Encapsulation-induced remarkable stability of a hydrogen-bonded heterocapsule

Article abstract of DOI:10.1002/chem.201203937

Remarkably enhanced stability of the self-assembled hydrogen-bonded heterocapsule 1×2 by the encapsulation of 1,4-bis(1-propynyl)benzene 3 a was found with K_a=1.14×10⁹ M^-1 in CDCl₃ and K_a2=1.59×10⁸ M^-2 in CD₃OD/CDCl₃ (10 % v/v) at 298 K. The formation of 3 a(1×2) was enthalpically driven (ΔH°<0 and ΔS°<0) and there was a unique inflection point in the correlation between ΔH° versus ΔS° as a function of polar solvent content. The ab initio calculations revealed that favorable guest-capsule dispersion and electrostatic interactions between the acetylenic parts (triple bonds) of 3 a and the aromatic inner space of 1×2, as well as less structural deformation of 1×2 upon encapsulation of 3 a, play important roles in the remarkable stability of 3 a(1×2). Copyright

Full text of DOI:10.1002/chem.201203937

FULL PAPER
DOI: 10.1002/chem.201203937
Encapsulation-Induced Remarkable Stability of a Hydrogen-Bonded
Heterocapsule
Keisuke Ichihara,[a] Hidetoshi Kawai,[b] Yuka Togari,[a] Emi Kikuta,[a] Hitomi Kitagawa,[a]
Seiji Tsuzuki,*[c] Kenji Yoza,[d] Masamichi Yamanaka,[a] and Kenji Kobayashi*[a]
Abstract: Remarkably enhanced stabil-
ity of the self-assembled hydrogen-
bonded heterocapsule 1·2 by the encap-
sulation of 1,4-bis(1-propynyl)benzene
3a was found with Ka =1.14ꢀ109 mꢀ1 in
CDCl3 and Ka2 =1.59ꢀ108 mꢀ2 in
CD3OD/CDCl3 (10% v/v) at 298 K.
DS8<0) and there was a unique inflec-
tion point in the correlation between
DH8 versus DS8 as a function of polar
solvent content. The ab initio calcula-
tions revealed that favorable guest–
capsule dispersion and electrostatic in-
teractions between the acetylenic parts
(triple bonds) of 3a and the aromatic
inner space of 1·2, as well as less struc-
tural deformation of 1·2 upon encapsu-
lation of 3a, play important roles in
Keywords: capsules
·
cavitands
·
host–guest systems
· hydrogen
The formation of 3a@
A
the remarkable stability of 3a@ACHTUNGTRENNUNG(1·2).
bonds · supramolecular chemistry
thalpically driven (DH8<0
Introduction
and guest encapsulation endows hydrogen-bonded capsules
with potential as functional materials.[7c,9]
The binding motifs with remarkable association constants
(Ka) in host–guest systems are of importance for the genera-
tion of thermodynamically stable supramolecular architec-
tures.[1–3] Contiguous quadruple hydrogen-bonding arrays
among multipoint hydrogen-bonding motifs for dimerization
are quite strong and useful building blocks for this pur-
Recently, we have reported that tetra(4-pyridyl)-cavitand
1 and tetrakis(4-hydroxyphenyl)-cavitands 2 self-assemble
into a heterocapsule 1·2 in a rim-to-rim fashion through four
pyridyl···phenol–hydrogen bonds in CDCl3, in which one
molecule of 1,4-disubstituted-benzene as a guest is encapsu-
lated to form guest@
explored a more appropriate guest molecule for enhancing
(1·2), as shown in Figure 1.[10] We have
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
pose.[1b,4] The construction of highly stable guest-encapsulat-
ing self-assembled hydrogen-bonded capsules, guest@cap-
sule, is also a very important subject,[5] in which guest@cap-
sule can be used as a modular unit.[6] Of the multipoint hy-
drogen-bonding motifs, the merits of using guest@capsule
are that its stability can be controlled by guest molecules[7,8]
the stability of guest@ACTHNGUTER(NNUG 1·2), the Ka value comparable to
those of contiguous quadruple hydrogen-bonding arrays.[4]
Herein, we report the remarkably enhanced stability of the
self-assembled hydrogen-bonded heterocapsule 1·2 by the
[a] K. Ichihara, Y. Togari, E. Kikuta, H. Kitagawa, Prof. M. Yamanaka,
Prof. K. Kobayashi
Department of Chemistry
Faculty of Science, Shizuoka University
836 Ohya, Suruga-ku, Shizuoka 422-8529 (Japan)
Fax : (+81)54-238-4933
E-mail: skkobay@ipc.shizuoka.ac.jp
[b] Prof. H. Kawai
Department of Chemistry
Faculty of Science, Tokyo University of Science
Kagurazaka 1-3, Shinjuku-ku, Tokyo 162-8601 (Japan)
[c] Prof. S. Tsuzuki
Nanosystem Research Institute
National Institute of Advanced Industrial Science and Technology
(AIST)
Tsukuba, Ibaraki 305-8568 (Japan)
Fax : (+81)29-851-5426
E-mail: s.tsuzuki@aist.go.jp
[d] Dr. K. Yoza
Bruker axs, 3-9-B Moriya
Kanagawa-ku, Yokohama 221-0022 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203937.
Figure 1. Self-assembly of cavitands 1 and 2 into a heterocapsule 1·2 and
its guest encapsulation, and guest molecules 3–6.
Chem. Eur. J. 2013, 19, 3685 – 3692
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3685

encapsulation of 1,4-bis(1-propynyl)benzene 3a and its de-
rivatives 3b–f (Figure 1). We also describe the stability of
3a@
ACHTUNGTRENNUNG
We further describe the ab initio calculations of 3a@AHCTUNGTRENNUNG
elucidate the origin of its remarkable stability, in which the
acetylenic parts of 3a are important for the 3a–1·2 disper-
sion and electrostatic interactions.
Results and Discussion
Herein, the pyridyl cavitands 1 and the phenol cavitand 2
were used with various side chains (Figure 1; a: R=
(CH2)6CH3, b: R=CH2CH
ACHTUNGTNER(NNUG CH3)2, and c: R=(CH2)3-O-
CH2CH[CH2-O-(CH2CH2O)3CH3]2).
