Hydrophilic Oligo(lactic acid)s Captured by a Hydrophobic Polyaromatic Cavity in Water

Article abstract of DOI:10.1002/anie.201800432

Biologically relevant hydrophilic molecules rarely interact with hydrophobic compounds and surfaces in water owing to effective hydration. Nevertheless, herein we report that the hydrophobic cavity of a polyaromatic capsule, formed through coordination-driven self-assembly, can encapsulate hydrophilic oligo(lactic acid)s in water with relatively high binding constants (up to K_a=3×10⁵ m^?1). X-ray crystallographic and ITC analyses revealed that the unusual host–guest behavior is caused by enthalpic stabilization through multiple CH–π and hydrogen-bonding interactions. The polyaromatic cavity stabilizes hydrolyzable cyclic di(lactic acid) and captures tetra(lactic acid) preferentially from a mixture of oligo(lactic acid)s even in water.

Full text of DOI:10.1002/anie.201800432

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Hydrophilic Oligo(Lactic Acid)s Captured by a Hydrophobic
Polyaromatic Cavity in Water
Authors: Shunsuke Kusaba, Masahiro Yamashina, Munetaka Akita,
Takashi Kikuchi, and Michito Yoshizawa
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201800432
Angew. Chem. 10.1002/ange.201800432
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10.1002/anie.201800432
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Hydrophilic Oligo(Lactic Acid)s Captured by a Hydrophobic
Polyaromatic Cavity in Water
Shunsuke Kusaba,[a] Masahiro Yamashina,[a] Munetaka Akita,[a] Takashi Kikuchi,[b] and Michito
Yoshizawa*[a]
Abstract: Bio-related hydrophilic molecules rarely interact with
hydrophobic compounds and surfaces in water due to effective
hydration. Nevertheless, here we report that the hydrophobic cavity
of a polyaromatic capsule, formed through coordination-driven self-
assembly, can encapsulate hydrophilic oligo(lactic acid)s in water
with relatively high binding constants (up to Ka = 3 × 105 M–1). The X-
ray crystallographic and ITC analyses revealed that the unusual
host-guest behavior is caused by enthalpic stabilization through
multiple CH-π and hydrogen bonding interactions. By the
polyaromatic cavity, hydrolyzable cyclic di(lactic acid) is stabilized
and tetra(lactic acid) is preferentially captured from a mixture of
oligo(lactic acid)s even in water.
bound from a mixture of oligo(lactic acid)s by the polyaromatic
cavity even in water.
Hydrophilicity and hydrophobicity are essentially incompatible so
that bio-related hydrophilic molecules and oligomers rarely
interact with hydrophobic molecules, surfaces, and pockets.[1]
There are a large number of reports on molecular cages and
capsules possessing hydrophobic cavities to efficiently bind
hydrophobic molecules in water predominantly through
hydrophobic effects.[2] However, hydrophilic bio-oligomers
comprising, e.g., amino acids with polar side chains, nucleic
acids, and saccharides are entirely hydrated in water (Figure 1a,
left) and thereby most of previously reported hydrophobic
cavities hardly or weakly interact with these substrates in
aqueous media.[3] We have recently found by chance that
molecular capsule 1 (Figure 1b),[4] which has a hydrophobic
cavity fully surrounded by multiple polyaromatic panels, enables
the selective encapsulation of hydrophilic and water-stable D-
sucrose from a mixture of natural disaccharides in water.[5] This
unusual finding stimulated us to explore the host capability of 1
toward hydrophilic and labile bio-related oligomers, oligo(lactic
acid)s, which so far could not be bound by previous synthetic
cages and capsules in water.[6]
Lactic acid (2a) is a unique biomolecule capable of self-
polycondensation upon simple heating. The monomer and
condensed oligomers (e.g., 3 and 4; Figure 1c) are hydrophilic
due to providing multiple hydrogen bonding sites. The hydrolytic
lability of the oligo- and poly(lactic acid)s has attracted much
interest for the development of biodegradable functional
materials.[7] Nevertheless, their supramolecular interactions
remain unclear at the molecular level[8] and the detailed host-
guest studies in aqueous solutions have been unregistered to
date.[9] Here we present that the polyaromatic cavity of capsule 1
functions as a synthetic container[10] for hydrophilic oligo(lactic
acid)s 3 and 4 in water (Figure 1a, right). Detailed NMR, ESI-
TOF MS, X-ray crystallographic, and isothermal titration
calorimetry (ITC) analyses reveal that multiple CH-π and
hydrogen bonding interactions contribute to the observed
aqueous host-guest behavior possibly assisted by solvent
effects. In addition, we report that the hydrolysis of cyclic
di(lactic acid) is suppressed and tetra(lactic acid) is favorably
Figure 1. a) Schematic representation of the encapsulation of a hydrophilic
bio-oligomer in water by the hydrophobic polyaromatic cavity of a molecular
capsule. b) Polyaromatic capsule 1 (R = -OCH2CH2OCH3) with a hydrophobic
cavity and c) mono- and oligo(lactic acid)s 2-4 as hydrophilic substrates.
