A Multistate Molecular Switch Based on the 6,8-Rearrangement in

Article pubs.acs.org/JPCB

A Multistate Molecular Switch Based on the 6,8-Rearrangement in Bromo-apigeninidin Operated with pH and Host−Guest Inputs Nuno Basílio,*,† Luís Cruz,*,‡ Victor de Freitas,‡ and Fernando Pina† †

LAQV, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal ‡ LAQV, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal S Supporting Information *

ABSTRACT: The equilibrium between 6- and 8-bromo-apigeninidin is quantitatively displaced toward the formation of the former in the presence of cucurbit[7]uril because of the selective recognition of the 6-bromo isomer by the host. This phenomenon permits us to conceive a unidirectional multistate switch addressed with host−guest inputs and enables the reversible activation and deactivation of the 6-/8-bromo-apigeninidin dynamic molecular multistate through coupled host−guest and pH inputs.

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depends on the pH of the solution, with AH+ being the major species under slightly acidic conditions (below pH ≈ 4), whereas at neutral pH, the PSS is composed of a mixture of A, B, and Cc.19 The photochemistry, kinetics, and equilibrium species are highly dependent on both the nature and position of the substituents in the flavylium core, making these compounds highly versatile. Some other features illustrate their versatility as molecular switches such as the light-addressed ring opening− closing of the hemiketal and redox chemistry of Ct bearing OH groups at position 6, which can be reversibly oxidized to pquinone.20,21 The number of species and the complexity of the multistate system can be further increased for flavylium compounds bearing 5-OH groups and different substituents at positions 6 and 8.22,23 Scheme 2 shows the dynamic network for 6-/8bromo-apigeninidin.24 The system is equivalent to two interconnected flavylium multistate systems. Upon dissolution of pure 8- or 6-bromo-apigeninidin at pH = 1, the system evolves into a mixture of both isomers in 1:1 ratio in ca. 10 h. This represents a problem for the characterization and possible application as multistate switches because it is convenient to find equilibrium conditions where one single species predominates. In the case of conventional flavylium systems, such conditions are achieved at pH = 1 where the flavylium cation is the main species.

INTRODUCTION Molecular switches, that is, molecules that can be reversibly interconverted between two or more states through the application of external stimuli, find widespread applications as basic building blocks in supramolecular chemistry and nanotechnology. Properties and functions such as stimuli-responsiveness, information processing, directional motion, and controlled transport rely on the switching abilities of these molecules.1−11 Whereas most systems are based on simple bistable molecular switches, the introduction of multistate molecular switches may be required to step into new levels of complexity and develop multifunctional/multistimuli-responsive molecular and supramolecular systems. Multistate molecular switches can be devised by integrating more than one bistable unit in dyads, triads, tetrads, and so forth or, alternatively, by taking advantage of molecules with intrinsic multistates.12−15 Flavylium compounds belong to an important family of such molecules, which includes anthocyanins, the natural pigments responsible for most of the blue and red colors found in flowers and fruits.16−18 These compounds display a pH- and light-dependent dynamic network of chemical reactions exemplified in Scheme 1. The flavylium cation (AH+) is the thermodynamically stable species at acidic pH values (below pH = 1), and for this particular compound, the trans-chalcone (Ct) predominates under moderately acidic and neutral conditions. Under light illumination at appropriate wavelength, the Ct can be photoisomerized to the cis-chalcone (Cc), which equilibrates fast with the hemiketal (B), AH+, and the quinoidal base (A) at the photostationary state (PSS). The mole fraction distribution of the species present at the PSS also © XXXX American Chemical Society

Received: April 11, 2016 Revised: June 8, 2016

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DOI: 10.1021/acs.jpcb.6b03694 J. Phys. Chem. B XXXX, XXX, XXX−XXX

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The Journal of Physical Chemistry B Scheme 1. Multistate System of 4′-Hydroxyflavylium in Acidic and Neutral Media

Scheme 2. Multistate System of 6-/8-Bromo-apigeninidin in Acidic and Neutral Media

by addition of the necessary amounts of base, buffer, and CB7 or 1-aminoadamantane (AD) to obtain the desired final pH and concentrations, from a previous equilibrated solution of flavylium cations at pH 1.0 in the presence or absence of CB7, depending on the experiment. The final sodium concentration was always constant and equal to 0.04 M. All of the fitting procedures were carried out using the program solver from Microsoft Excel.

