A Dynamic Hydrogen-Bonded Azo-Macrocycle for Precisely Photo-Controlled Molecular Encapsulation and Release

Article abstract of DOI:10.1002/anie.201906912

A light-responsive system constructed from hydrogen-bonded azo-macrocycles demonstrates precisely controlled propensity in molecular encapsulation and release process. A significant decrease in the size of the cavity is observed in the course of the E→Z photoisomerization based on the results from DFT calculations and traveling wave ion mobility mass spectrometry. These macrocyclic hosts exhibit a rare 2:1 host–guest stoichiometry and guest-dependent slow or fast exchange on the NMR timescale. With the slow host–guest exchange and switchable shape change of the cavity, quantitative release and capture of bipyridinium guests is achieved with the maximum release of 68 %. This work underscores the importance of slow host–guest exchange on realizing accurate release of organic cations in a stepwise manner under light irradiation. The light-responsive system established here could advance further design of novel photoresponsive molecular switches and mechanically interlocked molecules.

Full text of DOI:10.1002/anie.201906912

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Accepted Article
Title: A Dynamic Hydrogen-Bonded Azo-Macrocycle for Precisely
Photo-Controlled Molecular Encapsulation and Release
Authors: Zecong Ye, Zhiyao Yang, Lei Wang, Lixi Chen, Yimin Cai,
Pengchi Deng, Wen Feng, Xiaopeng Li, and Lihua Yuan
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201906912
Angew. Chem. 10.1002/ange.201906912
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10.1002/anie.201906912
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A Dynamic Hydrogen-Bonded Azo-Macrocycle for Precisely
Photo-Controlled Molecular Encapsulation and Release
Zecong Ye,[a] Zhiyao Yang,[a] Lei Wang,[b] Lixi Chen,[a] Yimin Cai,[a] Pengchi Deng,[a] Wen Feng,[a]
Xiaopeng Li,[b] and Lihua Yuan*[a]
Abstract: A light-responsive system constructed from hydrogen-
bonded azo-macrocycles demonstrates precisely controlled
propensity in molecular encapsulation and release process. A
significant decrease in the size of the cavity is observed in the
course of the E-Z photoisomerization based on the results from DFT
calculations and traveling wave ion mobility mass spectrometry.
These macrocyclic hosts exhibit a rare 2:1 host-guest stoichiometry
and guest-dependent slow or fast binding process on the NMR
timescale with a positive cooperativity. The host-guest behavior is
also corroborated by the findings from both the solid-state and
solution. With the slow host-guest exchange and switchable shape
change of the cavity, quantitative release and capture of bipyridinium
guests is achieved with the maximum release of 68%. This work
provides accurate and time-resolved control over the release
process, underscoring the importance of slow host-guest exchange
on achieving stepwise release of organic cations under light
irradiation. The light-responsive system established here could
advance further design of novel photoresponsive molecular switches
and mechanically interlocked molecules in supramolecular chemistry.
systems rely on light-responsive guests rather than light-
responsive hosts. This is largely due to a lack of molecular
strategy in constructing a photoresponsive host that can
undergo efficient photoisomerization and exhibit sufficient
changes in binding affinity upon isomerization.[14] In effect,
design of host macrocycles based on controllable pohto-
isomerization of steroisomers for stepwise or precise on-demand
release still represents a formidable task. To date, none of the
reported photoresponstive macrocycles is able to achieve
quantitatively controlled release of guest. This calls for a
molecular design of such hosts that allow for engulfing a guest
with sufficiently high affinity to ensure a slow H-G exchange on
the NMR time scale, but are also able to release the guest via,
e.g., cis-trans isomerization of azo-benzene subunits as a result
of decreased cavity shape. In our view, hydrogen-bonded (H-
bonded) macrocyles,[15] with their molecular backbones
containing optically photoresponsive moities, may constitute a
solution to this issue. Here, we report the design and synthesis
of photoresponsive azo-macrocycles 1 (Scheme 1) that integrate
molecular rigidity with a certain degree of flexibility amenable to
configurational change upon E-Z photoisomerization for
molecular encapsulation and precisely controllable release of
Manipulation of molecular encapsulation and release has long
been an active research subject that engenders wide interests
from chemists in mimicking the reversible binding processes of
biomolecules and proteins in nature.[1] The design of a variety of
well-defined artificial host systems ensues from this activity,
particularly those associated with implementation of allosteric
control[2] in response to external stimuli.[3] Of various stimuli,
utilization of light for controlling guest encapsulation presents
extraordinary advantages in that it enables fast response and
remote control over guest uptake and release.[4] In this regard,
crown ethers,[5] cyclodextrins,[6] calixarenes,[7] cucurbiturils,[8]
pillarenes,[9] metal–organic cages,[10] and other systems[11] with
molecular switches, either appended to the host or as a guest
molecule, are among the most studied hosts in creating efficient
photoresponsive host-guest (H-G) systems. Elegant examples
from recent reports include the use of flexible molecular boxes
containing azobenzene units for anion recognition,[12] and
tetracationic cyclophane incopoprated with photoactive elements
for binding and releasing reversibly aromatic molecules.[13] So
far, most of the known photocontrolled uptake and release
[a]
