Competitive inclusion of molecular photo-switches in host cavities

University of Groningen

Competitive inclusion of molecular photo-switches in host cavities

Huang, He; Juan, Alberto; Katsonis, Nathalie; Huskens, Jurriaan

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Tetrahedron

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10.1016/j.tet.2017.05.026

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in host cavities. Tetrahedron, 73(33), 4913-4917. https://doi.org/10.1016/j.tet.2017.05.026

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Competitive inclusion of molecular photo-switches in host cavities

He Huang

a,b

, Alberto Juan

b,c

, Nathalie Katsonis

a,b,**

, Jurriaan Huskens

c,*

a_{Bio-inspired and Smart Materials, MESAþ Institute for Nanotechnology, University of Twente, P.O. Box 217, 7500 AE, Enschede, The Netherlands} b_{Laboratory for Biomolecular Nanotechnology, MESAþ Institute for Nanotechnology, University of Twente, P.O. Box 217, 7500 AE, Enschede, The} Netherlands

c_{Laboratory for Molecular Nanofabrication, MESAþ Institute for Nanotechnology, University of Twente, P.O. Box 217, 7500 AE, Enschede, The Netherlands}

a r t i c l e i n f o

Article history: Received 5 April 2017 Received in revised form 4 May 2017

Accepted 8 May 2017 Available online 10 May 2017 Keywords:

Photochromic switches Supramolecular chemistry Dynamic molecular systems

a b s t r a c t

Azobenzene is a widely used guest molecule to build up dynamic photo-responsive host-guest systems. Here, we studied the host-guest complexation of a water-soluble, ortho-fluorinated azobenzene with two different host molecules, a cyclodextrin (b-CD) and a cucurbit[8]uril (CB[8]), and demonstrate that in the presence of both, the guest forms two stable supramolecular complexes selectively. In its trans-form, it favors binding tob-CD, whereas in its cis-form it favors complexation to CB[8]. Upon light-triggered photo-isomerization, the photoswitch was reversibly and selectively transferred from one host cavity to the other. This light-driven host exchange provides a new tool for supramolecular systems.

© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

1. Introduction

Host-guest chemistry is a useful tool to achieve functional ar-chitectures through a bottom-up approach by joining molecular building blocks by non-covalent interactions in a controlled man-ner.1e4Incorporating stimuli-responsive building blocks in these architectures arguably constitutes the most straightforward strat-egy to endow these supramolecular assemblies with dynamic functions.5,6We focus on using light as a stimulus, which is a clean energy source and leads to photo-isomerization of photochromic molecular switches without further chemical waste.7Among other photo-responsive molecular switches,8e10azobenzene derivatives have attracted special attention because their photo-isomerization brings changes both in their conformation and in their dipolar moment.11,12

Macrocyclic molecules with convergent binding sites are extensively employed as molecular host cavities.13Typically, cy-clodextrins are known to recognize and bind hydrophobic mole-cules as guests.2,14e16Host-guest interaction between azobenzenes and a

b

-cyclodextrin (

b

-CD) wasfirst reported in 198017_{: the} trans-form of the azobenzene was encapsulated into the hydrophobic cavity of

b

-CD, and the trans-to-cis photo-isomerization led to the disassembly of the host-guest complex.12,18e21 Cucurbiturils (CB)

constitute another class of macrocyclic hosts. Due to the strong charge-dipole and H-bonding interactions, as well as the hydro-phobic effect derived from the negative portals and rigid cavity, respectively, they form stable host-guest complexes with binding constants ranging up to ~1017M1with cationic or electro-positive guest molecules.21e25A photo-responsive complex can be formed between CB[8] and azobenzene photo-switches, on the condition that a methyl viologen is present that mediates the formation of a ternary complex.6,26e28