For the 6-/8-bromo-apigeninidin interconversion, we found these conditions by using an artificial macrocyclic receptor, cucurbit[7]uril (CB7),25−29 which has been previously shown to display good affinity for flavylium cations with a selectivity that depends on the nature and position of the substituents.30−32 In the present study, it was found that in the presence of CB7 (pH = 1) the equilibrium between 6- and 8bromo-apigeninidin is driven toward the formation of the former owing to its higher affinity for the macrocyclic host. This phenomenon was explored to devise a molecular switching system based on the reversible 6-/8-bromo-apigeninidin rearrangement that can be operated with macrocyclic host input and competitive reset. This input/reset concept was previously used by Pischel et al. to introduce examples of a supramolecular logic gate and a keypad lock by taking advantage of the superior host−guest binding ability and selectivity of cucurbiturils.33,34 Obviously, the applicability of switchable inclusion complexes based on cucurbiturils is not limited to molecular logic devices as demonstrated by some recent examples reporting their applications in catalysis, supramolecular polymers, switchable surfaces, drug-delivery, and so forth.35−42

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RESULTS AND DISCUSSION Figure 1a shows the absorption spectrum of a solution of 6- and 8-bromo-apigeninidin in equilibrium at pH = 1 (ca. 50% each) and the spectrum of the same solution immediately upon addition of 0.5 mM CB7. As can be observed, the shape of the absorption spectrum is considerably modified, indicating the formation of host−guest complexes between the receptor and flavylium dyes. After the addition of CB7, a time-dependent spectral evolution was observed (Figure 1b), reaching a new equilibrium in ca. 3 days at 25 °C (kobs = 1.3 × 10−5 s−1). The time-dependent spectral modifications are compatible with a slow rearrangement process with kobs comparable to kobs = 1.2 × 10−4 s−1 in the 20:80 ethanol/water mixture and in the absence of CB7.24 This suggests that the relative abundances of 6- and 8-bromo-apigeninidin are modified in the presence of CB7. This behavior can be predicted by taking into account the possibility of CB7 to display high affinity for one of the isomers. Similar experiments performed at 70 °C showed that the equilibrium is attained in less than 1 h (Figure 1c) with kobs = 1.4 × 10−3 s−1. Upon cooling to 25 °C, no spectral changes were observed, supporting the fact that in the presence of 0.5 mM CB7 the relative abundance of the isomers is independent of temperature.

EXPERIMENTAL SECTION

The 6- and 8-bromo-apigeninidin mixture of compounds and the host CB7 were available from previous studies.24,30−32 The pH of the solutions was adjusted by addition of HCl, NaOH, or Theorell and Stenhagen’s universal buffer,43 and the pH was measured in a PHM240 pH/ion meter (Radiometer; Copenhagen, Denmark). Ultraviolet and visible (UV−vis) absorption spectra were recorded in a Varian Cary 100 Bio or 5000 spectrophotometer. Direct pH jumps were carried out B


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The Journal of Physical Chemistry B

Figure 1. (a) Absorption of an equilibrated mixture of 6- and 8-bromo-apigenidin (pH = 1, 1.6 × 10−5 M) before and immediately after the addition of 0.5 mM CB7 (nonequilibrated). (b) Temporal evolution of the same solution after the addition of CB7 to reach a new equilibrium at 25.0 °C. (c) The same as in (b) at 70 °C (1.7 × 10−5 M). All experiments were carried out in H2O.

