stabilising, symmetrically arranged hydrogen bonding (H^a⋯guest) interactions for each atom, providing a total of twelve interactions per anion in the range of 2.3–2.6 Å. In order to accommodate the perchlorate anion, which is slightly larger than tetrafluoroborate, the volume of the cage molecule expands from 69 ų to 74 ų. This is achieved by adaptation of the cage through the expansion of the dihedral angle between the phenyl rings and the N_imine–Fe–N_pyridyl chelate planes (that is, the rotation of the ligand phenyl ring around the C₄–N_imine bond), which can be measured by the C₃–C₄–N_imine–C_imine torsion angle (φ). This expansion can occur while conserving idealised T-symmetry and maintaining the biphenyl dihedral at its optimum angle (55°).¹⁵

This rotation has several potential consequences. As φ approaches 0°, the phenyl ring and the pyridyl-imine approach coplanarity, bringing H^a and H^b (Fig. 1) away from the centre of the cage, increasing its cavity volume. As φ approaches 90°, the converse occurs; H^a and H^b move towards the centre of the cage, decreasing its volume. This flexibility allows cage 1-T to adapt to the size of a potential guest, while also allowing the H^a protons to be orientated to act as H-bond donors for a specific guest. The ideal angle for φ is approximately 69 ± 9°,¹⁵ which allows for H^b and H^c to avoid an energetically disfavourable transannular eclipse and also produces stabilising CH⋯π interactions between H^b and neighbouring phenyl rings.^15,27 These stabilising interactions are confirmed by ¹H NMR, with H^b experiencing significant shielding due to its proximity to the neighbouring phenyl rings (Fig. 2); the degree of the chemical shift change observed correlates with the strength of anion binding. A change in φ from its ideal angle is also associated with an enthalpic cost. As φ increases, stabilising CH⋯π interactions are broken. Additionally, as φ decreases, destabilising steric H^b–H^c clashes are introduced. The differences in binding constants between anions can be attributed to the degree to which the energetically disfavoured arrangements are adopted by 1-T in order to accommodate the guest with a favourable hydrogen-bonding arrangement. This hypothesis also explains the amplification of the 1-T diastereomer upon guest binding. Only this diastereomer can adopt both a symmetric ring of CH⋯π interactions and position its protons in a suitable manner to stabilise guest molecules without the energetic penalties arising from the steric proximity of H^b and H^c or between two neighbouring biphenylene H^a protons.¹⁵

Compared to tetrafluoroborate and perchlorate, hexafluorophosphate is both larger and does not have an ideal symmetry match to the cavity of 1-T. To accommodate this guest, the volume of the cage further expands to 87 ų. In the crystal structure of [PF₆⊂1-T] (Fig. 3c), four of the fluorine atoms point towards the faces, benefiting from hydrogen bonding interactions, and the remaining two point towards the vertices of the tetrahedron.

In contrast, iodide is significantly smaller than BF₄⁻, ClO₄⁻ or PF₆⁻, but it is also bound the most strongly by 1-T. In the X-ray structure, the 1-T cage was observed to enclose a volume of 66 ų, only slightly larger than the volume of 65 ų observed in the structure of 1-S₄ (1·8NTF₂). The H^a protons are arranged to provide an almost spherical arrangement of twelve stabilising hydrogen bond donors around the guest, both matching its symmetry and providing an ideal binding pocket^24,18, which is reflected in the strength of binding. The lower binding constants of the other halides can be rationalised by considering that smaller guests will increase the H^a⋯X⁻ distances resulting in weaker interactions.

Further supporting the hypothesis relating guest binding affinity to hydrogen bonding and stabilising CH⋯π interactions, we observed no correlation between host–guest fill ratios and the strength of binding. In the solid state, BF₄⁻ occupies 80% of the available volume of 1-T, ClO₄⁻ occupies 75%, PF₆⁻ occupies 85% and I⁻ occupies 53%, suggesting that in the presence of hydrogen bonding and electrostatic interactions, volume-occupation ratios are not a good predictor of guest binding affinity.²⁸

To further investigate the ability of 1-T to adapt upon guest binding, we undertook semi-empirical calculations to correlate φ with the volume of 1-T. PM3 minimisations were performed with φ values of 0–90° (see ESI†). As expected the minimum volume (58 ų) was found at 90°. At 0° a volume of 203 ų was obtained, with this structure representing the highest energy of those modelled. Thus, by changing φ the host is potentially capable of expanding its enclosed volume by 250%.