For facile monitoring host-guest interactions by 1H NMR
spectroscopy, we initially examined the interaction of capsule 1
with dimethylated lactic acid 2b in water. When a mixture of 1
(0.27 µmol) and 2b (0.54 µmol) was stirred in D2O (0.5 mL) at
room temperature, 1:2 host-guest complex 1•(2b)2 was formed
quantitatively within 10 min (Figure 2a).[11] Although 2b is well
soluble in water (>1.0 M) and cannot be extracted with common
organic solvents from water, the resultant host-guest structure is
stable enough for the characterization by standard NMR, MS,
and X-ray crystallographic analyses. The 1H NMR spectrum
clearly showed six methyl signals derived from encapsulated
(2b)2 in the range of –2.26 to 0.34 ppm (Figure 2c).[12] The large
upfield shifts (Δδmax = –3.75 ppm), compared with free 2b in D2O,
are caused by aromatic shielding effects within the shell of 1.
Quantitative formation of the 1:2 host-guest complex relative to 1
was confirmed by the 1H NMR integration and ESI-TOF MS
analysis. Prominent MS peaks observed at m/z 1246.0 and
[a]
S. Kusaba, Dr. M. Yamashina, Prof. Dr. M. Akita, Dr. M. Yoshizawa
Laboratory for Chemistry and Life Science
Institute of Innovative Research, Tokyo Institute of Technology
4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan
E-mail: yoshizawa.m.ac@m.titech.ac.jp
[b]
Dr. T. Kikuchi
Rigaku Corporation
3-9-12 Matsubaracho, Akishima, Tokyo 196-8666, Japan
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201800432
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– n+
919.0 were assigned to the [1•(2b)2 – n•NO3 ] species (n = 3
and 4, respectively; Figures 2d). Detailed host-guest interactions
were clarified by the single crystal X-ray analysis.[11,13] In the
crystal structure, two molecules of 2b occupy the isolated cavity
(0.5 mL) at room temperature gave rise to 1:1 host-guest
complex 1•3a (Figure 3a, top). The instant (<10 min) and
1
quantitative complex formation was evidenced by H NMR and
ESI-TOF MS analyses (Figure S12-15).[11] Proton signals
derived from the methyl and methine groups of 3a were
observed around –2.2 and 1.2 ppm, respectively, indicating the
encapsulation of 3a within 1 (Figure 3b). No proton signals
of
1 (Figure 2e, left), in which (i) two host-guest CH-
π (anthracene panel) interactions, (ii) seven host-guest
hydrogen bonding interactions between the pyridine α-
hydrogens (Hf) and the carbonyl groups,[14,15] and (iii) three
guest-guest hydrogen bonding interactions are observed (Figure
2e, right).
1
corresponding to empty 1 were found in the spectrum. The H
DOSY NMR spectrum indicated that the observed host and
guest peaks are derived from a single species (Figure S14).[11]
The ESI-TOF MS spectrum displayed marked peaks at m/z
– n+
1221.3 and 900.5 derived from the [1•3a – n•NO3 ] species (n
= 3 and 4, respectively; Figures S15).[11]
Figure 3. a) Encapsulation of linear di(lactic acid) 3a and the cyclic derivative
3b by capsule 1 in water. 1H NMR spectra (500 MHz, D2O, r.t.) of b) 1•3a and
c) 1•(3b)2. d) Hydrolysis of 3b (%) within/without 1 in water at r.t.
