Supramolecular enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylate mediated by capped γ-cyclodextrins: Critical control of enantioselectivity by cap rigidity

Article abstract of DOI:10.1021/jo800533y

(Graph Presented) A series of γ-cyclodextrins (CDs) modified with capping and noncapping aromatic group(s) were synthesized to mediate the enantiodifferentiating [4 + 4] photocyclodimerization of 2-anthracenecarboxylic acid (AC). The complexation behavior of these γ-CDs with AC was studied by circular dichroism, UV-vis, and NMR spectroscopy to reveal the formation of stable 1:2 host-guest complexes in all cases. The capped γ-CD with a biphenyl group bridging the A and D glucose units was shown to confine the included AC molecules most strictly among the capped and noncapped γ-CDs examined. Photocyclodimerization of AC mediated by capped γ-CDs considerably improved the yield and enantiomeric excess (ee) of the head-to-head photodimer 3. The ee and the absolute configuration of syn-head-to-tail photodimer 2 critically depended on the rigidity of capping. Thus, the flexibly capped and rim-substituted γ-CDs afforded 2 in moderate ee's of around 40%, whereas γ-CD with a rigid biphenyl cap gave the antipodal 2 in -58% ee. Interestingly, the ee of 2 mediated by flexibly capped γ-CDs was highly sensitive to the temperature variation as a consequence of large differential entropy changes in the enantiodifferentiation process. In contrast, the entropy effect does not appear to play a significant role in the photocyclodimerization of AC with rigidly capped γ-CDs. The differential enthalpy and entropy changes obtained for the enantiodifferentiating photocyclodimerization mediated by native and most of the modified γ-CDs gave an excellent enthalpy-entropy compensation plot with an exception of the biphenyl-capped γ-CD, indicating the operation of significantly different enantiodifferentiation mechanism within the rigidly capped cyclodextrin cavity.

Full text of DOI:10.1021/jo800533y

Supramolecular Enantiodifferentiating Photocyclodimerization of
2-Anthracenecarboxylate Mediated by Capped γ-Cyclodextrins:
Critical Control of Enantioselectivity by Cap Rigidity
Cheng Yang, Tadashi Mori, and Yoshihisa Inoue*
Department of Applied Chemistry, Osaka UniVersity, Suita 565-0871, Japan
inoue@chem.eng.osaka-u.ac.jp
ReceiVed March 8, 2008
A series of γ-cyclodextrins (CDs) modified with capping and noncapping aromatic group(s) were
synthesized to mediate the enantiodifferentiating [4 + 4] photocyclodimerization of 2-anthracenecarboxylic
acid (AC). The complexation behavior of these γ-CDs with AC was studied by circular dichroism, UV-vis,
and NMR spectroscopy to reveal the formation of stable 1:2 host-guest complexes in all cases. The
capped γ-CD with a biphenyl group bridging the A and D glucose units was shown to confine the included
AC molecules most strictly among the capped and noncapped γ-CDs examined. Photocyclodimerization
of AC mediated by capped γ-CDs considerably improved the yield and enantiomeric excess (ee) of the
head-to-head photodimer 3. The ee and the absolute configuration of syn-head-to-tail photodimer 2
critically depended on the rigidity of capping. Thus, the flexibly capped and rim-substituted γ-CDs afforded
2 in moderate ee’s of around 40%, whereas γ-CD with a rigid biphenyl cap gave the antipodal 2 in
-58% ee. Interestingly, the ee of 2 mediated by flexibly capped γ-CDs was highly sensitive to the
temperature variation as a consequence of large differential entropy changes in the enantiodifferentiation
process. In contrast, the entropy effect does not appear to play a significant role in the photocyclodimer-
ization of AC with rigidly capped γ-CDs. The differential enthalpy and entropy changes obtained for the
enantiodifferentiating photocyclodimerization mediated by native and most of the modified γ-CDs gave
an excellent enthalpy-entropy compensation plot with an exception of the biphenyl-capped γ-CD,
indicating the operation of significantly different enantiodifferentiation mechanism within the rigidly
capped cyclodextrin cavity.
Introduction
lecular interactions such as hydrogen bonding, hydrophobic, van
der Waals, and electrostatic interactions. Consequently, the use
of chiral hosts is a potentially very attractive strategy to
efficiently transfer the host’s chiral information to the interacting
guest substrate. In the past decade, a variety of chiral hosts,
Supramolecular photochirogenesis has recently received
considerable attention as a promising approach for controlling
the enantiodifferentiating process occurring in the excited
state.1,2 In contrast to the conventional photosensitization in
which weak short-lived interactions within an exciplex inter-
mediate have to be controlled, chiral hosts are able to intimately
interact with the substrate both in the ground and excited states
for a sufficient period of time by virtue of multiple supramo-
(1) (a) Inoue, Y.; Ramamurthy, V. Chiral Photochemistry; Marcel Dekker:
New York, 2004. (b) Tanaka, K.; Toda, F. Chem. ReV. 2000, 100, 1025. (c)
Griesbeck, A. G.; Meierhenrich, U. J. Angew Chem., Int. Ed. 2002, 41, 3147.
(d) Turro, N. J Pure Appl. Chem. 1995, 67, 199. (e) McClenaghan, N. D.;
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5786 J. Org. Chem. 2008, 73, 5786–5794
10.1021/jo800533y CCC: $40.75 2008 American Chemical Society
Published on Web 07/08/2008

Photocyclodimerization Mediated by Capped γ-Cyclodextrins
SCHEME 1. Enantiodifferentiating [4 + 4] Photocyclodimerization of 2-Anthracenecarboxylic Acid
including cyclodextrin,3 biomolecule,4 chirally modified zeolite,5
and chiral template,6 have been employed as molecular contain-
ers for mediating chiral photoreactions.
