Redox-Responsive Host-Guest Chemistry of a Flexible Cage with Naphthalene Walls

: "Naphthocage", a naphthalene-based organic cage reveals very strong binding (up to 10 10 M -1 ) to aromatic (di)cationic guests, i.e. the tetrathiafulvalene mono-and dication and methyl viologen. Intercalation of the guests between two naphthalene walls is mediated by C-H···O, C-H···π and cation···π interactions. The guests can be switched into and out of the cage by redox processes with high binding selectivity. Oxidation of the flexible cage itself in the absence of a guest leads to a stable radical cation with the oxidized naphthalene intercalated between and stabilized by the other two. Encapsulated guest cations are released from the cavity upon cage oxidation, paving the way to future applications in redox-controlled guest release or novel stimuli-responsive materials.


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ABSTRACT: "Naphthocage", a naphthalene-based organic cage reveals very strong binding (up to 10 10 M -1 ) to aromatic (di)cationic guests, i.e. the tetrathiafulvalene mono-and dication and methyl viologen.Intercalation of the guests between two naphthalene walls is mediated by C-H•••O, C-H•••π and cation•••π interactions.The guests can be switched into and out of the cage by redox processes with high binding selectivity.Oxidation of the flexible cage itself in the absence of a guest leads to a stable radical cation with the oxidized naphthalene intercalated between and stabilized by the other two.Encapsulated guest cations are released from the cavity upon cage oxidation, paving the way to future applications in redox-controlled guest release or novel stimuli-responsive materials.
In nature, flexible dynamic systems like proteins, fold to achieve sophisticated biological function. 1For example, enzymes rely on adaptive conformational changes (induced fit) 2 to strongly and selectively bind substrates in their active pockets. 3Flat aromatic DNA intercalators insert between base pairs through a dynamic local deformation of the DNA double helix. 4Conversely, the design of synthetic receptors relied mainly on the development of preorganized rigid structures to improve binding strength and selectivity.However, this preorganization comes with the drawbacks of reduced flexibility and adaptability.As an example, Stoddart's rigid cyclobis(paraquat-p-phenylene) macrocycle 5 (CBPQT 4+ , the "blue box") is frequently used for the complexation with planar electron-rich molecules to construct mechanically interlocked molecules.Such rigid structures cannot easily undergo conformational changes to respond to environmental changes.Rigid redox-responsive host-guest complexes have been extensively studied 6 aiming at stimuliresponsive supramolecular materials, whose properties can be mediated by redox-induced changes in charge and electron distribution.Conformationally flexible hosts, in contrast, can respond to different shapes of guests as well as environmental stimuli.
Recently, we developed a series of naphthol-based 7 receptors including the so-called "naphthocage" 8 (NC, Figure 1).NC is highly flexible as expressed in the self-inclusion conformation of the free cage, in which one of the naphthalene walls is intercalated between the other two.Its flexibility is also expressed in the fast naphthalene ring flips that interconvert the self-inclusion conformers with two host conformers of D 3 (NC-I) and C 2 symmetry (NC-II). 8Despite this remarkable flexibility, NC exhibits strong binding affinities up to 10 9 M -1 to organic cations such as Me 4 N + , ferrocenium (Fc + ) or acetylcholine.An astonishingly high binding selectivity (~10 15 ) was observed for Fc + over ferrocene Fc.