A
ACHTUNGTRENNUNG
Figure 3. Association of heterocapsule 1a·2a (5 mm) with guests
3
(10 mm) in CDCl3 at 298 K monitored by 1H NMR spectroscopy
(400 MHz): a) 1a·2a alone; b) 1a·2a+3a; c) 1a·2a+3b; d) 1a·2a+3c;
e) 1a·2a+3d; f) 1a·2a+3e; and g) 1a·2a+3 f. The representative signals
for the encapsulated and free guests are marked with filled and open cir-
cles, respectively.
X-ray crystal structure of 3b@
3b@(1b·2b), suitable for X-ray diffraction analysis, were ob-
tained by slow diffusion of benzene into a CHCl3 solution of
a 1:1:3 mixture of 1b, 2b, and 3b. Two kinds of 3b@(1b·2b)
ACHTUNGTNER(NUNG 1b·2b): Single crystals of
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
having slightly different conformations were found in the
unit cell (Figures 2 and S2 in the Supporting Information).
1H NMR study: Association of heterocapsule 1a·2a with
1
guests 3 in CDCl3: The H NMR spectra of 1a·2a with 3 in
1
CDCl3 at 298 K are shown in Figure 3. The H NMR signals
of 3@ACTHNUTRGENU(GN 1a·2a) and free 3 were independently observed and
the signals of the encapsulated 3 appeared as two sets of sig-
nals, because the electronic environment of the 1 unit is dif-
ferent from that of the 2 unit, indicating that 3 does not
1
tumble within 1a·2a on the NMR time scale. The H NMR
signals of propynyl methyl protons of the encapsulated 3
were shifted largely upfield by 3.81–3.89 ppm relative to
those of free 3 due to the ring-current effect of both the aro-
matic cavities of 1a·2a (Table 1). These values were shifted
more upfield by 0.3–0.4 ppm than those of the terminal
methyl protons of 4–6@
constants (Ka) of 1a·2a with 3 were very large, comparison
of the signal integrations between 3@(1a·2a) and standard
guest@(1a·2a), namely, competitive encapsulation experi-
(1a·2a).[10b,c] Because the association
ACHTUNGTRENNUNG
Figure 2. X-ray crystal structure of 3b@ACTHUNRGTNE(NUG 1b·2b): one of two slightly dif-
ferent conformers (occupancy factors of F1–F4=0.50) is shown.
AHCTUNGTRENNUNG
The propynyl groups at the 1,4-positions of the encapsulated
ACHTUNGTRENNUNG
3b are oriented toward both aromatic cavity ends of 1b·2b.
It is noteworthy that the cavity dimensions of 3b@
are slightly, yet unambiguously, different from those of the
previous reported 4c@
(1b·2b)[10c] and 5@(1b·2b),[10b] with
keeping average hydrogen-bonding distances between 1b
and 2b almost constant (Table S2 in the Supporting Infor-
mation). The molecular length of 3b is 1.23 and 1.14 ꢂ
longer than those of 4c and 5, respectively. The polar di-
ACHTUNGTRNE(NUNG 1b·2b)
Table 1. Association constants (Ka) and their free energies (DG8) of het-
erocapsule 1a·2a with guests 3–6 in CDCl3 at 298 K, and 1H NMR chemi-
cal-shift changes (Dd) of terminal methyl groups of encapsulated guests
relative to free guests.
G
ACHTUNGTRENNUNG
[a]
[b]
Guest
Ka [ꢀ106 Mꢀ1
]
DG8 [kcalmolꢀ1
]
Dd [ppm][c]
3a
3b
3c
3d
3e
3 f
1140
520
163
275
45.4
42.7
0.237
1.07
0.612
0.0812
0.0202
ꢀ12.3
ꢀ11.9
ꢀ11.2
ꢀ11.5
ꢀ10.44
ꢀ10.40
ꢀ7.41
ꢀ8.22
ꢀ7.89
ꢀ6.69
ꢀ5.87
ꢀ3.82, ꢀ3.81
ꢀ3.89, ꢀ3.87
ꢀ3.87, ꢀ3.87
ꢀ3.85, ꢀ3.83
ꢀ3.86, ꢀ3.85
ꢀ3.85, ꢀ3.85
ꢀ3.53, ꢀ3.50
ꢀ3.51, ꢀ3.50
ꢀ3.51, ꢀ3.41
ꢀ3.43, ꢀ3.37
ꢀ3.52, ꢀ3.47
mension in 3b@
4c@(1b·2b) and 5@
torial dimension of the 1b unit or the 2b unit in 3b@-
(1b·2b) is 0.20 and 0.18 or 0.19 and 0.16 ꢂ shorter than
those of the 1b units or the 2b units in 4c@(1b·2b) and 5@-
(1b·2b), respectively. Thus, 1b·2b can adjust the cavity di-
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
4a[d]
4b[d]
4c[d]
5[e]
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
6[e]
mensions, depending on the guest size, shape, and/or func-
tional group. In all cases, it is also noted that the equatorial
dimension of the 1b unit is 0.21–0.23 ꢂ shorter than that of
the 2b unit.
[a] Ka/Kaꢀstandard ={[G@ACTHNURTGENN(GU 1a·2a)][Gstandard]f}/{[Gstandard@ACHTUNGTRENN(UNG 1a·2a)][G]f}.
[b] DG8=ꢀRTlnKa. [c] Dd=(dencapsulated-Gꢀdfree-G). [d] See Ref. [10c].
[e] Ref. [10b].
3686
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ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 3685 – 3692

Remarkable Stability of a Hydrogen-Bonded Heterocapsule
FULL PAPER
ments, were used to estimate the Ka values of 1a·2a with
3.[10c,11,12] The Ka values of 1a·2a with 3 in CDCl3 at 298 K
are summarized in Table 1.