A major drawback of azobenzene switches, however, lies in their lack of thermal stability. Typically, the thermal relaxation of the unstable cis-isomer will drive any host-guest system back to equilibrium and results in the loss of UV input information. To maintain the cis-form, a continuous energy input is required.29For example, in the ternary complex (trans-Azo$ MV)3CB[8], the UV irradiation led to disassembly of the complex. Once the input of UV light was removed, the cis-azobenzene relaxed back to the trans-form in several hours, by which the supramolecular system rever-ted to the state before the UV irradiation.6

Here, we demonstrate the design and synthesis of a dynamic, supramolecular host-guest system, which is stable in both“on” and “off” states, in order to provide two supramolecular states. We have designed and synthesized an ortho-fluorinated azobenzene (1) as building block, as ortho-fluorination is known to stabilize the cis-isomer of the azobenzene considerably,30,31and report its dynamic complexation with two different host molecules, a cyclodextrin and a cucurbituril. We demonstrate that 1 can be reversibly

* Corresponding author. ** Corresponding author.

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http://dx.doi.org/10.1016/j.tet.2017.05.026

translocated from one cavity to the other selectively upon illumi-nation (Scheme 1).

2. Results and discussion

A neutral, water-soluble and thermally stable azobenzene switch 1 was designed and synthesized to mediate the dynamic supramolecular complexation (Scheme 1b,Fig. S1-S2). Directly af-ter synthesis, the ratio between trans-1 and cis-1 was trans:cis_{¼ 94:6. Upon irradiation by UV light (}

l

¼ 365 nm), the photo-stationary state was achieved yielding a ratio of trans:cis¼ 10:90. Upon irradiation with blue light (

l

¼ 420 nm) the back-isomerization to the trans form resulted in a photo-stationary state that was reached after 20 min irradiation, yielding a ratio of trans:cis¼ 57:43 (Fig. S3).

The inclusion of an acid-functionalizedfluorinated azobenzene into

b

-CD has been reported recently.32Interestingly, both the trans and cis-isomers could form supramolecular complexes with

b

-CD, and the binding affinity of the cis-isomer was even higher than that of the trans-isomer. In contrast, for non-fluorinated, traditional azobenzenes, the selectivity is in favor of binding of the trans-iso-mer.1,17,18Thefluorinated azobenzene reported earlier is symmet-ric; therefore we compared its supramolecular binding to

b

-CD to the behavior of switch 1, which is non-symmetric. We started by investigating the complexation between molecule 1 and

b

-CD by1H NMR (in D2O) and isothermal titration calorimetry (ITC, in H2O). Because of the absence of protonatable sites in the guest and hosts, the pH/pD was not controlled, nor were differences in pH/pD or the affinity constants considered here. ITC indicates that cis-1 has a higher binding affinity to

b

-CD (K¼ 4.8  103_M1_{) than trans-1} (K¼ 2.3  103_M1_{) (Table 1andFig. S4).}1_{H NMR titration} exper-iments confirmed these results (Fig. S5-S8). The orientation of the guest in the supramolecular complex was investigated by1H NMR Nuclear Overhauser Effect SpectroscopY (NOESY). The signal for Ha on trans-1 showed a stronger correlation with H3of

b

-CD than H5, while for Hbonly the correlation with H5was observed (Fig. S9). Likewise, in the cis-13

b

-CD complex, the correlation between Ha and H3was stronger than the Hae H5correlation, while Hbwas more correlated to H5than to H3(Fig. S10). The NOE effect thus indicates that, for both trans-13

b

-CD and cis-13

b

-CD, the guest molecule is binding from the secondary face of the

b

-CD cavity. The difference between the binding affinities of the trans and cis

complexes observed here is less than one order of magnitude. Therefore, upon illumination of such host-guest complexes, the photo-isomerization of the guest molecule cannot result in any significant changes in the distribution over the bound and unbound states. An additional component is thus required to release the azobenzene from the

b

-CD cavity, and thus to provide an“off” state to make the supramolecular system photo-switchable in its pref-erence for different hosts.

