Xylylene Clips for the Topology-Guided Control of the Inclusion and

Article Cite This: J. Org. Chem. 2018, 83, 5588−5597

pubs.acs.org/joc

Xylylene Clips for the Topology-Guided Control of the Inclusion and Self-Assembling Properties of Cyclodextrins Tania Neva,†,⊥ Thais Carmona,‡,⊥ Juan M. Benito,† Cédric Przybylski,§ Carmen Ortiz Mellet,*,∥ Francisco Mendicuti,*,‡ and José M. García Fernández*,† †

Instituto de Investigaciones Químicas (IIQ), CSIC−University of Sevilla, Avda. Americo Vespucio 49, 41092 Sevilla, Spain Department of Analytical Chemistry, Physical Chemistry and Chemical Engineering, Faculty of Chemistry, Edificio de Farmacia, Campus Universitario Ctra. Madrid-Barcelona, Km 33.600, 28871 Alcalá de Henares, Madrid, Spain § Institut Parisien de Chimie Moléculaire (IPCM), CNRS UMR 8232, Sorbonne Université, 4 place Jussieu, 75252 Paris Cedex 05, France ∥ Department of Organic Chemistry, Faculty of Chemistry, University of Sevilla, C/Profesor García González 1, 41012 Sevilla, Spain ‡

S Supporting Information *

ABSTRACT: The topology of β-cyclodextrin can be molded, from toroidal to ovoid basket-shaped, by the installation of an o- or m-xylylene moiety connecting two consecutive Dglucopyranosyl units through the secondary O-2(I) and O3(II) positions. This strategy can be exploited advantageously to precast the cavity for preferential inclusion of globular or planar guests as well as to privilege dimeric or monomeric species in water solution.

■

INTRODUCTION Since the pioneer work by Lehn,1,2 judicious combination of shaping and recognition elements in (poly)macrocyclic architectures has been profusely exploited to access molecular devices with tailored receptor properties and controlled abilities to form intricate supramolecular assemblies, including systems with adaptive, self-healing, bioactive or shape-memory capabilities.3−9 Aromatic building blocks are particularly attractive for these channels. They can play the role of rigid walls to build permanent cavities and/or act as functional components promoting noncovalent self-interactions as well as associations with third species, allowing several levels of organization to be implemented.10−14 In the case of pre-existing macrocyclic platforms, such as cyclodextrins (CDs), aromatic appendages have been employed as gatekeeper, capping, self-inclusion or cavity-extension modules.15−19 In most reported examples, however, the aromatic component is attached to the cyclooligosaccharide core through a single position and retains substantial mobility, which limits accurate three-dimensional definition. Doubly linked derivatives with restricted conformational freedom are, in principle, better suited for precise control of receptor topology.20 The methylated β-cyclodextrin (βCD) derivative 1, bearing an o-xylylene component attached to the secondary O-2(I) and O-3(I) positions at one out of the seven glucopyranoside residues through a hinge-type joint, is an iconic example that illustrates this notion.21 The aromatic ring © 2018 American Chemical Society

was found to adopt a semiopen conformation that modulates the inclusion properties and promotes the formation of headto-head (HH) dimers (Figure 1),22,23 which has been exploited

Figure 1. Structure of the O-2I,O-3I-(o-xylylene)-permethylated-βCD derivative 1 and schematic representation of the corresponding headto-head (HH) dimer.

in the design of stimuli-responsive gene delivery systems.24 Particularly appealing is the possibility of installing aromatic “clips” triggering conformational changes important enough to affect the symmetry of the CD platform and achieve a permanent cavity shape reorganization, a yet unattained goal in the field. Whereas the first members of the CD family are generally considered highly rigid nanosized molecular objects (molecular nanoparticles),25,26 featuring a well-defined inner space and Received: March 6, 2018 Published: April 23, 2018 5588