Z. C. Ye, Z. Y. Yang, L. X. Chen, Y. M. Cai, P. C. Deng, Prof. W.
Feng, Prof. L. H. Yuan
College of Chemistry, Key Laboratory for Radiation Physics and
Technology of Ministry of Education, Analytical and Testing Center,
Sichuan University, Chengdu 610064, China
E-mail: lhyuan@scu.edu.cn
[b]
L. Wang, Prof. X. P. Li
Department of Chemistry, University of South Florida, Tampa,
Florida 33620, United States
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. (a) Synthesis of azo-macrocycles 1a-1c, (b) photoisomerization of
1a, and (c) molecular guests G1-G4 used in this study.
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10.1002/anie.201906912
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guest species. In approaching this design, we utilized
intramolecular H-bonds to rigidify parts of the macrocyclic
backbone that ensures introvertion of amide oxygens available
for entrapping guests, while at the same time, incorporated azo-
groups to form remaining parts of the framework. Different from
previously reported azobenene-based macrocycles,[14] free
rotation of the phenylene spacers in 1 was restricted, thus
absorption band at max 337 nm and a weaker n–* absorption
band at max 445 nm. Upon exposure to UV irradiation at 365 nm,
1a experiences a dramatic decrease in the absorbance of the –
* band and a slight increase in the n–* absorbance over time,
indicating the E→Z photoisomerization. The photo-stationary
state is achieved in less than 1 min. Reversible conversion is
observed upon irradiation with blue light (BL) at 450 nm (Figure
S14). The interconvertible process of the photo-isomers could
be recycled for over 5 times without photo-fatigue (Figure S15).
These results suggest that the intrinsic photoisomerization
properties of the azo-benzene units, as seen in conventional
azo-macrocycles,[14] are retained after incorporation into the H-
bonded macrocycle.
locking the trans-configuration into
a planar shape with
functional groups pointing inwards. Recognition and release of
bipyridinium salts G1-G4 is achieved upon photoirradiation. The
quantitative release of viologen cations (G1, G2) is manipulated
by controlling irradiation time based on a slow H-G exchange
process.
Three azo-macrocycles 1a-1c were synthesized. Oxidation
of 2-alkoxy-5-amino-benzoate 9 by molecular oxygen in the
presence of metal copper (0), followed by hydrolysis with NaOH,
provided azo-diacid, which was then converted to diacyl chloride
12. Coupling reaction with Boc-protected compound 6 led to the
formation of the oligomer 13. Deprotection and the subsequent
coupling reaction with azo-diacid 12 provided the desired azo-
macrocycles 1a-1c as a yellow solid in yields of 73-78%
(Scheme S1). The high yield of cyclization derives largely from
the folding of oligomeric precursors via steric remote effect and
To retrieve information of all possible isomers from UV
irradiation, 1H NMR experiments were carried out in CDCl3.
Freshly prepared solution of 1a exhibits six distinct resonances
in aromatic and amide regions, corresponding to the E,E-1a as
the sole isomer (Figure S18a). Upon irradiation with UV light
(365 nm), two new sets of signals appear in the 6.4–10 ppm
region. The set with strong intensity is attributed to the Z,Z-
isomer as observed in most photoresponsive azo-macrocycles
(Figure S18).[14] The set of the weak signals, comprising four
singlets and several doublets and multiplets, reveals the loss of
symmetry of the molecular backbone, and thus suggests the
formation of E,Z-1a as the minor isomer in solution (Figures
S19-21). Taken together, these observations indicate that the
light-induced E→Z isomerization produces a mixture of three
different stereoisomers which, at the photostationary state, can
be identified as E,E-1a (10%), E,Z-1a (20%), and Z,Z-1a (70%).
While thermal conversion of Z,Z-1a to E,E-1a takes more than
11 days (Figure S22), irradiation with blue light induces a
complete conversion in less than 10 min (Figure S18e), which
indicates the high photosensitiveness for such an azo-
macrocycle.
1
intramolecular H-bonds.[16] The H NMR spectra, together with
different types of molecular characterizations, confirmed the
identities of all the precursors and macrocycles (Figures S1-
S13). Analysis of single crystal structure of 1b (Figures 1a and
S72), which shares the same backbone as 1a but bears shorter
side chains instead, reveals desired E configuration for both azo
groups, and a cavity that measures 8.3 Å between the two
diagonally arranged oxygen atoms. Given the fact that
cyclo[6]aramide (8.17 Å) in our prior work is capable of binding
bipyridinium salts,[15e] we envisioned that this H-bonded
macrocycle can also strongly bind a guest such as
a
bipyridinium cation (4.3 Å).
