A comparative study on the binding behaviors of β-cyclodextrin and its two derivatives to four fanlike organic guests

Article abstract of DOI:10.1021/jo801436h

(Figure Presented) Four fanlike organic compounds, 1-ethoxybenzene (EOB), 1-butoxybenzene (BOB), 1-dodecyloxybenzene (DOB), and 1-(dodecyloxy)-2- methoxybenzene (DOMB), were chosen as guests, and β-cyclodextrin (β-CD) and its two derivatives, mono(2-O-2-methyl)-β-CD and mono(2-O-2-hydroxy-propyl)-β-CD, were chosen as hosts. Energy changes involved in host-guest inclusion processes were clearly obtained by applying semiempirical PM3 calculations. According to this, probable structures of the host-guest inclusion complexes were proposed. The inclusion systems in aqueous solution were investigated by UV-vis spectroscopy and nuclear magnetic resonance (¹H NMR) titration, and the formation constants (K) of the inclusion complexes were determined using the Benesi-Hildebrand equation. Moreover, two solid inclusion complexes of β-CD with EOB and DOB were prepared and characterized by Fourier transform infrared spectra, X-ray powder diffraction, ¹H NMR, electrospray ionization mass spectrometry, and thermogravimetric analyses. Results showed that the host-guest stoichiometrics in the inclusion complexes were all 1:1 both in solid state and in aqueous solution. As for the same host, the values of K increased in the order EOB < BOB < DOB, in strong association with the fan handle in the fanlike molecules; that is to say, the K values increased with increasing carbon chain length of substituent on benzene ring. In addition, the K values of DOMB complexes were larger than those of DOB complexes for the same CD, indicating that the introduction of an extra o-methoxyl group on DOB further stabilized the CD inclusion complexes. The decomposition activation energies of EOB-β-CD and DOB-β-CD were very similar but significantly larger than that of free β-CD.

Full text of DOI:10.1021/jo801436h

A Comparative Study on the Binding Behaviors of ꢀ-Cyclodextrin
and Its Two Derivatives to Four Fanlike Organic Guests
Le Xin Song,*,† Hai Ming Wang,† Xue Qing Guo,‡ and Lei Bai†
Department of Chemistry and Department of Polymer Science and Engineering, UniVersity of Science and
Technology of China, Hefei, 230026 Anhui, China
solexin@ustc.edu.cn
ReceiVed July 7, 2008
Four fanlike organic compounds, 1-ethoxybenzene (EOB), 1-butoxybenzene (BOB), 1-dodecyloxybenzene
(DOB), and 1-(dodecyloxy)-2-methoxybenzene (DOMB), were chosen as guests, and ꢀ-cyclodextrin (ꢀ-
CD) and its two derivatives, mono(2-O-2-methyl)-ꢀ-CD and mono(2-O-2-hydroxy-propyl)-ꢀ-CD, were
chosen as hosts. Energy changes involved in host-guest inclusion processes were clearly obtained by
applying semiempirical PM3 calculations. According to this, probable structures of the host-guest inclusion
complexes were proposed. The inclusion systems in aqueous solution were investigated by UV-vis
spectroscopy and nuclear magnetic resonance (1H NMR) titration, and the formation constants (K) of the
inclusion complexes were determined using the Benesi-Hildebrand equation. Moreover, two solid inclusion
complexes of ꢀ-CD with EOB and DOB were prepared and characterized by Fourier transform infrared
1
spectra, X-ray powder diffraction, H NMR, electrospray ionization mass spectrometry, and thermo-
gravimetric analyses. Results showed that the host-guest stoichiometries in the inclusion complexes
were all 1:1 both in solid state and in aqueous solution. As for the same host, the values of K increased
in the order EOB < BOB < DOB, in strong association with the fan handle in the fanlike molecules;
that is to say, the K values increased with increasing carbon chain length of substituent on benzene ring.
In addition, the K values of DOMB complexes were larger than those of DOB complexes for the same
CD, indicating that the introduction of an extra o-methoxyl group on DOB further stabilized the CD
inclusion complexes. The decomposition activation energies of EOB-ꢀ-CD and DOB-ꢀ-CD were very
similar but significantly larger than that of free ꢀ-CD.
Introduction
simple derivatives of ꢀ-CD, in which the 2-OH group of one
of seven glucose units of ꢀ-CD is substituted by a methoxy
group or a hydroxypropyloxy group, respectively (Figure 1).
There are many theoretical and experimental studies on the
stoichiometries, structures, and stabilities of the supramolecular
inclusion complexes of CDs with guest molecules in solution,4-6
as well as a number of investigations on the preparations and
characterizations of solid CD inclusion complexes.7-9 It is found
that the stoichiometries and stabilities of CD inclusion com-
Cyclodextrins (CDs) are R-1,4-linked cyclic oligomers of
D-glucopyranose that possess the remarkable property to form
inclusion complexes with a wide variety of guests.1-3 ꢀ-CD,
one of the most common CDs, has the shape of a hollow
truncated cone with 14 secondary hydroxy groups around the
larger circumference of the cavity and 7 primary hydroxy groups
around the smaller opening. Mono(2-O-2-methyl)-ꢀ-CD (Mꢀ-
CD) and mono(2-O-2-hydroxypropyl)-ꢀ-CD (HPꢀ-CD) are two
(4) Bea, I.; Gotsev, M. G.; Ivanov, P. M.; Jaime, C.; Kollman, P. A. J. Org.
Chem. 2006, 71, 2056–2063.
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(6) Liu, Y.; Han, B. H.; Zhang, H. Y. Curr. Org. Chem. 2004, 8, 35–46.
(7) Giordano, F.; Novak, C.; Moyano, J. R. Thermochim. Acta 2001, 380,
123–151.
† Department of Chemistry.
‡ Department of Polymer Science and Engineering.
(1) Liu, Y.; Yang, Y. W.; Yang, E. C.; Guan, X. D. J. Org. Chem. 2004, 69,
6590–6602.
(2) Muller, A.; Wenz, G. Chem.-Eur. J. 2007, 13, 2218–2223.
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10.1021/jo801436h CCC: $40.75
Published on Web 10/08/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8305–8316 8305