Next, we studied the interaction between switch 1 and CB[8]. Thefirst experiment was performed by1_{H NMR spectroscopy. In} the 1:1 mixture of trans-1 and CB[8], the aromatic protons of 1 were almost not shifted (Fig. S11), meanwhile in the sample with cis-1 and CB[8], the aromatic protons Hawere shifted from

d

¼ 6.68 ppm to

d

¼ 6.28 ppm (Fig. S12). These results reveal the existence of a supramolecular interaction between cis-1 and CB[8]. This interac-tion was further investigated by titrating aqueous soluinterac-tions of trans-1 and cis-1 (c ¼ 0.5 mM) into an aqueous CB[8] solution (c¼ 0.05 mM), separately, monitored by ITC. The interaction be-tween trans-1 and CB[8] was too weak to be detected by ITC, whereas cis-1 formed a cis-13CB[8] complex with a binding af-finity of K ¼ 4.9  105_M1_{(Fig. S13).}

The thermodynamic values associated with the complexation of 1 into the

b

-CD and CB[8] cavities are summarized in Table 1. Overall, they indicate that 1 forms host-guest complexes with

b

-CD in both the trans and the cis-form, the binding affinity of the cis-form complex being higher than that of the trans-cis-form. In contrast, while no inclusion occurs between trans-1 and CB[8], cis-1 forms a supramolecular complex with CB[8], with a binding constant that is two orders of magnitude higher than that of

b

-CD. This behavior contrasts with the dynamic complexation of regular azobenzene, which is included into

b

-CD only in its trans-form and is released from the cavity upon UV irradiation, while no stable complex is formed with CB[8], neither in the trans nor in the cis-form.26e28 Moreover, trans-1 shows a positive entropy change upon complexation with

b

-CD, and the absolute value of this entropic change is higher than the enthalpic change (Table 1). These values indicate that, in the complex, there is a relatively high conforma-tional and transiconforma-tionalflexibility, and the main factor leading to the complexation is the hydrophobic interaction between the fluori-nated azobenzene moiety and the cavity. Meanwhile, the inclusion of cis-1 into

b

-CD is an enthalpy-driven process associated with a considerable entropy penalty, which indicates that Van der Waals interactions between the guest and the cavity resulting in a tightfit constitute the main driving force of the cis-13

b

-CD complexa-tion.33In the CB[8] complex, additional electrostatic interactions occur between host and guest, besides the Van der Waals and hy-drophobic interactions, which result here in an approximately two orders of magnitude higher binding affinity than those observed for the

b

-CD complexes.22Overall, considering that the difference be-tween the binding affinity of cis-13CB[8] is higher than either trans-13

b

-CD or cis-13

b

-CD by two orders of magnitude, these thermodynamic values support the possibility of a light-controlled, reversible, and competitive binding of the guest between the two different host molecules.

The competitive binding behavior was investigated by1H NMR

Scheme 1. a) Principle of using light to drive the selective inclusion of a molecular photo-switch in different molecular cavities. b) Molecular photo-switch 1 used in this study. c)b-Cyclodextrin (b-CD) cavity used in this study. d) Cucurbit[8]uril (CB[8]) cavity used in this study.

Table 1

Binding affinities and thermodynamic parameters for the host-guest interaction of azobenzene 1 with different hosts.

Guest Host K (M1) DH (kcal/mol) TDS (kcal/mol) trans-1 b-CD 2.3 103 _{2.1 2.5}

cis-1 b-CD 4.8 103 _{9.2 4.2}

trans-1 CB[8] e e e

cis-1 CB[8] 4.9 105 _{9.6 1.8} H. Huang et al. / Tetrahedron 73 (2017) 4913e4917

in a three-component system comprising 1:

b

-CD: CB[8]¼ 1: 1: 1 (c¼ 0.5 mM in D2O). We note that this concentration is above the solubility limit (0.05 mM) of CB[8], so that when CB[8] is not complexed to the guest, part of the host is dispersed in the sample without complete dissolution. The proton Hawas monitored and compared to the samples of pure 1 and of 1 with the different host molecules separately. For the pure trans-1, the Hasignal was found at

d

¼ 6.89 ppm, and this signal was not shifted in the mixture of trans-1 and CB[8]. In the sample of trans-1 and

b

-CD, the proton Ha was shifted to

d

¼ 6.93 ppm. In the three-component sample, the signal of Hawas found at

d

¼ 6.93 ppm, which confirmed the for-mation of the trans-13

b

-CD complex (Fig. 1).