Results from DFT calculations (B3LYP/6-31G(d,p), Figures
S23-25) revealed a significant decrease in the size of the cavity
and an increase of energy (Figure S26) of 1 upon E → Z
photoisomerization. Consistent with this conclusion is the
observation from traveling wave ion mobility mass spectrometry
(TWIM-MS) experiments (Figures 2 and S27-28). TWIM-MS
technique is known to be an advanced tool for differentiating
isomers, particularly when the change of molecular shape is
involved.[17] The presence of three drift time peaks of [1a+2H]2+
corresponding to the same m/z value clearly indicates the
existence of three isomers. It is noticeable that the peak of Z,Z-
Figure 1. X-ray crystal structures of (a) azo-macrocycle E,E-1b (top view) and
(b) E,E-1b (side view), (c) rotaxane [3]R-C5 containing a structure similar to
E,E-1b2⊃G1 (side view). (d) Geometry-optimized molecular structure
(B3LYP/6-31G(d,p)) of E,E-12⊃G3 (side view). All peripheral R1-R3 groups are
replaced by CH3 for simplicity. The counterions, solvent molecules and some
of the hydrogens have been omitted for clarity.
The light-induced isomerization of 1 was first probed by
electronic absorption spectroscopy. A freshly prepared solution
of the azo-macrocycle exhibits a strong characteristic –*
Figure 2. (a) ESI-MS spectra and (b) TWIM-MS plot (m/z vs drift time) of 1a
after UV irradiation.
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10.1002/anie.201906912
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isomer appeared at 5.51 ms, while E,E-isomer and E,Z-isomer
showed up at 6.96 and 6.29 ms, respectively. The shorter drift
time for Z,Z-1a indicated a more compact structure with respect
to that of E,E or E,Z-1a, thereby offering the possibility to
extrude guest out of the cavity.
H-bonding and N+···O ion-dipole interactions that are reinforced
by face to face - stacking interactions (Figure S73). Therefore,
the strong positive cooperativity in binding the guest with 1a
should originate from the cooperative interplay of multipoint
weak interactions. The energy-minimized structures for 1a2⊃G1
and 1a2⊃G3 complexes from DFT calculations also provide
evidence for the observed stabilization of the encapsulated
guests (Figures 1d and S57-59).
Given the presence of four introverted electron-rich carbonyl
oxygen atoms in the cavity, the H-bonded azo-macrocycles are
expected to accommodate small electron-deficient cationic
guests. Therefore, bipyridinium salts G1-G4 (Scheme 1) were
selected to test the encapsulation of guests in CDCl3/CD3CN
(1:1, v/v). In all cases, proton resonances of guests shifted
downfield and aromatic resonances associated with internal
protons changed differently (Figures S29-S32), indicative of H-G
complexation. For example, in the case of 1a, protons H1 and H2
of G1 experience a downfield shift (∆δ = 1.1, 1.33 ppm). Two
signals from free guest are observed in the presence of one
equiv. of G1, and disappear upon addition of second equiv. of
the host (Figure 3a-3c). This indicates a slow exchange between
host and guest on the NMR time scale. In sharp contrast, the
binding of G3, a structural isomer of G1, exhibits a fast
exchange (Figure S31). Interestingly, a 2:1 binding mode is
obtained for 1a and 1b and all guests examined (Figures S33-
40).
To further explore the encapsulation potential of the azo-
macrocycles, UV-vis titration experiments (Figures S41-48) were
conducted in CHCl3/CH3CN (1:1, v/v). A large binding constant
up to 1012 M-2 was achieved with 4K2/K1 ＞ 14 (Table 1),
indicating a positive cooperativity in the binding event. The
formation of the 2:1 complexes is also evidenced by 2D NOESY
and mass spectrometry (Figures S49-56). Another piece of
supportive evidence for the 2:1 complex 1a2 ⊃ G1 is from
analysis of the single crystal structure of its analogue, a
[3]rotaxane (Figure 1c) formed through one-pot synthesis with
an isolated yield of 85%. In this tightly packed complex, G1 is
inserted into two macrocycles, being orientated obliquely with
respect to the two wheels and engaged in multiple C−H···O
Table 1. Association constantsa for complexation of various guests (G1-
G4) by host 1a in CHCl3/CH3CN (1:1, v/v) at 298 K.