DOI: 10.1021/acs.joc.8b00602 J. Org. Chem. 2018, 83, 5588−5597

Article

The Journal of Organic Chemistry

arrangement (3.39 Å), is not much different from that encountered between two vicinal trans-diequatorial O-substituents in pyranoid rings (2.84 Å; Figure 2A). An o-xylylene segment was therefore expected to interconnect the nonvicinal diol positions in 3 (Scheme 1) similarly as in 1, without

overall topology, a survey of the literature reveals that they bear non-negligible flexibility. Thus, the glucopyranosyl subunits can undergo 360° “tumbling” or dynamic tilting about the glycosidic linkages under a suitable driving force, e.g., selfinclusion of a voluminous substituent27 or the presence of strong hydrogen bond-donating groups located at the primary rim,28 eventually inducing an oval-type shape. Inversion of the ring chair conformation, from 4C1 to 1C4, in a single glucopyranosyl subunit has also been observed in per-Omethylated β-cyclodextrin (2) in the solid state.29,30 Interestingly, such one-ring conformational flip results in a drastic alteration of the overall CD shape, from conical to ellipsoidal torus, and a significant reduction of the accessible cavity volume as compared with a noninverted structure (Figure 2).31 The

Scheme 1. Synthesis of the O-2I,O-3II-(o- and m-Xylylene)permethylated-βCD Derivatives 4 and 5, Respectively

Figure 2. 3D views of the two limit structures of per-O-methyl-βcyclodextrin (2) as determined by X-ray, namely the torus-shaped structure with all D-glucopyranosyl units in the 4C1 conformation (A; Cambridge Crystallographic Data Centre supplementary publication no. CCDC-239740) and the oblate oval structure with one of the seven D-glucopyranosyl units in the opposite 1C4 conformation (B; CCDC-101208). The O-2(I)−O-3(I) and O-2(I)−O-3(II) distances (A) and the O-2(I; 4C1 unit)−O-3(II; 1C4 unit) distance (B) are indicated.

imparting significant strain in the macroring. On the contrary, the m-xylylene moiety imposed a greater O-2(I)−O-3(II) separation (5.51 Å; Figure 2B) that could only be achieved by twisting the conformation of one of the glucopyranosyl units, resulting in an ellipsoidal topology. Indeed, reactions of 3 with α,α′-dibromo-o- or m-xylene proceeded smoothly and selectively to afford the target products 4 (77%) and 5 (73%), respectively (Scheme 1). We were delighted to observe remarkable differences in the 1 H NMR spectra of the corresponding xylylene-armed derivatives 4 and 5 (Figure 3 and SI). The relatively narrow resonance dispersion in the 1H NMR spectrum of CD 4 (Figure 3, bottom) quite contrasts the large anisotropy induced by the m-xylylene bridge in derivative 5 (Figure 3, top). 2D NMR experiments confirmed the all-axial arrangement of the H-2, H-3, H-4 and H-5 sugar ring protons in 4, typical from glucopyranosyl units in the 4C1 chair conformation (Figures S16−S18), with proton−proton vicinal coupling constants (3JH,H) about the pyranoid rings in the 9−10 Hz range. Spatial correlation (2D ROESY, Figure S17) experiments did not show any cross-peak between aromatic and glucose protons, pointing to a relatively open conformation of the xylylene appendage. In the case of CD 5, the NMR experiments were indicative of a significant distortion at the (O-3)-xylylenated glucopyranosyl unit II. Homonuclear correlation (COSY and TOCSY) experiments (Figure 4 and Figures S21 and S22) showed the absence of scalar coupling between the H-3II and H-4II protons, suggestive of a dihedral angle (ØH‑3−C‑3−C‑4−H‑4) close to 90°. As a consequence, this sugar residue shows two independent spin systems for H-1II−H-2II−H-3II and H-4II−H-5II−H-6II protons, respectively (Figure 4 and Figure S21), the latter exhibiting broader signals. The data are compatible with the existence of a certain degree of conformational flexibility at this area, probably resulting from relatively slow chemical exchange between the inverted 1C4 chair arrangement and pseudoenvelop