Figure 2. a) Host-guest interactions between capsule 1 and lactic acid 2a or
the dimethylated derivative 2b in water. 1H NMR spectra (500 MHz, D2O, r.t.)
of b) 1 and c) 1•(2b)2. d) ESI-TOF MS spectrum (H2O, r.t.) of 1•(2b)2. e) X-ray
crystal structure of 1•(2b)2 (the peripheral substituents are replaced by
hydrogen atoms for clarity) and the highlighted host-guest and guest-guest
interactions (red and blue dash lines are CH-π and hydrogen bonding
interactions, respectively).
In contrast to 3a, two molecules of cyclic di(lactic acid) 3b,
so-called lactide, were readily encapsulated by capsule 1 in a
quantitative fashion under the same conditions described above
(Figure 3a, bottom). The structure of 1:2 host-guest complex
1•(3b)2 was confirmed by detailed NMR (Figure 3c) and ESI-
TOF MS analyses.[11,16] It is worthy of note that encapsulated
lactides (3b)2 are stabilized toward hydrolysis due to isolation
from the aqueous phase by the polyaromatic shell of 1, whereas
free 3b is promptly hydrolyzed in water at room temperature to
form 3a. Although the hydrolysis of free 3b was completed for
~30 h, only 23% of 3b within 1 was hydrolyzed under the same
conditions (Figure 3d). In the 1H NMR spectra of 1•(3b)2 in D2O,
upfield-shifted signals for encapsulated (3b)2 around –1.9 and
1.1 ppm decreased slowly due to the hydrolysis (Figure S21).[11]
The relative hydrophobicity of 3b is higher than that of 3a so that
the competitive binding experiment of 3a and 3b with 1 in water
resulted in the selective formation of 1•(3b)2.
In contrast to dimethylated 2b, no host-guest interaction
was observed between capsule 1 and lactic acid 2a even under
various conditions (Figure S8-9).[11] Alternately, monomethylated
lactic acids 2c (X = -CH3, Y = -H) and 2d (X = -H, Y = -CH3)
1
weakly interacted with 1 in water at room temperature. In the H
NMR spectra, the host aromatic signals were definitely shifted
and the guest aliphatic signals were greatly broadened due to
host-guest interactions in the cavity of 1 (Figure S10-11).[11]
Competitive host-guest interactions of 1 with the lactic acid
monomers demonstrated the preferential binding series of 2b >>
2c ≈ 2d >> 2a. On the basis of these findings, we presumed that
hydrophilic oligo(lactic acid)s, which provide multiple methyl and
carbonyl groups, could be encapsulated in the polyaromatic
cavity of capsule 1 even in water through multiple host-guest
CH-π and hydrogen-bonding interactions.
Next, we evaluated the binding ability of capsule 1 toward
oligo(lactic acid)s in water. The minimum volume (~430 Å3)[17] of
the cavity of 1 is large enough to bind one molecule of up to
penta(lactic acid), a calculated volume of which is 350 Å3. A
mixture of oligo(lactic acid)s, prepared by thermal condensation
of 2a under neat conditions (100 ºC, 10 h), contained di(lactic
Expectedly, linear di(lactic acid) 3a and the cyclic
derivative (3b) were also captured in the cavity of 1 in water.
Simple mixing capsule 1 (0.27 µmol) and 3a (0.54 µmol) in D2O
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10.1002/anie.201800432
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acid) to octa(lactic acid), as confirmed by ESI-TOF MS analysis
(Figure S23).[11] All of the obtained oligomers were well soluble
in water.[18] When an excess of the mixture (~0.1 mg) was
dissolved in water in the presence of 1 (0.27 µmol) at room
temperature, the MS and NMR analyses revealed the
quantitative formation (with respect to 1) of a mixture of 1:1 host-
guest complexes including only trimer 4a, tetramer 4b, or
pentamer 4c (Figure 4a). The ESI-TOF MS spectrum showed
the ESI-TOF MS spectrum (Figure 4c, left). The 1H NMR
spectrum of 1•4b showed highly upfield-shifted peaks (Δδ = –
2.1-3.6 ppm) for the methyl groups (Figure 4c, right), implying
tight encapsulation of 4b by 1 through CH-π and hydrogen
1
bonding interactions.[19] The H NOESY NMR analysis indicated
the close contact between the guest CH3 groups and the host
aromatic panels (Ha,b’) in the cavity (Figure S35e).[11] The X-ray
crystallographic analysis of 1•4b further supported the solution-
state host-guest interactions.[11,13] In the crystal structure, the
encapsulated 4b is fully covered by the polyaromatic shell of 1
(Figure 4e, left) with multiple CH-π (with the anthracene panels)
and hydrogen bonding (with the pyridine rings) interactions
(Figure 4e, right). No host-guest interactions between the Pd(II)
centers of 1 and the carboxy or hydroxy group of 4b were
observed in the structure.
