Contrasting pKa Shifts in Cucurbit[7]uril Host–Guest Complexes

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Contrasting pKa Shifts in Cucurbit[7]uril Host−Guest Complexes Governed by an Interplay of Hydrophobic Effects and Electrostatic Interactions Nuno Basílio,* Sandra Gago, A. Jorge Parola, and Fernando Pina Laboratório Associado para a Química Verde (LAQV), Rede de Química e Tecnologia (REQUIMTE), Departmento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal S Supporting Information *

ABSTRACT: Cucurbit[7]uril inclusion complexes with guests bearing dimethylamino groups show the expected upward pKa shifts, whereas their diethylamino counterparts display a decrease in pKa due to the preferential stabilization of the unprotonated form. These results identify the diethylamino group as the substituent of choice to avoid receptor-assisted protonation of guest molecules and present new evidence for the role of the hydrophobic effect as a driving force in cucurbituril complexation.

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INTRODUCTION Cucurbit[n]urils (CBn) are water-soluble macrocyclic receptors holding a rigid barrel-shaped hydrophobic cavity and highly electronegative portals lined by carbonyl groups.1,2 Owing to these structural and electronic characteristics, CBn display high affinity and selectivity for guest molecules with complementary size, shape, and charge/polarity. Their remarkable binding properties enabled the development of potential applications based on the reversible formation of host−guest complexes within the fields of sensing, catalysis, self-assembled materials, drug delivery, etc.3−17 Likewise, fundamental investigations on CBn molecular recognition also contributed to progress the knowledge on crucial aspects of supramolecular chemistry and noncovalent interactions in aqueous media. Some examples include recent reports on the nonclassical hydrophobic effect associated with the release of high-energy water molecules from hydrophobic cavities, which was invoked to rationalize the exceptionally high binding affinities of CBn receptors toward some neutral organic guests.18−25 Although CBn can display high affinity for some neutral guests, these molecules are traditionally known for their ability to selectively complex organic cations. In fact, for most basic guests, such as amines, CBn display stronger affinity for the positively charged protonated species (BH+) with association constants from 1 to more than 4 orders of magnitude higher in comparison with those determined for the respective neutral conjugated bases (B). The higher stability of the complexes formed with the protonated guest leads to upward complexation-induced pKa shifts that are proportional to the relative stabilization of this species with respect to this conjugated base. © 2017 American Chemical Society

Mathematically, this is elegantly expressed by eq 1, where Ka and K′a are the acid dissociation constants of the guest in bulk solution and in the encapsulated form, respectively, whereas KBH+ and KB are the association constants for the formation of the complex with BH+ and B, respectively.

K ′a = K a

KB KBH+

(1)

According to eq 1, for guests with KBH+ values more than 4 orders of magnitude higher than KB, complexation-induced pKa shifts higher than 4 units are predicted.26−28 This special feature has been explored in the framework of supramolecular catalysis, drug delivery, indicator displacement assays, and dye stabilization, which in the case of the flavylium family compounds is of major importance for their applications, for example, as food colorants and dye-sensitized solar cells.29−35 The trend in the recognition properties of CBn, showing selectivity factors (KBH+/KB) for positively charged species covering various orders of magnitude, depending on the guest, is not completely understood and, consequently, in most cases, the magnitude of the pKa shifts cannot be predicted. Herein, by using flavylium cations and water-soluble trans-chalcones (Scheme 1) to form inclusion complexes with cucurbit[7]uril (CB7), we show that the magnitude of this shift is very sensitive to small structural variations. Our study puts in evidence that whereas guests with dimethylamino groups display the Received: November 25, 2016 Accepted: December 29, 2016 Published: January 9, 2017 70

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Scheme 1. Structures of 4′-(N,N-Dialkylamino)-7-hydroxyflavylium Cations 1a/1b and Water-Soluble trans-Chalcones 2a/2b

Figure 1. (a) Spectral variations observed upon gradual addition of CB7 to a solution of 1a (8.9 μM) in 1.5 M HCl. (b) The same experiment for 1b (7.0 μM) in 0.25 M HCl.

Figure 2. (a) Spectral modifications observed upon gradual addition of CB7 to a solution of 2a (25 μM) at pH = 9; (b) the same for 2b (20 μM).