The association of 1a·2a with 3a was found to be Ka =
1.14ꢀ109 mꢀ1 in CDCl3 at 298 K. This Ka value is the largest
among the guests investigated herein and is comparable to
those of contiguous quadruple hydrogen-bonding arrays.[4]
The Ka values of 1a·2a with guests decreased in the order:
3a>3b>3d>3c>3e>3 f@4a>5>6. Thus, the 1-propyn-
yl group is the most favorable functional group among 1,4-
disubstituted-benzene guests. The order of 3a–f@ACTHNUGTRNEUNG(1a·2a)
would be related to the steric hindrance between the alkoxy
groups of 3c–f and the equatorial walls of 1a·2a. The
1H NMR signals of the capsule moiety were extremely
broadened in 3c–e@
(1a·2a) (Figure 3 g) relative to those in 3a@
3b@(1a·2a) (Figure 3b and c). This different behavior re-
sults from the slow rotation of the encapsulated 3c–e along
the long axis of 1a·2a and from the inhibition of rotation
for the encapsulated 3 f on the NMR time scale.[10c]
ACHTUNGTRENNUNG
Figure 4. Plots of the ratio of the encapsulated 3c to free 3c (guest ex-
G
ACHTUNGTRENNUNG
change ratio) in CDCl3 at 298 K as a function of time (min), monitored
by 1H NMR spectroscopy, upon addition of 3a (10 mm) to 3c@
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
and free 3c (5 mm each), and upon addition of 3c (10 mm) to 3a@
and free 3a (5 mm each).
ACHTUNGTRENNUNG
The observed association-free energy difference (DDG8=
ꢀ4.94 kcalmolꢀ1) for the encapsulations of 3a and 4a in
1a·2a was close to the theoretical calculation value of
DDG8=ꢀ4.56 kcalmolꢀ1 (see below). The ITC measure-
ments for the association of 1a·2a with 3a showed Ka =
(1.75ꢁ0.39)ꢀ108 mꢀ1 in CDCl3 at 298 K, and the thermody-
namic parameters of enthalpy change DH8=ꢀ11.49ꢁ
0.15 kcalmolꢀ1 and extremely small entropy change[2,13]
DS8=ꢀ0.864ꢁ0.046 calmolꢀ1 Kꢀ1 (Figure S11 in the Sup-
porting Information).[14] Hence, the Ka value of 1a·2a with
3a estimated by the 1H NMR competition experiments
would be considered reasonable.
The encapsulation of 3 in 1a·2a occurred instantaneously.
However, once 3@
and out of 1a·2a is too slow on the NMR time scale. In con-
trast to 4@
(1a·2a),[10c] the exchange cross-peak between the
ACHTUNGTRENNUNG(1a·2a) is formed, the exchange of 3 in
ACHTUNGTRENNUNG
encapsulated and free 3 in the 2D NOESY spectrum was
not observed at 298 K, even at mixing time 1 s, and only
marginally observed at 323 K (Figures S12–S17 in the Sup-
porting Information). Thus, 3@
thermodynamically much more stable than 4@
guest exchanges between 3c@(1a·2a) and 3a and between
3a@(1a·2a) and 3c occurred on human time scale: it took
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
120 min to reach thermodynamic equilibration in CDCl3 at
298 K (Figure 4).
Figure 5. Association of 1, 2a (4 mm each), and 3a (8 mm) in various sol-
1
vents at 298 K monitored by H NMR: a) 3a@
(1a·2a) in [D6]DMSO/CDCl3 (20% v/v); c) 3a@
CDCl3 (20% v/v); d) 3a@(1a·2a) in CH3OH/CDCl3 (20% v/v); e) 3a@-
(1c·2a) in [D6]acetone; and f) 3a@(1c·2a) in D2O/[D6]acetone
(14.3% v/v).
ACHTUNGTRENNUNG
Formation of 3a@ACHTUNGTRENNUNG(1·2a) in polar solvents: In general, hydro-
A
ACHTUNGTRENNUNG
gen-bonded capsules dissociate upon addition of small
amounts of polar solvents that compete for hydrogen-bond
donors or acceptors.[7b] In polar solvents used in this work,
1a and 2a also exist as monomers instead of 1a·2a in the
absence of guests (Figure S18 in the Supporting Informa-
tion). However, guests, such as 3a and 4a, induced the for-
mation of 1a·2a. The association of 1a (hereafter, 1),[15] 2a,
and guests obeys Equation (1). The exchange of free guest
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
Information). The results of Ka2 (mꢀ2) in the polar solvents
at 298 K are summarized in Table 2. As a reference, appar-
ent association constants (Kapp, mꢀ1)[11a] according to Equa-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
and guest@
(1·2a) was slow on the NMR time scale even in
tion (2) are also summarized in Table S3 in the Supporting
Information.
the polar solvents (Figures 5 and S18–S28 in the Supporting
Chem. Eur. J. 2013, 19, 3685 – 3692
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3687

S. Tsuzuki, K. Kobayashi et al.
Table 2. Association constants (Ka2) of 1a, 2a, and 3a, or 4a according to [Eq. (1)] and DG8(298 K) in polar sol-
vents at 298 K, and their thermodynamic parameters (DH8 and DS8).
ure S21 in the Supporting Infor-
mation). These NMR results in-
dicate hydrogen bonds in the
capsule formation of 1 and 2a
with encapsulation of 3a. Thus,
the 3a–1·2a interactions sup-
port the hydrogen bonds be-
tween 1 and 2a in the polar sol-
vents.