Song et al.
FIGURE 1. Structural features of ꢀ-CD, its two derivatives, and four fanlike guest molecules.
plexes, both in aqueous solution and in solid state, vary markedly
with the shape, volume, and polarity of organic guest
molecules.10-12 There are many reports on the inclusion systems
between CDs and aliphatic or aromatic organic guests.13-15
However, few efforts have been made to evaluate the relation-
ship between aromatic ring and aliphatic chain in CD inclusion
complexes of fan-shaped guest molecules. Moreover, the
investigation on the influence of the structural differences among
a set of similar guest molecules on the properties of CD
inclusion complexes, such as the interaction energy, preparation
analysis, spectral property, thermal behavior, and decomposition
kinetics, is important and significant not only in academic studies
but also in industrial applications.
According to these views, four organic compounds, 1-ethoxy-
benzene (EOB), 1-butoxybenzene (BOB), 1-dodecyloxybenzene
(DOB), and 1-(dodecyloxy)-2-methoxybenzene (DOMB), are
chosen as guests, and ꢀ-CD, Mꢀ-CD, and HPꢀ-CD are chosen
as hosts. It should be noted that EOB, BOB, and DOB not only
possess a rigid benzene-ring backbone but also have a flexible
aliphatic side chain structure with different lengths linked
directly to a carbon atom of the benzene ring (Figure 1). DOMB
is a simple derivative of DOB, in which one H atom of the
benzene ring in the ortho position of the ether oxygen bond is
substituted with a methoxyl group. The structural frame of an
ancient fan widely used in old China, which is made up of a
fan face and a fan handle, is shown in Figure 1. The fanlike
guest molecules in the manuscript are composed of two parts,
benzene ring and side chain. The benzene ring is somewhat
like the fan face, and the side chain on the benzene ring looks
like the fan handle.
in water are examined using a semiempirical PM3 method in
order to obtain information about the formation, structures, and
stabilities of the 12 CD inclusion complexes.
Second, the binding behaviors of CDs to the guests in the 12
inclusion systems are investigated in detail by UV-vis spec-
1
trophotometry and H NMR titration methods. Many reports
have confirmed that some cyclic aromatic guests like a fan face,
either without a handle such as benzene13 or with a very short
fan handle such as phenol,13 do not interact strongly with CDs.
Our aim was to examine the relationship between the side chain
length of the substituent on the aromatic ring of guests and the
binding abilities of CDs to the guests. In other words, this work
focused on evaluating the effect of the side chain as a fan handle
on the stabilities of inclusion complexes based on theoretical
and experimental studies.
Third, significant efforts have been dedicated to the com-
parison in preparation, spectral property, and thermal decom-
position kinetics between the CD inclusion complexes of similar
structural units, i.e., EOB and DOB.
We believe that a comprehensive insight into the influence
of the competitive complexation of side chain and benzene ring
in a guest molecule with CDs on the formations, stoichiometries,
stabilities, and decomposition behaviors of CD complexes will
facilitate understanding of the nature of inclusion phenomena
between CDs and guests.
Results and Discussion
Differences in the Values of ∆Ec, ∆Ef, and ∆Ei of Dif-
ferent Inclusion Complexes. The inclusion complexations
between CDs and the fanlike guests in water were investigated
using the PM3 method16 in the present work. The calculated
values of ∆Ec, ∆Ef, and ∆Ei of 12 CD inclusion complexes in
water, as well as the values of the distances (Z) between the
center of the cavities of CDs and the ether oxygen atoms of the
guest molecules, are listed in Table 1. Although two different
starting geometries were considered in the formation of an
inclusion complex, only the lowest ∆Ei value of the inclusion
complex is given in Table 1. Similarly, only the geometry at
the lowest calculated ∆Ei value is regarded as the optimized
complex geometry of the inclusion complex. The values of Z
First, the formation processes of the inclusion complexes of
ꢀ-CD and its two derivatives with the four fanlike organic guests
(9) Song, L. X.; Wang, H. M.; Yang, Y.; Xu, P. Bull. Chem. Soc. Jpn. 2007,
80, 2185–2195.
(10) Kano, K.; Hasegawa, H. J. Am. Chem. Soc. 2001, 123, 10616–10627.
(11) Braga, S. S.; Goncalves, I. S.; Herdtweck, E.; Teixeira-Dias, J. J. C.
New J. Chem. 2003, 27, 597–601.
(12) Liu, Y.; Cao, R.; Chen, Y.; He, J. Y. J. Phys. Chem. B 2008, 112, 1445–
1450.
(13) (a) Rekharsky, M. V.; Inoue, Y. Chem. ReV 1998, 98, 1875–1917. (b)
Bertrand, G. L.; Han, S. M.; Armstrong, D. W. J. Phys. Chem. 1989, 93, 6863–
6867.
(14) Rodriquez-Llamazares, S.; Yutronic, N.; Jara, P.; Englert, U.; Noyong,
M.; Simon, U. Eur. J. Org. Chem. 2007, 4298–4300.
(15) Liu, Y.; Fan, Z.; Zhang, H. Y.; Yang, Y. W.; Ding, F.; Liu, S. X.; Wu,
X.; Wada, T.; Inoue, Y. J. Org. Chem. 2003, 68, 8345–8352.
(16) Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209–220.
8306 J. Org. Chem. Vol. 73, No. 21, 2008

Binding BehaVior of Cyclodextrin to Fanlike Guests
ꢀ-CD in water. As can be seen in Figure 3A, DOB-ꢀ-CD has
the most negative value of ∆Ei near the wider rim of ꢀ-CD
cavity, i.e., Z ) 200 pm, ∆Ei ) -49.0 kJ ·mol-1
.
Figure 3B shows that the inclusion system of DOMB with
ꢀ-CD has the most negative value of ∆Ei just in the center of
the cavity of ꢀ-CD, i.e., Z ) 0 pm, ∆Ei ) -55.0 kJ ·mol-1
.
The highly negative values of ∆Ei of the two inclusion
complexes predict that both DOB and DOMB can form stable
complexes with ꢀ-CD in water. The big difference in the values
of Z or ∆Ei between the two inclusion complexes of ꢀ-CD is
ascribed to the contribution of a single o-methoxy group. These
observations indicate that the introduction of an o-methoxy
group on the DOB molecule promotes the inclusion complex-
ation between host and guest and further stabilizes the inclusion
complex.
FIGURE 2. ∆Ef, ∆Ec, and ∆Ei values of the inclusion complexes of
ꢀ-CD, Mꢀ-CD, and HPꢀ-CD with EOB 1, BOB 2, DOB 3, and DOMB
4 in water.
The PM3 optimized structures of DOB-ꢀ-CD and DOMB-ꢀ-
CD in water are schematically illustrated in Figure 4. From
Figure 4A and C, it is apparent that no intermolecular hydrogen
bonds form between the guest molecules and the OH groups of
ꢀ-CD in the optimized structures of the two inclusion complexes.
Moreover, the side view of DOMB-ꢀ-CD in Figure 4D displays
that the benzene ring in the DOMB molecule is partly included
into the inner cavity of ꢀ-CD, while the carbon chain on the
benzene ring exposes itself to the outside of the cavity from
the narrower opening. However, the side view of DOB-ꢀ-CD
in Figure 4B shows that the benzene ring in DOB is not almost
included in the cavity of ꢀ-CD, while five of 12 carbon atoms
on the ether oxygen chain penetrate into the cavity. The findings
imply that the inner cavity of ꢀ-CD does not bear a structurally
selective character with respect to the benzene ring of a guest
with a long carbon chain.
TABLE 1. ∆Ec, ∆Ef, and ∆Ei in kJ ·mol-1 of 12 Host-Guest
Inclusion Complexes in Water
inclusion complex
∆Ec
∆Ef
∆Ei
Z (pm)
EOB-ꢀ-CD
-34.3
-40.8
-57.2
-63.4
-32.3
-38.8
-61.9
-69.7
-38.5
-48.1
-63.7
-71.4
-3.8
4.4
8.2
8.4
2.4
-2.5
6.8
9.2
3.5
-38.1
-36.4
-49.0
-55.0
-29.9
-41.3
-55.1
-60.5
-35.0
-43.8
-54.0
-60.9
300
300
200
0
400
300
0
100
200
300
0
BOB-ꢀ-CD
DOB-ꢀ-CD
DOMB-ꢀ-CD
EOB-Mꢀ-CD
BOB-Mꢀ-CD
DOB-Mꢀ-CD
DOMB-Mꢀ-CD
EOB-HPꢀ-CD
BOB-HPꢀ-CD
DOB-HPꢀ-CD
DOMB-HPꢀ-CD
4.3
9.7
10.5
0
In order to further evaluate the effect of the flexibility of the
long carbon chain to the inclusion complexations between hosts
and guests, a new starting geometry is considered, i.e., when a
guest molecule is inserted into the cavity of ꢀ-CD, its long
carbon chain is assumed to be in a folded position. Based on
the starting geometry, the values of ∆Ec, ∆Ef, and ∆Ei of the
inclusion complexes of the four fanlike guests with CDs in water
are determined and listed in Table 2.
A remarkable difference between the data in Table 1 and
Table 2 is that the values of Z are quite different from each
other between the long carbon chain in the guests in an extended
position and a folded position. For instance, there are 100 pm
of |∆Z| for the complex of ꢀ-CD with DOB and 300-400 pm
of |∆Z| for the complexes of the two ꢀ-CD derivatives with
DOB.
were obtained corresponding to the lowest ∆Ei values in the
inclusion systems.
As shown in Table 1, the sufficiently large negative values
of ∆Ei ranging from -60.9 to -29.9 kJ·mol-1 clearly reveal
that the formations of the 12 inclusion complexes are all
energetically favorable. In other words, the complexes can be
thermodynamically stable in water, since the ∆Ei values are a
reflection of the degree of stability of the complexes.17
Figure 2 shows that there are very small absolute values of
∆Ef on the upper side of the figure as compared with the values
of ∆Ec or ∆Ei on the lower side of the figure for the inclusion
complexes. As can be directly seen in Table 1, the values of
∆Ef are in the narrow range from -3.8 to 10.5 kJ ·mol-1
.
With the exception of two inclusion systems, i.e., EOB-ꢀ-
CD (-3.8 kJ ·mol-1) and BOB-Mꢀ-CD (-2.5 kJ ·mol-1), the
other 10 systems show positive ∆Ef values, suggesting that the
deformation behaviors of CD and guest in these systems give
a negative contribution to the formations and stabilities of the
10 inclusion complexes. Interestingly, the values of ∆Ef appear
to increase in the approximate order EOB < BOB < DOB <
DOMB for the same CD. This result can be attributed to the
increase of flexibility of the carbon chains with the increase of
the chain length of the alkoxy groups in the guest molecules.
Further, the bar graph of ∆Ei in Figure 2 seems to have a
trend similar to that of ∆Ec for the 12 inclusion complexes.
Clearly, the stabilities of the inclusion complexes increase in
the following sequence: EOB < BOB < DOB < DOMB for
the same CD.
Similarly, a large energy difference (|∆∆E| > 9 kJ·mol-1
)
in ∆Ec or ∆Ei between the data in Table 1 and Table 2 has
been observed for the complexes of CDs with DOB. These
results show that modifying the long carbon chain in DOB from
an extended to a folded position leads to a positive contribution
to the inclusion complexation between DOB and ꢀ-CD or its
two simple derivatives.
Figure 5 displays the PM3 optimized structure of DOB-ꢀ-
CD in water when the long carbon chain in DOB is in a folded
position. Likewise, there are no intermolecular hydrogen bonds
between DOB and ꢀ-CD (see Figure 5A). Accordingly, it is
reasonable that the formation of DOB-ꢀ-CD is mainly driven
by van der Waals force and hydrophobic interaction.
Inclusion Complexation Processes and Proposed Inter-
molecular Interaction Modes. Figure 3 illustrates the details of
the inclusion complexation processes of DOB and DOMB with
(17) Song, L. X.; Wang, H. M.; Xu, P.; Zhang, Z. Q.; Liu, Q. Q. Bull. Chem.
Soc. Jpn. 2007, 80, 2313–2322.
J. Org. Chem. Vol. 73, No. 21, 2008 8307