In the case of 1a, upon addition of CB7, the absorption band centered at 530 nm (flavylium) decreases and the band centered at 428 nm increases (protonated flavylium). This result is in line with the displacement of the acid−base equilibrium toward the dicationic species and therefore with an expected complexation-induced upward pKa shift. On the other hand, in the case of 1b, the equilibrium is shifted toward the monocationic species upon addition of CB7, suggesting that the complexes formed with this species are more stable than those formed with the dicationic species. This behavior is compatible with an unexpected downward pKa shift and is in contrast to that observed for 1a. Fitting the absorbance data reported in Figure 1 to a 1:1 binding model allows the recovery of the apparent binding constants for 1a (K = (7.9 ± 0.8) × 105 M−1) and 1b (K = (2.6 ± 0.3) × 105 M−1). However, these association constants cannot be compared, as the experiments were performed for different concentrations of H+, which is a known competitor for CB7 complexation.37 Additionally, under

traditional upward pK a shifts, their counterparts with diethylamino substituents revealed downward pKa shifts. These results establish the diethylamino group as the substituent of choice for applications where the complexation-assisted protonation should be avoided and provide new hints into the recognition properties of CBn receptors.

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RESULTS AND DISCUSSION

Flavylium derivatives 1a and 1b (Scheme 1) were previously investigated and were found to form inclusion complexes of equivalent stability with CB7 at pH = 2.36 The amino groups in flavylium compounds are weakly basic with pKa values of −0.35 ± 0.05 and 0.60 ± 0.02 for 1a and 1b, respectively (see Figure S1). Figure 1 shows the spectral variations observed for 1a and 1b upon addition of CB7 in the presence of a concentration of HCl required to adjust the H+ activity near the pKa value. 71

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Figure 3. 1H NMR spectra of 2a (0.5 mM, pD = 9) and 2b (0.5 mM, pD = 7) in the absence and presence of CB7 (1.2 and 0.5 mM for 2a and 2b, respectively). pD = pH* + 0.4, where pH* is the direct reading taken from the pH meter; see ref 39.

Supporting Information). Nevertheless, the phenyl ring of 2a (Δδ = −0.586, −1.092, and −0.336 ppm for protons g, f, and e, respectively) seems to be completely included in the hydrophobic cavity, whereas in the case of 2b (Δδ = −0.628, −0.638, −0.702, and 0.021 ppm for protons h, g, f, and e), the diethylamino group is deeply enclosed in the CB7 cavity with the phenyl ring partially exposed to the solvent, as shown in Scheme 2.36 On the other hand, ITC experiments afforded binding constants compatible with those obtained by UV−vis and revealed that the association process is enthalpy driven with a small unfavorable entropic component (Table 1). The higher enthalpic change observed for 2b is in line with the

these conditions, the apparent binding constants also depend on the pKa value of the guest and on the association constants for complexation of monocationic and dicationic species.38 Owing to the very acidic and, thus, unfavorable conditions required for the determination of pKa of the inclusion complexes and the association constants of the dicationic species, it was decided to investigate other possible guests with higher pKa values (which also would confirm the generality of the observed behavior). With this purpose in mind, watersoluble trans-chalcones 2a and 2b (Scheme 1) were readily synthesized through a Claisen−Schmidt condensation. The N-protonation of the trans-chalcones, 2a and 2b, can be readily followed by ultraviolet−visible (UV−vis) absorption spectroscopy affording pKa values of 3.50 ± 0.02 and 4.90 ± 0.03, respectively (see Figure S2), with the diethylamino substituted 2b being more basic, as expected. The formation of inclusion complexes between both trans-chalcones and CB7 was also investigated by UV−vis absorption spectroscopy at pH = 9. Upon addition of increasing concentrations of CB7, the characteristic absorption of 2a (centered at 425 nm) and 2b (centered at 440 nm) gradually decreases and a new red-shifted band (ca. 50 nm) concomitantly appears (Figure 2). The spectral variations were fitted to a 1:1 binding model with K = (3.9 ± 0.4) × 104 M−1 and K = (2.3 ± 0.2) × 105 M−1 for 2a and 2b, respectively. To rationalize the observed selectivity for 2b, complementary 1 H NMR (Figure 3) and isothermal titration calorimetry (ITC) (see Figure S3) experiments were carried out. The complexation-induced chemical shifts (Δδ) observed upon addition of CB7 to 2a and 2b suggest that the amino groups and the respective phenyl ring are included within the cavity of the receptor (complementary 2D NMR experiments were carried out for complete assignment of the 1H NMR signals, see the

Scheme 2. Proposed Structures for the Inclusion Complexes Formed between 2a and 2b with CB7