Finally, ITC experiments were carried out for the formation
of 1•4b in H2O to gain insights into the host-guest binding
thermodynamics. The titration study at 25 ºC revealed that the
ΔH and TΔS values are –39.8 kJ mol–1 and –8.32 kJ mol–1,
respectively (Figure 5a and Table 1),[11] suggesting that the
investigated host-guest formation is an enthalpically favorable
– 4+
clear peaks at, e.g., m/z 918.5 for [1•4a – 4•NO3 ] , 936.8 for
– 4+
– 4+
[1•4b – 4•NO3 ] , and 954.8 for [1•4c – 4•NO3 ] (Figure 4b,
left). There were no MS peaks for the capsules encapsulating
other oligomers. The integral of the upfield-shifted 1H NMR
signals derived from the encapsulated oligomers revealed a
0.46 : 1.0 : 0.32 ratio of products 1•4a, 1•4b, and 1•4c (Figure
4b, right). The observed, preferential binding ability of capsule 1
toward tetra(lactic acid) 4b most likely stems from the energetic
balance between the enthalpic host-guest interactions and the
entropic structural restriction of the linear and flexible guest
molecule.
process. The binding constant in water is relatively high (Ka
=
3.3 × 105 M–1).[20] The large negative enthalpy change is
interpreted as the energetic contribution of multiple host-guest
CH-π and hydrogen bonding interactions upon guest
encapsulation (Figure 4e) possibly in conjunction with the
enthalpic effects produced by the release of high-energy water
from the cavity.[21,22] On the other hand, the near-zero entropy
change suggests that entropic gains from dehydration are
comparable to entropic losses from the conformational
restriction of the flexible guest in the confined cavity.
Thermodynamic parameters were also obtained for the
formation of 1•3a and 1•(3b)2 using the ITC analysis (Figure 5b
and S39).[11] The small negative enthalpy and positive entropy
changes for 1•3a (Table 1) are caused by the fewer interaction
sites (i.e., two methyl and two carbonyl groups) and shorter
length (i.e., dmax = 0.7 nm) of dimer 3a as compared with 4b.
Accordingly, the binding constant of 3a for 1 is 2.6-times smaller
than that of 4b. The formation of 1:2 host-guest complex 1•(3b)2
is driven by enthalpic stabilization (ΔH = –32.8 and –24.5 kJ
mol–1). The first guest bound in the host cavity (Ka = 1.8 × 105 M–
1) exerts a negative allosteric effect on the second guest (Ka =
1.1 × 104 M–1), probably because of the guest’s hydrophilicity.
Figure 4. a) Selective encapsulation of oligo(lactic acid)s 4a-c by capsule 1 in
water. ESI-TOF MS (H2O; left) and 1H NMR (500 MHz, D2O, r.t.; right) spectra
of b) the host-guest complexes after combining 1 with a mixture of oligo(lactic
acid)s and c) 1•4b. d) Optimized structure of 4b (DFT calculation, B3LYP/6-
31G* level) and e) X-ray crystal structure 1•4b (the peripheral substituents are
replaced by hydrogen atoms for clarity) and the highlighted host-guest and
guest-guest interactions (red and blue dash lines are CH-π and hydrogen
bonding interactions, respectively).