A volume of 203 ų suggests that larger anions such as, OTf⁻, NTf₂⁻ and SbF₆⁻ should be able to fit inside the cavity, however, they were not observed to do so. This can be explained by the energetic penalty (steric clashes and breaking CH⋯π interactions) that the cage must pay to adapt to guests with larger volumes. The magnitude of the larger anions' binding enthalpy is therefore not sufficient to overcome the energetic penalty of rearrangement, an effect which is exacerbated as the H^a protons rotate away from the cavity, resulting in less favourable arrangements of hydrogen bond donors and leaving only dispersion forces to stabilise any host–guest complex. It therefore appears to be more energetically favourable for the system of 1 to remain empty than adapt to bind any of these larger anions.

The kinetics of guest exchange and diastereomer interconversion were examined by NMR. The rate constants and the corresponding activation energies are summarised in Table 2. The measurement of these values was facilitated by three observations. Firstly, the exchange of guest and unencapsulated tetrafluoroborate molecules in [BF₄⊂1-T]·7BF₄, while slow on the T₂ timescale, was fast enough to give rise to exchange peaks in ¹⁹F EXSY NMR experiments. This allowed the determination of the rates of tetrafluoroborate exchange.

Table 2 Apparent first order rate constants (k) and activation energies (ΔG^‡) for the interconversion of diastereomers and guest exchange in 1. Each process corresponds to the analogously labelled equilibrium constant given in Fig. 4a

System	Process	k (s^−1)	ΔG^‡ (kcal mol^−1)
a Determined by ^19F–^19F EXSY NMR.b Determined by ^19F NMR.c Estimated by the disappearance of free PF6^− and represents a value for the inclusion of the guest into the total system of cages rather than a specific diastereomer.d Determined by ^1H NMR.
[BF4⊂1-T]^7+^a	kin	0.020 ± 0.002	19.75 ± 0.06
	kout	0.148 ± 0.015	18.56 ± 0.06
[PF6⊂1]^7+^b	kin^c	0.0006 ± 0.0001	21.81 ± 0.1
	k^′TC	11 ± 1 × 10^−6	24.19 ± 0.05
	k^′TS	16 ± 1 × 10^−6	23.97 ± 0.04
	k^′SC	1.0 ± 1.0 × 10^−6	25.6 ± 0.6
	k^′ST	44 ± 3 × 10^−6	23.97 ± 0.04
	k^′CS	1.4 ± 1.0 × 10^−6	25.4 ± 0.4
	k^′CT	42 ± 2 × 10^−6	23.40 ± 0.03
“Empty” [1]^8+^d	kTC	4.7 ± 0.8 × 10^−6	24.7 ± 0.1
	kTS	10.0 ± 0.6 × 10^−6	24.25 ± 0.04
	kSC	17 ± 2 × 10^−6	23.93 ± 0.07
	kST	8.6 ± 0.5 × 10^−6	24.33 ± 0.03
	kCS	77 ± 7 × 10^−6	23.04 ± 0.05
	kCT	19 ± 3 × 10^−6	23.87 ± 0.09

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Secondly, in the ¹⁹F NMR of 1·8PF₆ all three diastereomers could be observed. Given that it crystallised exclusively as [PF₆⊂1-T]·7PF₆, we were able to follow the conversion of [PF₆⊂1-T] to the equilibrium [PF₆⊂1-T] : [PF₆⊂1-S₄] : [PF₆⊂1-C] ratio of 59 : 26 : 15 over time, permitting the calculation of the rates of diastereomer interconversion for [PF₆⊂1]. The rate constants for each process were found to be similar, although substantially slower than the rate of tetrafluoroborate exchange.

The addition of PF₆⁻ to a solution of the empty cage, 1·8NTf₂, also allowed us to estimate the rate of uptake of this guest into the host complex by ¹⁹F NMR, which was found to be slower than the corresponding process observed in the case of tetrafluoroborate.

Thirdly, the empty cage, 1·8NTf₂, was observed to crystallise exclusively as 1-S₄ equilibrating to a 1-T : 1-S₄ : 1-C₃ ratio of 32 : 49 : 19 when redissolved, a process that could be monitored over several days. The rate constants for this process are very similar to the rates found for [PF₆⊂1], suggesting that a similar mechanism for interconversion of diastereomers occurred in the presence or absence of a guest.