Guest
Solvent
Ka2
[Mꢀ2
DG8(298 K)
DH8
DS8
[a]
[b]
[c]
[c]
G
]
[kcalmolꢀ1
]
[kcalmolꢀ1
]
[calmolꢀ1 Kꢀ1
]
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
[D6]DMSO/CDCl3 (10% v/v)
[D6]DMSO/CDCl3 (15% v/v)
[D6]DMSO/CDCl3 (20% v/v)
[D6]DMSO/CDCl3 (25% v/v)
[D6]DMSO/CDCl3 (30% v/v)
[D6]DMSO/CDCl3 (40% v/v)
CD3OD/CDCl3 (10% v/v)
CD3OD/CDCl3 (15% v/v)
CD3OD/CDCl3 (20% v/v)
CD3OD/CDCl3 (25% v/v)
CD3OD/CDCl3 (30% v/v)
CD3OD/CDCl3 (35% v/v)
[D6]acetone
D2O/[D6]acetone (1.6% v/v)
D2O/[D6]acetone (14.3% v/v)
D2O/[D6]acetone (25% v/v)
[D6]DMSO/CDCl3 (10% v/v)
CD3OD/CDCl3 (10% v/v)
[D6]acetone
6.32ꢀ108
1.82ꢀ108
2.58ꢀ107
1.50ꢀ107
6.35ꢀ106
7.61ꢀ105
1.59ꢀ108
2.10ꢀ107
3.00ꢀ106
1.07ꢀ106
5.85ꢀ105
3.45ꢀ105
2.98ꢀ109
9.19ꢀ106
2.30ꢀ105
1.46ꢀ105
9.03ꢀ105
4.33ꢀ104
6.32ꢀ106
1.16ꢀ105
ꢀ12.0
ꢀ11.3
ꢀ10.1
ꢀ9.79
ꢀ9.28
ꢀ8.02
ꢀ11.2
ꢀ9.98
ꢀ8.83
ꢀ8.22
ꢀ7.86
ꢀ7.55
ꢀ12.9
ꢀ9.49
ꢀ7.31
ꢀ7.04
ꢀ8.12
ꢀ6.32
ꢀ9.27
ꢀ6.91
ꢀ16.2
ꢀ14.2
ꢀ11.2
ꢀ14.3
ꢀ14.8
ꢀ14.2
ꢀ14.6
ꢀ12.9
ꢀ13.9
ꢀ14.2
ꢀ15.0
ꢀ17.7
ꢀ14.1
ꢀ9.96
ꢀ3.87
ꢀ15.0
ꢀ18.6
ꢀ20.6
ꢀ11.5
ꢀ9.72
ꢀ16.9
ꢀ19.9
ꢀ23.7
ꢀ33.8
Thermodynamics of 3a@ACHTUNGTRENNUNG(1·2a)
in polar solvents: As shown in
Table 2 and Figures S29–S32
(vanꢃt Hoff plots) in the Sup-
porting Information, in polar-
solvent systems used in this
work, the formations of 3a@-
3a[d,e]
3a[d]
3a[d]
3a[d]
4a
ꢀ24.3
ꢀ57.0
ꢀ20.8
ꢀ16.4
ꢀ42.8
ꢀ33.8
ACHUTNGRENNU(G 1·2a) and 4a@HCATUNGTREN(NNGU 1·2a) were en-
4a
thalpically driven (DH8<0 and
DS8<0), suggesting a nonclassi-
cal hydrophobic effect.[17]
There is a unique correlation
between thermodynamic pa-
4a[d]
4a[d]
D2O/[D6]acetone (1.6% v/v)
[a] Ka2 =[Guest@
tained by vanꢃt Hoff plots: lnKa2 =ꢀ
[e] Competitive formation of 3a@(1c·2a) and 4a@CAHTUNGTRENNUNG
ACHTUNGTRENNUNG(1a·2a)]/ACHTUTNGRENNUG{[1a]fACHTUNGRETG[NNNU 2a]fACHNUTGTRENNNUG
[Guest]f} [Eq. (1)]. [b] DG8(298 K) =ꢀ298R lnKa2. [c] DH8 and DS8 were ob-
(DH8/R)(1/T)+(DS8/R). [d] Cavitand 1c was used in place of 1a.
(1c·2a) was used to estimate the Ka2 value.
N
ACHTUNGTRENNUNG
G
rameters in 3a@ACTHNUGRTNEUNG(1a·2a) and
polar solvents. In 10–40% v/v
aprotic [D6]DMSO/CDCl3 (Fig-
ure 6a,c), there was a critical inflection point in the correla-
tion between DH8 versus DS8 for the formation of 3a@-
Ka2 ¼ ½guest@ð1 ꢂ 2 aÞꢃ=f½1ꢃf½2 aꢃf½guestꢃfg
Kapp ¼ ½guest@ð1 ꢂ 2 aÞꢃ=f½1 ꢂ 2 aꢃf½guestꢃfg
ð1Þ
ð2Þ
(1a·2a). For ꢅ20% [D6]DMSO, with increasing amounts of
[D6]DMSO, the DH8 and DS8 contributions decreased and
increased, respectively (but still kept DH8<0 and DS8<0),
probably due to a contribution of the desolvation effect.[7b]
Desolvated aprotic [D6]DMSO would not hydrogen bond
with bulk [D6]DMSO molecules, leading to increase of the
Addition of [D6]DMSO as an aprotic polar solvent or
CD3OD as a protic polar solvent destabilized 3a@(1a·2a)
AHCTUNGTRENNUNG
(Figures S19, S20, and S24a,b in the Supporting Informa-
tion). However, the association constants still kept Ka2 =
6.32ꢀ108 mꢀ2 (Kapp =2.44ꢀ104 mꢀ1) in 10% v/v [D6]DMSO/
CDCl3 and Ka2 =1.59ꢀ108 mꢀ2 (Kapp =1.17ꢀ104 mꢀ1) in 10%
DS8 contribution for the formation of 3a@ACTHUNRTGNEUNG(1a·2a). On the
other hand, for ꢄ20% [D6]DMSO, with increasing amounts
v/v CD3OD/CDCl3.[16] The formation of 3a@
ACHTUNGTRENNUNG
showed
Ka2 =2.98ꢀ109 mꢀ2
[D6]acetone and Ka2 =1.46ꢀ105 mꢀ2 (Kapp =239mꢀ1) in 25%
v/v D2O/[D6]acetone (Figures S23 and S24c in the Support-
ing Information).[15] The thermodynamic stability of 3a@-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
[D6]DMSO/CDCl3, DDG8=ꢀ4.86 kcalmolꢀ1 in 10% v/v
CD3OD/CDCl3, DDG8=ꢀ3.65 kcalmolꢀ1 in [D6]acetone,
and DDG8=ꢀ2.58 kcalmolꢀ1 in 1.6% v/v D2O/[D6]acetone
(Table 2). It is thus understood how 3a strongly stabilizes
1·2a much more than 4a.
ACHTUNGTRENNUNG(1·2a) appeared at d=10.73 in CDCl3, 10.89 in 20% v/v
[D6]DMSO/CDCl3, 10.89 even in 20% v/v CH3OH/CDCl3,
and 11.00 ppm in [D6]acetone (Figure 5). These chemical
shifts remained almost unchanged in the range of at least 1–
5 mm of 3a@ACHTUNGTRENNUNG(1·2a), and in the range of 10–50%
[D6]DMSO/CDCl3 (Figure S19 in the Supporting Informa-
tion) and in the range of 10–35% CH3OH/CDCl3 (Fig-
Figure 6. Correlations between thermodynamic parameters for the forma-
tion of 3a@
ACHTUNGRTNEN(UNG 1a·2a): plots of DH8 versus DS8 in a) [D6]DMSO/CDCl3
(10–40% v/v); and b) CD3OD/CDCl3 (10–35% v/v); plots of DH8,
298DS8, and DG8(298K) as
a
function of c) [D6]DMSO content; and
d) CD3OD content.