Figure 2. (a) Absorption spectrum of an equilibrated mixture of 6- and 8-bromo-apigeninidin (pH = 1, 1.8 × 10−5 M) in the presence of 0.5 mM CB7 and immediately after the addition of 3 mM AD to dissociate the 6-/8-bromo-apigeninidin/CB7 inclusion complexes (nonequilibrated). The red and purple lines correspond to the spectra of pure 6- and 8-bromo-apigeninidin, respectively. The overlap of the spectrum of 6-bromoapigeninidin (red line) with that acquired immediately after the addition of AD shows that CB7 drives the equilibrium toward the quantitative formation of this isomer. (b) Temporal evolution of the same solution after the addition of AD to reach a new equilibrium. All experiments were carried out at 25.0 °C in H2O.

equilibrated solution and the UV−vis absorption spectra were acquired immediately (Figure 2a). AD forms a highly stable inclusion complex with CB7 (K = 4 × 1012 M−1) and therefore

To obtain further insights into the composition of 6-/8bromo-apigeninidin interconversion equilibrium in the presence of 0.5 mM CB7 at pH = 1, AD (3 mM) was added to the C


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Figure 3. 1H NMR spectra of 6- and 8-bromo-apigeninidin (0.2 mM) in D2O/CD3OD (95:5, v/v) with DCl = 0.1 M: (a) before the addition of CB7, (b) after the addition of 10 equiv of CB7 and heating at 60 °C for 4 h to reach equilibrium, (c) immediately (ca. 5 min) after the addition of 15 equiv of AD, and (d) the same as in (c) after reaching equilibrium (ca. 24 h).

Scheme 3. Unidirectional Four-State Switching System Based on the Interconversion between 6- and 8-Bromo-apigeninidin in the Presence of CB7 at pH = 1

guest(s) from the CB7 cavity. The obtained UV−vis spectrum superimposes with that of pure 6-bromo-apigeninidin (Figure 2a), showing a great selectivity for this isomer. As expected, after the addition of AD, the system relaxes to the equilibrium

is expected to displace quantitatively the 6-/8-bromoapigeninidin guests to the solution through competitive binding.44 The observed spectral changes depicted in Figure 2a are compatible with the quantitative release of the flavylium D


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Figure 4. (a) Absorption spectra of an equilibrated solution of 6- and 8-bromo-apigeninidin (pH = 1, 1 × 10−5 M) in the presence of different concentrations of CB7. (b) Absorbance registered at 468 nm as a function of CB7 concentration. (c) Total molar fraction of 6-bromo-apigeninidin (free and complexed with CB7) plotted against CB7 concentration. All experiments were carried out at 25.0 °C in H2O.

Scheme 4. Four-State Thermodynamic Cycle Accounting for the Rearrangement and Complexation Processes of 6-/8-Bromoapigeninidin in the Presence of CB7

mixture of isomers observed in the absence of CB7 with a kobs = 9.8 × 10−5 s−1 (Figure 2b). The above UV−vis evidence for the selectivity of CB7 for the 6-bromo-apigeninidin isomer and its amplification from the equilibrium with the 8-bromoapigeninidin were confirmed by 1H NMR experiments (Figure 3). As can be observed in Figure 3a, the 1H NMR spectrum presents two sets of signals in good agreement with the existence of 6- and 8-bromo-apigeninidin in a slow equilibrium in the chemical shift time scale. After the addition of 10 equiv of CB7 and allowing the mixture to reach equilibrium at 60 °C for ca. 4 h, only a single set of signals can be observed (Figure 3b). It is worth noting that no singlet corresponding to proton 8 (or proton 6) is observed because of deuterium exchange after heating in acidic media.45 The observation of a single set of signals supports the selective binding of one isomer and its amplification from the equilibrium mixture. This was confirmed by the competitive dissociation of the host−guest complex after the addition of AD. Before reaching equilibrium (Figure 3c), only a single set of signals, with frequencies different from those of the complex, can be observed. After equilibrium is reached (Figure 3d), two sets of signals appear again in the 1H NMR spectrum owing to the presence of both isomers. A comparison of the spectrum of the inclusion complex (Figure 3b) with that of free 6-bromo-apigeninidin (Figure 3c) shows that the signals of protons 2′,6′ and 3′,5′ are displaced upfield, whereas the signals attributed to proton 4 are displaced downfield. This complexation-induced chemical shift pattern suggests that the complex is formed through the inclusion of