The kinetic data provide mechanistic insights into the dynamics of the system. The large differences in rate constants between guest exchange and stereoisomerisation suggests that separate mechanisms are responsible for the two processes. The slow rates of diastereomer interconversion are consistent with either the Bailar twist or de-ligation mechanisms that have been proposed for related cages,^{15,20,21,29,30} while the much faster rates of guest exchange suggests a through-face process.²⁹ The latter is consistent with the observation that the larger PF₆⁻ is encapsulated 33 times more slowly than BF₄⁻.

Interestingly, the barrier to direct conversion of T to S₄ is similar to that of T to C₃ in both the cases of [PF₆⊂1] and empty 1. These data are inconsistent with a Bailar twist. The activation energy for the concerted double Bailar twist (required for T to S₄) should be twice that for a single Bailar twist (T to C₃). Such a high barrier precludes the concerted double twist, yet the T to S₄ stereoisomerisation process is observed. Therefore we conclude that diastereomer interconversion takes place by a deligation process as the enthalpic cost associated with a sequential deligation need not be greater than that for single deligation.

Conclusions

The system of cage molecules presented here responds across distinct levels of complexity to the addition of anionic guests. Many anions can be selectively encapsulated and are stabilised within the host's cavity by an array of hydrogen bond donors. Iodide is bound with particularly high affinity. The determination of guest binding constants, diastereomer ratios and kinetic parameters provides a full understanding of the system. Not only does the cage adapt on the molecular level to provide a tailored guest-binding pocket, it also adapts on a system-wide level through diastereomer interconversion, producing synergistically enhanced anion binding. This two-fold adaptation is a feature of the responses to external stimuli displayed by biological systems, something that has not previously been observed in synthetic systems. Complex and functional synthetic systems of this type will lead to the design of more effective systems for host–guest recognition and the development of systems approaching the complexity of those that exist in nature.

Acknowledgements

This work was supported by the EPSRC, the Netherlands Organisation for Scientific Research, NWO and the Marie Curie IIF scheme of the 7th EU Framework Program. The authors thank the Diamond Light Source (UK) for synchrotron beamtime on I19 (MT6791) and the EPSRC National Crystallography Service for data collection. Mr C. Wood is thanked for the preparation of [Fe(MeCN)₆]·2PF₆. Mrs E.F.V. Dry, Mr C. Browne and Mr D. Howe are thanked for their assistance.