3688
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Chem. Eur. J. 2013, 19, 3685 – 3692

Remarkable Stability of a Hydrogen-Bonded Heterocapsule
FULL PAPER
of [D6]DMSO, the DH8 and DS8 contributions increased and
decreased, respectively, due to a nonclassical hydrophobic
effect that is attributed mainly to a gain in the capsule–guest
dispersion interactions.[17b] The results recorded in
[D6]DMSO/CDCl3 suggest that the dispersion interaction of
1a·2a with 3a is inherently strong and effective. In 10–35%
v/v protic CD3OD/CDCl3 (Figure 6b,d), there was an inflec-
tion point at 15% CD3OD in
(BSSE)[22] correction by the counterpoise method.[23] The
calculated interaction energies between 1·2 and 3a or 4a
and stabilization energies by formation of 3a@
4a@(1·2), and differences of each energy term (DE) be-
tween 3a@(1·2) and 4a@
ACHTUNGTRENN(UNG 1·2) and
A
ACHTUNGTRENNUNG
A
ACHTUNGERTN(NUNG 1·2) are summarized in
Table 3.[19,20] Details of energy terms are shown in footnote
of Table 3.
the correlation between DH8
Table 3. Interaction energy between heterocapsule 1·2 and guest 3a or 4a, stabilization energy (Eform) by for-
mation of guest@(1·2), and difference of each energy term (DE) between 3a@(1·2) and 4a@
(1·2).[a]
versus DS8. The DH8 and DS8
contributions also increased
and decreased, respectively,
with increasing amounts of
CD3OD. In this case, favorable
changes in solvent cohesive in-
teractions would be more im-
portant,[17,18] compared with
[D6]DMSO/CDCl3. In both
cases, the encapsulation process
shows an enthalpy–entropy
compensation effect.[17c]
G
E
ACHTUNGTRENNUNG
[b,c]
[c,d]
[e]
[f]
[g]
[h]
[i]
Guest@(1·2)
(1·2)
(1·2)
G
Eint
EHF
Ees
Erep
Ecorr
Edef
Eform
3a@
4a@
N
ꢀ28.25
ꢀ25.82
DEint
ꢀ2.43
6.47
4.82
DEHF
1.66
ꢀ9.15
ꢀ9.82
15.62
14.64
DErep
0.99
ꢀ34.72
ꢀ30.64
1.87
4.00
DEdef
ꢀ2.13
ꢀ26.38
ꢀ21.82
DEes
DEcorr
DEform
3a@
A
E
0.67
ꢀ4.09
ꢀ4.56
[a] Energy [kcalmolꢀ1]. Geometries for 3a@
U
.
[c] BSSE was corrected by the counterpoise method. [d] Interaction energy calculated at the HF level.
[e] Electrostatic energy calculated as interactions between distributed multipoles of the interacting 1·2 and the
guest. See Ref [19]. [f] Erep =EHFꢀEes. Erep is mainly exchange-repulsion energy. [g] Electron correlation contri-
bution to total interaction energy. Ecorr =EintꢀEHF. Ecorr is mainly dispersion energy. [h] Sum of the increases of
energies of 1·2 and guest by the deformation of molecular geometries associated with the formation of guest@-
A
ACHTUNGTREN(NUNG 1·2) from an isolat-
.
Ab initio molecular-orbital cal-
culations: Origin of the remark-
able stability of 3a@ACHTNUTGRNEUNG(1·2): Pre-
viously, Tsuzuki et al. reported that ab initio calculation
with the MP2 level electron-correlation correction is a very
powerful tool for evaluating and studying the interaction en-
ergies for large systems, such as 1·2 complexes with
guests.[19] The interaction energies were calculated for 3a@-
The large negative electron-correlation contributions to
the interaction energies (Ecorr) compared with the electro-
static energies (Ees) show that the dispersion interactions are
the major source of the attraction of 1·2 with guests in the
gas phase. The large DEcorr (ꢀ4.09 kcalmolꢀ1) and small
DEes (0.67 kcalmolꢀ1) values indicate that larger dispersion
interaction is mainly responsible for greater stability of 3a@-
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHUTGTNREN(NUG 1·2) compared with 4a@ACHTUGNTREN(NUGN 1·2). Thus, the difference of total
interaction energy (DEint) is ꢀ2.43 kcalmolꢀ1. Smaller defor-
AHCTUNGTRENNUNG
mation energy (Edef) is also an important source of greater
guests 3a and 4a were optimized at the HF/6-31G* level
(Figure 7). The interaction energies were calculated by using
the same basis set with the basis set superposition error
stability of 3a@ACHTUNGTRENNUNG
fore, the difference of the stabilization energies by the for-
mation of the complexes from isolated 1·2 and guests
(DEform =DEint +DEdef) is ꢀ4.56 kcalmolꢀ1. This value well
reproduces the experimentally observed thermodynamic
free-energy difference of DDG8=ꢀ4.94 kcalmolꢀ1 in CDCl3
at 298 K. Thus, larger dispersion interaction between the
1-propynyl groups of 3a and the aromatic inner space of 1·2
and less structural deformation of 1·2 upon encapsulation of
3a, compared with those of 4a@
ACHTUNGTRENNUNG
in the remarkable stability of 3a@AHCUTNGTRENNUNG
The interactions of the acetylenic parts (triple bonds) of
3a with 1 and 2 contribute largely to the strong attraction
between 3a and 1·2. Intermolecular interaction energies
(Eint) were calculated at the MP2/6-31G* level for the
model complexes shown in Figure 8. The geometries of
3a@1 and 3a@2 were prepared from that of 3a@ACHTNUTRGNE(UNG 1·2) by re-
moving 2 or 1. The 7@1 and 7@2 (7: 2-butyne) are the
models for evaluating the interactions of the methyl acety-
lenic parts of 3a with 1 and 2.[24] The 8@1 and 8@2 (8: meth-
ane) are the models for evaluating the interactions of the
terminal methyl groups of 3a with 1 and 2.[24] The results
Figure 7. Geometries optimized for a) 3a@ACTHNUTRGENN(UG 1·2); and b) 4a@ACHTUGNTREN(NUNG 1·2) calcu-
lated at the HF/6-31G* level.