head-to-tail (HT) photodimer 2 in up to 41% ee but head-to-
head (HH) photodimer 3 in poor ee of <5%. We have
endeavored to improve the stereochemical outcomes of the
supramolecular photocyclodimerization of AC by introducing
functional group(s) into the γ-CD rim, modifying the framework
of the γ-CD, and manipulating entropy-related factors.9b–e
An intriguing issue concerning the CD-mediated photochi-
rogenesis is the vital role of entropy, whose degree of commit-
ment varies significantly depending on the structure of CD
employed. The enantiodifferentiating photoisomerization of (Z)-
cyclooctene to chiral (E)-isomer included and sensitized by
ꢀ-CD benzenecarboxylates was found to be almost independent
of the reaction temperature, indicating a trivial contribution of
the entropy term.8b However, the entropy factor was demon-
strated to play an important role in the enantiodifferentiating
photoisomerization of (Z,Z)-1,3-cyclooctadiene sensitized by
γ-CD-naphthoxylacetate.8j As far as the photocyclodimerization
of AC is concerned, the entropy-related factors such as
temperature, solvent, and pressure appear to be pivotal in
determining the product chirality for all γ-CD derivatives
hitherto examined. These results indicate that ꢀ- and γ-CD
cavities possess much different characters in particular from the
entropic point of view. In this context, it is interesting to mention
that the inherently low-entropic environment of ꢀ-CD’s rigid
cavity can be made flexible by permethylating the hydroxyl
groups of ꢀ-CD.8d
As a natural consequence of the above discussion, we became
interested in examining the chiral photoreaction mediated by
capped CDs, which possess more rigid skeletons and are
expected to behave differently from their parent CD.10 The
photocyclodimerization of AC mediated by γ-CD with a rigid
bridging cap was found to give the photoproduct antipodal to
that obtained by using native and modified γ-CDs without a
bridging cap.9e In the present study, we expanded the variation
of CD hosts with capping modification and further examined
in detail the AC photocyclodimerization mediated by a series
of γ-CD derivatives with flexible and rigid caps, as well as the
relevant noncapping substituent(s), to elucidate the critical
dependence of this supramolecular photochirogenic reaction
upon capping modification and rigidity of the cap.
R-, ꢀ-, and γ-Cyclodextrins (CDs) are truncated cone-shaped
macrocyclic molecules composed of 6-8 glucose residues,
respectively. Their hydrophobic cavities of varying sizes
(4.5-8.5 Å) are capable of encapsulating a wide range of
organic guests in aqueous solutions through the hydrophobic
interaction.7 Since CDs are soluble in water, readily available,
inherently chiral, and transparent in most UV-vis regions, they
have been extensively used in CD-mediated chiral photoreac-
tions.8 We have recently reported the enantiodifferentiating [4
+ 4] photocyclodimerization of 2-anthracenecarboxylic acid
(AC) with native and modified γ-CDs (Scheme 1).9 Photocy-
clodimerization of AC in the presence of native γ-CD gives
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M.; Hou, Z.-J.; Liu|, Y. J. Org. Chem. 2000, 65, 8041. (c) Inoue, Y.; Dong,
S. F.; Yamamoto, K.; Tong, L.-H.; Tsuneishi, H.; Hakushi, T.; Tai, A. J. Am.
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Lett. 2002, 43, 9229. (f) Shailaja, J.; Karthikeyan, S.; Ramamurthy, V
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P.; Hoornaert, G.; Van der Eycken, E. Org. Lett. 2001, 3, 1173. (i) Mori, T.;
Weiss, R. G.; Inoue, Y. J. Am. Chem. Soc. 2004, 126, 8961. (j) Yang, C.; Mori,
T.; Wada, T.; Inoue, Y. New J. Chem. 2007, 31, 697.
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4147. (b) Rudzinski, C. M.; Young, A. M.; Nocera, D. G. J. Am. Chem. Soc.
2002, 124, 1723. (c) Tabushi, I.; Shimokawa, K.; Shimizu, N.; Shirakata, H.;
Fujita, K. J. Am. Chem. Soc. 1976, 98, 7855. (d) Fujita, K.; Shinoda, A.; Imoto,
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J. Org. Chem. Vol. 73, No. 15, 2008 5787

Yang et al.
SCHEME 2. Flexibly Capped (5, 6), Rigidly Capped (7),
and Rim-Substituted γ-Cyclodextrins (8, 9a-d) Employed as
Modified Chiral Hosts
FIGURE 2. UV-vis spectral changes of 2-anthracenecarboxylic acid
([AC] ) 0.5 mM) in aqueous solution upon gradual addition of 5 from
0 to 1.2 mM.
TABLE 1. Stepwise 1:1 and 1:2 Association Constants (K1 and K2)
for Complexation of 2-Anthracenecarbolate with Native, Capped, or
Primary Rim-Substituted γ-Cyclodextrins (γ-CDs) in Aqueous
Solution at 20 °C
host
γ-CDa
5
6
7
8
9a
9b
9c
9d
K1 (M-1
)
K2 (M-1
)
K2/K1
K1K2 (× 106 M-2
)
Result and Discussion
182
1580
1390
1280
6870
280
350
320
270
56700
16400
16200
12500
3130
10800
7450
7620
312
10
12
10
0.46
39
21
24
31
10.3
25.9
22.5
16.0
21.5
3.0
2.6
2.4
2.2
Synthesis. Capped γ-CDs 5-9 (Scheme 2) were synthesized
by reacting native γ-CD with relevant aryl(di)sulfonyl (di)chlo-
rides. The obtained γ-CD derivatives 5-7 were converted to
the corresponding diazido-γ-CDs, the regiochemistry of which
was determined through the HPLC comparison of the resulted
diazido-γ-CDs with the authentic samples reported earlier.9b
Complexation of AC with Capped γ-CDs. Each aromatic
group in 8 and 9a-d is attached to one of the glucose units
and therefore retains considerable flexibility, whereas that in 5,
6, and 7 is bridging two transannular glucose units to function
as a rigid cap. As exemplified for 5 in Figure 1, most of the
capped γ-CDs exhibit a positive induced circular dichroism
8320
a Reference 9a.
a right-handed screw, according to the first-positive, second-
negative sign of the apparently exciton-coupling La band.