the phenyl ring inside the cavity of the host, whereas the region comprising proton 4 is located near the carbonyl portals.31 The experimental observations discussed above can be summarized in Scheme 3. This system is equivalent to a fourstate molecular switch comprising two thermodynamically stable and two metastable states. The existence of two metastable states provides unidirectionality to the switching cycle as the microscopic path to depart from the initial state and reach the next thermodynamically stable state (i.e., the amplified 6-bromo-apigeninidin−CB7 complex) is different from that followed to reset the system with AD and return to the initial state. Conversely, by taking Scheme 3 as the reference, this molecular switch can only be operated in the clockwise direction (green arrow) going from the mixture of isomers through the mixture of complexes to reach the next thermodynamically stable state. At this point, the system can return to the initial state only through the release of “pure” 6bromo-apigeninidin, as it is impossible to return directly to the mixture of complexes and use this path to achieve the initial state (red arrow). Similarly, it is also not possible to switch directly from the initial mixture of free isomers to the amplified 6-bromo-apigeninidin species without forming the mixture of complexes first. UV−vis experiments similar to those described above were carried out in the presence of different concentrations of CB7 at pH = 1. Figure 4a shows the equilibrated absorption spectra of 6-/8-bromo-apigeninidin as a function of CB7 concentration. The spectral modifications can be attributed to host−guest E


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Figure 5. (a) Absorption spectra obtained after a pH jump from 1 to 3.7 with simultaneous addition of 3 mM AD to a solution of 6-bromoapigeninidin (8.6 × 10−6 M) in the presence of 0.5 mM CB7. (b) (1) Absorption spectrum obtained immediately after the pH and AD jump in (a); (2) pH jump from 1 to 3.7 starting from a mixture of 6- and 8-bromo isomers in the absence of CB, and (3) absorption spectrum obtained by subtracting 50% of spectrum (1) from spectrum (2) and normalized by dividing the resulting spectrum by 0.5. This spectrum is compatible with that obtained for the quinoidal base of the pure 8-bromo isomer. All experiments were carried out at 25.0 °C in H2O.

Scheme 5. Activation/Deactivation of the Dynamic Molecular Network through pH Jumps Coupled with Host−Guest Inclusion/Release Processes

complexation and the modification of the relative abundance of 6- and 8-bromo isomers. Figure 4b,c shows the variation of the absorbance at 468 nm and total mole fraction of 6-bromo species (free and complexed) with increasing concentrations of CB7, respectively. The mole fraction of the 6-bromo isomer was calculated by spectral deconvolution of the spectra

obtained immediately after dissociation of the host−guest complexes with AD, as described above. Quantitative information can be obtained by considering a four-state thermodynamic cycle (see Scheme 4) that accounts for the complexation of 6- and 8-bromo-apigeninidin with CB7, with K6Br and K8Br being the respective association constants, and F


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Figure 6. (a) pH-dependent spectra recorded immediately after simultaneous addition of base and 3 mM AD to equilibrated solutions of 6-bromoapigeninidin (8.6 × 10−6 M) in the presence of 0.5 mM CB7 at pH = 1 in ethanol/water mixtures (1:4). (b) The same spectra after reaching equilibrium.

Figure 7. pH-dependent spectra of 6-/8-bromo-apigeninidin taken immediately after a pH jump from equilibrated solutions at pH = 1 to higher pH values in H2O. (a) In the absence of CB7 (8.1 × 10−6 M), (b) in the presence of 0.5 mM CB7 (6.6 × 10−6 M), and (c) in the presence of 3 mM CB7 and absence of buffer (1 × 10−5 M of 6-/8-bromo-apigeninidin).

× 105 M−1 and K8Br = (5 ± 4) × 103 M−1 and calculate K′i = 6 × 10−3. From these values, it is evident that the bromo substituent at position 8 destabilizes the inclusion complex and provides the basis for the observed regioselectivity. The present strategy can be used to activate the flavylium network of chemical reactions from a single state (i.e., starting 6-bromo-apigeninidin isomer) to the complex multistate system by means of pH jumps and addition of AD. The experiments were carried out in H2O/EtOH (4:1, v/v) to compare the spectra of the species with those previously reported. Figure 5a shows the UV−vis spectral variations observed upon a pH jump and addition of AD from pH = 1 to 3.7. The spectrum obtained immediately after the pH jump (see Figure 5b) is compatible with that observed for the pure quinoidal base of the 6-bromo isomer.24 For comparison, the spectrum obtained immediately after the pH jump to pH = 3.7 starting from the mixture of isomers is also shown. The spectrum of the quinoidal base of the 8-bromo isomer can be obtained after spectral deconvolution using the last two spectra. Returning to Figure 5a, the time-dependent spectral variations are attributed to the initial formation of the 6-bromo quinoidal base, which evolves into a mixture of up to 10 different species (Scheme 5). The pseudofirst-order rate constant (kobs = 4.7 × 10−4 s−1) is compatible