Chem. Eur. J. 2013, 19, 3685 – 3692
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3689

S. Tsuzuki, K. Kobayashi et al.
toxy groups of 4a and the inner protons of the methylene-
[10c]
ꢀ
ꢀ
bridge rims (O CHinHout O) of 1·2
is no such interaction in 3a@
(0.67 kcalmolꢀ1) between 3a@
(1·2) and 4a@
to gain the Ees. There
AHCTUNGTRENNUNG
N
ACHTUNGTRENNUNG
tively small. This would be attributed to a favorable electro-
static interaction between the acetylenic parts of 3a and
inner protons of the methylene-bridge rims of 1·2. The Ees
calculated for the model complexes support this idea. The
Ees calculated for 7@1 and 7@2 are close to those for 3a@1
and 3a@2, as shown in Table 4. The Ees calculated for 8@1
and 8@2 are very small. The calculations clearly show that
the interactions of the acetylenic parts of 3a with 1 and 2
are the origin of the large electrostatic interaction in 3a@-
AHCTUNGTREG(NNNU 1·2). Hydrogen atoms of aromatic molecules have positive
charges. The hydrogen atoms of pyridyl groups of 1 and
phenol groups of 2 are close to the acetylenic part of 3a.
The hydrogen atoms of methylene-bridge rims of 1 and 2,
which have positive charge, are also close to the acetylenic
parts of 3a. The attractive electrostatic interactions of the
acetylenic parts of 3a with these positively charged hydro-
gen atoms are the source of the attractive electrostatic inter-
actions.
Figure 8. Interaction energies calculated for model complexes
[kcalmolꢀ1].
are summarized in Table 4. The Eint calculated for 3a@1 and
3a@2 are ꢀ14.61 and ꢀ13.57 kcalmolꢀ1, respectively. They
correspond to the interactions of 3a with 1 and 2, respec-
Conclusion
Table 4. Interaction energy of 1 and 2 with guests 3a, 7, and 8.[a]
The self-assembled hydrogen-bonded heterocapsule 1·2 can
finely tune the cavity dimensions, depending on the nature
of guest. We have demonstrated that the perfect match of
dimensions, as well as dispersion and electrostatic interac-
tions of the acetylenic parts (triple bonds) of 3a with the aro-
matic inner space of 1·2 and the conformational rigidity of
3a extraordinarily enhance the thermodynamic stability of
3a@ACTHUNRTGNEUNG(1·2). The 3a–1·2 interactions support the hydrogen
bonds between 1 and 2 in polar solvents. We also found that
there is an inflection point in the correlation between DH8
[b,c]
[c,d]
[e]
[f]
[g]
Complex
Eint
EHF
Ees
Erep
Ecorr
3a@1
3a@2
7@1
7@2
8@1
ꢀ14.61
ꢀ13.57
ꢀ10.89
ꢀ9.52
ꢀ2.35
ꢀ2.14
4.42
2.13
4.32
3.13
5.93
5.73
ꢀ4.99
ꢀ4.39
ꢀ4.44
ꢀ4.39
ꢀ0.14
ꢀ0.20
9.41
6.52
8.76
7.52
6.07
5.93
ꢀ19.03
ꢀ15.70
ꢀ15.21
ꢀ12.65
ꢀ8.28
8@2
ꢀ7.87
[a] Energy [kcalmolꢀ1]; geometries are shown in Figure 8. [b–g] See foot-
notes [b–g] in Table 3.
versus DS8 for the formation of 3a@CAHTUNGTREN(NUGN 1·2) as a function of
tively. The Eint calculated for 7@1 and 7@2 are ꢀ10.89 and
ꢀ9.52 kcalmolꢀ1, respectively. The sum of the Eint values is
ꢀ20.41 kcalmolꢀ1, which is 72% of the Eint between 3a and
1·2. The Eint calculated for 8@1 and 8@2 are ꢀ2.35 and
ꢀ2.14 kcalmolꢀ1, respectively. They are very weak in com-
parison with the interactions of 3a with 1 and 2, indicating
that the interactions of the terminal methyl groups of 3a
with 1 and 2 do not play an important role in stabilizing
3a@1·2, although the hydrogen atoms of the methyl groups
have (CH/p) contacts with the aromatic cavity ends of 1 and
2. These results show that the interactions of the acetylenic
parts of 3a with 1 and 2 have paramount importance for the
strong attraction between 3a and 1·2.
polar-solvent content. The guest@(1·2) offers the great ad-
ACHTUNGTRENNUNG
vantage that its thermodynamic stability is controlled by
guests 3–6 in the range Ka =1ꢀ109–1ꢀ104 mꢀ1 in CDCl3 at
298 K. This implies that the unit of guest@ACTHNUGRTENUNG(1·2) is a promis-
ing candidate as an affinity-variable supramolecular synthon
for supramolecular architectures, such as supramolecular
polymers.[1b,3,6a,b,25]
Experimental Section
General: 1H and 13C NMR spectra were recorded at 400 and 100 MHz,
respectively, on a JEOL JNM-AL400 spectrometer. IR spectra were re-
corded on a JASCO FT/IR-460Plus spectrometer. High-resolution ESI-
TOF-MS and EI-TOF-MS were performed on a JEOL JMS-T100LP and
a JEOL JMS-T100GCV, respectively. The isothermal titration calorimet-
ric (ITC) experiment was performed on a TA Instruments Nano-ITC 2G.
Recycle preparative HPLC was performed on a Japan Analytical Indus-
try LC-918 by using polystyrene gel columns (JAIGEL 1H and 2H) with
CHCl3 as an eluent. The CDCl3 employed in all the 1H NMR and ITC
experiments was stored over K2CO3 prior to use, and the other NMR sol-
The large attractive electrostatic interactions (Ees =
ꢀ9.15 kcalmolꢀ1) were calculated for 3a@
ACHTUNGTREN(NUGN 1·2), as presented
in Table 3. This shows that the electrostatic interaction is
one of important sources for the strong attraction, although
the attraction by the electrostatic interaction is weaker than
the dispersion interaction. In 4a@
ACHTUNGERTN(NUNG 1·2), there are C=O···HC
interactions between the carbonyl oxygen atoms of the ace-
3690
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Chem. Eur. J. 2013, 19, 3685 – 3692

Remarkable Stability of a Hydrogen-Bonded Heterocapsule
FULL PAPER
vents were used without any pretreatment. Tetra(4-pyridyl)-cavitands
[2] For extraordinarily large Ka in a non hydrogen-bonded host-guest
system, see: M. V. Rekharsky, T. Mori, C. Yang, Y. H. Ko, N. Selva-
palam, H. Kim, D. Sobransingh, A. E. Kaifer, S. Liu, L. Isaacs, W.