To elucidate the interactions between capsule 1 and the
oligo(lactic acid)s, we synthesized pure tetra(lactic acid) 4b
(Figure 4d) from 3a in six steps[11] and subsequently obtained
1:1 host-guest complex 1•4b in quantitative yield by simple
combination of 1 and 4b in water. Prominent molecular ion
Figure 5. ITC titrations (H2O, 298 K) of (a) 4b and (b) 3a in the presence of
1.[11]
– 4+
peaks, e.g., at m/z 936.5 for [1•4b – 4•NO3 ] , were observed in
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10.1002/anie.201800432
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COMMUNICATION
Table 1. Thermodynamic parameters and binding constants (Ka) for the
formation of 1•4b, 1•3a, and 1•(3b)2 obtained by ITC experiments (H2O, 298
K).[11]
[3]
Examples for molecular cages for hydrophilic (polar) substrates in
water: a) S. Tashiro, M. Tominaga, M. Kawano, B. Therrien, T. Ozeki,
M. Fujita, J. Am. Chem. Soc. 2005, 127, 4546–4547; b) S. Tashiro, M.
Kobayashi, M. Fujita, J. Am. Chem. Soc. 2006, 128, 9280–9281; c) T.
Sawada, M. Yoshizawa, S. Sato, M. Fujita, Nat. Chem. 2009, 1, 53–56;
d) B. Sookcharoenpinyo, E. Klein, Y. Ferrand, D. B. Walker, P. R.
Brotherhood, C. Ke, M. P. Crump, A. P. Davis, Angew. Chem. Int. Ed.
2012, 51, 4586–4590; e) P. Rios, T. S. Carter, T. J. Mooibroek, M. P.
Crump, M. Lisbjerg, M. Pittelkow, N. T. Supekar, G.-J. Boons, A. P.
Davis, Angew. Chem. Int. Ed. 2016, 55, 3387–3392.
ΔH
Ka
Entry
TΔS
ΔG
[kJ mol–1
]
[M–1
]
[kJ mol–1
]
[kJ mol–1
]
1•4b
1•3a
–39.8 ± 0.23
–14.6 ± 0.84
–8.32
14.5
–31.5
–29.1
(3.27 ± 0.17) × 105
(1.25 ± 0.35) × 105
(1.79 ± 0.15) × 105[a]
(1.11 ± 0.05) × 104[b]
[4]
[5]
N. Kishi, Z. Li, K. Yoza, M. Akita, M. Yoshizawa, J. Am. Chem. Soc.
2011, 133, 11438–11441.
1•(3b)2 –32.8 ± 0.37[a]
–2.78[a]
–1.46[b]
–30.0[a]
–23.1[b]
–24.5 ± 0.59[b]
M. Yamashina, M. Akita, T. Hasegawa, S. Hayashi, M. Yoshizawa, Sci.
Adv. 2017, 3, e1701126.
[6]
[7]
A. Galana, P. Ballester, Chem. Soc. Rev. 2016, 45, 1720–1737.
a) A. Jiménez, M. Peltzer, R. Ruseckaite (Eds.), Polylactic Acid Science
and Technology: Processing, Properties, Additives, and Applications,
RSC, 2015; b) M. Laura, D. Lorenzo, R. Androsch (Eds.), Synthesis,
Structure and Properties of Poly(Lactic Acid), Springer, 2018.
a) S. Inkinen, M. Hakkarainen, A.-C. Albertsson, A. Södergård,
Biomacromolecules 2011, 12, 523–532; b) S. Lazzari, F. Codari, G.
Storti, M. Morbidelli, D. Moscatelli, Polym. Degrad. Stab. 2014, 110,
80–90; c) N. Kameno, S. Yamada, T. Amimoto, K. Amimoto, H. Ikeda,
N. Koga, Polym. Degrad. Stab. 2016, 134, 284–295; d) K. Nomura, H.
Ohara, Mini Rev. Org. Chem. 2017, 14, 35–43.
a) Synthetic host for lactic acid monomer (up to Ka = ~700 M–1) in
CHCl3: T. Barboza, R. Pinalli, C. Massera, E. Dalcanale, Cryst. Eng.
Comm. 2016, 18, 4958–4963; b) Biological hosts (i.e., lactate
dehydrogenases) for lactic acid monomer: J. J. Holbrook, A. Liljas, S. J.