the rearrangement equilibrium of the free and complexed species, with equilibrium constants Ki and K′i , respectively. From this cycle, it can be easily demonstrated that Ki′ = KiK8Br/ K6Br. The equilibrium concentrations of all species can be calculated using the following equations derived from the equilibrium and mass balance expressions (K 6Br + K 6BrK i + K8BrK i + K8BrK i 2)[6‐Br]2 + (1 + K i + {K 6Br + K iK8Br}[CB7]0 − {K 6Br + K8BrK i}[6‐Br]0 )[6‐Br] − [6‐Br]0 (1)

=0

[8‐Br] = K i[6‐Br] [CB7] =

[CB7]0 (1 + K 6Br[6‐Br] + K8BrK i[6‐Br])

(2)

(3)

[6‐Br@CB7] = K 6Br[6‐Br][CB7]

(4)

[8‐Br@CB7] = K8Br[8‐Br][CB7]

(5)

A global fitting of the absorption and mole fraction data reported in Figure 4 was carried out to obtain K6Br = (2.5 ± 1) G


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FCT/MEC (SFRH/BPD/72652/2010 and SFRH/BPD/ 84805/2012, respectively).

with the formation of steady-state concentrations of hemiketal and Cc, followed by fast isomerization and 6,8-rearrangement to achieve the final multistate equilibrium. Addition of acid to achieve pH = 1 and 9 μmol of CB7 (for a final volume of 3 mL) is expected to restore the system to the 6-bromo-apigeninidin@ CB7 complex, deactivating the multistate network through the amplification of a single component. Experiments similar to those described above were carried out for different pH values, allowing us to obtain a pKa = 2.4 for the formation of the quinoidal base of 6-bromo-apigeninidin and pK′a = 2.3 to achieve the final equilibrium (see Figure 6). The system was also explored in water in the absence and presence of 0.5 and 3 mM CB7, and pKa values of 2.40, 3.45, and 3.60 were obtained, respectively (Figure 7). The trend observed in pKa values with the concentration of CB7 is in line with the preferential stabilization of the cationic species relative to that of the neutral base, as generally observed for cucurbituril host−guest complexes.46−48 However, the final equilibrium in the absence of CB7 could not be achieved due to the precipitation of the quinoidal bases. Nevertheless, the pKa shifts observed in the presence of CB7 may open the possibility of using only host/guest inclusion and release inputs to activate and deactivate the multistate system without pH jumps.

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CONCLUSIONS In conclusion, CB7 selectively binds 6-bromo-apigeninidin and amplifies it from an equilibrated mixture with the 8-bromo isomer. This allows the conception of a unidirectional four-state switch at pH 1 through host−guest inclusion and competitive displacement inputs and to activate and deactivate the 6-/8bromo-apigeninidin multistate network by coupling the pH jump with the mentioned supramolecular inputs. Unidirectional multistate switching systems constitute an important challenge for the development of molecular machines able to perform mechanical work and, consequently, accomplish important functions such as directional motion.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.6b03694. Deduction of equations (PDF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Tel: +351 212 948 355. Fax: +351 212 948 550 (N.B.). *E-mail: [email protected]. Tel: +351 220402558. Fax: +351 220402659 (L.C.). 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, which is financed by national funds from FCT/MEC (UID/QUI/50006/2013) and cofinanced by the ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER007265). The NMR spectrometers are part of The National NMR Facility, supported by Fundaçaõ para a Ciência e a Tecnologia (RECI/BBB-BQB/0230/2012). L.C. and N.B. gratefully acknowledge the post-doctorate grants from the H


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