Template-directed self-assembly of dynamic covalent capsules with polar interiors

A covalent molecular capsule based on reversible imine bonds and polar interior is prepared by the template-directed self-assembly of a tetraaldehyde calix[4]pyrrole scaffold with a diamine linker.


General Methods and Instrumentation
Starting materials and reagents were purchased from Sigma Aldrich and used as received.
All reactions were performed under argon atmosphere unless specified. Anhydrous solvents were obtained from a solvent purification system SPS-400-6 from Innovative Technologies, Inc. All solvents were of HPLC grade quality, commercially obtained and used without Experimental procedure for imine capsule formation: In a NMR tube, 2 mg of calixpyrrole 3 are dissolved in 600 μL of CDCl3. 1,2-bis(4pyridyl)acetylene N,N'-dioxide (0.5 equivalents, 0.24 mg) are added. Once capsule formation is complete as judged by NMR analysis, diamine (ethylenediamine or (1R,2R)-(−)-1,2diaminocyclohexane; 2 equivalents) is added. The NMR tube is agitated for a couple of minutes and then polyimine capsule is quantitatively formed. No further purification is required.    Figure S1 for proton assignment. Bound protons marked with primed letters and numbers.
We rationalized that the absence of a suitable template was responsible for the formation of insoluble polymeric aggregates. Aryl extended calix [4]pyrroles are known to bind amine Noxides forming kinetically and thermodynamically highly stable 1:1 inclusion complexes. In these complexes, four convergent hydrogen bonds are established between the oxygen atom of the N-oxide group and the calixpyrrole. This process could be used to preorganize the core of 3 into the cone conformation, in which the four formyl groups are arranged in the orientation needed for the covalent assembly of the dimeric capsule. In fact, the addition of 1 equiv of trimethylamine N-oxide 8 to a CDCl3 solution of tetraaldehyde 3 produced the diagnostic proton signals (Fig. S3) expected for the formation of the 1:1 inclusion complex, 83. The pyrrole NHs of bound 3 (H d , δ = 10.23 ppm; Δδ = -2.61 ppm) experienced a significant downfield shift. The singlet of the methyl protons for the included trimethyl Noxide guest appeared upfield shifted (δ = 0.90 ppm; Δδ = 2.36 ppm) as a result of the strong shielding effect exerted by the four meso-aryl substituents of the host. Contrary to our expectations, the addition of two equiv of 1,2-ethylenediamine 4 to the CDCl3 solution of the 83 complex also produced a white precipitate. The analysis of the solution using 1 H NMR spectroscopy produced complex proton signals that suggested the formation of multiple aggregated species (Fig. S4).    Figure S1 for proton assignment. Protons for the 1:1 inclusion complex marked with primed letters and numbers.
At 298 K the 1 H NMR spectrum of a mixture of calix[4]pyrrole 3 and 0.5 equiv of bis-Noxide 9 shows relatively sharp proton signals (Fig S6 and Figure S5b). We assigned the observed signals to the protons of calix[4]pyrrole 3 involved in a chemical exchange process between free and bound receptor (1:1 complex). Owing to the similarity in chemical shift values for the protons of 3 in the free and bound state, the exchange kinetics does not produce significant broadening to the signals. On the contrary, the signals of the protons for the guest bis-N-oxide 9 are broadened beyond detection. This is due to the significant changes in chemical shift values experienced by the protons in the bound guest. Specifically, the aromatic protons for the pyridyl residue of 9 included in the aromatic cavity of 3 in the 1:1 complex were upfield shifted by 3.8 ppm (ortho to the N atom) and 0.6 ppm (meta to the Natom). For the 1:1 complex, the aromatic protons of the pyridyl residue located in the cavity defined by the triple bonds suffered reduced changes in their chemical shifts compared to free 9. The broadening of the aromatic signals of 9 was mainly caused by a dynamic equilibria S10 involving the chemical exchange between the two bound pyridyl residues. We considered that although the amount of free 9 in solution was small, the chemical exchange between the two pyridyl units of bound 9 probably occurred though a decomplexation/complexation process. Figures S6 (@213 K) and S5d show the proton assignments for the 1:1 complex. The proton assignment is based on integral values, expected chemical shift values and symmetry of the complex. Figure S7. 1 H NMR titration of a CDCl3 solution of calix[4]pyrrole 3 with 1,2-bis(4pyridyl)acetylene N,N'-dioxide a) 0 eq. b) 0.25 eq. c) 0.5 eq. d) 1 eq. e) 1.5 eq. *Residual solvents. See Figure S1 for proton assignment. Protons for the 2:1 capsule marked with primed letters and numbers.    Figure S1 and Figure S7 for proton assignment. Bound protons marked with primed letters and numbers. Figure S11. ROESY NMR spectrum of a CDCl3 solution of calixpyrrole 3, 1,2-bis(4pyridyl)acetylene N,N'-dioxide and ethylenediamine in a 1:0.5:2 molar ratio. See Figure S1 and Figure S7 for proton assignment. Bound protons marked with primed letters and numbers.
We performed VT-NMR experiments using 1 mM CDCl3 solutions of 61 and 62 (Figs. S12 and S16, respectively). For the 61 complex, at 213 K, we observed four separate doublets for the aromatic protons, H b ' and H c ', of the meso-aryl substituents. The H c ' protons broadened beyond detection at room temperature. Moreover, at 213 K, the β-pyrrolic, H a 'and the methylene protons of the ethylene linker, H en , resonated as diastereotopic signals. At room temperature the rotation around the Cmeso-aryl bond and the conformational motion of the ethylene spacer are fast on the NMR time scale producing the broadening and coalescence of the corresponding proton signals. Figure S12. Variable temperature 1 H NMR spectra of a CDCl3 solution of calixpyrrole 3, 1,2-bis(4-pyridyl)acetylene N,N'-dioxide and ethylenediamine in a 1:0.5:2 molar ratio. See Figure S1 and Figure S7 for proton assignment. Bound protons marked with primed letters and numbers. S16 Figure S13. 1 H NMR spectrum of a CDCl3 solution of calixpyrrole 3, 1,2-bis(4pyridyl)acetylene N,N'-dioxide and (1R,2R)-(−)-1,2-diaminocyclohexane in a 1:0.5:2 molar ratio. *Residual solvent. See Figure S1 for proton assignment. Bound protons marked with primed letters and numbers. Figure S14. COSY NMR spectrum of a CDCl3 solution of calixpyrrole 3, 1,2-bis(4pyridyl)acetylene N,N'-dioxide and (1R,2R)-(−)-1,2-diaminocyclohexane in a 1:0.5:2 molar ratio. See Figure S1, Figure S7 and Figure S13 for proton assignment. Bound protons marked with primed letters and numbers.  Figure S1, Figure S7 and Figure S13 for proton assignment. Bound protons marked with primed letters and numbers.  Figure S1, Figure S7 and Figure S13 for proton assignment. Bound protons marked with primed letters and numbers. Figure S17. Selected region of a ROESY NMR spectrum of a CDCl3 solution of calixpyrrole 3, 1,2-bis(4-pyridyl)acetylene N,N'-dioxide and (1R,2R)-(−)-1,2-diaminocyclohexane in a 1:0.5:2 molar ratio performed at 253 K. See Figure S1 and Figure S7 for proton assignment. Bound protons marked with primed letters and numbers.  Figure S1 and Figure S13 for proton assignment. Bound protons marked with primed letters and numbers.   Figure S1 for proton assignment.