Molecular capsule constructed by multiple hydrogen bonds: self-assembly of cavitand tetracarboxylic acid with 2-aminopyrimidine

Abstract

Two molecules of cavitand tetracarboxylic acid and four molecules of 2-aminopyrimidine assemble into a capsule via 16 hydrogen bonds, as shown by ¹H NMR titration and X-ray crystallographic analysis; in the solid state, two molecules of nitrobenzene are encapsulated in the capsule.

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Error correction through thermodynamic equilibration, minimization of synthetic effort by use of modular subunits and control of assembly processes through subunit design are characteristic of supramolecular approaches to self-assembly.^1,2 Carcerands, in which two calix[4]resorcinarene cavitands are held together by four covalent linkages, have been synthesized and well-characterized by Cram and others, and have attracted considerable attention from the viewpoint of stabilization of reactive intermediates and microvesicles for drug delivery by confinement of guest molecules inside the capsules away from bulk phases.³ Recently, the field of molecular capsules has advanced to a stage where self-assembly through noncovalent interactions such as hydrogen bonds and metal coordination has proved to be a reliable tool.^4,5 Based on hydrogen bonds, homodimers of functionalized cavitands in solution^6,7 and multicomponent assemblies of calix[4]resorcinarenes with solvent water or alcohol molecules as linkers in the solid state^8,9 have been reported. Metal-bridged assemblies of functionalized cavitands have also proved to be a viable alternative.¹⁰ We have chosen the cavitand tetracarboxylic acid 1 as a concave subunit¹¹ and 2-aminopyrimidine (2-AP) as a hydrogen-bonded linker subunit. Our strategy for capsule formation is based on the combination of carboxylic acids with 2-AP to form a 2∶1 hydrogen-bonded complex in the solid state.¹² Herein we report the construction of capsule 2 from six components via 16 hydrogen bonds: two molecules of 1 are indirectly held together in a rim-to-rim fashion by hydrogen bonding bridges involving four molecules of 2-AP (Scheme 1).

Scheme 1

The cavitand 1 alone has a low solubility in CHCl₃ at room temperature {<5 mM for 1a [R = (CH₂)₆CH₃] and <1 mM for 1b [R = (CH₂)₂Ph]}. On the other hand, in the presence of 2 equiv. of 2-AP, 1 becomes very soluble in CHCl₃ (>100 mM). The titration of a suspension of 1a in CDCl₃ at 25 °C with aliquots of 2-AP was monitored by ¹H NMR spectroscopy. Fig. 1 shows the chemical shift changes for the NH₂ protons of 2-AP and the inward and outward methylene protons at the rim of 1a as a function of 2-AP/1a.† Below the 2∶1 ratio of 2-AP/1a, the NH₂ protons of 2-AP apparently give a saturated downfield shift (Δδ_obs = 2.95 ppm), independent of 2-AP/1a, while the methylene protons of 1a are increasingly shifted downfield upon addition of 2-AP. At the 2∶1 stoichiometry of 2-AP/1a, the mixture becomes completely homogeneous.† Beyond the 2∶1 ratio, the former chemical shift changes decrease due to the average of signals between the free and complex 2-AP, whereas the latter ones remain unchanged. The fact that both titration curves have an inflection point at the 2∶1 stoichiometry of 2-AP/1a indicates that an n∶2n complex of 1a with 2-AP is formed via hydrogen bonds and that this formation may be a cooperative process. The cavitand 1a and 2-AP possess four and two hydrogen bonding sites, respectively. In principle, 1∶2 and/or 1∶4 complexes of 1a with 2-AP may be conceivable. In such complexes, however, half of the hydrogen bonding sites still remain intact. The titration data obtained here suggests the formation of a capsule 2a in solution from two molecules of 1a and four molecules of 2-AP (Scheme 1).‡ The capsule 2a in CDCl₃ was disrupted upon addition of DMSO-d₆ as a cosolvent.

Fig. 1 Chemical shift changes for (a) the NH₂ protons of 2-AP and (b) the inward and (c) outward methylene protons at the rim of 1a as a function of 2-AP/1a in CDCl₃ at 25 °C.

The stability of 2a was evaluated by the dilution method in CDCl₃ at 25 °C using ¹H NMR, where the ratio of 2-AP/1a is maintained at 2∶1. The chemical shift changes for the NH₂ protons of 2-AP decreased at less than 10 mM of 2-AP. The association constant for the formation of 2a calculated from a nonlinear curve fitting was estimated to be K_a = 3.7 × 10¹⁹ M⁻⁵ in CDCl₃ at 25 °C with Δδ_sat = 2.96 ppm and a correlation coefficient r = 0.99.§ This corresponds to an average ΔG° = −1.6 kcal mol⁻¹ per hydrogen bond.¹³

Recrystallization of a mixture of 1 and 2-AP from various solvents such as p-xylene, anisole–CHCl₃ and nitrobenzene–CHCl₃ gave co-crystals composed of 1∶2-AP = 1∶2 without exception. The IR spectra showed a shift (10 cm⁻¹) to lower wavenumbers of the ν_{C[double bond, length half m-dash]O} for 1 upon adduct formation. The O–H stretching bands appeared at 2500 and 1900 cm⁻¹, which are characteristic of a carboxylic acid hydrogen bonded to an aromatic ring nitrogen.¹² When pyridine was used in place of 2-AP, co-crystals of 1∶pyridine = 1∶4 were obtained. These results support the formation of 2 from 1 and 2-AP in the solid state.