1
To elucidate the influence of the capping modifications of
γ-CD on the complexation behavior with AC, we carried out
the UV-vis and NMR spectral studies. As can be seen from
Figure 2, the addition of capped γ-CD to an aqueous solution
of AC resulted in a pronounced bathochromic shift of the AC’s
1La transition, suggesting an imitate stacking of two AC
molecules in a γ-CD cavity.
Possessing a large hydrophobic cavity, native γ-CD forms
1:1 and 1:2 host-guest complexes in a sequential manner with
a small 1:1 association constant (K1 ) 182 M-1 at 20 °C) and
a much larger 1:2 association constant (K2 ) 56700 M-1 at 20
°C).9a
1
(ICD) signals at the La band around 230 nm and a negative
ICD signals at the 1Lb band around 260 nm, suggesting that the
aromatic group perching on the primary rim of γ-CD is
considerably tilted.12 The only exception is 9a, whose two tosyl
groups are close to each other and the possible ICD signals at
the 1La band were overwhelmed by the intense exciton coupling
signals. Two tosyl groups in 9a are deduced to be arranged in
K1
AC + γ-CD y\z AC γ-CD
K2
AC + AC γ-CD y
\
z 2AC γ-CD
The association constants for stepwise 1:1 and 1:2 complex-
ation of capped γ-CD with AC were determined by UV-vis
spectral titration. As listed in Table 1, the K1 values obtained
with capped γ-CDs 5-7 are consistently higher by a factor of
FIGURE 1. Circular dichroism spectra of 5 (blue), 7 (black), 9a (red),
and 9c (green) in aqueous solution at 25 °C.
(11) See Supporting Information.
(12) Kodaka, M. J. Am. Chem. Soc. 1993, 115, 3702.
5788 J. Org. Chem. Vol. 73, No. 15, 2008

Photocyclodimerization Mediated by Capped γ-Cyclodextrins
FIGURE 3. 1H NMR spectra of (a) AC (1.0 mM), (b) AC (4.0 mM) + 5 (3.0 mM), (c) 5 (4.0 mM), (d) 9c (3.0 mM) + AC (3.0 mM), and 7 (3.0
mM) in the absence of AC (e) and presence of (f) 0.5 mM, (g) 2.0 mM, and (h) 4.0 mM AC in D2O buffer solutions (pD 9.5) at ambient temperatures.
The signals marked by asterisk and triangle are assigned to the aromatic protons of capped γ-CDs and AC, respectively.
7-9 than that of native γ-CD. The enhanced K1 values may be
accounted for in terms of the reduced surface of AC molecule
exposed to aqueous solution as well as the increased van der
Waals interaction with the bridging aromatic moiety. The
primary rim of capped γ-CD should be more hydrophobic than
that of native γ-CD due to the aromatic capping, and the first
included AC molecule is likely to orient its hydrophilic
carboxylate group to the secondary rim of γ-CD with the
aromatic moiety being hidden beneath the cap.
In general, the first binding of AC is enhanced but the second
is retarded by primary-rim modification, regardless of capping
(5-7) or substitution (8, 9a-d). A series of A,X-ditosylated
γ-CDs 9a-d show only modest improvement of K1 by a factor
of 1.5-1.9. This is possibly due to the partial self-inclusion of
the tosyl group that hinders to some extent the inclusion of AC.
In contrast, biphenylsulfonated γ-CD 8 gives the largest K1 value
as high as 6870 M-1 (a 38-fold enhancement), implying that
the biphenyl moiety functions as a spacer that efficiently
fills the space remaining upon inclusion of the first AC.
However, the K2 value for 8 is 2.4-3.5 or 18-fold smaller than
those for other capped CDs 9a-d or native γ-CD, respectively.
As a result of the enhanced K1 and reduced K2, biphenyl-
substituted 8 gives an unusual K2/K1 ratio of 0.46, which is
inverted from those for native, rim-substituted, and other capped
CDs. Interestingly, the overall association constants (K1K2) for
capped 5-7 and biphenyl-substituted 8 are 1 order of magnitude
larger than those for the relevant rim-substituted 9a-d, most
probably due to the generally increased hydrophobicity of the
cavity.
The K2 values for capped γ-CDs are roughly 10-fold higher
than the relevant K1 values, which is attributable to the more
efficient van der Waals and π-π interactions upon inclusion
of the second AC molecule.9a However, the K2 values for capped
CDs are significantly (3.5- to 4.5-fold) smaller than the K2 for
native γ-CD, in sharp contrast to the large enhancement in K1.
This may be rationalized in terms of the relatively limited
positional and rotational freedoms for the second AC molecule
due to the presence of capping moiety and/or the hydrophobic
nature of the bridging cap that hinders the inclusion in favorable
head-to-tail fashion.
The NMR spectral study clearly revealed the restricted
motions of ACs included in the cavity of rigidly capped γ-CDs.
As shown in Figure 3, addition of AC into a D2O solution of 5
resulted in large upfield shifts of the proton signals of both
diphenyl ether moiety and AC. The nonanomeric proton signals
of free 5 are packed in a narrow region of 3.3-3.9 ppm with
two protons located at 2.91 and 3.02 ppm. Upon inclusion of
AC, these signals are distributed over a much wider range of
2.2-4.1 ppm. These anisotropic NMR shifts indicate that AC
molecules cannot freely rotate within the cavity of rigidly capped
γ-CD, unevenly shielding/deshielding the individual glucose
units. This is reasonable because the aromatic group transan-
nularly bridging two glucose units will significantly decrease
the primary opening of γ-CD and obstruct the motion of AC
molecule inserted in the narrowed window. For the simply
(di)tosylated γ-CDs, the substituent introduced still holds
considerable freedoms and the guests are less confined, which
is supported by the fact that the nonanomeric signals of 9c
appear in a narrow range of 3.2-3.8 ppm even after complex-
ation with AC (Figure 3d).