Notes and references

1. J. Ricard, Emergent Collective Properties, Networks and Information in Biology, Elsevier, Amsterdam, 2006.
2. M. B. Elowitz and S. Leibler, Nature, 2000, 403, 335–338; A. Aderem, Cell, 2005, 121, 511–513.
3. R. F. Ludlow and S. Otto, Chem. Soc. Rev., 2008, 37, 101–108.
4. P. T. Corbett, J. K. M. Sanders and S. Otto, Angew. Chem., Int. Ed., 2007, 46, 8858–8861.
5. J. W. Sadownik and D. Philp, Angew. Chem., Int. Ed., 2008, 47, 9965–9970.
6. P. T. Corbett, J. Leclaire, L. Vial, K. R. West, J.-L. Wietor, J. K. M. Sanders and S. Otto, Chem. Rev., 2006, 106, 3652–3711.
7. M. M. Safont-Sempere, G. Fernández and F. Würthner, Chem. Rev., 2011, 111, 5784–5814.
8. S. A. Kauffman, The origins of order, Oxford University Press, Oxford, 1993; R. M. Lemmon, Chem. Rev., 1970, 70, 95–109; G. M. Whitesides and R. F. Ismagilov, Science, 1999, 284, 89–92; S. Mann, Acc. Chem. Res., 2012 DOI:10.1021/ar200281t.
9. E. Mayr, The Growth of Biological Thought: Diversity, Evolution, and Inheritance, Belknap Press, Cambridge, Massachuscetts, 1982.
10. J. Rabone, Y.-F. Yue, S. Y. Chong, K. C. Stylianou, J. Bacsa, D. Bradshaw, G. R. Darling, N. G. Berry, Y. Z. Khimyak, A. Y. Ganin, P. Wiper, J. B. Claridge and M. J. Rosseinsky, Science, 2010, 329, 1053–1057; G. J. Halder, C. J. Kepert, B. Moubaraki, K. S. Murray and J. D. Cashion, Science, 2002, 298, 1762–1765; S. Mirtschin, A. Slabon-Turski, R. Scopelliti, A. H. Velders and K. Severin, J. Am. Chem. Soc., 2010, 132, 14004–14005.
11. J.-M. Lehn, Chem. Soc. Rev., 2007, 36, 151–160.
12. S. Freye, J. Hey, A. Torras-Galán, D. Stalke, R. Herbst-Irmer, M. John and G. H. Clever, Angew. Chem., Int. Ed., 2012, 51, 2191–2194.
13. P. Mal, B. Breiner, K. Rissanen and J. R. Nitschke, Science, 2009, 324, 1697–1699; I. A. Riddell, M. M. J. Smulders, J. K. Clegg and J. R. Nitschke, Chem. Commun., 2011, 47, 457–459; W. Meng, B. Breiner, K. Rissanen, J. D. Thoburn, J. K. Clegg and J. R. Nitschke, Angew. Chem., Int. Ed., 2011, 50, 3479–3483; I. A. Riddell, M. M. J. Smulders, J. K. Clegg, Y. R. Hristova, B. Breiner, J. D. Thoburn and J. R. Nitschke, Nat. Chem., 2012, 4, 751–756; N. Ousaka, J. K. Clegg and J. R. Nitschke, Angew. Chem., Int. Ed., 2012, 51, 1464–1468; R. A. Bilbeisi, J. K. Clegg, N. Elgrishi, X. d. Hatten, M. Devillard, B. Breiner, P. Mal and J. R. Nitschke, J. Am. Chem. Soc., 2012, 134, 5110–5119.
14. Y. R. Hristova, M. M. J. Smulders, J. K. Clegg, B. Breiner and J. R. Nitschke, Chem. Sci., 2011, 2, 638–641.
15. W. Meng, J. K. Clegg, J. D. Thoburn and J. R. Nitschke, J. Am. Chem. Soc., 2011, 133, 13652–13660.
16. M. D. Ward, Chem. Commun., 2009, 4487–4499; R. Chakrabarty, P. S. Mukherjee and P. J. Stang, Chem. Rev., 2011, 111, 6810–6918; R. W. Saalfrank, H. Maid and A. Scheurer, Angew. Chem., Int. Ed., 2008, 47, 8794–8824; M. Yoshizawa, J. K. Klosterman and M. Fujita, Angew. Chem., Int. Ed., 2009, 48, 3418–3438; P. Jin, S. J. Dalgarno and J. L. Atwood, Coord. Chem. Rev., 2010, 254, 1760–1768; M. D. Pluth, R. G. Bergman and K. N. Raymond, Acc. Chem. Res., 2009, 42, 1650–1659; J. K. Clegg, F. Li, K. A. Jolliffe, G. V. Meehan and L. F. Lindoy, Chem. Commun., 2011, 47, 6042–6044; C. R. K. Glasson, J. K. Clegg, J. C. McMurtrie, G. V. Meehan, L. F. Lindoy, C. A. Motti, B. Moubaraki, K. S. Murray and J. D. Cashion, Chem. Sci., 2011, 2, 540–543; T. K. Ronson, J. Fisher, L. P. Harding, P. J. Rizkallah, J. E. Warren and M. J. Hardie, Nat. Chem., 2009, 1, 212–216; M. Albrecht and R. Froehlich, Bull. Chem. Soc. Jpn., 2007, 80, 797–808; O. Chepelin, J. Ujma, P. E. Barran and P. J. Lusby, Angew. Chem., Int. Ed., 2012, 51, 4194–4197; B. Breiner, J. K. Clegg and J. R. Nitschke, Chem. Sci., 2011, 2, 51–56.