Steindel, M. G. Rossmann, The Enzymes, 1975, 11, 191–292.
[a] For the formation of 1:1 host-guest complex 1•3b and [b] for the formation
of 1•(3b)2.
In conclusion, we have elucidated unique host-guest
interactions between hydrophilic oligo(lactic acid)s and the
hydrophobic cavity of a polyaromatic capsule in water. The
polyaromatic cavity can efficiently capture one molecule of di- to
[8]
[9]
penta(lactic acid)s and shows
a binding preference for
tetra(lactic acid) with a relatively high binding constant (~3 × 105
M–1). The observed, unusual host-guest interactions in water are
driven by enthalpic stabilization through multiple and effective
CH-π (polyaromatic ring) and hydrogen bonding interactions.
Furthermore, the hydrolysis of cyclic di(lactic acid) is largely
suppressed in the cavity. The present results expand the
potential host functions of the polyaromatic nanospace (e.g.,
unusual transformation and efficient catalysis) not only for
hydrophobic synthetic molecules but also for hydrophilic bio-
related molecules and oligomers in water.
[10] Host capability toward hydrophobic molecules: a) N. Kishi, Z. Li, Y. Sei,
M. Akita, K. Yoza, J. S. Siegel, M. Yoshizawa, Chem. Eur. J. 2013, 19,
6313–6320; b) N. Kishi, M. Akita, M. Yoshizawa, Angew. Chem. Int. Ed.
2014, 53, 3604–3607; c) M. Yamashina, Y. Sei, M. Akita, M. Yoshizawa,
Nat. Commun. 2014, 5, 4662; d) M. Yamashina, M. Sartin, Y. Sei, M.
Akita, S. Takeuchi, T. Tahara, M. Yoshizawa, J. Am. Chem. Soc. 2015,
137, 9266–9269; e) M. Yamashina, S. Matsuno, Y. Sei, M. Akita, M.
Yoshizawa, Chem. Eur. J. 2016, 22, 14147–14150; f) S. Matsuno, M.
Yamashina, Y. Sei, M. Akita, A. Kuzume, K. Yamamoto, M. Yoshizawa,
Nat. Commun. 2017, 8, 749.
Acknowledgements
This work was supported by JSPS KAKENHI (Grant No.
JP25104011/JP26288033/JP17H05359) and “Support for
Tokyotech Advanced Researchers (STAR)”. We thank Dr.
Takane Imaoka (Tokyo Institute of Technology) for supporting
ITC experiments. M.Ya. thanks the JSPS for an Overseas
Research Fellowship.
[11] See the Supporting Information.
[12] The 1H NMR spectrum of 1 in D2O showed the desymmetrized signals
derived from the anthracene frameworks: the protons Hb-e split into
eight signals (Figure 2b). The proton signals of 2b are also
desymmetrized in the confined cavity (Figure 2c). 1H DOSY
measurement revealed that the host (Ha-l) and guest (HA-D) signals are
on a single band (Figure S4).[11]
Keywords: coordination capsule, oligo(lactic acid)s, CH-
π interactions, hydrogen-bonding interactions, water
[13] a) Pale yellow single crystals were obtained by slow concentration of a
H2O solution of 1•(2b)2 and 1•4b at room temperature for 45 and 30 d,
respectively.[11]
[14] a) K. Yazaki, N. Kishi, M. Akita, M. Yoshizawa, Chem. Commun. 2013,
49, 1630–1632; b) D. P. August, G. S. Nichol, P. J. Lusby, Angew.
Chem. Int. Ed. 2016, 55, 15022–15026.
[15] In the 1H NMR spectrum of 1•(2b)2 (Figure 2c), the downfield shift (Δδ =
+0.03 ppm) of the pyridine α-hyproton (Hf) of 1 is also indicative of the
host-guest hydrogen bonding interactions in water.
[1]
[2]
J. W. Steed, J. L. Atwood, Supramolecular Chemistry, 2nd ed., Wiley,
Hoboken, 2009.
Recent reviews: a) M. D. Ward, P. R. Raithby, Chem. Soc. Rev. 2013,
42, 1619–1636; b) M. M. J. Smulders, I. A. Riddell, C. Browne, J. R.