The restricted motion of AC is more evident for rigidly
capped γ-CD 7. As shown in Figure 3e-h, the proton signals
of AC immediately shift to much higher field at 0.5 mM
concentration. Further increasing concentration of AC only leads
to slight upfield shifts of AC protons. This indicates that ACs
exist primarily as 1:2 host-guest complexes even at the low
concentration, for which the large K2 value is responsible. On
the other hand, the signals of CD moiety gradually dispersed
to a much wider range upon addition of AC to show a chemical
shift of up to 1.81 ppm in the presence of 4 mM AC (Figure
3h). This substantial anisotropic effect indicates that the biphenyl
capping induces higher rigidity to CD than the diphenyl ether
bridge does and thus more severely restricts the motion of the
included AC molecules. This idea is further supported by the
fact that 5 shows four aromatic proton signals while 7 gives
eight, revealing that the free rotation of the benzene rings is
allowed in 5 but prohibited in 7 in the NMR time scale. On the
basis of these results, we conclude that the degree of host
rigidification induced by capping increases in the order 8, 9a-d
< 5, 6 < 7.
Photocyclodimerization of AC with Capped γ-CDs: Criti-
cal Control of Enantioselectivity by Cap Rigidity. Photolyses
of AC mediated by these capped γ-CDs were carried out under
argon atmosphere, using a high pressure mercury lamp fitted
with a glass filter (UV-35). The photoproducts were analyzed
by chiral reversed-phase HPLC to give the chemical yields,
product ratios, and ee values shown in Table 2. In water at 0
°C, photocyclodimerization of AC in the presence of native
γ-CD affords the HH photodimers 3 and 4 in a low combined
yield of 12%. In contrast, the use of capped γ-CDs considerably
J. Org. Chem. Vol. 73, No. 15, 2008 5789

Yang et al.
TABLE 2. Photocyclodimerization of 2-Anthracenecarboxylate in the Presence/Absence of Native, Capped, or Primary Rim-Substituted
γ-CDs in Water and 50% Aqueous Methanola
relative yield (%)b
ee (%)b c
,
host
solvent
H2O
50% MeOH
H2O
temp (°C)
1
2
3
4
2
3
HH/HTd
γ-CD
0
-45
40
25
15
0
40
25
15
0
42.9
46.4
35.9
35.7
35.1
34.2
34.3
35.0
37.4
38.8
39.1
39.0
39.2
40.1
38.4
37.3
40.3
40.0
39.6
42.0
46.3
51.3
40.3
40.5
43.0
42.2
46.4
49.9
40.1
38.4
37.8
41.0
43.9
44.4
40.1
38.2
39.6
39.3
41.2
41.1
42.6
42.1
41.9
43.7
44.6
42.7
45.5
33.2
36.8
36.4
33.4
31.1
21.8
21.6
20.8
20.6
22.8
24.4
28.0
26.8
25.9
23.0
39.3
40.2
38.6
37.1
33.0
26.8
40.7
38.0
36.5
35.4
32.9
28.5
38.5
38.6
38.7
35.6
34.3
31.0
36.9
36.5
38.6
32.6
29.8
24.7
38.5
40.2
42.7
34.9
32.2
28.7
6.9
13.3
15.3
15.7
16.1
16.8
22.7
22.4
21.2
20.5
24.9
22.9
20.1
24.2
25.0
28.5
11.8
10.9
11.7
14.6
13.3
14.3
10.1
11.7
10.6
15.0
13.5
14.5
12.1
12.6
12.3
16.2
14.1
16.3
13.4
14.0
11.7
20.4
19.3
23.7
11.7
10.4
9.1
4.7
7.1
37.1
28.8
13.7
14.1
15.2
16.2
9.3
9.6
9.5
9.5
-0.8
-8.7
0.13
0.26
0.38
0.39
0.47
0.53
0.78
0.77
0.72
0.68
0.62
0.58
0.49
0.49
0.56
0.66
0.26
0.25
0.28
0.26
0.26
0.28
0.23
0.27
0.26
0.29
0.26
0.28
0.27
0.30
0.31
0.31
0.28
0.33
0.30
0.34
0.28
0.39
0.41
0.52
0.23
0.22
0.17
0.27
0.30
0.40
5
6
7
12.0
12.2
15.9
17.9
21.2
20.9
20.6
20.0
13.2
13.7
12.7
8.9
10.7
11.1
8.5
8.9
10.1
6.2
7.4
7.6
8.9
9.7
9.9
7.3
7.2
7.0
-15.1
-15.4
-15.6
-15.6
-21.9
-23.0
-23.3
-24.0
-16.1
-15.4
-14.1
-33.1
-35.4
-35.9
-11.4
-10.6
-8.2
-26.6
-30.8
-35.1
-3.8
-5.6
-7.5
-17.7
-21.4
-25.4
-10.9
-11.4
-11.7
-25.9
-22.9
-20.2
-9.7
H2O
H2O
30
15
0
-53.0
-55.8
-57.6
-33.6
-37.6
-40.4
27.7
32.5
37.4
14.1
17.4
20.4
27.3
32.1
39.1
8.4
18.4
22.3
25.9
27.5
33.0
9.7
17.4
21.7
25.2
30.9
37.4
13.1
21.6
24.3
24. 7
29.9
36.9
17.9
28.8
34.4
50% MeOH
H2O
0
-30
-45
30
15
0
8
50% MeOH
H2O
0
-30
-45
30
15
0
9a
9b
9c
9d
50% MeOH
H2O
0
-30
-45
30
15
0
9.3
10.4
11.2
7.2
7.7
8.3
50% MeOH
H2O
0
-30
-45
30
15
0
9.5
11.4
10.1
7.7
9.7
10.5
7.3
7.3
6.3
6.3
7.7
-9.1
-8.2
-27.5
-31.0
-35.0
-5.3
-4.1
-2.4
-21.5
-21.1
-21.6
50% MeOH
H2O
0
-30
-45
30
15
0
0
-30
-45
50% MeOH
15.2
15.5
19.2
9.3
a Aqueous buffer solution (pH 9) containing 0.8 mM AC and 2 mM γ-CD irradiated at 366 nm under argon atmosphere using a high-pressure
mercury lamp equipped with a glass filter (Toshiba UV-35). b Relative yield and ee determined by using a tandem column of Intersil ODS-2 (GL
Science) and Chiralcel OJ-R (Daicel). c Positive/negative ee sign corresponds to the excess of the first-/second-eluted enantiomers, respectively. d HH/HT
) ([3] + [4])/([1] + [2]).