Chen, S. Moghaddam, M. K. Gilson, K. Kim, Y. Inoue, Proc. Natl.
Acad. Sci. USA 2007, 104, 20737–20742.
1a[26] and 1b[10b] and tetrakis(4-hydroxyphenyl)-cavitands 2a[10a] and
2b[10b] (a: R=(CH2)6CH3, b: R=CH2CH
ACHTNUTRGNE(UNG CH3)2) were synthesized ac-
cording to the literature procedures. Synthetic procedures for 3a–f are
shown in the Supporting Information.
[3] a) T. Haino, E. Hirai, Y. Fukazawa, K. Kashihara, Angew. Chem.
2010, 122, 8071–8075; Angew. Chem. Int. Ed. 2010, 49, 7899–7903;
b) F. Tancini, R. M. Yebeutchou, L. Pirondini, R. De Zorzi, S. Gere-
mia, O. A. Scherman, E. Dalcanale, Chem. Eur. J. 2010, 16, 14313–
14321.
Synthesis of tetra(4-pyridyl)-cavitand with oligoether side chain (1c;
Scheme 1): Under Ar, to a mixture of tetraiodo cavitand with oligoether
side chain 9c (375 mg, 0.13 mmol),[27] 4-pyridineboronic acid (198 mg,
[4] a) F. H. Beijer, R. P. Sijbesma, H. Kooijman, A. L. Spek, E. W.
Meijer, J. Am. Chem. Soc. 1998, 120, 6761–6769; b) G. B. W. L.
Ligthart, H. Ohkawa, R. P. Sijbesma, E. W. Meijer, J. Am. Chem.
Soc. 2005, 127, 810–811; c) T. Park, S. C. Zimmerman, S. Nakashi-
ma, J. Am. Chem. Soc. 2005, 127, 6520–6521; d) B. A. Blight, C. A.
Hunter, D. A. Leigh, H. McNab, P. I. T. Thomson, Nat. Chem. 2011,
3, 246 and references cited therein.
[5] a) J. Rebek, Jr., Acc. Chem. Res. 2009, 42, 1660–1668; b) T. Schrçd-
er, S. N. Sahu, D. Anselmetti, J. Mattay, Isr. J. Chem. 2011, 51, 725–
742.
Scheme 1.
[6] a) R. K. Castellano, D. M. Rudkevich, J. Rebek, Jr., Proc. Natl.
Acad. Sci. USA 1997, 94, 7132–7137; b) R. K. Castellano, R. Clark,
S. L. Craig, C. Nuckolls, J. Rebek, Jr., Proc. Natl. Acad. Sci. USA
2000, 97, 12418–12421; c) J. M. C. A. Kerckhoffs, M. G. J. ten Cate,
M. A. Mateos-Timoneda, F. W. B. van Leeuwen, B. Snellink-Ruꢄl,
A. L. Spek, H. Kooijman, M. Crego-Calama, D. N. Reinhoudt, J.
Am. Chem. Soc. 2005, 127, 12697–12708.
[7] a) S. Mecozzi, J. Rebek, Jr., Chem. Eur. J. 1998, 4, 1016–1022; b) T.
Amaya, J. Rebek, Jr., J. Am. Chem. Soc. 2004, 126, 14149–14156;
c) E. S. Barrett, T. J. Dale, J. Rebek, Jr., J. Am. Chem. Soc. 2007,
129, 8818–8824.
[8] a) K. Kobayashi, K. Ishii, S. Sakamoto, T. Shirasaka, K. Yamaguchi,
J. Am. Chem. Soc. 2003, 125, 10615–10624; b) K. Kobayashi, K.
Ishii, M. Yamanaka, Chem. Eur. J. 2005, 11, 4725–4734.
[9] a) E. Huerta, G. A. Metselaar, A. Fragoso, E. Santos, C. Bo, J. de
Mendoza, Angew. Chem. 2007, 119, 206–209; Angew. Chem. Int.
Ed. 2007, 46, 202–205; b) H. Dube, M. R. Ams, J. Rebek, Jr., J. Am.
Chem. Soc. 2010, 132, 9984–9985.
1.61 mmol), [PdCl2ACHTUNGTRENNUNG(PPh3)2] (24.0 mg, 0.034 mmol), AsPh3 (79.6 mg,
0.26 mmol), and Cs2CO3 (655 mg, 2.01 mmol) were added 1,4-dioxane
(14 mL) and H2O (0.6 mL). This mixture was stirred at 1108C for 48 h
under Ar. After cooling to RT, the reaction mixture was filtered and
washed with CH2Cl2 to remove Pd black. After evaporation of the fil-
trate, the residue was purified by column chromatography on silica gel
eluted with EtOH/EtOAc (4:1) containing Et3N (3% v/v). After evapo-
ration of the fractions containing 1c, the residue was dissolved in CHCl3
and filtered to remove trace amount of silica gel. The evaporation of the
filtrate gave 1c as a pale yellow solid (146 mg, 46% yield). M.p.: 1548C;
1H NMR (CDCl3): d=8.60 (d, J=6.0 Hz, 8H), 7.36 (s, 4H), 6.97 (d, J=
6.0 Hz, 8H), 5.30 (d, J=6.6 Hz, 4H), 4.94 (t, J=7.8 Hz, 4H), 4.21 (d, J=
6.6 Hz, 4H), 3.65–3.48 (m, 128H), 3.37 (s, 24H), 2.47–2.40 (m, 8H), 2.24–
2.18 (m, 4H), 1.78–1.69 ppm (m, 12H); 13C NMR (CDCl3): d=152.3,
149.5, 141.9, 138.4, 127.0, 124.9, 120.8, 100.4, 71.9, 70.59, 70.54, 70.50,
69.7, 69.4, 59.0, 40.2, 36.2, 27.3, 26.7 ppm; HRMS (ESI): m/z calcd for
C136H204N4O44 +Na+: 2620.37461 [M+Na+]; found: 2620.37236.