Song et al.
FIGURE 3. Curves of ∆Ei versus Z during inclusion complexation: (A) DOB-ꢀ-CD and (B) DOMB-ꢀ-CD systems.
FIGURE 4. Optimized structures of DOB-ꢀ-CD and DOMB-ꢀ-CD: top view (A) and side view (B) of DOB-ꢀ-CD; top view (C) and side view
(D) of DOMB-ꢀ-CD when the long carbon chain in DOB or DMOB is in an extended position.
TABLE 2. ∆Ec, ∆Ef, and ∆Ei in kJ ·mol-1 of EOB, BOB, DOB,
2) in the present study. Consequently, analyses and experiments
are performed to gain further insight into the inclusion behaviors
and DOMB Complexes of CDs in Watera
inclusion complex
∆Ec
∆Ef
∆Ei
Z (pm)
of the hosts and guests, including the formation, stoichiometries,
structures, and stabilities of the inclusion complexes of the CDs
with the fanlike guest molecules.
EOB-ꢀ-CD
-34.6
-44.4
-74.3
-74.8
-38.1
-47.3
-72.6
-80.6
-40.2
-42.7
-76.0
-75.9
4.2
4.8
7.9
9.7
3.7
4.9
8.5
11.4
4.0
-30.4
-39.6
-66.4
-65.1
-34.4
-42.4
-64.1
-69.2
-36.2
-46.1
-67.2
-65.8
500
200
300
300
300
400
400
400
300
300
300
400
BOB-ꢀ-CD
DOB-ꢀ-CD
Direct Evidence of Intermolecular Interaction between
DOMB-ꢀ-CD
EOB-Mꢀ-CD
BOB-Mꢀ-CD
DOB-Mꢀ-CD
DOMB-Mꢀ-CD
EOB-HPꢀ-CD
BOB-HPꢀ-CD
DOB-HPꢀ-CD
DOMB-HPꢀ-CD
1
the Four Fanlike Guests and ꢀ-CD from H NMR Titra-
tions. Different chemical shift changes (∆δ) of the protons on
the benzene ring (H-a), methoxy group (H-b), methylene (H-c,
H-d, and H-e), and end methyl group (H-f) in DOMB with
increasing molar fractions of DOMB in mixed solutions of ꢀ-CD
and DOMB are clearly observed during 1H NMR titration
experiments (Figure 6A).
-3.4
8.8
10.1
a According to the starting geometry in which the long carbon chain
of DOB and DOMB is assumed to be in a folded position.
Further, a bigger decrease of the chemical shift (δ) values
for H-3 and H-5 protons of ꢀ-CD than those for H-2 and H-4
protons with an increase in the relative concentration of DOMB
is observed in Figure 6B.
The side view of DOB-ꢀ-CD in Figure 5B indicates that
the benzene ring in DOB is fully included into the cavity of
ꢀ-CD, whereas nine of 12 carbon atoms on the ether oxygen
chain also have been accommodated in the cavity. This
configuration implies that there is a close distance between the
carbon or hydrogen atoms on the benzene ring and on the ether
oxygen chain of DOB in DOB-ꢀ-CD. Since the arrangement
of DOB-ꢀ-CD has an advantage (∆∆Ei, -17.4 kJ ·mol-1) in
the energy of formation in comparison with the other arrange-
ment, i.e., the long carbon chain of DOB in an extended position,
we believe that there may be an interaction between the benzene
ring and carbon chain of DOB in DOB-ꢀ-CD. Nevertheless,
further and more detailed evidence is necessary to provide solid
proof that the benzene ring and carbon chain of DOB are
simultaneously accommodated in the cavity of ꢀ-CD.
These phenomena can be attributed to the formation of the
inclusion complex of DOMB with ꢀ-CD because the H-3 and
H-5 protons are inside the cavity of ꢀ-CD.
Upon complexation, the protons of the methoxy group in
DOMB are affected most, next the benzene ring protons, then
the methylene protons, and finally the protons of the end methyl
group located at the end of the carbon chain. This observation
strongly suggests that the benzene ring of DOMB as well as
the methoxy group in the benzene ring is likely to be deeply
embedded into the cavity of ꢀ-CD, and there is a relatively weak
interaction between ꢀ-CD and the long carbon chain of DOMB
especially the end of the long chain.
According to Figure 6B, the maximum ∆δ values of the H-3
and H-5 protons of ꢀ-CD after complexation with DOMB are
-0.042 and -0.069 ppm, respectively. The considerably large
Similar phenomena also occur in the inclusion systems of ꢀ-CD
and its two derivatives with EOB, BOB, and DOMB (see Table
8308 J. Org. Chem. Vol. 73, No. 21, 2008