enhances the HH yield in general to 33-41% under the same
condition. This result seems reasonable, as the increased
hydrophobicity around the capped primary rim of 5-7 hinders
penetration of AC’s anionic carboxylate moiety into the primary
side and destabilizes the HT orientation to enhance the HH/HT
ratio. This conclusion is reinforced by the fact that primary rim-
substituted γ-CDs 8, 9a-d also give the HH dimers in 15-24%
combined yield in water at 0 °C, which is appreciably higher
than that (11%) obtained with native γ-CD. Certainly, the
transannularly capped γ-CDs 5-7 is more effective in improv-
ing the HH yield than the substituted γ-CDs.
and 9.5% upon photocyclodimerization with diphenyl ether-
capped γ-CDs 5 and 6. Intriguingly, the use of biphenyl-capped
γ-CD 7 resulted in the formation of antipodal 2 in a much higher
58% ee. These results clearly indicate that the original diaste-
reoselectivity upon HT complex formation with native γ-CD,
or the enantioselectivity of 2 derived therefrom, is not signifi-
cantly affected by simple primary-rim substitution (8, 9a-d)
but appreciably altered (reduced) by flexible capping (5, 6) and
even inverted by rigid capping to give a better ee for the
antipodal product (7). It is particularly interesting to mention
that the structural difference between 5 and 7 is only one oxygen
atom, which however leads to the strikingly different stereo-
chemical outcomes.
Photocyclodimerization of AC mediated by rim-substituted
γ-CDs 8, 9a-d in water at 0 °C gave HT dimer 2 in 33-39%
ee, which is comparable to that (37% ee) obtained with native
γ-CD. However, the ee of 2 is significantly reduced to 16.2%
Energetic considerations allow us to quantitatively evaluate
the stability difference between the diastereomeric HT com-
5790 J. Org. Chem. Vol. 73, No. 15, 2008

Photocyclodimerization Mediated by Capped γ-Cyclodextrins
FIGURE 4. CPK models of rigidly A,D-capped 7 (a) and flexibly A,D-capped 5 in different conformations (b and c).
plexes precursor to enantiomeric 2, by using the relationship
between the differential free energy and the enantiomer ratio:
∆∆G° ) -RT ln[(100 + % ee)/(100 - % ee)]. In this
evaluation, we use biphenylsulfonyl- or A,D-ditosyl-substituted
8 and 9c as noncapped references structurally related to 7 and
also diphenyl ether-bridged 5 as a reference with a flexible cap.
Both of the noncapped hosts afford photodimer 2 in 37.4% ee,
and native γ-CD gives almost the same result (37.1% ee) in
water at 0 °C (Table 2). This means that one of the diastereo-
meric HT complexes, precursor to the first-eluted (on chiral
HPLC) enantiomer of 2, is favored by 1.8 kJ mol-1 over the
antipodal complex. The flexible capping in 5 reduces the ee to
16.2%, which is equivalent to the free energy difference of 0.7
kJ mol-1 in favor of the same precursor complex. In contrast,
rigidly capped 7 affords antipodal 2 in 57.6% ee, indicating
that the precursor complex to the second-eluted enantiomer of
2 is favored by 3.0 kJ mol-1. Thus, the free energy change
induced by rigid capping amounts to 4.8 kJ mol-1, which is
FIGURE 5. Representative temperature-dependence (differential Ey-
much greater than that (1.1 kJ mol-1) caused by flexible capping.
The fact that the supramolecular complexation/photocy-
clodimerization process is extremely sensitive to the cap rigidity
not only reveals a critical correlation between the host structure
and its function but also provides us with a practical tool for
modifying the host structure to critically control the supramo-
lecular complexation and the subsequent photochirogenesis.
CPK model examinations show that the biphenyl bridge in 7
is tightly fixed over the space surrounded by the A, B, C, and
D glucose units (Figure 4a). AC molecule can penetrate only
through the narrowed window formed by the biphenyl and the
E, F, G, and H glucose units. The existence of an oxygen atom
in the bridge of 5 makes the cap moiety flexible enough to lean
against the A-D glucose rim (Figure 4b), allowing AC
molecules to penetrate through the opening surrounded by E-H
glucose units or to occupy the CD cavity near the A-D glucose
units (Figure 4c). In comparison to 7,9e 5 and 6 allow a wider
variety of conformationally different diastereomeric precursor
complexes, which most probably leads to the formation of 2 in
lower ee.
The ee of HH dimer 3 is susceptible not only to capping
modification but also to simple substitution, but no product
chirality inversion occurs, both of which are very different from
the behavior of the ee of HT dimer 2. Thus, native γ-CD gives
almost racemic 3 (-0.8% ee) in water at 0 °C, while rim-
substituted 8, 9a-d afford 3 in better ee’s (-8.2%, -7.5%,
-11.7%, -8.2%, and -2.4%, respectively) and capped 5-7
in much higher ee’s (-15.6%, -24.0%, and -14.1%, respec-
tively) under the same conditions. By performing the photore-
ring) plots of the enantiomeric excesses (ee’s) of 2 obtained in the
photocyclodimerization of AC mediated by flexibly capped 5 (b) and
6 (9); rigidly capped 7 (2); and rim-substituted 8 (0), 9c (O), and 9d
(4) in aqueous solution.
action with 7 in 50% aqueous methanol at -45 °C, the chemical
and optical yields of 3 can be optimized to 28.5% and -35.9%
ee, respectively. The noncapped reference hosts 8 and 9c also
afford 3 in similar ee values (-35.1% and -35.0%, respec-
tively). We may conclude therefore that the diastereoselectivity
of HH precursor complex is more critically controlled by
substitution and capping modification.
Temperature Effects: Opposite Behavior of Capped
versus Substituted γ-CDs. The photocyclodimerization of AC
mediated by γ-CD derivatives 5-9 was carried out over the
temperature ranges from +45 to 0 °C in water and from 0 to
-45 °C in 50% aqueous methanol to give the results shown in
Table 2.