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Table 1. Thermodynamic Parameters Obtained for the Formation of CB7 Inclusion Complexes with Unprotonated 2a and 2b 2a 2b

KUV−vis (×105 M−1)

KITC(×105 M−1)

ΔG (kJ mol−1)

ΔH (kJ mol−1)

−TΔS (kJ mol−1)

0.39 ± 0.04 2.3 ± 0.2

0.47 ± 0.04 2.8 ± 0.4

−26.6 ± 0.2 −31.1 ± 0.4

−29.0 ± 0.5 −34.9 ± 0.5

2.4 ± 0.5 3.8 ± 0.6

Figure 4. (a) Spectral modifications observed upon gradual pH variations in an aqueous solution of 2a (25 μM) in the presence of 430 μM of CB7 and (b) the same for 2b (20 μM) with 250 μM of CB7. The dotted lines in the insets represent the curve simulated using the pKa value of the free guests.

incorporation of the diethylamino group into the CB7 cavity, as observed from 1H NMR. This group displays an optimal packing coefficient of 55% for the truncated cavity of CB7, contributing for a more efficient release of high-energy water molecules from the hydrophobic pocket of the receptor when compared with the dimethylamino group of 2a.18,36,40 The acid−base dissociation equilibria of the inclusion complexes were investigated by titrating solutions of 2a and 2b in the presence of CB7 in excess to ensure near quantitative formation of the complex (93 and 98% for 2a and 2b, respectively). For the dimethylamino derivative, the pKa increased from 3.50 ± 0.02 in the absence to 6.22 ± 0.02 in the presence of 430 μM of CB7 (Figure 4a). This observation is in line with the general understanding of cucurbituril recognition properties, showing higher affinity for the protonated cationic species. In fact, from the complexationinduced pKa shift (ΔpKa = 2.7) and using the previously determined binding constant for the conjugate base (K = 3.9 × 104 M−1), it is possible to estimate a value of KH = 2 × 107 M−1 for the protonated trans-chalcone 2a. On the other hand, for the inclusion complex with 2b, a small decrease in pKa is actually observed (ΔpKa = −0.2) from 4.90 ± 0.03 to 4.71 ± 0.03 (Figure 4b, this experiment was repeated with 350 μM of CB7 and a value of 4.58 ± 0.03 was obtained, thus confirming the negative pKa shift; see Figure S18), demonstrating the lack of selectivity of CB7 for the protonated diethylamino derivative (KH = 1.4 × 105 M−1). The KH values were obtained directly by titrating the guests with CB7 at pH = 2, but the spectral variations are small (see Figure S4). Nevertheless, values of KH > 1 × 107 M−1 and KH = (1.4 ± 0.2) × 105 M−1 were, respectively, determined for 2a and 2b, in good agreement with the values estimated from the observed complexation-induced pKa shifts. The complexation-induced chemical shifts observed in the 1 H NMR (see Figure S7 and S8) for the protonated forms of 2a and 2b at pD = 2 are similar for both compounds. Particularly, the signals of the aromatic protons of the aniline group are shifted upfield in both cases, whereas the magnitude of the shift

is lower for diethylamino protons of 2b. Conversely, this suggests that the binding mode is similar for 2a in the basic and protonated forms, whereas in the case of 2b, the diethylamino group is displaced from the interior of the cavity to the proximity of the portals upon protonation. The co-conformational movement is due to a change in the complexation driving force from hydrophobic to electrostatic (ion−dipole), which is associated with a relevant energetic penalty. The net result is a lower binding constant for the protonated form of 2b and hence a downward pKa shift.

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CONCLUSIONS

In conclusion, the present work shows that the general assumption regarding the selectivity of CB7 receptor for positively charged species has exceptions and reveals a simple structural motif to avoid or reverse this selectivity. This can be achieved by substitution of dimethylamino by diethylamino groups in selected guests, leading to an inversion of the pHdependent selectivity and consequently of the complexationinduced pKa shift. These results support the increasing evidence for the higher contribution of enthalpic hydrophobic effects over ion−dipole interactions in the complexation of specific guests with cucurbiturils.16,18 It is also remarkable that this effect arises from a small structural variation within similar guest molecules. In addition to an obvious fundamental interest, we envisage that such contrasting pKa shifts observed for a family of structurally similar guest molecules can find applications in several fields such as molecular machines, pHdriven self-sorting systems, or in selective supramolecular catalysis, where reactants might be not selectively recognized but selectively activated by complexation-assisted protonation.29,41