Binding BehaVior of Cyclodextrin to Fanlike Guests
FIGURE 5. PM3 optimized structure of DOB-ꢀ-CD: top view (A) and side view (B) in water according to the starting geometry in which the
long carbon chain of DOB is assumed to be in a folded position. (C) DOB at the geometry in the optimized complex.
FIGURE 6. Plots of ∆δ values of protons of DOMB (A) and ꢀ-CD
FIGURE 7. UV-vis spectra of (A) BOB and (B) DOMB (5.0 × 10-5
(B) versus the concentration ratios of DOMB to ꢀ-CD.
mol·dm-3). The concentrations of ꢀ-CD are in the range from 0.0 to
5.0 × 10-3 mol·dm-3
.
TABLE 3. Maximum ∆δ Values of Protons of EOB, BOB, DOB,
DOMB, and ꢀ-CD upon Complexation
The absorption spectrum of free BOB shows a narrow band
and a broad band with the maximum at about 196.7 and 219.8
nm, respectively. Interestingly, the narrow band at 196.7 nm
shifts gradually to the blue, and the intensity of the band
decreases with increasing concentration of ꢀ-CD. These changes
indicate that BOB is experiencing a less polar environment in
the case of increasing concentration of ꢀ-CD. Considering that
the cavity of ꢀ-CD is a less polar microenvironment than
aqueous solution, the absorption result suggests the formation
of ꢀ-CD inclusion complex of BOB from water to the cavity.20
In the case of the system of DOMB with ꢀ-CD, similar
phenomena have been observed from Figure 7B. For example,
the absorption intensity (A) of DOMB after complexation with
ꢀ-CD decreases with increasing concentration of ꢀ-CD, and the
two peaks at 241.6 and 285.5 nm shift to 234.0 and 283.1 nm,
respectively, with the addition of ꢀ-CD. Furthermore, similar
phenomena are also observed in all other 10 inclusion systems,
thereby confirming that there exists an intermolecular interaction
between CDs and the fanlike guests.
∆δꢀ-CD
proton
EOB
BOB
DOB
DOMB
H-a
H-b
H-c
H-d
H-e
H-f
0.037
0.046
0.028
-0.043
-0.049
-0.037
-0.036
0.011
-0.035
-0.040
-0.030
-0.027
-0.025
0.018
-0.038
-0.043
-0.034
-0.036
-0.023
-0.020
-0.020
0.008
ꢀ-CD
proton
∆δEOB
∆δBOB
∆δDOB
∆δDOMB
H-1
H-2
H-3
H-4
H-5
H-6
0.012
0.024
-0.041
0.027
-0.035
0.021
0.016
0.027
-0.048
-0.014
-0.041
0.015
0.016
0.023
0.017
0.023
-0.042
-0.025
-0.069
0.019
-0.042
-0.027
-0.047
0.013
upfield shifts of both H-3 and H-5 can be explained by the ring
current effect of the benzene ring of DOMB.18,19
The constitutions of the inclusion complexes are deter-
mined to be 1:1 by means of the continuous variation method
(Job’s plot).21,22 The plots describing the interactions between
four fanlike guests and ꢀ-CD are representatively shown in
Figure 8.
Figure 8 depicts the changes (∆A) in the absorption of the
four fanlike guests with increasing the concentration of ꢀ-CD
In addition, the ∆δ value of the H-5 protons is larger than
that of the H-3 protons under different concentrations of DOMB.
This may be because there is a relatively strong interaction
between the H-5 protons of ꢀ-CD and the benzene ring of
DOMB.
Similar phenomena also occur in the inclusion systems of
ꢀ-CD with EOB, BOB, and DOB (see Table 3) in this study.
Hence, the results from NMR titrations provide a direct evidence
for the formation of the inclusion complexes of ꢀ-CD with the
four fanlike guests.
(18) Funasaki, N.; Yamaguchi, H.; Ishikawa, S.; Neya, S. J. Phys. Chem. B
2001, 105, 760–765.
(19) Yoshikiyo, K.; Matsui, Y.; Yamamoto, T.; Okabe, Y. Bull. Chem. Soc.
Jpn. 2007, 80, 1124–1128.
(20) (a) Song, L. X.; Wang, H. M.; Yang, Y. Acta Chim. Sinica 2007, 65,
1593–1599. (b) Wagner, D. B.; Stojanovic, N.; Leclair, G.; Jankowski, C. K.
J. Inclusion Phenom. Macrocyclic Chem. 2003, 45, 275–283.
(21) Bardelang, D.; Rockenbauer, A.; Karoui, H.; Finet, J. P.; Tordo, P. J.
Phys. Chem. B 2005, 109, 10521–10530.
(22) Tilloy, S.; Crowyn, G.; Monflier, E.; van Leeuwen, P. W. N. M.; Reek,
J. N. H. New J. Chem. 2006, 30, 377–383.
Formations and Stoichiometries of the Inclusion Com-
plexes of CDs with the Fanlike Guests in Solution. Typical
UV-vis absorption spectra of BOB and DOMB upon addition
of ꢀ-CD in aqueous solution at 298 K are shown in Figure 7A
and B, respectively.
J. Org. Chem. Vol. 73, No. 21, 2008 8309

Song et al.
TABLE 4. Calculated K Values of the 12 Inclusion Complexes at
298 K in Solution
K (mol·dm-3
)
guest
ꢀ-CD
Mꢀ-CD
HPꢀ-CD
EOB
BOB
DOB
DOMB
145.8 ( 7.2
373.6 ( 17.6
3613.5 ( 72.3
4890.2 ( 68.5
154.9 ( 8.1
253.4 ( 10.1
586.2 ( 17.7
4340.6 ( 106.3
7180.7 ( 86.2
619.7 ( 34.1
5158.4 ( 148.3
5880.2 ( 126.2
FIGURE 8. Equimolar Job’s plots for binding of ꢀ-CD to four fanlike
guests at 298 K in water solutions with [guest] + [ꢀ-CD] ) 1.0 ×
Second, the association ability of DOMB with the CDs is
obviously higher than that of DOB, which means a positive
effect of introduction of an extra methoxy group at the ortho
position of the ether-oxygen bond of the phenyl ring on
complexation.
10-4 mol·dm-3
.
Third, the K values of the inclusion complexes of the same
CD with the guests increase in the order EOB < BOB , DOB.
That is to say, the stability of the CD inclusion complexes of
DOB or DOMB with a long chain is almost 10-fold that of the
inclusion complexes of the same CD and EOB or BOB with a
short chain. The finding shows the contribution of the alkyl chain
of the fanlike guests to the binding affinity between host and
guest molecules. According to the results described in Tables
1-4, we can presume that during the inclusion complexations
between the CDs and the fanlike guests, both the benzene ring
plane like a fan face and the carbon chain like a fan handle are
simultaneously accommodated in the cavity of a CD molecule.
Such an inclusion behavior (see Figure 5B) effectively increases
the intermolecular interaction so as to improve the stabilities
of the complexes.
The sequence results obtained from UV-vis spectroscopic
measurements are in good accordance with those of both PM3
calculation and 1H NMR titration experiment. In order to further
estimate the effect of the alkyl chain on the benzene ring of the
guests on their association behaviors with ꢀ-CD, it is necessary
to prepare and characterize the solid inclusion complexes of
ꢀ-CD with the guests.
Preparation Analysis of Solid Inclusion Complexes. Two
solid ꢀ-CD inclusion complexes, EOB-ꢀ-CD and DOB-ꢀ-
CD, were prepared as described in the experimental section.
The results of elemental analyses: EOB-ꢀ-CD, Anal. Calcd
for C50H80O36 ·2H2O: C, 46.86; H, 6.63. Found: C, 46.61; H,
6.76; DOB-ꢀ-CD, Anal. Calcd for C60H100O36 ·5H2O: C, 48.45;
H, 7.45. Found: C, 48.44; H, 7.41. Therefore, the binding
stoichiometries of ꢀ-CD to EOB and DOB in the two solid
complexes are 1:1.
The yields of the two complexes were calculated on the basis
of the initial concentration of ꢀ-CD. EOB-ꢀ-CD has a yield
of 45.6% in contradistinction to the value of 23.9% for DOB-ꢀ-
CD under the same dry conditions.
FIGURE 9. Plots of ([CD] ·[BOB])/∆A versus ([CD] + [BOB]).
where the total concentration of ꢀ-CD and guest is kept constant
of 1.0 × 10-4 mol·dm-3. The four experimental curves go
through maximum values at a molar fraction of 0.5, indicating
a 1:1 stoichiometry of the inclusion complexes. Similar
phenomena occur also in the inclusion systems of ꢀ-CD
derivatives and the fanlike guests. Therefore, the intermo-
lecular interactions between CDs (H) and the guests (G) can
be represented by eq 1:
H + G ) HG
(1)
where HG represents an inclusion complex formed between H
and G.
K Values and Stability Comparison of the Inclusion
ComplexesinSolution.Figure9showstheplotsof([CD] ·[BOB])/
∆A versus ([CD] + [BOB]). The initial concentration of BOB
is kept at 5.0 × 10-5 mol·dm-3, while the concentrations of
ꢀ-CD and its two derivatives are in the range from 0.0 to 5.0 ×
10-3 mol·dm-3. A linear least-squares fits to the plots. As can
be seen, the fits to the plots are all excellent, with the correlation
coefficients of more than 0.990. The K values of inclusion
complexes of CDs with the fanlike guests are determined by
the slopes and intercepts of the linear plots based on the equation
shown in the experimental section. For the other nine inclusion
systems, the dependencies are also linear in the investigated
concentration range, further confirming that the stoichiometries
of the inclusion complexes in solution are 1:1.17,23
The calculated K values of the 12 inclusion complexes are
summarized in Table 4. It is interesting to speculate on the
possible implications of the observed binding abilities of CDs
to the fanlike guests.
First, the binding ability of ꢀ-CD to the four fanlike guests
is lower than that of its two derivatives. This result indicates
that the substitution of one methyl group or one hydroxypropyl
group for the hydrogen atom on one 2-OH group can strengthen
the association between the host and guest molecules.
IR, XRD, and ESI-MS Analyses of the Solid Inclusion
Complexes. FT-IR data of ꢀ-CD and its two inclusion com-
plexes are listed in Table 5. The free ꢀ-CD shows strong
absorption bands at 3417.6 and 1028.7 cm-1, attributing to υOH
and υC-O vibrations. There are a series of peaks at 820-1180
cm-1, which are assigned to the υC-O and υC-C vibrations in
the fingerprint region. FT-IR spectrum of EOB displays two
sharp peaks at 1600.5 and 1496.9 cm-1, corresponding to the
υCdC vibration in the aromatic ring, and two strong peaks at
1244.9 and 1047.56 cm-1 due to υC-O vibration. DOB has IR
peaks at 1650.3 and 1461.6 cm-1 resulting from the υCdC
vibration of aromatic region. The peaks at 1109.5 and 1042.3
cm-1 are assigned to υC-O vibration.
(23) Cao, Y. J.; Xiao, X. H.; Lu, R. H.; Guo, Q. X. J. Mol. Struct. 2003,
660, 73–80.
8310 J. Org. Chem. Vol. 73, No. 21, 2008