Lowering temperature does not appear to greatly alter the
product distribution but consistently enhances the enantiose-
lectivities of 2 and 3. It is to note that photocyclodimerization
of AC with rim-substituted γ-CDs 8, 9a-d is more sensitive
to the temperature change than that with capped γ-CDs 5-7.
Interestingly, the ee of 2 almost increases in common from
25-28% at 30 °C to 33-39% at 0 °C in the photocyclodimer-
ization of AC mediated by rim-substituted CDs 8, 9a-d, while
the ee of 3 is kept low (mostly <12%). Over the same
temperature range, the ee values of both 2 and 3 obtained with
capped γ-CDs 5-7 exhibit only slight changes of 0-5%. We
J. Org. Chem. Vol. 73, No. 15, 2008 5791

Yang et al.
TABLE 3. Differential Entropy (∆∆S) and Enthalpy (∆∆H)
Changes for the Formation of Enantiomeric 2 in the
Photocyclodimerization of 2-Anthracenecarboxylate Mediated by
Capped (5-7) and Substituted γ-Cyclodextrins (8, 9a-d)
upon enantioface-selective inclusion of the second AC molecule
into a 1:1 γ-CD-AC complex in the ground state and therefore
the obtained differential parameters are thermodynamic in
nature.
2
3
As can be seen from Table 3, rim-substituted γ-CDs 8, 9a-d
afford in general much larger ∆∆H and ∆∆S values than capped
γ-CDs 5-7 in both water and aqueous methanol solutions. In
view of the flexible skeleton of γ-CD, it is reasonable that these
substituted γ-CDs form two diastereomeric complexes with
substantially different enthalpic changes (arising from the van
der Waals contacts within the cavity) and entropic changes (from
the conformational alteration and desolvation upon complex-
ation). Indeed, the entropy term is known to play an important
role in the enantiodifferentiating photoreactions conducted in
the cavity of γ-CD,8j,9d but not in the cavity of ꢀ-CD.8b
Therefore, the results obtained with the rim-substituted γ-CDs
are in line with our previous observations, suggesting that they
bind substrates in an induced-fit manner.16
∆∆H
∆∆S
∆∆H
∆∆S
solvent
H2O
host (kJ mol-1) (J mol-1 K-1) (kJ mol-1) (J mol-1 K-1
)
5
6
7
8
9a
9b
9c
9d
-1.0
-0.1
3.0
-6.2
-6.1
-3.6
-5.0
-6.2
1.8
-1.5
-3.3
-2.8
-2.7
-4.1
-0.8
1.4
0.2
0.2
0.9
-0.9
0.8
-1.5
2.1
1.7
1.8
0.4
-1.4
-0.7
1.9
-1.3
0.0
-2.0
-0.8
-5.8
-3.0
-6.9
3.3
5.0
3.7
-0.6
-9.4
-3.9
2.2
-16.3
-15.6
-7.6
-11.7
-16.3
0.8
-3.1
-10.7
-8.8
-7.8
-12.0
50% MeOH 7
8
9a
9b
9c
9d
-5.3
-3.6
In this context, it is unusual that capped γ-CDs 5-7 afford
only negligible differential entropies of 0.2-1.4 J mol-1 K-1
,
which are 1-2 orders of magnitude smaller than those for
noncapped γ-CDs 8, 9a-d. This result is compatible with the
idea that the capped CD skeleton is restricted in motion and
hence does not greatly alter its original conformation upon
diastereodifferentiating complexation with ACs. This is the first
experimental demonstration of the reaction control by the low-
entropy environment existing in capped γ-CD cavity.
plotted the logarithm of the enantiomer ratio of 2 as a function
of reciprocal temperature to quantitatively analyze the enana-
tiodifferentiating process and thus to elucidate the origin of this
contrasting temperature-dependence behavior. As illustrated in
Figure 5, all of the data obtained for each capped γ-CD (5-7)
fall on a good straight line, indicating that a single enantiod-
ifferentiation mechanism operates in the temperature range
employed. By using the Eyring equation, the differential
enthalpy change (∆∆H) and entropy change (∆∆S) for the
formation of antipodal products are calculated from the slope
and intercept, respectively.13 The ∆∆H and ∆∆S values obtained
for capped CDs 5-7 and substituted CDs 8, 9a-d in water
and 50% aqueous methanol are summarized in Table 3.
Before analyzing the ∆∆H and ∆∆S values obtained, it is
better to discuss the essential enantiodifferentiating step in this
supramolecular photocyclodimerization and the nature of the
differential parameters obtained from the temperature-depen-
dence studies. The size of γ-CD cavity is not large enough to
allow swapping of two AC molecules included in the cavity,
and therefore the equilibrium between two diastereomeric
complexes is established only through consecutive dethreading
and rethreading of AC. It is accepted in general that the
association rate constant (ka) for a guest molecule to penetrate
Synchronized with the much reduced ∆∆S values, the ∆∆H
values for 5 and 6 are also decreased significantly to 0.1-1.0
kJ mol-1, leading to the modest enantioselectivities for 2
(9.5-16.2% ee). Despite the similarly low ∆∆S of 0.2-0.8 kJ
mol-1, much larger ∆∆H values of 1.8 and 3.0 kJ mol-1 are
observed for rigidly capped 7, indicating that the significant
enantioselectivity (57.6% ee) obtained with 7 is absolutely
enthalpic in origin. This observation indicates that without
causing major conformational changes in 7, one of the diaster-
eomeric AC pairs, precursor to the dominant enantiomer of 2,
fits more nicely into the rigidly capped γ-CD cavity than its
antipodal one does. We may say therefore that the complemen-
tarity of the preferred diastereomeric AC pair with the cavity
of 7 is close to that in a classical lock-and-key model.17
In a previous paper,8d we demonstrated that the inherently
low-entropy environment of the native ꢀ-CD cavity can be
modified to a highly entropy-susceptive one by breaking the
hydrogen-bonding network on the secondary rim through
permethylation of ꢀ-CD’s hydroxyl groups. Thus, the present
work demonstrates that the opposite process to build up a low-
entropy cavity from a highly flexible, conformationally diverse
one is also feasible through sophisticated modification and that
the resulting low-entropy environment contributes to the
development of efficient chiral supramolecular (photo)reactions.