When cis-1 was used as obtained upon UV irradiation, the Ha signal of proton of the cis-isomer in the absence of a host appeared at

d

¼ 6.68 ppm. In the complex cis-13

b

-CD, this signal was shifted to

d

¼ 6.74 ppm, while in the complex cis-13CB[8], this signal was observed to

d

¼ 6.28 ppm. When both

b

-CD and CB[8] were present, the signal of proton Hawas found at

d

¼ 6.28 ppm, which confirmed that the cis-13CB[8] complex had formed selectively (Fig. 2), in agreement with the measured differences in binding affinity (Table 1). We note that apparently the binding affinity of cis-1 for CB[8] is sufficiently strong to pull all undissolved host into solution, even in the presence of well-dissolved and competing

b

-CD.

To study the photo-responsiveness of the competitive complexation in situ, we prepared a three-component sample consisting of 1,

b

-CD, and CB[8], which was irradiated while measuring UV/Vis absorption and1_{H NMR spectra. We chose a ratio} of 1:

b

-CD: CB[8]¼ 1: 10: 1 (c ¼ 0.05 mM) to stay below the sol-ubility limit of CB[8], but at the same time have a sufficiently high

b

-CD concentration to still observe binding of the guest. The experiment was started from the trans-form as the initial state. In the UV/Vis absorption spectra, for trans-1, two major absorbance peaks are present at

l

¼ 335 nm and

l

¼ 428 nm, which are associated to

p

-

p

* and n-

p

* transitions, respectively (Fig. 3). Upon irradiation with UV light (

l

¼ 365 nm), the decrease of the

p

-

p

* absorbance confirms that trans-1 isomerizes to the cis-form. Moreover, the n-

p

* absorbance decreased as well, and the associ-ated peak blue-shifted to

l

¼ 418 nm. When the cis-isomer mixture was irradiated with blue light, the UV/vis spectrum indicated cis-to-trans conversion. The incomplete cis-cis-to-trans conversion, which is in agreement with1H NMR experiments (Fig. S3), is attributed to the minor change of the n-

p

* absorbance upon switching. The cis-1_{3CB[8] complex was kept in the dark for up to two weeks, after} which the UV/Vis absorption spectrum did not show any significant change, thus confirming that cis-1 is thermally stable.

In the1H NMR experiments, initially, the signal of Hawas found at

d

¼ 6.93 ppm, which suggested that the trans-1 was bound to

b

-CD. Following irradiation with UV light (

l

¼ 365 nm), this signal decreased and eventually disappeared entirely after 10 min, while another group of signals appeared at

d

¼ 6.28 ppm. These results suggested that during the UV irradiation, trans-1 was converted into cis-1 and was consequently transferred from the

b

-CD cavity to the CB[8] cavity. Even though the

b

-CD concentration was ten times higher than that of CB[8], cis-1 still preferred to bind to the CB[8] cavity. Subsequently, the cis-to-trans isomerization was performed with blue light illumination (

l

¼ 420 nm). Under illumination, the signal at

d

¼ 6.28 ppm decreased and the signal at

d

¼ 6.93 ppm re-appeared, which indicates that cis-1 was converted into trans-1 and concomitantly transferred back from the CB[8] cavity to the

b

-CD cavity. After 30 min the photo-stationary state was reached with a trans:cis ratio of 57:43, which is in agreement with UV/Vis ab-sorption experiments (Fig. 4). The rate of photo-isomerization of cis to trans appeared to be on the order of 0.14 min1, both in the absence (Fig. S14) and presence (Fig. 4) of CB[8], which indicates

Fig. 1. Comparison of1_{H NMR spectra of a) trans-1 withb-CD and CB[8] (1:1:1 ratio),} b) trans-1 with CB[8] (1:1 ratio), c) trans-1 withb-CD (1:1 ratio), d) trans-1. The con-centration of 1 was in all cases 0.5 mM.