Here, we investigate the binding of NC to aromatic dications (Figure 1b) of tetrathiafulvalene and methyl viologen -two of the most widely used redox-switchable building blocks in supramolecular chemistry. 9These dications, whose shapes do not exactly match that of the cage's cavity, intercalate between two naphthalene walls with unexpected binding strength.Not only the guests are redox-responsive resulting in switchable host-guest complexes, but also the host can be reversibly oxidized to control guest release.For the complex of NC with electron-poor MV 2+ , a single crystal structure was obtained (Figure 2).MV 2+ is intercalated into the cage cavity (Figure S1).Both enantiomers of the C 1 symmetric complex are incorporated in the crystal (Figures S2-S3).The dihedral angle along the bond connecting the two pyridinium rings is 33.8 o .The two naphthalene walls flanking the guest do not perfectly parallel the inner pyridinium ring of the guest.This results  Typical upfield shifts of ca. 2 ppm of guest signals 5 and 6 in the 1 H NMR spectrum of the complex (Figures 3 and S13) evidence binding of the dication inside the cavity.This is supported by cross peaks between host and guest signals in the 2D ROESY spectra (Figures S14 and S15).The broad signals for protons 1 and 2 of the free host sharpen upon complex formation.Two sets of signals are observed: two more intense doublets (red labels, Figure 3) can be assigned to the complex of conformer NC-I (67%), the six smaller doublets (blue labels) to the complex with NC-II (33%).Also, two sets of signals are observed for the guest protons 5 and 6 integrating in a 67 : 33 ratio.The observation of separate sets of signals for both complex conformers confirms guest exchange to be slow on the NMR time scale. 1 H, 1 H EXSY experiments (Figures S20-S24) with MV 2+ @NC reveal two sets of off-diagonal cross peaks that translate into exchange rates of k I = 0.66 s -1 (t 1/2 = 1.05 s) and k II = 1.19 s -1 (t 1/2 = 0.58 s) for MV 2+ @NC-I and MV 2+ @NC-II, respectively (Figures S25-S26). 10From the C 1 symmetry of the complex in the crystal, one would have expected a more complicated NMR spectrum.Consequently, we can conclude that the guest must be mobile within the cavity being able to shift back and forth quickly between the three cage portals.On time average, this dynamic process results in sets of signals as expected for the D 3 (NC-I) and C 2 (NC-II) symmetric conformers.At the same time, it rationalizes, why only one set of guest protons appears for the guest in each of the two complexes.This behavior is reminiscent of Huc's helical foldamer complexes, in which guest shuttling inside the helix is much faster than disand reassembly of the complex. 11duction of the guest in MV 2+ @NC to the corresponding radical cation MV •+ and neutral MV significantly differs from that of free MV 2+ . 12Addition of 1 equiv.NC cathodically shifts the first reduction potential (Figure S27), while the second one broadens (Figure S28) indicating the reduction to occur inside the cage.At higher scan rates (1-20 V•s -1 ), the cyclic voltammograms (CVs) reveal significant new signals, which correspond to the MV •+ /MV reduction inside NC (Figure S29).Digital simulations based on a six-membered square scheme provide thermodynamic and kinetic parameters (Figure S30, Table 1).The dissociation rate obtained for MV 2+ @NC is well comparable to the EXSY data.The simulations also reveal the radical cation MV •+ to be a reasonable guest for NC.Furthermore, neutral MV leaves the cage with quite a high dissociation rate.Reduction of MV 2+ to its neutral counterpart thus allows switching between the host-guest complex and the empty host and thus controls guest release.In contrast, TTF can be reversibly oxidized to a stable radical cation (TTF •+ ) and a dication (TTF 2+ ). 13 1 H NMR spectra show TTF not to be encapsulated inside NC (Figure S31).However, strong binding was observed for TTF •+ and TTF 2+ as demonstrated by CV (Figure 4).Both anodic peak potentials for TTF oxidations cathodically shift after addition of 1 equiv.NC.The most significant effect is observed for the TTF/TTF •+ cathodic peak potential, which shifts by -0.5 V (Figure S32) indicating complex dissociation after reducing TTF •+ to TTF.The second oxidation (TTF •+ /TTF 2+ ) occurs inside the cage (Figure S33).Digital simulations based on the square scheme in Figure 4c Page 2 of 5