Rare Deviation from the Enthalpy-entropy Compensa-
tionObservedforRigidlyCappedγ-CD7.Theenthalpy-entropy
compensation is an intriguing phenomenon that is widely
observed for essentially all chemical and biological reactions
and equilibria.18,19 It provides a powerful tool for analyzing,
understanding, and even predicting the thermodynamic behavior
based on the existing experimental data.20 We have demon-
into the cavity of a supramolecular host like CD is normally in
14
a range of 107-108 M-1 s-1
.
Since the second association
constants K2 determined experimentally for this capped
γ-CD-AC system are in a range of 3000-16000 M-1, the
dissociation rate constants (kd) for the 1:2 host-guest complex
are estimated to be 104-105 s-1. Therefore the residence time
of AC in the 1:2 host-guest complex is much longer than the
lifetime of an excited AC molecule (the fluorescence lifetime
of AC is ca. 16 ns). On the basis of this estimation and the fact
that the quantum efficiency of photocyclodimerization within
the γ-CD cavity is high (Φ ) 0.4-0.5),15 we may safely
conclude that the product’s ee is determined essentially by the
stability difference of two diastereomeric complexes formed
(13) (a) Inoue, Y.; Yokoyama, T.; Yamasaki, N.; Tai, A. J. Am. Chem. Soc.
1989, 111, 6480. (b) Hoffmann, R.; Inoue, Y. J. Am. Chem. Soc. 1999, 121,
10702.
(16) (a) Corbett, P. T.; Tong, L. H.; Sanders, J. K. M.; Otto, S. J. Am. Chem.
Soc. 2005, 127, 8902. (b) Kasai, K.; Aoyagi, M.; Fujita, M. J. Am. Chem. Soc.
2000, 122, 2140.
(14) (a) Zhang, X.; Gramlich, G.; Wang, X.; Nau, W. M. J. Am. Chem. Soc.
2002, 124, 254. (b) Dyck, A. S. M.; Kisiel, U.; Bohne, C. J. Phys. Chem. B
2003, 107, 11652.
(17) Bender, M. L.; Van Etten, R. L.; Clowes, G. A.; Sebastian, J. F. J. Am.
Chem. Soc. 1966, 88, 2318.
(15) Tamaki, T.; Kokubu, T.; Ichimura, K. Tetrahedron 1987, 43, 1485.
5792 J. Org. Chem. Vol. 73, No. 15, 2008

Photocyclodimerization Mediated by Capped γ-Cyclodextrins
the mechanism of enantiodifferentiation in this supramolecular
photochirogenesis system. The exemption of rigidly capped CD
7 is in line with the above observation that the photodimerization
with 7 gives the same enantiomer of 3 in ee’s comparable to
those obtained by using flexibly capped γ-CDs rather than leads
to the chirality inversion of product 2, and also with the
conclusion that the tight bridging in 7 significantly limits the
conformational freedoms as compared with the flexibly capped
5, 6 and rim-substituted 8, 9a-d.
The contrasting behavior observed reveals a distinct role of
the rigid capping in the formation of 2 and 3, which can be
rationalized in terms of the structures of diastereomeric com-
plexes which are precursor to the corresponding photodimers.
The HH-oriented AC pairs, precursor to 3, are deduced to orient
their carboxylate moiety to the secondary rim due to the
increased hydrophobicity and narrowed opening of the primary
rim of rigidly capped 7. It is energetically favorable for the
aromatic moiety of AC to hide beneath the cap than to protrude
into bulk water through the narrow window, a conformation
that the HT AC pairs are forced to take. Therefore, the HH AC
pairs will not be significantly restricted even in the cavity of
rigidly capped γ-CD 7, and the same enantiodifferentiation
mechanism operates for the formation of 3 is followed with all
modified γ-CDs. The above results demonstrate that the entropy
effect on the supramolecular photochirogenesis system is not a
simple function of the rigidity of CD frame, but also critically
correlated with the host-guest complexation models.
FIGURE 6. Entropy-enthalpy compensation plots of the differential
thermodynamic parameters obtained for dimer 2 in this work (2) and
in ref 9b (4), and for dimer 3 in this work (b) and in ref 9b (O). The
data points for 2 obtained with rigidly capped 7 are indicated by an
arrow. The red and blue regression lines are for 2 (excluding the data
obtained with 7) and 3, respectively.
strated that the enantiodifferentiation mechanism of the photo-
cyclodimerization of AC with native and modified γ-CDs is
essentially unchanged even when one of the glucose units is
converted to an altrose on the basis of the nice compensatory
entropy-enthalpy relationship observed.9d
To examine the validity of global entropy-enthalpy com-
pensation, we plotted the ∆∆H values against the ∆∆S values
for the formation of dimers 2 and 3 mediated by primary rim-
modified 5-8 and 9a-d in water and 50% aqueous methanol
and also those reported for the same photoreaction mediated
by secondary rim- and skeleton-modified γ-CDs.9d As can be
seen from Figure 6, the ∆∆H and ∆∆S values for the formation
of 2 (red symbols), excepting the data obtained with 7 (indicated
by an arrow), are nicely fitted to a single regression line that
satisfies the equation ∆∆H ) 0.37∆∆S - 0.4 (r ) 0.97), while
those for 3 (blue symbols) fall on a different regression line:
∆∆H ) 0.30∆∆S - 0.6 (r ) 0.98), indicating that the equipodal
temperatures for the formation of 2 and 3 are 370 and 300 K,
respectively. This seems reasonable since the HT and HH dimers
are formed from different diastereomeric precursor complexes.