K1/M-1
(× 104)
5.7 ± 0.6
58 ± 7.0
0.37 ± 0.07
0.18 ± 0.06
K2/M-1
(× 105)
7.2 ± 0.8
20 ± 2.4
8.8 ± 1.8
4.7 ± 1.5
K12/M-2
(× 1010)
4.10
119
0.32
b
Guest
NMR
H-G Exchange
Slow
G1
G2
G3
G4
50
14
96
101
Slow
Fast
Fast
0.09
a The association constant Ka values were obtained by UV-vis titration spectroscopy†,
b
with the concentration of the host fixed at 50 μM;  represents the cooperativity
factors and is defined as  = 4K2/K1.
Upon the exposure of the 1a2⊃G1 complex to UV light
irradiation, the E→Z isomerization of the host occurred, leading
to the release of G1. The first indication for the release of G1
came from the 1H NMR spectra, which exhibit significantly
upfield-shifted H1 and H2 resonances (∆δ = 1.0, 1.29 ppm)
(Figures 3c-d and S64). This result can be attributed to the
larger binding affinity of E,E-1a with G1 compared to Z,Z-1a
isomer. Indeed, when G1 was added into a Z-predominant
isomeric mixture of 1c, much smaller chemical shift changes (∆δ
= 0.15, 0.04 ppm) for protons from the guest were observed
when compared to those for the same protons in 1c2⊃G1 (∆δ =
1.12, 1.36 ppm) (Figure S62). Most protons from host backbone
were shifted downfield, rather than upfield, indicating the
destruction of the tight 2:1 complex because of the substantial
decrease in cavity size going from E,E-1c to Z,Z-1c. Additionally,
favourable orientation of amide oxygens towards the interior of
the cavity is lost upon UV light irradiation, lessening the
originally established concerted H-bonding interactions between
the host and guest. This was supported by the calculated
structures of Z,Z-1 and Z,Z-1⊃G1 complex (Figures S60-61).
With the slow exchange for 1a and G1/G2, the possibility of
quantitative release of guests under various irradiation time was
explored. Upon increasing the UV irradiation time for 1a2⊃G1, a
steady decrease in the intensity of the signals for the bound
guest was observed along with increases in signals of the free
guest (Figures 4 and S63). Integration of these two different
types of protons allows calculation of the percentage of the
released guest. Specifically, after UV irradiation for 6 min, 18%
of the G1 was released, followed by another 16% for 4 min.
Finally, the maximum release of 67% was achieved at 25 min
(Figures 4, S64), which is very close to the amount of Z,Z-1a
(70%) among three isomers in the photostationary state.
Nevertheless, a reverse guest-catching process under blue light
is completed rapidly in only 3 min (Figures S65-66). The light-
controlled catch-and-release process is almost the same for 1a2
⊃ G2 (Figure S68), but different from those H-G systems
exhibiting fast exchange process, where the bound guest G3 (or
G4) and free guest coexist indiscriminately in the 1H NMR
spectra (Figures S69-70). We deem that the marriage of
balanced rigidity associated with internal hydrogen bonds and
photo-switchable azo groups provides a semi-rigid framework
with introverted amide oxygen atoms that allow only the guest
Figure 3. Partial 1H NMR spectra (CDCl3/CD3CN, 1:1, v/v) of (a) G1, (b) 1a:G1
= 1:1, (c) 1a:G1 = 2:1, (d) 1a:G1 = 2:1 after UV irradiation, (e) 1a, (f) 1a:G3 =
2:1 after UV irradiation, (g) 1a:G3 = 2:1 before UV irradiation and (h) G3.
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The slow host-guest exchange as a result of the unique 2:1
binding strengthened by the strong positive cooperativity is
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Figure 4. Photocontrolled host-guest systems. Schematic representation of
photocontrolled stepwise quantitative release and capture of guest G1
(viologen) from host 1a (azo-macrocycle).
In conclusion, we have demonstrated how carefully desi-
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encapsulation of guests in a precise manner via a slow
exchange process of the host-guest complexation. The
combination of molecular photo-switches into optimized organic
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Acknowledgements
This work is supported by the National Natural Science
Foundation of China (21572143) and Open Project of State Key
Laboratory of Supramolecular Structure and Materials
(SKLSSM201831). Analytical & Testing Center of Sichuan
University is acknowledged for NMR analysis (Dr. Deng).
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Keywords: host-guest systems • hydrogen-bonded macrocycle
• photochemistry • precise release • supramolecular chemistry
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Page No. – Page No.
A Dynamic Hydrogen-Bonded Azo-
Macrocycle for Precisely Photo-
Controlled Molecular Encapsulation and
Release
Text for Table of Contents
A photoresponsive host-guest system based on hydrogen-bonded azo-macrocycles and viologen in slow exchange demonstrates
precisely controlled molecular encapsulation and release in a stepwise manner. The results highlight the potential application for
more advanced photocontrolled molecular machines.
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