Binding BehaVior of Cyclodextrin to Fanlike Guests
peaks at 12.7° (I3) and 13.5°, and the intensities of the peaks
rapidly decrease, indicating a more amorphous character in the
complex.
Third, the strong sharp peak at 19.3° (I2) in free ꢀ-CD is
obviously shifted to a lower 2θ value in EOB-ꢀ-CD (18.3°,
I1) and in DOB-ꢀ-CD (18.2°, I2). In addition, the diffraction
peak of ꢀ-CD becomes wider after inclusion.
The above results suggest that there is an intermolecular
interaction in solid state between ꢀ-CD and the two guests. What
is more, the remarkable differences between the diffraction
patterns of EOB-ꢀ-CD and DOB-ꢀ-CD reflect that the effect
of the chain length of the guests on their interactions with ꢀ-CD.
ESI-MS is a useful technique to examine the formation and
composition of an inclusion complex. As an example, Figure
11 depicts the ESI-MS spectrum of EOB-ꢀ-CD in the range
of m/z from 1185 to 1445. It exhibits three peaks at m/z values
of 1187.0, 1253.9, and 1432.8 due to ꢀ-CD·2H2O, EOB-ꢀ-
CD, and EOB-ꢀ-CD·10H2O, respectively. The result confirms
the quantitative formation of the 1:1 inclusion complex between
EOB and ꢀ-CD even in the case of ESI experiments.
It can be noted from Table 6 that no peaks at around m/z of
1396 due to DOB-ꢀ-CD are observed in its spectrum, except
the reflections corresponding to two hydrates (ꢀ-CD·3H2O and
DOB-ꢀ-CD·2H2O).
FIGURE 10. XRD spectra of ꢀ-CD, EOB-ꢀ-CD, and DOB-ꢀ-CD.
TABLE 5. FT-IR and XRD Data of ꢀ-CD and Its Two Complexes
FT-IR υC-O (cm-1
)
ꢀ-CD
EOB-ꢀ-CD
DOB-ꢀ-CD
1028.7
1079.8
1157.4
1030.7
1079.4
1155.9
1025.8
1156.3
1180.1
XRD 2θ (deg)
EOB-ꢀ-CD
peak
ꢀ-CD
DOB-ꢀ-CD
I1
I2
I3
12.6
19.3
9.1
18.3
12.7
18.9
11.8
18.2
5.9, 6.7
The results indicate that under the ESI-MS conditions the
ꢀ-CD complexes of the two guests with the same aromatic ring
but different carbon chain lengths have different stabilities but
the same host-guest stoichiometry.
Three narrow, strong, carbon single-bonded oxygen (C-O)
stretching vibrations of ꢀ-CD appear at 1028.7, 1079.8, and
1157.4 cm-1.9 Upon inclusion, the characteristic vibration bands
will be slightly shifted to 1030.7, 1079.4, and 1155.9 cm-1 in
EOB-ꢀ-CD and to 1025.8, 1180.1, and 1156.3 cm-1 in
DOB-ꢀ-CD. Similarly, the vibration bands due to EOB and
DOB also present small shifts after inclusion.
Such small differences in the IR bands of ꢀ-CD, EOB, and
DOB between values before and after inclusion are ascribed to
the fact that there are no chemical bonds formed between the
host and guest molecules.
The XRD patterns of ꢀ-CD and its inclusion complexes with
EOB and DOB are shown in Figure 10. The 2θ values of the top
three peaks of each curve in Figure 10 are listed in Table 5.
I1denotes the first strongest peak, I2 the second, and I3 the third.
EOB and DOB are liquid at room temperature, so there are no
XRD data available.
Figure 10 indicates that the I1, I2, and I3 in free ꢀ-CD are
located at 2θ values of 12.6°, 19.3°, and 9.1°,17 but they appear
at 18.3°, 18.9°, and 12.7° in EOB-ꢀ-CD, and 11.8°, 18.2°, and
5.9° and 6.7° in DOB-ꢀ-CD. Hence, there are clear differences
among the XRD patterns of ꢀ-CD and its two complexes.
First, free ꢀ-CD in the low angle range of 5.0-10.0° has a
strong sharp peak and a very weak peak at 2θ values of 9.1°
(I3) and 6.4°, respectively. However, EOB-ꢀ-CD has two weak
peaks at 9.0° and 9.5° and a broad weak peak at 6.6°. DOB-ꢀ-
CD has only two strong peaks at 5.9° and 6.7° (I3). Interestingly,
the peak at 9.1° in free ꢀ-CD disappears completely in DOB-ꢀ-
CD.
1H NMR Spectral Analysis of the Obtained Solid Inclusion
Complexes in Solution. The ∆δ values of the protons in ꢀ-CD,
EOB, and DOB between free and complexed forms in DMSO-
d6 are listed in Table 7. As an example, Figure 12 displays the
1H NMR spectrum of DOB-ꢀ-CD in DMSO-d6.
First, the formations and chemical compositions of the
inclusion complexes are further confirmed by comparing the
relative integral areas of the proton signals between ꢀ-CD and
1
the guest molecules. For example, the H NMR spectrum of
DOB-ꢀ-CD in Figure 12 reveals that the stoichiometry of DOB
binding to the ꢀ-CD receptor is 1:1. This is a good agreement
with the result of elemental analysis.
Second, the proton signals of H-3 and H-5 inside ꢀ-CD cavity
are shifted upfield in the complexes. As shown in Table 7, the
signals of H-3 and H-5 are more affected than those of H-2
and H-4 outside the cavity of ꢀ-CD, suggesting that the guests
have penetrated into the cavity. This observation is confirmed
by the fact that upon complexation the proton signals of EOB
and DOB are to some extent shifted upfield. Further, the protons
due to the aromatic ring (H-a and H-b) and methylene (H-c) of
DOB have a larger ∆δ value than those of its end methyl group
in DOB-ꢀ-CD, suggesting that the aromatic ring is located
inside the cavity.
Third, the proton signals of H-3, located close to the wider
rim of the cavity, are less shifted in comparison with those of
H-5, located close to the other rim of the cavity, indicating that
the interaction between the guests and ꢀ-CD takes place in the
region from the center to the small opening of the cavity.
Figure 13A is the 1H NMR spectrum of the physical mixture
(1:28, molar ratio) of DOB with a large excess of 1-bromo-
dodecane. Figure 13B is the 1H NMR spectrum of the product
formed by ꢀ-CD with the mixture, which was prepared using
the method described in the Experimental Section. Although
the composition of the two guests in the mixture is distinct,
Second, free ꢀ-CD has the strongest peak at 12.6° (I1), but
the peak is shifted to lower 2θ value for DOB-ꢀ-CD (I1, 11.8°)
because of the enlarged lattice spacings of the complex. As is
expected, this reveals that, due to the existence of the long alkyl
chain on the benzene ring, DOB cannot be fully accommodated
in the cavity of ꢀ-CD, and thus the complex gets longer than
ꢀ-CD in the direction of the cavities. In the case of EOB-ꢀ-
CD, the peak due to the free ꢀ-CD (12.6°) is changed into two
J. Org. Chem. Vol. 73, No. 21, 2008 8311

