Photo-responsive host-guest complexation directs dynamic covalent condensation of phenyl boronic acid andd-fructose

Article abstract of DOI:10.1039/d1cc00090j

Inspired by the way templates have been used to drive dynamic combinatorial libraries by molecular recognition, we exploited the photo-responsive host-guest interaction of an azo-based photoswitch with permethylated cyclodextrin to reversibly manipulate t

Full text of DOI:10.1039/d1cc00090j

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Photo-responsive host–guest complexation
directs dynamic covalent condensation of phenyl
boronic acid and D-fructose†
Cite this: Chem. Commun., 2021,
57, 3207
Received 6th January 2021,
Accepted 22nd February 2021
Florian Klepel
and Bart Jan Ravoo
*
DOI: 10.1039/d1cc00090j
rsc.li/chemcomm
Inspired by the way templates have been used to drive dynamic macrocycles with hydrazone exchange.11 The E-isomer of
combinatorial libraries by molecular recognition, we exploited the ortho-borylated azobenzene forms a N–B Lewis pair, which
photo-responsive host-guest interaction of an azo-based photoswitch increases the formation constant for the dynamic covalent
with permethylated cyclodextrin to reversibly manipulate the dynamic boronic ester formation with diols and carbohydrates.12 Kalow
covalent interaction of a phenyl boronic acid and D-fructose by irradia- et al. used this effect to develop photo-responsive hydrogels.13
tion with light.
Optimization of the azobenzene substitution enabled desirable
properties, such as higher formation constants and photo
In dynamic covalent reactions, covalent bonds are continuously stationary states (PSS).14 We note that the formation constant
broken and reformed. If the equilibration is fast enough, the of boronic esters can also be controlled pH-15 or redox-16
product distribution is under thermodynamic control.1 Thus, responsively.
the dynamic combinatorial library (DCL) will adapt to its
Our study aims to develop a dynamic covalent system which
environment and respond to stimuli such as pH,2 heat,3 responds rapidly to conformation changes of a molecular
mechanical stress4 or molecular recognition.5 Light is a particularly photoswitch. This system is based on an arylazopyrazole
attractive stimulus to modulate dynamic covalent reactions. UV (AAP), which is a class of molecular photoswitches which
light can be used as an initiator of radical dynamic covalent exhibit photoisomerization very similar to azobenzenes, but
reactions.6 Another approach towards control over dynamic cova- generally possess superior photochemical properties such as a
lent reactions by light is the incorporation of molecular photo- high PSS (close to 100%) and long half-life time.17 The n - p*
switches in DCLs. Hecht et al. developed diarylethenes whose band in AAP is red shifted compared to azobenzenes. There-
reactivity in dynamic covalent reactions can be controlled with fore, green light (l = 520 nm) can be used for E - Z photo-
light.7 In a recent example, a hydroxyl group undergoes an umpo- isomerization. AAPs in their E-form, alike azobenzenes, have
lung reaction under UV irradiation to become a ketone, which a higher binding affinity towards to host molecules such as
participates in dynamic imine chemistry.8 Blue light can reverse b-cyclodextrin (b-CD) than the corresponding Z-isomers. The
this process.
hostguest interaction is therefore photo-responsive. For this
Azobenzenes have also been used to modulate DCLs. Jurczak purpose, we synthesized an AAP with a boronic acid group in
et al. used azobenzene carboxylates as templates for dynamic the meta-position, which allows for dynamic covalent inter-
disulfide macrocycles.9 Photoisomerization of the azo group action with diols such as D-fructose (bAAP, Fig. 1).
(UV light: E - Z, blue light: Z - E) caused shifts in the DCL
composition. Beeren et al. used the photoresponsive azoben-
zene–cyclodextrin interaction to select for a- or b-cyclodextrin
(a- or b-CD) in a dynamic enzyme driven transglycosylation.10
Azobenzenes can also engage directly in dynamic covalent
reactions. Marcey et al. reported a DCL of azobenzene
Center for Soft Nanoscience and Organisch-Chemisches Institut,
¨
¨
¨
¨
Westfalische Wilhelms-Universitat Munster, Busso-Peus-Strasse 10, Munster 48149,
Germany. E-mail: b.j.ravoo@uni-muenster.de
Fig. 1 Dynamic covalent condensation of phenyl boronic acid bAAP and
diol D-fructose.