17. M. E. Belowich and J. F. Stoddart, Chem. Soc. Rev., 2012, 41, 2003–2024; S. J. Rowan, S. J. Cantrill, G. R. L. Cousins, J. K. M. Sanders and J. F. Stoddart, Angew. Chem., Int. Ed., 2002, 41, 899–952; B. Brisig, E. C. Constable and C. E. Housecroft, New J. Chem., 2007, 31, 1437–1447; B. Conerney, P. Jensen, P. E. Kruger and C. MacGloinn, Chem. Commun., 2003, 1274–1275; H. B. T. Jeazet, K. Gloe, T. Doert, O. N. Kataeva, A. Jager, G. Geipel, G. Bernhard, B. Buchner and K. Gloe, Chem. Commun., 2010, 46, 2373–2375; S. E. Howson, A. Bolhuis, V. Brabec, G. J. Clarkson, J. Malina, A. Rodger and P. Scott, Nat. Chem., 2012, 4, 31–36; S. Yi, V. Brega, B. Captain and A. E. Kaifer, Chem. Commun., 2012, 48, 10295–10297.
18. J.-F. Ayme, J. E. Beves, D. A. Leigh, R. T. McBurney, K. Rissanen and D. Schultz, Nat. Chem., 2012, 4, 15–20.
19. C. R. K. Glasson, G. V. Meehan, C. A. Motti, J. K. Clegg, P. Turner, P. Jensen and L. F. Lindoy, Dalton Trans., 2011, 40, 10481–10490.
20. R. W. Saalfrank, B. Demleitner, H. Glaser, H. Maid, D. Bathelt, F. Hampel, W. Bauer and M. Teichert, Chem.–Eur. J., 2002, 8, 2679–2683.
21. T. Beissel, R. E. Powers, T. N. Parac and K. N. Raymond, J. Am. Chem. Soc., 1999, 121, 4200–4206.
22. C. R. K. Glasson, G. V. Meehan, J. K. Clegg, L. F. Lindoy, P. Turner, M. B. Duriska and R. Willis, Chem. Commun., 2008, 1190–1192; R. Custelcean, P. V. Bonnesen, N. C. Duncan, X. Zhang, L. A. Watson, G. Van Berkel, W. B. Parson and B. P. Hay, J. Am. Chem. Soc., 2012, 134, 8525–8534; M. Scherer, D. L. Caulder, D. W. Johnson and K. N. Raymond, Angew. Chem., Int. Ed., 1999, 38, 1588–1592.
23. Y. Li, M. Pink, J. A. Karty and A. H. Flood, J. Am. Chem. Soc., 2008, 130, 17293–17295; S. Kubik, R. Kirchner, D. Nolting and J. Seidel, J. Am. Chem. Soc., 2002, 124, 12752–12760; Q.-Q. Wang, V. W. Day and K. Bowman-James, Angew. Chem., Int. Ed., 2012, 51, 2119–2123; J. L. Sessler, P. A. Gale and W.-S. Cho, Anion Receptor Chemistry, Royal Society of Chemistry, 2006.
24. T.-S. Huang and F.-J. Lu, Environ. Toxicol. Chem., 1991, 10, 179–184; J. Sakurada, S. Takahashi and T. Hosoya, J. Biol. Chem., 1987, 262, 4007–4010.
25. R. Custelcean, J. Bosano, P. V. Bonnesen, V. Kertesz and B. P. Hay, Angew. Chem., Int. Ed., 2009, 48, 4025–4029.
26. C. A. Hunter, Angew. Chem., Int. Ed., 2004, 43, 5310–5324.
27. C. He, L.-Y. Wang, Z.-M. Wang, Y. Liu, C.-S. Liao and C.-H. Yan, J. Chem. Soc., Dalton Trans., 2002, 134–135.
28. S. Mecozzi and J. Rebek, Jr, Chem.–Eur. J., 1998, 4, 1016–1022.
29. A. V. Davis, D. Fiedler, G. Seeber, A. Zahl, R. Van Eldik and K. N. Raymond, J. Am. Chem. Soc., 2006, 128, 1324–1333; A. V. Davis and K. N. Raymond, J. Am. Chem. Soc., 2005, 127, 7912–7919; S. Zarra, M. M. J. Smulders, Q. Lefebvre, J. K. Clegg and J. R. Nitschke, Angew. Chem., Int. Ed., 2012, 51, 6882–6885.
30. R. W. Saalfrank, H. Maid, A. Scheurer, R. Puchta and W. Bauer, Eur. J. Inorg. Chem., 2010, 2903–2906.

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Footnote

† Electronic supplementary information (ESI) available: Experimental details of the synthesis and characterisation of products, details of the X-ray structural determinations and titrations, derivations of the binding model, details of the kinetics studies, molecular modelling and volume calculations. See DOI: 10.1039/c2sc21486e

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