Unprecedentedly, the thermodynamic parameters for 2 ob-
tained with rigidly capped 7 in water and aqueous methanol
appreciably deviate upward from the regression line obtained
without including these two points; see Figure 6. Interestingly,
the parameters obtained for 2 by using flexibly capped CDs 5
and 6 do not show any deviation. This obvious difference in
thermodynamic behavior between the rigidly and flexibly capped
CDs indicates that there exists a critical cap rigidity to switch
Conclusions
In this study, we have synthesized a series of capped and
rim-substituted γ-CDs as chiral hosts for mediating the enan-
tiodifferentiating photocyclodimerization of AC. All of the
γ-CDs form stable 1:2 host-guest complexes with AC. The
HH/HT ratio is significantly improved by using substituted and
in particular capped γ-CDs. The ee of chiral HT dimer 2 is
unusually insensitive to the rim substitution but is significantly
affected by the capping modification; the flexibly capped CDs
give the same enantiomer in smaller ee’s, whereas the rigidly
capped CD affords the antipodal product in a greatly enhanced
ee of 58%. In contrast, the ee of chiral HH dimer 3 is much
more sensitive to the modification and is greatly enhanced to
35% by rim-substitution and to 36% by rigid capping.
A clear deviation from the compensatory enthalpy-entropy
relationship is found for the thermodynamic parameters obtained
in the photocyclodimerization with rigidly capped CD 7,
indicating a switching of the enantiodifferentiation mechanism.
Such structural fine-tuning may be used for critically manipulat-
ing the stereochemical outcomes of supramolecular photochi-
rogenesis.
Experimental Section
(18) (a) Leffler, J. E.; Grunwald, E. Rates and Equilibria of Organic
Reactions; Wiley: New York, 1963; reprint version from Dover, New York,
1989. (b) Grunwald, E.; Steel, C. J. Am. Chem. Soc. 1995, 117, 5687. (c) Exner,
O. Correlation Analysis of Chemical Data; Plenum: New York, 1988.
(19) Very recently, the only exceptions from the compensatory enthalpy-
General. FAB-MS spectra were measured on a JEOL JMS-
DX303 mass spectrometer. NMR spectra were recorded on a JEOL
JNM-EX 400 spectrometer; all chemical shifts are reported against
the acetonitrile signal used as an internal standard. UV-vis
absorption spectra were recorded on a JASCO V-550 spectropho-
tometer. Circular dichroism spectra were measured on a JASCO
J-810 spectropolarimeter.
Materials. 4,4′-Oxydibenzene-1-sulfonyl chloride, biphenyl-4,4′-
disulfonyl dichloride and γ-CD were purchased from Tokyo Kasei.
6A,6X-Ditosyl-γ-CDs 9a-d, the capped γ-CD 7, and the rim-
entropy relationship have been reported for
a cucurbit[7]uril-ferrocene
system: Rekharsky, M. V.; Mori, T.; Yang, C.; Ko, Y. H.; Selvapalam, N.; Kim,
H.; Sobransingh, D.; Kaifer, A. E.; Liu, S.; Isaacs, L.; Chen, W.; Moghaddam,
S.; Gilson, M. K.; Kim, K.; Inoue, Y. Proc. Natl. Acad. Sci. U.S.A. 2007, 104,
20737.
(20) For earlier examples and analyses of the compensatory enthalpy-entropy
relationship in various supramolecuar systems, see: Inoue, Y.; Wada, T. AdVances
in Supramolecular Chemistry; Gokel, G. W., Ed.; JAI Press: Greenwich, CT,
1997; Vol. 4, pp 55-96.
J. Org. Chem. Vol. 73, No. 15, 2008 5793

Yang et al.
substituted γ-CD 8 were synthesized according to the procedures
described in the literature.21,9e
7.26-7.24 (d, 2H, J ) 8.4 Hz), 4.97-4.93 (m, 6H), 4.84 (m, 2H),
4.74 (m, 1H), 4.22 (m, 2H), 3.84 (m, 3H), 3.81-3.50(m, 21H),
3.48-3.35(m, 19H), 3.04-3.00 (d, 1H, J ) 12.4 Hz), 2.90-2.87(d,
1H, J ) 12.0 Hz). Data for 6. Yield 98.6 mg, 3.1%. HR-MS (FAB):
m/z calcd for C60H86NaO45S2 [M + Na]+, 1613.38, found 1613.38.
1H NMR (D2O/CD3OD ) 1:1 v/v): 7.95-7.93 (d, 4H, J ) 8.8
Hz), 7.26-7.24 (d, 4H, J ) 8.4 Hz), 5.08-4.94(m, 8H), 4.53-4.50
(d, 2H, J ) 10.4 Hz), 3.36-3.31 (dd, 2H, J ) 9.6, 10.4 Hz),
3.84-3.68 (m, 20H), 3.64-3.45 (m, 20H), 3.41-3.23 (m, 4H).
Synthesis of Capped γ-CDs 5 and 6. 4,4′-Oxydibenzene-1-
sulfonyl chloride (1.47 g, 4 mmol) was added to a solution of γ-CD
(2.6 g, 2 mmol) in dry pyridine (100 mL). The reaction mixture
was stirred for 2 h at room temperature. To the resulting mixture
was added ethanol (10 mL) to quench the reaction, and the solvent
was removed in vacuo. The residue obtained was dissolved in
distilled water and subjected to reversed-phase HPLC to give 5 as
white solid (292 mg, 9.2%). HR-MS (FAB): m/z calcd for
1
C60H86NaO45S2 [M + Na]+, 1613.38, found 1613.38. H NMR
Supporting Information Available: The NMR and MS
spectra of capped γ-CDs. This material is available free of
charge via the Internet at http://pubs.acs.org.
(D2O/DMSO-d6 ) 2:3 v/v): δ 7.97-7.95 (d, 2H, J ) 8 Hz),
7.93-7.91 (d, 2H, J ) 8.4 Hz), 7.38-7.35 (d, 2H, J ) 8.4 Hz),
(21) Fujita, K.; Yamamura, H.; Imoto, T.; Fujioka, T.; Mihashi, K. J. Org.
Chem. 1988, 53, 1943.
JO800533Y
5794 J. Org. Chem. Vol. 73, No. 15, 2008