Fig. 2. Comparison of1_{H NMR spectra of a) cis-1 withb-CD and CB[8] (1:1:1 ratio), b)} cis-1 with CB[8] (1:1 ratio), c) cis-1 withb-CD (1:1 ratio), d) cis-1. The concentration of 1 was in all cases 0.5 mM.

Fig. 3. UV/Vis absorption spectra of 1, b-CD and CB[8] (1:10:1 ratio in water, c¼ 0.05 mM) for the trans-cis (a) and cis-trans (b) conversions as induced by illumi-nation withl¼ 365 andl¼ 420 nm light, respectively

that the complexation of cis-1 by CB[8] did not affect the rate of photo-isomerization.

3. Conclusions

We have shown the dynamic complexation of the water-soluble and thermally stable molecular photo-switch 1 with two different host molecules,

b

-CD and CB[8]. In this three-component system, molecule 1 can form two stable supramolecular complexes, 1₃

b

-CD in its trans form and 13CB[8] in its cis form. Upon photo-switching, 1 could be reversibly transferred between the two host cavities. By synthetic modi_{fication of the photo-switch,}31_{the now} still rather incomplete cis-to-trans conversion may be further optimized. This competitive inclusion can be further used in the development of photoresponsive host-guest supramolecular sys-tems, such as cargo carriers, molecular logic gates, and other su-pramolecular materials.

4. Experimental section 4.1. Chemicals

CB[8] was purchased from Strem Chemicals and all other chemicals were purchased from Sigma-Aldrich. They were used as purchased, without further purification.

4.2. Synthetic procedures

Azobenzene switch 1 was synthesized in two steps. In thefirst

step, ortho-_{fluorinated benzene-azophenol (FA-OH) was} synthe-sized by a diazonium reaction. 2,6-Difluoro aniline (0.387 g, 3 mmol, 1 eq) and 1.0 mL of concentrated hydrochloric acid were dissolved in 7.5 mL of water. This solution was cooled to 0C and stirred. To this stirred solution was added a solution of sodium nitrite (0.249 g, 3.3 mmol, 1.1 eq) in water (4.5 mL) dropwise. The temperature was controlled between 0C and 5C during the addition. The resulting suspension was added to an ice bath-cooled solution of 3,5-difluorophenol (0.429 g, 3.3 mmol, 1.1 eq) and so-dium hydroxide (0.400 g, 10 mmol, 3.3 eq) in water, dropwise. The suspension was acidified with 1 M HCl to pH ¼ 2, and extracted with dichloromethane. The organic layer was collected and dried over MgSO4. Then the dichloromethane was evaporated, the mixture was puri_{fied by column chromatography, and 0.432 g of} product was isolated as a dark red solid, yield¼ 53%.1_{H NMR in} CD3CN:

d

¼ 7.49 (1H, m), 7.19 (2H, t. J ¼ 8.8 Hz), 6.69 (2H, dd, J1¼ 11.2 Hz, J2¼ 2.8 Hz) (Fig. S1).