driving force underpinning this topological rearrangement is the ejection of water molecules from the CD cavity during the crystallization process. Inspection of the two limit structures reveals that the interspace distances between the secondary hydroxyl groups surrounding the inverted monosaccharide in the oval conformer are notably different as compared to that existing between equivalent protons in the C7-symmetrical undeformed structure (Figure 2). We conceived that aromatic segments imposing distance restraints in that region could then act as cavity shape regulators, allowing discrimination between the circular and ellipsoidal arrangements. As a proof of concept, here we report that xylylene clips connecting the O-2(I) and O3(II) positions in consecutive glucopyranosyl subunits of βCD are able to promote distortion of the macrocyclic framework and produce dissymmetrical cavities in a tunable fashion, dramatically impacting the inclusion and self-assembling aptitudes.

■

RESULTS AND DISCUSSION We took advantage of the methodology developed by Sollogoub and co-workers for position-selective hydrolysis of ether groups in fully protected CDs, using DIBAL·H, to optimize the synthesis of the key diol precursor 3.32,33 Surprisingly, whereas the potential of DIBAL·H to access a variety of primary face-functionalized CD derivatives with surgical precision has been the object of intense efforts,34−41 the opportunities of the procedure for multipoint decoration of the secondary rim remain much less explored.42−47 A preliminary analysis suggested that the distance spanning the O-2(I) and O-3(II) atoms in the all-4C1 ground state circular 5589


Article


Figure 3. Selected regions of the 1H NMR (600 MHz, D2O, 298 K) spectra of CD derivatives 4 (bottom) and 5 (top) illustrating the conformational disparities imposed by the o- and m-xylylene clips, respectively.

Figure 4. 2D TOCSY NMR (600 MHz, D2O, 298 K) spectrum of CD 5. TOCSY cross peaks of the 4C1 glucopyranosyl units are highlighted in the blue box. The spin system of the distorted glucopyranosyl unit (II) is broken between H-3II and H-4II. The two sets of cross peaks (H-1II−H-2II−H3II and H-4II−H-5II−H-6a,bII) are highlighted in the red box.

The circular dichroism spectra of 4 and 5, recorded at 25 °C in water solution, further evidenced notable dissimilarities in their molecular topologies. Both compounds presented an intense band at ≈220 nm and a much weaker band at ≈260− 265 nm, but whereas the second one remained positive on going from the o-xylylene-armed derivative (4) to the mxylylene clipped isomer (5), the first band shifted from positive to negative. The sign and intensity of the induced circular dichroism (ICD) bands depend on the orientation of the electronic transition moments of the aromatic chromophore relative to the macroring pseudo-7-fold rotational axis. The relevant electronic transition moment directions for the xylylene moiety, A1 and B2, and their assignment are indicated in Figure 5 (see the SI, Figure S1, for the corresponding UV− visible absorption spectra).49 By applying the ICD rules,50−52 the circular dichroism spectrum of 4 agrees with the location of the o-xylylene appendage outside the CD cavity with the B2 transition moment perpendicularly orientated relative to the main axis of the macroring and the A1 direction slightly away from the perpendicularity, in a semiopen type conformation. In the case of 5, the ICD data support instead a fully open

conformations in which the region around the C-4II vertex is flattened to release steric constrain. Increasing the temperature reduced the line width of the H-3II and H-4II resonances, in agreement with a faster conformational equilibration. In any case, the data support the hypothesis that the 4C1 conformation is no longer accessible for this glucose unit. The remarkable large upfield shifts of the H-1I and 4II resonances and the downfield shift of the H-3II resonance in 5 (δH‑1(I) 3.84, δH‑4(II) 1.65, δH‑3(II) 4.27 ppm; Figures S20 and S21) as compared with 4 (δH‑1(I) 5.3, δH‑4(II) 3.71−3.65, δH‑3(II) 3.68−3.56 ppm; Figures S15 and S16) are also compatible with the presumed conformational switch. This is accompanied by a decreased H-2II/H-3II coupling constant in 5 (J2,3 4.0 Hz) and is reminiscent of the scenario encountered for the 1C4 unit of permethylated 3I,6I-anhydro-β-cyclodextrin.48 Additionally, the 2D ROESY spectrum of 5 (Figure S22) revealed very intense cross-peaks of the apical aromatic proton with H-3II and with one of the protons of the benzylic methylene group attached at position O-2I, suggesting that the xylylene clip adopts a tight conformation closely orienting H-3II to the aromatic ring. 5590