† Electronic supplementary information (ESI) available: Experimental procedures,
synthesis, calculations, additional data. See DOI: 10.1039/d1cc00090j
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Fig. 2 (A) 1H-NMR of bAAP in D2O after irradiation with UV light (left) and green light (right) for determination of the photo stationary state (PSS). Signals
of the methyl groups on the AAP moiety normalized to a total of 2.00. (B) Top: UV/Vis spectra of bAAP as synthesized, after irradiation with green light and
UV light. Bottom: Photoswitching over 5 cycles.
For synthesis of bAAP 3-bromoaniline was used as starting
Table 1 Thermodynamic data of host molecules binding to bAAP as
material since borylated derivatives yielded no stable product
determined by ITC
during diazotation. The bromide was substituted in a Miyaura
DG [kJ
DH [kJ
DS [J molÀ1
KÀ1
borylation. bAAP also includes a hydrophilic chain for better
water solubility. bAAP exhibits excellent photo physical proper-
ties, such as a long half-life time of t1/2 = 13 d (Fig. S1, ESI†), a
high photo stationary state of PSSE–Z = 91% (Fig. 2A) and fully
reversible switching behavior over several cycles (Fig. 2B).
While esters of the E- and Z-isomer with D-fructose should
have roughly the same formation constant, steric shielding of
the boronic acid function by a host–guest interaction of AAPs
Light
Host
K [MÀ1
]
molÀ1
]
molÀ1
]
]
Green
UV
Green
UV
Green
UV
b-CD
8.2 Â 102
9.3 Â 102
24.6 Â 102
30.6 Â 102
14.5 Â 102
5.3 Â 102
À16.6
À16.9
À19.3
À19.9
À18.0
À15.6
À7.0
À10.6
À2.6
À3.5
À6.4
À1.9
32.1
21.4
56.1
55.1
39.1
45.8
CB[8]
Me-b-CD
and CDs should drive the equilibrium towards hydrolysis. Both interaction with D-fructose is very similar in strength to unsub-
types of interactions, covalent and non-covalent, are dynamic stituted phenyl boronic acid (PBA, K = 43.7 Â 102 MÀ1).18 The
and therefore compete for unbound bAAP. Consequently, since Z-isomer is slightly more acidic (pKa = 8.43, Fig. S3, ESI†) than the
the strength of the host–guest interaction is photo-responsive, E-isomer (pKa = 8.55). It is generally assumed that changes in pKa
the boronic acid diol condensation is modulated as well affect the equilibrium of the ester formation.19 Fortunately, a
(Fig. 3). Such a supramolecular system can be considered a higher formation constant of the Z-isomer aids our goal, since it is
photo-responsive D-fructose receptor or alternatively a dual- also this isomer that is designed to form more boronic ester with
responsive host–guest interaction.
D-Fructose in presence of the host. Notably, this is the opposite
The individual interactions were characterized by isothermal behavior regarding boronic ester formation constants of E- and
titration calorimetry (ITC, summarized in Table 1). First the ester Z-isomers compared to ortho-substituted azobenzene boronic
formation with D-fructose was confirmed (Fig. S2, ESI†). With acids.12,13
formation constants of K = 43.3 Â 102 MÀ1 after irradiation with
We previously used b-CD20 as well as CB[8]21 as a host for
green light and K = 60.5 Â 102 MÀ1 with UV light respectively, the photo-responsive interactions. Unfortunately, while both hosts
Fig. 3 A competitive equilibrium shifts by photo-responsive host guest chemistry. Green light (520 nm) shifts the equilibrium towards host guest
complexation. UV light (350 nm) shifts the equilibrium towards the bAAP-D-fructose ester.