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MATERIALS AND METHODS Materials. All solvents and chemicals employed for synthesis and for preparation of samples were of reagent grade and were used as received. Ultrapure Millipore grade 73

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Scheme 3. Claisen−Schmidt Condensation To Obtain 2a and 2b

water was used. Cucurbit[7]uril and flavylium cations were available from previous studies.36 Synthesis of 2a and 2b. 2a and 2b were synthesized using a similar procedure (Scheme 3). 4′-(1-Sulfo-4-butyloxy)acetophenone sodium salt (0.1 g, 0.34 mmol) and 4(dimethylamino)benzaldehyde (0.051 g, 0.34 mmol) or 4(diethylamino)benzaldehyde (0.060 g, 0.34 mmol) were dissolved in 0.4 mL methanol and the solution was cooled in an ice bath. After addition of 0.044 mL of 40% NaOH, the solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted in 5 mL of distilled water, neutralized with 1 M HCl, and extracted with diethyl ether. The aqueous phase was concentrated by evaporation, and the crude product was purified by reverse-phase (C18) column flash chromatography with gradient elution from 100% H2O to 70% H2O/30% CH3CN. After evaporation of the solvent and drying in high vacuum, 2a (0.094 g, 69% yield) and 2b (0.110 g, 75% yield) were obtained as orange solids. 2a. 1H NMR (400 MHz, deuterium oxide) δ 7.94 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 15.5 Hz, 1H), 7.60 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 15.5 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 4.10 (t, J = 5.8 Hz, 2H), 2.96−2.87 (m, 8H), 1.90−1.8051 (m, 4H). HRMS (electrospray ionization (ESI)) m/z calcd for C21H24NNaO5S [M-Na+]: 402.1381; found: 402.1400. 2b. 1H NMR (400 MHz, deuterium oxide) δ 7.92 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 15.4 Hz, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 15.4 Hz, 1H), 7.01 (d, J = 8.7 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 4.08 (t, J = 5.4 Hz, 2H), 3.36 (q, J = 7.1 Hz, 4H), 2.91 (t, J = 7.4 Hz, 2H), 1.85 (t, J = 4.3 Hz, 5H), 1.08 (t, J = 7.1 Hz, 6H). HRMS (ESI) m/z calcd for C23H28NNaO5S [M − Na+]: 430.1694; found: 430.1691. Methods. The pH of the solutions was adjusted with HCl and NaOH and measured with a Crison basic 20+ pH meter. UV/vis absorption spectra were recorded using a Varian Cary 100 Bio or a Varian Cary 5000 spectrophotometer. NMR experiments were run on a Bruker AMX 400 instrument, operating at 400 MHz (1H) and 101 MHz (13C). The solutions for NMR were prepared in D2O and the pD adjusted with DCl or NaOD. Corrections due to isotope effects were applied using the equation pD = pH* + 0.4, where pH* is the reading taken from the pH meter.39 The mass spectra were obtained in a LTQ Orbitrap XLTM mass spectrometer. The capillary voltage of the ESI was set to 3000 V. The capillary temperature was 275 °C. The sheath gas flow rate (nitrogen) was set to 5 (arbitrary unit as provided by the software settings). The capillary voltage was −35 V, and the tube lens voltage was −200 V.

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Additional spectroscopic experiments, ITC, and 2D NMR spectra (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Nuno Basílio: 0000-0002-0121-3695 A. Jorge Parola: 0000-0002-1333-9076 Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Associated Laboratory for Sustainable Chemistry − Clean Processes and Technologies − LAQV. The latter is financed by national funds from FCT/ MEC (UID/QUI/50006/2013) and co-financed by the ERDF under the PT2020 Partnership Agreement (POCI-01-0145FEDER-007265). FCT/MEC is also acknowledged through the National Portuguese NMR Network RECI/BBB-BQB/0230/ 2012, and Projects PTDC/QEQ-QFI/1971/2014 and POCI01-0145-FEDER-016387 “SunStorageHarvesting and storage of solar energy”, funded by the European Regional Development Fund (ERDF), through COMPETE 2020Operational Programme for Competitiveness and Internationalisation (OPCI). N.B. gratefully acknowledges a postdoctoral grant from FCT/MEC (SFRH/BPD/84805/2012). We are grateful to Dr. Sofia Pauleta for allowing us to use the Isothermal Titration Calorimeter (FCT-ANR/BBB-MET/0023/2012) and ́ Bonifácio for technical assistance with the ITC to Dr. Cecilia experiments.

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

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