Article


methyl substituent (black arrow in Figure 5) partially blocks the cavity entrance. It was then expected to act as a guest selector element operating in conjunction with the shape restriction imposed by the oblate ovaloid contour. To test this notion, sodium adamantane-1-carboxylate (AC) and methyl 2-naphthoate (MN) were chosen as globular and planar guest probes, respectively. AC forms a tight complex with per-O-methyl-βCD 2 in water (association constant Ka = 606 ± 43 M−1 determined by isothermal titration calorimetry;59 1262 ± 130 M−1 as determined in this work by 1H NMR titration) and was found to form an even stronger 1:1 complex with receptor 4 (Ka = 5489 ± 1353 M−1), as determined from 1H NMR titration experiments (Figure 6A).60,61 MM and MD computational

Figure 6. (A) 1H NMR titration plots for the complexation of 4 and AC determined for several representative proton signals, with indication of the resulting association constant for the corresponding 1:1 complex (Ka(1:1)). (B) 3D view of the optimized (MM/MD) structure of the 4:AC inclusion complex (oxygen in red, carbon in tan; H atoms have been removed and the aromatic ring is highlighted in green in the host, whereas the AC guest is colored in light blue). Penetration of the AC guest into the cavity through the secondary rim was found to proceed with lower energy barriers as compared to penetration through the primary rim (see the SI, Figure S8). Figure 5. Upper panel: (A) circular dichroism spectra of 4 in water solution (concentrations below 235 nm: 0.1, 0.2, 0.4, 0.6, and 0.8 mM; concentrations above 235 nm: 1.0, 3.0, 4.8, and 8.0 mM); (B) ICD spectra of 5 in water solution (concentration below 235 nm: 0.08, 0.2, 0.4, 0.6, 0.8, and 1.08 mM; concentration above 235 nm: 0.5, 1.02, 2.0, 5.9, 8.0, and 9.96 mM). The electronic transition moment directions in the xylylene chromophore are represented. Medium and lower panels: 3D-views of the optimized (MM) structures of 4 and 5 (oxygen in red, carbon in tan); H atoms have been removed and the aromatic ring is highlighted in green for the sake of clarity. The black arrow in the structure of 5 points to the O-3(II)-methyl group at the glucopyranosyl unit in the 1C4 conformation, oriented toward the entrance of the oblate ovoid cavity.

calculations supported inclusion of the adamantane motif in the cavity (Figure 6B), which is in agreement with the experimentally observed intermolecular NOE contacts involving H-5 and H-3 protons in the host (see the SI, Figure S28). In sharp contrast, AC was totally excluded from the cavity of the distorted isomer 5: no complex formation could be detected by 1H NMR or circular dichroism. Differently from AC, planar aromatic guests such as MN can complement not only toroidal but also elliptic topologies.62 The corresponding binding isotherms for complex formation of MN with 4 and 5 in water, obtained by plotting the ratio (R) between the intensities (I1 and I2) of the two characteristic bands in the fluorescence emission spectrum of MN (λ1 at 385−386 nm and λ2 at 365−366 nm; see the SI) against the concentration of the host, fitted to a 1:1 complex stoichiometry in both cases, with rather similar Ki values (Figure 7A). Van’t Hoff plots evidenced significantly different thermodynamic signatures, however, with a less favorable enthalpy term but a favorable entropic contribution for the latter inclusion process (Figure 7B). In principle, rotational motion of the planar naphthalene guest was expected to be seriously hampered on moving from the circular hollow in 4 to the narrower elliptical cavity of 5, which would lead to the opposite trend in the entropic term.63 The data suggest that the presence of the fully open aromatic element in 5 enables an alternative complexation mode tolerating more degrees of freedom, probably by extending the cavity. Further experimental observations were in agreement with this hypothesis. Thus, the R value extrapolated at infinite concentration of the guest (R∞),