Song et al.
FIGURE 11. ESI-MS spectrum of EOB-ꢀ-CD.
FIGURE 13. 1H NMR spectra (300 MHz, DMSO-d6, 298 K): (A) the
physical mixture (1:28, molar ratio) of DOB and 1-bromododecane
and (B) their complexes of ꢀ-CD. The insets (C and D) are the
magnification of the spectra (A and B) ranging from 6.8 to 7.4 ppm.
FIGURE 12. 1H NMR spectrum (300 MHz, DMSO-d6, 298 K) of the
inclusion complex of ꢀ-CD with DOB.
conclude that the DOB molecule with an aromatic ring prefers
to be bound noncovalently to the cavity of ꢀ-CD.
As shown in Figure 14, several cross-peaks related to spatial
interactions between the aromatic and aliphatic protons of DOB
and the inside-cavity protons of ꢀ-CD clearly appears. For
example, the NOE cross-peaks (peaks A) between H-3/H-5
protons of ꢀ-CD cavity and H-a/H-b protons are observed,
suggesting that the benzene ring of DOB is included into the
ꢀ-CD cavity. Meantime, the NOE cross-peaks between H-d/
H-e protons of the aliphatic chain and H-3/H-5 of the ꢀ-CD
cavity are also observed (peaks B and C), indicating that the
aliphatic moiety of DOB also has interactions with the inside-
cavity protons of ꢀ-CD, i.e., the aliphatic carbon chain of DOB
is partly inserted in the cavity of ꢀ-CD.
TABLE 6. ESI-MS Data of EOB-ꢀ-CD and DOB-ꢀ-CD
ESI-MS
complex
m/z
composition
ꢀ-CD-EOB
1187.0
1253.9
1432.8
1187.0
1432.0
C42H70O35 ·3H2O
C42H70O35 ·C8H10O
C42H70O35 ·C8H10O·10H2O
C42H70O35 ·3H2O
C42H70O35 ·C18H30O·2H2O
ꢀ-CD-DOB
TABLE 7. ∆δ (ppm) Values of the Protons in ꢀ-CD, EOB, and
DOB between Free and Complexed Forms
ꢀ-CD
∆δꢀ-CD
Furthermore, a cross-peak (peak D) between the H-b protons
of the benzene ring and H-c protons of DOB is also clearly
observed, confirming that the long carbon chain in DOB is in
a folded position. Based on the results discussed above, we thus
conclude that both the aromatic and aliphatic moieties of DOB
are synchronously included into the ꢀ-CD cavity. This conclu-
sion is just in good accordance with the results of theoretical
PM3 calculation.
proton
∆δEOB
∆δDOB
proton
EOB
DOB
H-1
H-2
H-3
H-4
H-5
H-6
0.012
0.021
-0.028
0.024
-0.051
0.012
0.014
0.026
-0.034
0.026
-0.052
0.008
H-a
H-b
H-c
H-d
H-e
H-f
0.013
0.018
0.025
-0.029
-0.026
-0.021
-0.023
-0.014
-0.012
-0.015
Differences in TG Profiles between Free ꢀ-CD and Its
Two Inclusion Complexes. The TG curves of free ꢀ-CD,
EOB-ꢀ-CD and DOB-ꢀ-CD at a constant heating rate of 5
K·min-1 are shown in Figure 15. Obviously, the shapes of the
three TG curves are quite different from one another. In order
to conveniently make a direct comparison, the thermal decom-
upon complexation their proportions in the product are ap-
proximately the same based on the relative integral intensities
of the signals in the 1H NMR spectrum of their ꢀ-CD complexes.
Hence, even if there exists a competitive complexation between
DOB and 1-bromododecane for ꢀ-CD, in general we can
8312 J. Org. Chem. Vol. 73, No. 21, 2008

Binding BehaVior of Cyclodextrin to Fanlike Guests
In the range of Step C from 475 to 618 K, the two inclusion
complexes begin to decompose rapidly. Differently, ꢀ-CD has
a very slow small mass loss at the beginning of the region and
begins to lose its mass sharply at a higher temperature of 554
K. Since the molecular mass of ꢀ-CD is much higher than those
of the two guests, the results indicate that the existence of the
fanlike guest molecules leads to advanced decomposition of
ꢀ-CD possibly because the intermolecular interaction between
ꢀ-CD and the guests is weaker than that between the ꢀ-CD
molecules. And then, the three curves almost intersect at a point
at about 597 K again. During the temperature range of about
475-597 K the residual masses of the two complexes are
considerably lower than that of ꢀ-CD.
In Step D, free ꢀ-CD, EOB-ꢀ-CD and DOB-ꢀ-CD begin
to further decompose, but their decomposition rates obviously
decrease, especially that of free ꢀ-CD when compared with in
Step C. During the stage, the residual masses of the two
complexes are markedly higher than that of free ꢀ-CD. For
example, the residual masses of free ꢀ-CD, EOB-ꢀ-CD and
DOB-ꢀ-CD are 21%, 26% and 28% at 723 K (see Figure 15).
The finding demonstrates that the fanlike guests can dramatically
retard the thermal decomposition of ꢀ-CD at the high temper-
ature range from 597 to 700 K.
FIGURE 14. ROESY spectrum of DOB-ꢀ-CD with a mixing time
of 200 ms at 300 K.
Similarities in Thermal Decomposition Kinetics of the
Two Solid Inclusion Complexes. The TG profiles of EOB-ꢀ-
CD and DOB-ꢀ-CD at heating rates of 5, 10, 15, 20, and 25
K·min-1 (ꢁ1-ꢁ5) are depicted in Figure 16A and B, respectively.
The thermal decomposition processes of the two inclusion
complexes can be divided into three consecutive stages, i.e., a
slow stage, a rapid stage and a moderate stage. The kinetics of
the thermal decomposition process of an inclusion complex can
be described as follows:
-Ea
RT
dR
dt
) k f(R) ) A exp
f(R)
(2)
(
)
where R is the fraction of the inclusion complex that undergoes
decomposition at the heating time t, f(R) is a function of (R),
and k, A, Ea, R, and T are the rate constant, pre-exponential
factor, activation energy, molar gas constant, and absolute
temperature of the degradation process of the inclusion complex,
respectively.
FIGURE 15. TG profiles of free ꢀ-CD, EOB-ꢀ-CD, and DOB-ꢀ-
CD at the heating rate of 5.0 K ·min-1
.
position processes of the three samples in the range from 300
to 723 K are roughly divided into four steps (A-D) using green
lines in Figure 15.
Through a series of mathematical treatments, eq 2 can be
changed into the following form, i.e., the so-called Flynn-
Wall-Ozawa (FWO) equation:24
Free EOB and DOB are both liquid, but they are solidified
in the presence of ꢀ-CD at room temperature. Because of the
low melting points and high boiling points, the guests in their
complexes of ꢀ-CD will melt and volatilize with increasing
temperature. As would be expected, in the range of Step A from
room temperature to about 371 K, free ꢀ-CD loses its water
molecules. The two complexes lose their respective water
molecules, and the guests in the complexes melt and volatilize.
The step for free ꢀ-CD or EOB-ꢀ-CD is sharper than that for
DOB-ꢀ-CD. This is because the boiling point of DOB with a
big molecular mass is much higher than that of EOB with a
low molecular mass.
In Step B, free ꢀ-CD almost completely does not lose its
mass, and EOB-ꢀ-CD has a very slow small mass loss.
However, DOB-ꢀ-CD shows an obvious mass loss, and the
rate of the loss is accelerated at 459 K. The three curves intersect
at a point whose abscissa is equal to 475 K. Before 475 K of
the stage the residual mass of ꢀ-CD is slightly lower than that
of EOB-ꢀ-CD but obviously lower than that of DOB-ꢀ-CD.
The observations can be explained by the high boiling point of
DOB.
AEa
R
Ea
ln ꢁ ) ln
- 5.3305 - 1.0516 - ln F(R) (3)
(
)
RT
where F(R) is a power series expansion for the integration of
the exponential term of eq 2. So, for a constant degree of
conversion, the plot of ln ꢁ versus 1/T should theoretically result
in a straight line, whose slope is approximately -1.0516Ea/R.
As shown in Figure 17, there exists a very good linear
correlation between ln ꢁ and 1/T. The correlation coefficient
(r) values of the linear fit lines of EOB-ꢀ-CD and DOB-ꢀ-
CD are in the range from 0.984 to 0.990 and from 0.992 to
0.999, respectively.
According to the slopes of the straight lines in Figure 17,
the Ea values of the decomposition processes of the inclusion
complexes at different mass losses are calculated. The average
values of Ea for EOB-ꢀ-CD and DOB-ꢀ-CD are 122.34 (
(24) Popescu, C. Thermochim. Acta 1996, 285, 309–323.
J. Org. Chem. Vol. 73, No. 21, 2008 8313