Nitschke, Chem. Soc. Rev. 2013, 42, 1728–1754; c) K. Harris, D. Fujita,
M. Fujita, Chem. Commun. 2013, 49, 6703–6712; d) M. Han, D. M.
Engelhard, G. H. Clever, Chem. Soc. Rev. 2014, 43, 1848–1860; e) L.
Xu, L.-J. Chen, H.-B. Yang, Chem. Commun. 2014, 50, 5156–5170; f)
A. M. Castilla, W. J. Ramsay, J. R. Nitschke, Acc. Chem. Res. 2014, 47,
2063–2073; g) T. R. Cook, P. J. Stang, Chem. Rev. 2015, 115, 7001–
7045; h) C. J. Brown, F. D. Toste, R. G. Bergman, K. N. Raymond,
Chem. Rev. 2015, 115, 3012–3035; i) M. Yoshizawa, M. Yamashina,
Chem. Lett. 2017, 46, 163–171; j) R. A. S. Vasdev, D. Preston, J. D.
Crowley, Chem. Asian. J. 2017, 12, 2513‒2523; k) L.-J. Chen, H.-B.
Yang, M. Shionoya, Chem. Soc. Rev. 2017, 46, 2555‒2576.
[16] ESI-TOF MS spectrum of 1•(3b)2 showed prominent peaks at m/z
–
n+
1925.9, 1263.3, and 932.0, assignable to the [1•(3b)2 – n•NO3
2-4) species (Figures S18).[11]
]
(n =
[17] The minimum value of the capsule cavity was calculated from the
crystal structure of 1•(1-adamantanecarboxylic acid) by using Material
Studio (Accelrys Software Inc., Connolly radius = 1.4 Å).[10a]
[18] C. F. van Nostrum, T. F.J. Veldhuis, G. W. Bos, W. E. Hennink,
Polymer 2004, 45, 6779–6787.
[19] The FT-IR analysis of 1•4b, 1•(3b)2, and 1•(2b)2 also indicated the
presence of host-guest hydrogen bonding interactions (Figure S40).[11]
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[20] Tetramer 4b is well soluble in water (>20 mM) and cannot be extracted
with CHCl3 and AcOEt from the aqueous solution, likely because the
carbonyl, carboxyl, and hydroxy groups on the helical framework are
involved in efficient hydrogen bonding interactions with solvating water
molecules (Figure 4d). The dipole moments of 4b and dimer 3a,
estimated preliminary by DFT calculation (B3LYP/6-31G* level, gas
phase), are relatively high (4.7 and 3.7 D, respectively).
W. M. Nau, H.-J. Schneider, Angew. Chem. Int. Ed. 2014, 53, 11158–
11171; c) A. J. Metherell, W. Cullen, N. H. Williams, M. D. Ward, Chem.
Eur. J. 10.1002/chem.201704163.
[22] The preliminary X-ray crystallographic analysis of empty capsule 1
suggested the presence of water molecules, most of which are severely
disordered, in the cavity. The cavity volume of 1 is changeable (ca.
430-690 Å3) depending on the size, shape, and number of the
encapsulated guest.[10a] Thus, further studies are needed to discuss the
hydrophobic effect in the present host-guest system.
[21] a) F. Biedermann, V. D. Uzunova, O. A. Scherman, W. M. Nau, A. De
Simone, J. Am. Chem. Soc. 2012, 134, 1531-15323; b) F. Biedermann,
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10.1002/anie.201800432
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
S. Kusaba, M. Yamashina, M. Akita, T.
Kikuchi, and M. Yoshizawa*
Page No. – Page No.
Hydrophilic Oligo(Lactic Acid)s
Captured by a Hydrophobic
Polyaromatic Cavity in Water
The hydrophobic cavity of a polyaromatic capsule can efficiently encapsulate
hydrophilic oligo(lactic acid)s in water. The X-ray crystallographic and ITC analyses
revealed that the unusual host-guest behavior is caused by enthalpic stabilization
through multiple CH-π and hydrogen bonding interactions. By the polyaromatic
cavity, hydrolyzable cyclic di(lactic acid) is stabilized and tetra(lactic acid) is
preferentially captured from a mixture of oligo(lactic acid)s even in water.
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