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bind to bAAP, only minor changes in the binding affinity can be shows a minimum at l = 422 nm and a maximum at l = 323 nm
observed (Fig. S4 and S5, ESI†). The boronic acid moiety might (Fig. 4A). The Z-isomer exhibits an axial chirality because of its
be too polar and sterically too demanding for the b-CD cavity. twisted structure. However, when bAAP by itself is converted to
Also, while the ester formation constant of D-glucose and PBAs the Z-isomer, no axial enantiomer is preferred causing
is low, it cannot be ruled out that bAAP reacts covalently to the a racemic mixture. Since the Z-isomer binds only weakly to
b-CD hydroxyl groups, which might interfere with the host– Me-b-CD, photoisomerization of bAAP with UV-light in the
guest interaction. While selectivity remains poor, CB[8] binds presence of the host does not significantly influence axial
somewhat stronger to the Z-isomer. Additionally, considering chirality and the observed CD signal remains weak. For the
that the Z-isomer also reacts more readily with D-fructose, we bAAP-fructose ester, a different behavior is observed. Upon
would likely observe little effect in the dual system. We subse- irradiation with UV-light, a maximum at l = 440 nm and a
quently tested permethylated b-CD (Me-b-CD), which not only minimum at l = 305 nm are observed (Fig. 4B). This hints at a
inhibits boronic acid esterification, but also offers a larger and preference of one of the enantiomers, though the relatively
more flexible opening of the hydrophobic cavity.22
weak signal might indicate a low enantiomeric excess. The
Indeed, ITC confirms photo-responsive hostguest inter- E-isomer of the ester does not cause a CD signal, likely because
action of bAAP with Me-b-CD. The binding constant after the AAP moiety and the fructose can rotate easily around the
irradiation with green light (K = 14.5 Â 102 MÀ1, Fig. S6, ESI†) C–B bond. Notably the intensity of the spectrum is reversed for
is roughly three times higher than after irradiation with UV the interaction with L-fructose (Fig. 4C).
light (K = 5.3 Â 102
M
À1, Fig. S6B, ESI†). The host guest
The concentrations of the hostguest complex and ester can
interaction is entropy driven (DS = 39.1 to 45.8 J molÀ1
K
À1). be calculated by applying the binding constant measured by
Large positive DS values for host guest complexes with b-CD are ITC. Since only the host guest complex or ester contribute
usually attributed to release of water from the host cavity significantly to the CD signal if observed at the PSS (either
caused by a hydrophobic interaction.23
UV-light: E - Z, green light: Z - E), also unknown concentra-
Further characterization of the system was performed using tions, such as in a mixture of all three components, can be
CD spectroscopy. This method can be used to detect UV/Vis quantified. Fig. 4D and E show such a tertiary system. The
active chiral species in enantiomeric excess. The planar E-bAAP system can be fully reversibly cycled between both states by
is not chiral, but it can form a chiral host guest complex due to alternating irradiation with UV and green light (5 min each) for
the interaction with the chiral Me-b-CD cavity. The CD signal at least 5 times (Fig. 4D). CD signal intensities are lower
Fig. 4 CD spectra of bAAP (500 mM) after irradiation with UV or green light in presence of (A) Me-b-CD (4500 mM), (B) D-fructose and (C) L-fructose.
(D) Top: CD spectra of a solution of bAAP (500 mM), D-fructose (2000 mM) and Me-b-CD (4500 mM). Bottom: CD signals at 440 nm and 305 nm plotted
over 5 switching cycles. (UV followed by green irradiation.) (E) Comparison of experimentally observed and calculated concentrations according to the
model (see ESI†).
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offers significant potential for development of supramolecular
materials and systems that are dual responsive to signaling
molecules and light.
We are grateful to the Deutsche Forschungsgemeinschaft
(DFG SFB 858) for funding.
Conflicts of interest
There are no conflicts to declare.
Notes and references
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