Song et al.
FIGURE 16. TG profiles of EOB-ꢀ-CD (A) and DOB-ꢀ-CD (B) at heating rates of 5, 10, 15, 20 and 25 K ·min-1 (ꢁ1-ꢁ5).
FIGURE 17. FWO plots of the ꢀ-CD inclusion complexes of EOB (A) and DOB (B).
11.10 and 120.74 ( 6.41 kJ · mol-1, respectively, which are
significantly larger than the average Ea value of 86.2 kJ ·mol-1
of free ꢀ-CD25 according to the same method. The finding
demonstrates that the thermal decomposition behaviors of the
survived ꢀ-CD in an inclusion complex are influenced by the
released guest molecules.26,27 This influence is realized through
the change of intermolecular interaction between ꢀ-CD mol-
ecules because of the existence of guests.26
There is only a slight difference between the average Ea values
of EOB-ꢀ-CD and DOB-ꢀ-CD. The result suggests that the
large difference in the TG profiles between two inclusion
complexes is not consequentially associated with the large
difference in the kinetics of their thermal decomposition
processes.
provide a better understanding of what kinds of combinations
between a selected aromatic ring unit and an appropriate side
chain of organic guests are most likely to promote the formation
and stability of CD inclusion complexes of the guests.
Experimental Section
Materials. ꢀ-CD was recrystallized twice from deionized water.
Mꢀ-CD, HPꢀ-CD, 1-bromoethane, 1-bromobutane, and 1-bromo-
dodecane were used without further purification. All reagents are
of analytical reagent grade, unless stated otherwise.
Instruments. Elemental analyses were carried out on an
elemental analyzer. TG curves were recorded on a thermogravi-
metric analyzer at constant heating rates of 5 (ꢁ1), 10 (ꢁ2), 15 (ꢁ3),
20 (ꢁ4), and 25 K ·min-1 (ꢁ5) under a nitrogen atmosphere with
gas flow of 25 mL ·min-1. The TG plot of free ꢀ-CD was recorded
at the heating rate of 5 K ·min-1. In the current case approximately
10 mg of a solid sample as crystalline powder was used in an
alumina crucible every time. XRD analyses of the solid complexes
were performed on a X-ray diffractometer. The samples were
irradiated with monochromatized Cu KR and analyzed with 5° e
2θ e 40°. Tube voltage and current were 40 kV and 40 mA,
respectively. FTIR transmission spectroscopy measurements were
taken with a spectrometer in KBr discs in the range of 4000-400
cm-1. ESI-MS analysis was performed on an LTQ linear ion trap
mass spectrometer. The interface was operated at positive ion mode
at a spray voltage of 5000 V, capillary voltage of 16 V, and capillary
temperature of 548 K. Electronic spectroscopy of aqueous samples
of guest molecules, with and without ꢀ-, Mꢀ-, and HPꢀ-CD were
performed on a UV-vis recording spectrophotometer over the
wavelength range between 200 and 800 nm, using quartz cells with
Conclusion
The results of theoretical and experimental studies in the
present work show a significant relationship between the side
chain length of the substituent on the aromatic ring of the fanlike
guests and the binding abilities of CDs to the guests. That is to
say, the aromatic guests with a longer fan handle, such as DOB
and DOMB, have much stronger interactions with the CDs when
compared with those with a short fan handle, such as EOB and
BOB. Also, the structural transformation of side chains from
an extended form to a folded form leads to a positive
contribution to the inclusion complexation between host and
guest. The binding mode of a side chain unit that is held in a
folded position by the CD cavity could be very useful for site-
selective reactions in organic synthesis. Even a minor structural
modification on the 2-OH group of one of seven glucose units
of the host ꢀ-CD as well as on the benzene ring of the guest
DOB can make a large difference in terms of both decreasing
∆Ei and increasing K. It is hoped that further research will be
continued, so that data obtained from experimental work will
1
a 1 cm optical path at room temperature. H NMR spectra of two
solid complexes, EOB-ꢀ-CD and DOB-ꢀ-CD, were obtained on
a NMR spectrometer at 300 MHz at 298 K using DMSO-d6 as
solvent.
General Procedure for the Preparation and Characterization
of EOB, BOB, DOB, and DOMB. EOB was synthesized according
to a similar method described in the literature.28 After being dried
with anhydrous sodium sulfate and removal of the solvent in a
vacuum, it was separated by distillation to give EOB, a colorless
(25) Song, L. X.; Teng, C. F.; Xu, P.; Wang, H. M.; Zhang, Z. Q.; Liu,
Q. Q. J. Inclusion Phenom. Macrocyclic Chem. 2008, 60, 223–233.
(26) Xu, P.; Song, L. X.; Wang, H. M. Thermochim. Acta 2008, 469, 36–
42.
(28) McKillop, A.; Fiaud, J. C.; Hug, R. P. Tetrahedron 1974, 30, 1379–
1382.
(27) Xu, P.; Song, L. X. Acta Phys.-Chim. Sin. 2008, 24, 729–736.
8314 J. Org. Chem. Vol. 73, No. 21, 2008