In the second step, a mixture of FA-OH (0.084 g, 0.31 mmol, 1.5 eq), K2CO3(0.058 g, 0.42 mmol, 2 eq) and Ts-PEG (MW¼ 900 Da, 0.058 g, 0.42 mmol, 1 eq) in 7 mL of MeCN was stirred and refluxed overnight. Then the reaction mixture was cooled down to room temperature, and the MeCN was removed under vacuum. The residue was dissolved in dichloromethane, and washed with water. The organic phase was collected and dried over MgSO4. After the dichloromethane was evaporated, the mixture was purified by column chromatography, and 0.066 g of product was isolated as a dark red liquid, yield_{¼ 30%.}1_{H NMR in CDCl}

3:

d

¼ 7.27 (1H, m), 6.99 (2H, t, J¼ 8.8 Hz), 6.68 (2H, d, J ¼ 11.2 Hz), 4.14 (2H, t, J ¼ 4.4 Hz), 3.83 (2H, t, J¼ 4.8 Hz), 3.59 (48H, m), 3.50 (2H, m), 3.33 (3H, s).13_C NMR in CDCl3:

d

¼ 161.88, 157.40 (C-F, d, J ¼ 190 Hz), 155.11 (C-F, d, J¼ 185 Hz), 132.08, 130.41, 126.07, 112.51, 99.52, 71.93, 70.95, 70.56, 68.91, 59.04. From the1H NMR the molecular weight was calculated as 870, which confirmed that there is on average 13.5 ethylene glycol units on the PEG moiety. Mass spectrometry showed signals at m/z¼ 724.89, 768.88, 812.88, 856.87, 900.87, corresponding to 1 with 10e14 ethylene glycol units (Fig. S2).

4.3. Irradiation experiments

A H€onle bluepoint LED lamp was employed as a UV light source (

l

¼ 365 nm) for ex-situ NMR experiments and UV/Vis absorption measurements. Blue light (

l

¼ 420 nm) was provided by an Edmund MI-150 visible lamp equipped with an Edmund 420± 2 nm filter. The photo-stationary states were determined by 1_{H NMR in D}

2O (c¼ 0.5 mM).

For in-situ NMR experiments, a T7070 1 PowerStar LED lamp from ILS was employed as a UV light source, a N5050 1 PowerStar LED lamp from ILS was employed as a blue light source, and the opticalfibers were purchased from Edmund.

4.4. Instrumentation and methods

Ex-situ NMR data was recorded on a 400 MHz Bruker spec-trometer. In-situ NMR data was measured on a 600 MHz Bruker spectrometer by water suppression mode. The light was introduced via an optical_{fiber into the NMR tube. The total irradiation time was} 30 min, and spectra were recorded every 4 min. All chemical shifts were referenced to the internal CDCl3signal at 7.24 ppm, CD3CN at 1.94 ppm, D2O at 4.80 ppm or TSP at 0 ppm (only for water sup-pression). For UVeVis absorption and ITC titrations, stock solutions were prepared in MilliQ water. UV/Vis spectra were recorded in a conventional quartz cell in a Perkin Elmer Lambda 850 spectrophotometer.

ITC titrations were performed using a MicroCal™ VPC micro-calorimeter. Each ITC titration was performed with 60 injections of

Fig. 4.1_{H NMR spectra of the in-situ switching experiments of 1:b-CD: CB[8]¼ 1: 10:} 1 (c¼ 0.05 mM), showing (from bottom to top for 0e30 min of illumination) the a) trans-cis and b) cis-trans conversions as induced by illumination withl¼ 365 nm and

l¼ 420 nm light, respectively.

H. Huang et al. / Tetrahedron 73 (2017) 4913e4917 4916

5

m

L each. A solution of

b

-CD in water (c¼ 2.5 mM) was titrated to the trans-1 or cis-1 solution (c¼ 0.25 mM). Alternatively, a solution of trans-1 or cis-1 (c¼ 0.5 mM) was titrated to a CB[8] solution (c¼ 0.05 mM).

Acknowledgments

This work was supported by the European Research Council (Starting Grant 307784) and the Dutch Science Foundation (NWO Aspasia 015.007.007).

Appendix A. Supplementary data

Supplementary data related to this article can be found athttp:// dx.doi.org/10.1016/j.tet.2017.05.026.

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