X-ray data collection and crystal-structure determination of 3b@ACHTNUTGRNEUNG(1b·2b):
[10] a) K. Kobayashi, R. Kitagawa, Y. Yamada, M. Yamanaka, T. Sue-
matsu, Y. Sei, K. Yamaguchi, J. Org. Chem. 2007, 72, 3242–3246;
b) H. Kitagawa, M. Kawahata, R. Kitagawa, Y. Yamada, M. Yama-
naka, K. Yamaguchi, K. Kobayashi, Tetrahedron 2009, 65, 7234–
7239; c) H. Kitagawa, Y. Kobori, M. Yamanaka, K. Yoza, K. Ko-
bayashi, Proc. Natl. Acad. Sci. USA 2009, 106, 10444–10448.
[11] a) T. Martꢅn, U. Obst, J. Rebek, Jr., Science 1998, 281, 1842–1845;
b) B. W. Purse, S. M. Butterfield, P. Ballester, A. Shivanyuk, J. Re-
bek, Jr., J. Org. Chem. 2008, 73, 6480–6488.
The data were recorded by using a Bruker APEXII CCD area detector,
by using MoKa graphite monochromated radiation (l=0.71073 ꢂ). The
structure was solved by direct methods by using the program SHELXS-
97.[28] The refinement and all further calculations were carried out by
using SHELXL-97.[28] The hydrogen atoms were included in calculated
positions and treated as riding atoms by using the SHELXL default pa-
rameters. The nonhydrogen atoms were refined anisotropically by using
weighted full-matrix least-square method on F2. Crystal data and struc-
ture refinement are listed in Table S1 in the Supporting Information, and
ORTEP view is shown in Figure S2 in the Supporting Information.
[12] Because guest exchanges between 3@
ACHTUNGTNER(NUNG 1a·2a) and standard guest@-
AHCTUNGTRENNUNG
CCDC-893646 (3b@ACHTUNGTRENNUNG(1b.2b)) contains the supplementary crystallographic
mixture of 1a·2a, 3, and a standard guest in a 1:2:n ratio (n=2–5) in
CDCl3 was heated at 323 K for 4 h to reach thermodynamic equili-
bration in competitive encapsulation experiments before the meas-
urements of Ka at 298 K. In the competitive encapsulation experi-
ments, the following combinations were used: 4b versus 3e, 4b
versus 3 f, 3c versus 3e, 3c versus 3 f, 3c versus 3b, 3a versus 3b, 3a
versus 3c, 3a versus 3d (Figure S10 in the Supporting Information),
3a versus 3e, and 3a versus 3 f.
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_-
request/cif.
Acknowledgements
[13] H. Zeng, R. S. Miller, R. A. Flowers II, B. Gong, J. Am. Chem. Soc.
2000, 122, 2635–2644.
This work was supported in part by a Grant-in-Aid from JSPS (No.
22350060 (K.K.)) and Grant-in-Aid for Scientific Research on Innovative
Areas “Emergence in Chemistry (K.K.)” and “Advanced Molecular
Transformations by Organocatalysts (S.T.)” from MEXT.
[14] The Ka value determined by the ITC experiment was one order of
magnitude smaller than that estimated by the 1H NMR competition
experiment. The reason is that the former measurement was con-
ducted in 1/100 concentration compared with the latter, so the effect
of H2O content in CDCl3 as a hydrogen-bonding inhibitor could not
be ignored.
[1] a) H.-J. Schneider, Angew. Chem. 2009, 121, 3982–4036; Angew.
Chem. Int. Ed. 2009, 48, 3924–3977; b) T. F. A. de Greef, M. M. J.
Smulders, M. Wolffs, A. P. H. J. Schenning, R. P. Sijbesma, E. W.
Meijer, Chem. Rev. 2009, 109, 5687–5754 and references cited there-
in.
[15] In D2O/[D6]acetone, 1c with oligoether side chains was used instead
of 1a (Figure 1) because of low solubility of 1a.
[16] It is known that a Rebekꢃs self-assembled cylindrical capsule very
tightly encapsulates (E)-4,4’-dimethylstilbene with Ka2 =9.0ꢀ105 mꢀ2
Chem. Eur. J. 2013, 19, 3685 – 3692
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3691

S. Tsuzuki, K. Kobayashi et al.
in CD3OD/
[D12]mesitylene (10% v/v) at 300 K.[7b] It is also known
gar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N.
Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W.
Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J.
Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C.
Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari,
J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cio-
slowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaro-
mi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng,
A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian, Inc., Wall-
ingford CT, 2004.
that contiguous quadruple DDAA–AADD hydrogen-bonding
a
array of ureidopyrimidone shows Ka =170mꢀ1 in [D6]DMSO/CDCl3
(10% v/v) at 298 K.[4a] It is thus understood how 3a@
ACHTNUTRGNEUNG(1a·2a) is ther-
modynamically so stable.
[17] a) E. L. Piatnitski, R. A. Flowers II, K. Deshayes, Chem. Eur. J.
2000, 6, 999–1006; b) E. A. Meyer, R. K. Castellano, F. Diederich,
Angew. Chem. 2003, 115, 1244–1287; Angew. Chem. Int. Ed. 2003,
42, 1210–1250; c) D. H. Leung, R. G. Bergman, K. N. Raymond, J.
Am. Chem. Soc. 2008, 130, 2798–2805.
[18] Protic polar solvents with high cohesive interactions prefer to inter-
act with bulk solvent molecules rather than to solvate the comple-
mentary apolar surfaces of host and guest molecules, namely, desolv-
ACHTUNGTRENNUNGation of host and guest molecules from surrounding protic polar sol-
vent molecules and the resulting rearrangement of the hydrogen-
bonding network with bulk solvent molecules would be a primary
driving force for determining guest encapsulation. The substitution
of less favorable dispersion interactions between protic polar solvent
molecules and the complementary surfaces of the host and guest
molecules by more favorable dispersion interactions between the hy-
drocarbon surfaces in the host–guest complex would also be a major
contribution to the favorable enthalpic driving force in protic polar
solvents. See Ref. [17].
[22] B. J. Ransil, J. Chem. Phys. 1961, 34, 2109–2118.
[23] S. F. Boys, F. Bernardi, Mol. Phys. 1970, 19, 553–566.
[24] The positions of the atoms in 7 and 8 were taken from those in 3a.
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7 and 8, were optimized at the HF/6-31G* level.
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Received: November 3, 2012
Published online: January 29, 2013
3692
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