Binding BehaVior of Cyclodextrin to Fanlike Guests
liquid (2.06 g, 84.3%), bp 169 °C. 1H NMR (300 MHz, CDCl3) δH
7.21-7.26 (2H, m, aromatic H), 6.85-6.92 (3H, m, aromatic H),
between a guest and CD can be calculated as the sum of the
complexation energy and the deformation energies of CD and the
guest.17,38,39
3.95 (2H, q, J 7.0 Hz, OCH2), 1.37 (3H, t, J 7.2 Hz, CH2CH3); 13
C
Preparation of Solutions in UV-vis Absorption Spectroscopy
Measurements of the Inclusion Systems between CDs and the
Four Fanlike Guests. Stock solutions of guests were prepared by
dissolving the guest compounds in water-ethanol (3:1, v:v). On
the basis of our observation, the four guests were soluble in the
mixed solvent. In UV-vis spectroscopy measurements, all analyte
solutions were freshly prepared by dilution of stock solutions. The
concentrations of the guests in sample solutions were kept constant
at 5.0 × 10-5 mol·dm-3, while the concentration of CD varied
between 0 to 5.0 × 10-3 mol·dm-3 in order to determine the
binding constants of CD to the guests. All sample solutions to be
detected were prepared by mixing CD with a guest in water-ethanol
(3:1, v:v) before use and kept stirring at 298 K for 30 min.
Determination of Chemical Stoichiometries in the Inclusion
Complexes of CDs and the Four Fanlike Guests in Solution. Job’s
continuous variation method22,40 was applied to determine the
stoichiometries of the inclusion complexes of CDs with the
guests. In the measurements, a series of solutions were prepared,
each having a total concentration ([CD] · [guest]) of 1.0 × 10-4
mol · dm-3 while the [CD]:[guest] ratio value increased from 0
to 1.
NMR (75 MHz, CDCl3) δC 159.1, 129.5, 120.6, 114.6, 63.3, 14.9.
By means of the method described above, BOB and DOB were
obtained as colorless liquids. The yields of BOB and DOB were
1
86.4% and 77.3%, respectively. BOB, bp 210 °C, H NMR (300
MHz, CDCl3) δH 7.21-7.26 (2H, m, aromatic H), 6.85-6.91 (3H,
m, aromatic H), 3.91 (2H, q, J 6.3 Hz, OCH2), 1.75 (2H, dq, J1 6.6
Hz, J2 6.7 Hz, OCH2CH2), 1.51 (2H, m, 2H, OCH2CH2CH2), 0.96
(3H, t, J 7.2 Hz, CH2CH3); 13C NMR (75 MHz, CDCl3) δC 159.3,
129.4, 120.5, 114.6, 67.6, 31.5, 19.4, 13.9. DOB, bp 197 °C (12
torr), 1H NMR (300 MHz, CDCl3) δH 7.25-7.33 (2H, m, aromatic
H), 6.87-6.96 (3H, m, aromatic H), 3.95 (2H, t, J 6.6 Hz, OCH2),
1.80 (2H, dq, J1 6.7 Hz, J2 6.7 Hz, OCH2CH2), 1.25-1.50 [18H,
m, OCH2CH2(CH2)9], 0.88 (3H, t, J 6.6 Hz, CH2CH3); 13C NMR
(75 MHz, CDCl3) δC 159.1, 129.4, 120.4, 114.4, 67.8, 31.9, 29.34,
29.26, 26.0, 22.7, 14.1.
DOMB was prepared and purified by a previous method.29 After
the reaction was finished, the product, in the form of finely divided
crystals, was filtered, washed with water (50.0 mL), extracted with
dichloromethane (2 × 50.0 mL), and concentrated in vacuo to give
the essentially pure DOMB as an acicular crystal (6.93 g, 79.0%),
1
mp 47 °C. H NMR (300 MHz, CDCl3) δH 6.89 (4H, s, aromatic
Determination of Formation Constants of the Inclusion Com-
plexes of CDs with the Fanlike Guests. The determination of
formation constants (K) of ꢀ-CD and its derivatives to the guests
was realized by UV-vis spectroscopy titration experiments. The
K values were calculated by applying least-squares fit to the plots
of ([CD] ·[guest])/∆A versus ([CD] + [guest]), according to the
modified Benesi-Hildebrand equation:10,41
H), 4.01 (2H, t, J 6.9, OCH2), 3.86 (3H, s, OCH3), 1.84 (2H, m,
OCH2CH2), 1.26-1.55 (18H, m, OCH2CH2(CH2)9], 0.88 (3H, t, J
6.6, CH2CH3).13C NMR (75 MHz, CDCl3) δC 150.3, 121.2, 110.8,
68.9, 56.3, 31.7, 29.7, 26.0, 22.6, 14.1.
Theoretical Studies of the Inclusion Complexations between
CDs and the Four Fanlike Guests. PM3 method implemented in
the MOPAC30 software package was chosen to investigate the
inclusion complexation between three CD molecules and four guest
molecules in water. The initial geometry of ꢀ-CD was constructed
on the basis of available crystallographic data31 and fully optimized
without any restrictions. The coordinates of Mꢀ- and HPꢀ-CD were
obtained with the help of GaussView software, by substituting the
C-2 OH group of one glucopyranose unit in ꢀ-CD with a methoxy
group and a hydroxypropyloxy group, respectively. The geometries
of the four guest molecules were also fully optimized. The optimum
positions of complex formation were determined by trying several
starting points rather than by a global search.9,32-35
The complexation energy (∆Ec) between CD and a guest
molecule is the difference between the energy of the inclusion
complex at the lowest energy configuration and the sum of energies
of CD and the guest in their respective optimized equilibrium
geometry.17,36 The deformation energy (∆Ef) is the difference
between the sums of energies of two partners of an inclusion
complex at their respective equilibrium geometries and at the
geometry in the complex.17,36 Interaction energy (∆Ei) is the
difference between the energy of the complex at the lowest-energy
configuration and the sum of the energies of both partners at the
geometry of the complex.17,37,38 Accordingly, the interaction energy
[G][CD]
1
1
)
+
([G] + [CD])
(4)
∆A
K∆ε ∆ε
In eq 4, [G] and [CD] are the equilibrium concentrations of guest
and CD, respectively. ∆ε is the difference between the extinction
coefficients of free and complexed guest. ∆A is the difference
between the absorbances of free and complexed guest at the same
wavelength.
1H NMR Titration Measurements of the Interaction between
ꢀ-CD and the Four Guests. 1H NMR titrations were performed by
addition of a stock solution of the guests to a solution of ꢀ-CD at
298 K using DMSO-d6 as solvent. The chemical shifts of protons
of ꢀ-CD and the guests were recorded with the concentration of
the guests ranging from 0 to 2.5 × 10-1 mol·dm-3, keeping that
of ꢀ-CD constant (5.0 × 10-3 mol·dm-3). All liquid samples before
use were kept for 3 h under ultrasonic vibration at room temperature.
2D-NMR ROESY Experiment of the Interaction between
ꢀ-CD and DOB. Two-dimensional rotating frame nuclear Over-
hauser effect spectroscopy (ROESY) experiment was carried out
on a Bruker AV400 spectrometer at 400 MHz. A Bruker standard
sequence was necessary to make an observation of an intermolecular
nuclear Overhauser effect (NOE) between ꢀ-CD and DOB. The
data consisted of 16 scans collected over 1024 complex points and
for a spectral width of 4006 Hz. A mixing time of 200 ms, a
repetition delay of 2.0 s, an acquisition time of 0.167 s, and a 90°
pulse width of 12.5 µs at 1 dB power attenuation were used. The
data were zero-filled to 2048 × 512 points and processed by
applying a π/2 shifted Q-sine window in both dimensions. Small
cross-peaks were neglected because their magnitude was close to
that of noise.
(29) Boden, N.; Bushby, R. J.; Cammidge, A. N.; El-Mansoury, A.; Martin,
P. S.; Lu, Z. B. J. Mater. Chem. 1999, 9, 1391–1402.
(30) Stewart, J. J. P. J. Mol. Model. 2007, 13, 1173–1213.
(31) Lindner, K.; Saenger, W. Carbohydr. Res. 1982, 99, 103–115.
(32) Li, X. S.; Liu, L.; Guo, Q. X.; Chu, S. D.; Liu, Y. C. Chem. Phys. Lett.
1999, 307, 117–120.
(33) Liu, L.; Guo, Q. X. J. Inclusion Phenom. Macrocyclic Chem. 2004, 50,
95–103.
(34) Castro, R.; Berardi, M. J.; Cordova, E.; de Olza, M. O.; Kaifer, A. E.;
Evanseck, J. D. J. Am. Chem. Soc. 1996, 118, 10257–10268.
(35) Yu, Y. M.; Chipot, C.; Cai, W. S.; Shao, X. G. J. Phys. Chem. B 2006,
110, 6372–6378.
Preparation of Solid ꢀ-CD Inclusion Complexes of EOB and
DOB. Solid inclusion complexes were prepared by mixing a guest
with ꢀ-CD and stirring for 48 h at 298 K. The initial molar ratio of
guest to ꢀ-CD (1 mmol, 1.14 g) was 10:1 in deionized water. During
(36) Piel, G.; Dive, G.; Evrard, B.; Van Hees, T.; de Hassonville, S. H.;
Delattre, L. Eur. J. Pharm. Sci 2001, 13, 271–279.
(37) Pascal, B.; Maud, G.; Georges, D.; Adelin, A.; Valery, B.; Bruno, P.;
Didier, C.; Geraldine, P.; Luc, D.; Brigitte, E. J. Pharm. Pharmaceut. Sci. 2005,
8, 164–175.
(39) Klamt, A.; Schuurmann, G. J. Chem. Soc., Perkin Trans. 2 1993, 799–
805.
(38) Wang, H. M.; Song, L. X. Chem. Lett. 2007, 36, 596–597.
(40) Job, P. Ann. Chim. 1928, 9, 113–203.
J. Org. Chem. Vol. 73, No. 21, 2008 8315

Song et al.
stirring, a white precipitation was observed. After the reaction
ended, the white precipitation was filtered, washed with deionized
water (3 × 5.0 mL) and anhydrous ethanol (3 × 3.0 mL) and then
dried under vacuum. Two solid inclusion complexes, EOB-ꢀ-CD
(yield, 45.6%) and DOB-ꢀ-CD (yield, 23.9%), were obtained in
this manner and stored in a vacuum desiccator over silica gel until
further required.
BOB, DOB, and DOMB; details of materials and instruments;
and details of theoretical studies. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO801436H
1
Supporting Information Available: H NMR and FTIR
(41) Benesi, H. A.; Hildebrand, J. H. J. Am. Chem. Soc. 1949, 71, 2703–
2707.
spectra as well as preparation and purification of guests EOB,
8316 J. Org. Chem. Vol. 73, No. 21, 2008