conformation with A1 and B2 quasi-parallel and quasiperpendicular, respectively, to the CD main axis. Computational studies (MM and MD; see the SI for experimental details) were in full agreement with the experimental ICD results. Indeed, the rigidity of the glycosidic bonds between the glucopyranose units connected by the xylylene clip prevents capped conformations to be accessed for both 4 and 5. The optimized structures are depicted in Figure 5. The above results confirm that whereas the o-xylylene bridge in 4 preserves the typical toroidal shape of βCD, the m-xylylene clip in 5 traps the elusive ovoid topology, a feature only observed previously in solution for βCD derivatives modified with anhydro bridges.53−58 The semiopen conformation of 4 is, in principle, compatible with the inclusion of a variety of hydrophobic guests, with the only limitation imposed by the βCD cavity size. In the case of 5, in spite of the fully open disposition of the aromatic ring, the inside-oriented O-2(II) 5591


Article


The xylylene equipped βCD derivatives 4 and 5 exhibited negative solubility coefficients in water: when heated, clear (25 °C) 5 mM (for 4) and 20 mM (for 5) solutions became turbid at 30 and 50 °C, respectively, and returned to their original state upon cooling. A negative water solubility coefficient is a characteristic feature of monomeric methylated CD derivatives such as 2, being ascribed to disruption of the solute-water interactions and the prevalence of solute−solute interactions that become increasingly more attractive when the temperature is augmented, a hydrophobic effect.65,66 This phenomenon is significantly more pronounced for methylated CD derivatives with aromatic appendages eliciting self-assembling into dimeric species,67 e.g., compound 1.22,23 In such a case, the hydrophobic aromatic moiety is sandwiched in the dimer (Figure 1), facilitating solvation and preventing unspecific aggregation at low temperatures, whereas heating results in dimer disruption, exposure of the aromatic ring and precipitation. The higher susceptibility of 4 as compared with 5 to precipitate from water solutions upon heating might thus be interpreted in terms of differences in their propensity to self-assemble into supramolecular dimers. In agreement with this hypothesis, ICD spectra of 4 recorded in water at increasing temperatures (Figure 8A) evidenced a monotonous decline in the ellipticity value measured at the most intense transition band (220 nm; Figure 8B), compatible with a temperature-dependent monomer/dimer equilibrium, whereas ellipticity values remained constants with temperature in the case of 5 (see also the SI,

Figure 7. Plots of the ratio (R) between the intensities (I1 and I2) of the two characteristic bands in the fluorescence emission spectrum of MN (λ1 at 385−386 nm and λ2 at 365−366 nm) against the concentration of the host (4 or 5) at different temperatures in water, with indication of the derived association constant (Ka) values (A), linear Van’t Hoff representations with indication of the resulting enthalpic and entropic contributions to the complexation process (B) and 3D-views of the two limit optimized structures (MM/MD) of the 5:MN complex, probably in slow chemical exchange in water solution (C; oxygen in red, carbon in tan; H atoms have been removed and the aromatic ring is highlighted in green in the host, whereas the MN guest is colored in orange). Penetration of the MN guest into the cavity through the secondary rim was found to proceed with lower energy barriers as compared to penetration through the primary rim in both cases (see Figure S9).

known to be independent of the instrumental conditions and broadly used to probe the polarity of the surrounding medium (R∞ decreases from 1.1 to 1.2 in bulk water to

Xylylene Clips for the Topology-Guided Control of the Inclusion and

Recommend Documents