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Journal of the American Chemical Society  4b, S34) and yields the kinetic and thermodynamic parameters as a set of selfconsistent values (Table 1) showing virtually no binding of TTF, strong binding of TTF •+ , and extremely strong binding of TTF 2+ (3.1 × 10 10 M -1 ).A comparison of TTF 2+ and MV 2+ shows that both guests can be switched in and out by redox-stimuli with quite high binding selectivity factors (10 10 to 10 12 ).
During these electrochemical studies, we found that the empty cage itself can also be oxidized.The cyclic voltammograms of free NC surprisingly show two signals (~1:2 ratio) for the stepwise oxidations of the three naphthalene rings (Figures 5a and  S39).The first oxidation yields radical cation NC •+ , which is stabilized by self-inclusion of the oxidized naphthalene between the other two walls.Two-electron oxidation further leads to NC 3(•+) and charge repulsion-driven unfolding of the selfinclusion conformation of the  1).(c) Six-membered square scheme used for digital simulations (G = guest).
cage.Cyclic voltammograms at different scan rates confirm a reversible first and at least a quasi-reversible second oxidation (Figure S40).The peak potential difference of 0.21 V corresponds to a radical-cation stabilization energy of 20 kJ•mol -1 for NC •+ .The energetically stabilized NC •+ state is further underpinned by spectroelectrochemistry (SEC).CW-EPR SEC (Figures 5b and  S41) reveals an isotropic signal at g = 2.003 upon oxidation of NC.In contrast, CV and CW-EPR experiments of the control Monomer revealed one-electron oxidation at E 1/2 = 0.73 V vs. Fc/Fc + followed by an irreversible chemical reaction along an EC i mechanism (Figure S42).Thus, the self-inclusion conformation significantly stabilizes the NC •+ state and surprisingly allows reversible generation of a stable naphthalene radical cation, as additionally indicated by UV/Vis-NIR spectroelectrochemistry (Figure S43).Upon addition of 1 equiv.Fc to free NC, the first oxidation wave vanishes as result of occupied cage.Only one broad three-electron oxidation wave is observed (Figure S44).The potential of Fc + @NC (E 1/2 = 0.80 V vs. Fc/Fc + ) is 70 mV higher than that of Monomer.This increase is a result of the encapsulated cationic guest.Starting from the crystal structure of the self-inclusion conformation of free NC, 8 S1).
The oxidation of NC releases encapsulated guests as demonstrated for MV 2+ , cobaltocenium (Cc + ) 8 , trimethylsulfonium (TMS + ), tetrmethylphosphonium (TMP + ), choline (Ch + ) and acetyl choline (Ach + ) that are among the strongest guests for NC known so far. 1 H NMR spectra (Figures S46-S53) indicate chemical oxidation of MV 2+ @NC, Cc + @NC, TMS + @NC, TMP + @NC, Ch + @NC or Ach + @NC by NOPF 6 to result in a (likely full) oxidation of NC and liberates the encapsulated MV 2+ , Cc + , TMS + , TMP + , Ch + and Ach + , respectively.However, the oxidation to NC 3(•+) is a quasireversible process and is potentially followed by a slow decomposition (Figure S40 and S42).Thus, a chemical reduction using reductants such as Zn or NaBH 4 , was not successful and the redox-controlled release process appears to be irreversible.In summary, we report the extremely strong complexation of the TTF 2+ and MV 2+ dications inside the "naphthocage" with affinities up to 3.1 × 10 10 M -1 .The strong binding occurs through intercalation with the aromatic guests located inside the cage cavity between two naphthalene walls.Additionally, both guests and the free cage are redox-active.The guests can be switched into (TTFTTF 2+ ) and out (MV 2+ MV) of the cage with high selectivity by oxidation and reduction, respectively.The cage can be reversibly oxidized to its radical cation, which is stabilized by self-inclusion of the oxidized naphthalene.The oxidation of the cage can be applied for controlled guest release from the cage cavity, which paves the way for novel applications in redoxcontrolled guest release or in stimuli-responsive materials.

Figure 1 .
Figure 1.Chemical structures of (a) naphthocage (NC) and (b) methyl viologen (MV 2+ , the counterions are PF 6 -), tetrathiafulvalene (TTF) and control compound Monomer.NC is chiral (only one enantiomer is shown here).Numbering on the structures corresponds to the assignments of the NMR signals in Figure 3.

Table 1 .a
Thermodynamic and kinetic parameters obtained by digital simulations of the cyclic voltgammograms.a,b CVs measured in 1,2-dichloroethane/acetonitrile (1:1) at 298 K with n-Bu 4 NPF 6 electrolyte (0.1 M). b for evaluation of the accuracy of the simulations see Figure S35.c from isothermal titration calorimetry.d Simulations did not provide reliable rate constants.
a spin density plot of NC •+ (Figures 5c and S45) obtained by DFT calculations (COSMO/B3LYP-D3(BJ)) illustrates the radical cation to be mainly delocalized on the naphthalene unit in the cavity.The comparison of calculated oxidation energy differences (NC/NC •+ and Monomer/Monomer •+ ) also indicates an energetically favorable NC/NC •+ oxidation (Table
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