Single crystals suitable for X-ray diffraction analysis were grown by allowing a hot solution of 1b and2-AP in nitrobenzene to slowly cool to room temperature.¶ As shown in Fig. 2, the molecular structure after symmetry operations unambiguously reveals the capsule 2b in which two molecules of the hemispherical cavitand 1b associate indirectly in a rim-to-rim fashion by hydrogen bonding bridges involving four molecules of 2-AP located on an equatorial position. The NH₂ protons and aromatic ring nitrogens of 2-AP form hydrogen bonds with the acid carbonyl oxygens and OH protons of 1b, respectively. The hydrogen bonding distances of N(H)⋯O are 2.866(7), 2.841(7), 2.897(7) and 2.872(7) Å, and those of N⋯(H)O are 2.770(7), 2.604(7), 2.711(6) and 2.718(6) Å. Thus, the capsule 2b is constructed via 16 hydrogen bonds between two molecules of 1b and four molecules of 2-AP. The dihedral angles between the carboxylic acid groups and the resorcinol rings of 1b are almost perpendicular (83.5, 85.7, 105.9 and 80.2°), probably due to the electronic repulsion between the oxygen atoms of their moieties. This orientation plays an important role in the formation of the capsule. The capsule 2b features dimensions of ca. 9 × 15 Å. Two molecules of nitrobenzene are encapsulated in the cavity of 2b in an antiparallel fashion with an inter-ring distance of ca. 3.3 Å. They are oriented with the nitro groups towards the equatorial windows of 2b.

Fig. 2 Molecular structure of capsule 2b (a) without and (b) with encapsulated nitrobenzenes. Nitrobenzenes which are not located inside the cavity and hydrogen atoms except for NH₂ protons of 2-AP and acid protons of 1b are omitted for clarity. Dashed lines represent intermolecular hydrogen bonds.

In summary, we have demonstrated the capsule 2, composed of two molecules of the cavitand tetracarboxylic acid 1 and four molecules of 2-aminopyrimidine, as a hydrogen-bonded linker. Exploration of linkers such as bipyridine derivatives and transition metals in order to control the cavity size of the capsules is currently underway in our laboratory.

References

1. J.-M. Lehn, Supramolecular Chemistry: Concepts and Perspectives, VCH, Weinheim, 1995..
2. G. M. Whitesides, E. E. Simanek, J. P. Mathias, C. T. Seto, D. N. Chin, M. Mammen and D. M. Gordon, Acc. Chem. Res., 1995, 28, 37; D. S. Lawrence, T. Jiang and M. Levett, Chem. Rev., 1995, 95, 2229.
3. D. J. Cram and J. M. Cram, Container Molecules and Their Guests, Royal Society of Chemistry, Cambridge, 1994;; A. Jasat and J. C. Sherman, Chem. Rev., 1999, 99, 931.
4. For molecular capsules via hydrogen bonds, see: M. M. Conn and J. Rebek Jr.,Chem. Rev., 1997, 97, 1647;; J. de Mendoza, Chem. Eur. J., 1998, 4, 1373; J. Rebek Jr., Acc. Chem. Res., 1999, 32, 278.
5. For molecular capsules via metal coordination, see: M. Fujita, D. Oguro, M. Miyazawa, H. Oka, K. Yamaguchi and K. Ogura, Nature, 1995, 378, 469;; B. Olenyuk, A. Fechtenkötter and P. J. Stang, J. Chem. Soc., Dalton Trans., 1998, 1707.
6. R. G. Chapman and J. C. Sherman, J. Am. Chem. Soc., 1995, 117, 9081; R. G. Chapman, G. Olovsson, J. Trotter and J. C. Sherman, J. Am. Chem. Soc., 1998, 120, 6252.
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Footnotes

† The concentration of 1a is 20 mM if completely soluble in CDCl₃. The equilibrium is reached immediately. At the 2∶1 stoichiometry of 2-AP/1a, the signal of the acid protons of 1a was observed at δ 16.00 at −30 °C. Irradiation of the C(4,6) hydrogens of 2-AP showed a 3% NOE at the acid protons of 1a at −30 °C.

‡ No evidence for the encapsulation of guests into 2a in CDCl₃ is available, probably due to favorable accommodation of CDCl₃ as a bulk phase in 2a.

§ A constant ratio [2-AP]∶[1a] = 2∶1, and the assumption that free 1a, free 2-AP and capsule 2a are the only components present, give eqn. (1),

[2-AP] = {(Δδ_obs/Δδ_sat)/[K _a(1 – (Δδ_obs/Δδ_sat))⁶] }^0.2(1) (1)

where Δδ_obs = δ_obs – δ_free and Δδ_sat = δ_sat – δ_free are the observed and saturated chemical shift changes of the NH₂ protons of 2-AP, respectively.

¶ Crystal data for 1b·2(2-AP)·6(PhNO₂): C₁₁₂H₉₆N₁₂O₂₈, M = 2058.05, crystal size 0.52 × 0.45 × 0.40 mm, triclinic, space group P1̄, a = 17.79(2), b = 19.78(1), c = 15.047(5) Å, α = 107.32(4), β = 96.18(3), γ = 79.05(5)°, U = 4955(6) ų, Z = 2, D_c = 1.379 g cm⁻³, μ(Mo-Kα) = 1.00 cm⁻¹, 2θ_max = 50.2°. Intensity data (11593) were measured on a Rigaku RAXIS-II diffractometer at 120 K. The final least-squares refinement based on F for 8815 unique reflections [with I > 3.0ς(I)] and 1396 parameters converged with R = 0.110 and R_w = 0.124. CCDC 182/1489. See http://www.rsc.org/suppdata/cc/a9/a908315d/ for crystallographic data in .cif format.

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