Supramolecular catalysis by cucurbit[7]uril and cyclodextrins: Similarity and differences

Article abstract of DOI:10.1021/jo902398z

(Chemical Equation Presented) To understand the analogies and differences between the cucurbituril and cyclodextrin cavities different solvolytic reactions have been studied in the presence of cucurbit[7]uril, CB7, and β-CD or its methylated derivative, DM-β-CD. Solvolysis of 1-bromoadamantane has been used as a test to evaluate the ability of the cavities to solvate the Br^- leaving group. Obtained results show that in both cases the polarity inside the cavity is similar to that of a 70% ethanol:water mixture. Solvolysis of substituted benzoyl chlorides shows a great difference between the CB7 and DM-β-CD cavity. Solvolysis of electron withdrawing substituted benzoyl chlorides (associative mechanism) is catalyzed by DM-β-CD and inhibited by CB7. However, solvolysis of electron donating substituted benzoyl chlorides (dissociative mechanism) is catalyzed by CB7 and inhibited by DM-β-CD. These experimental behaviors have been explained on the basis of different solvolytic mechanisms. Participation of the hydroxyl groups of the cyclodextrin as a nucleophile can explain the catalytic effect observed for solvolysis of benzoyl chlorides reacting by an associative mechanism. Solvolysis of benzoyl chlorides reacting by a dissociative mechanism is catalyzed by CB7 due to the ability of the CB7 cavity to stabilize the acylium ion developed in the transition state by electrostatic interactions.

Full text of DOI:10.1021/jo902398z

pubs.acs.org/joc
Supramolecular Catalysis by Cucurbit[7]uril and Cyclodextrins:
Similarity and Differences
,†
‡
†
Nuno Basilio,† L. Garcı
a-Rıo,* J. A. Moreira, and M. Pessego
^
´ ´
†
´
´
´
Departamento de Quımica Fısica, Facultad de Quımica, Universidad de Santiago, 15782 Santiago, Spain and
´
‡
´
ꢀ
^
CIQA, Departamento de Quımica, Bioquımica e Farmacia, Faculdade de Ciencias e Tecnologia,
Universidade do Algarve, Campus das Gambelas, 8005-139 Faro, Portugal
luis.garcia@usc.es
Received November 11, 2009
To understand the analogies and differences between the cucurbituril and cyclodextrin cavities
different solvolytic reactions have been studied in the presence of cucurbit[7]uril, CB7, and β-CD or
its methylated derivative, DM-β-CD. Solvolysis of 1-bromoadamantane has been used as a test to
evaluate the ability of the cavities to solvate the Br- leaving group. Obtained results show that in
both cases the polarity inside the cavity is similar to that of a 70% ethanol:water mixture.
Solvolysis of substituted benzoyl chlorides shows a great difference between the CB7 and DM-
β-CD cavity. Solvolysis of electron withdrawing substituted benzoyl chlorides (associative
mechanism) is catalyzed by DM-β-CD and inhibited by CB7. However, solvolysis of electron
donating substituted benzoyl chlorides (dissociative mechanism) is catalyzed by CB7 and inhibited by
DM-β-CD. These experimental behaviors have been explained on the basis of different solvolytic
mechanisms. Participation of the hydroxyl groups of the cyclodextrin as a nucleophile can explain the
catalytic effect observed for solvolysis of benzoyl chlorides reacting by an associative mechanism.
Solvolysis of benzoyl chlorides reacting by a dissociative mechanism is catalyzed by CB7 due to the
ability of the CB7 cavity to stabilize the acylium ion developed in the transition state by electrostatic
interactions.
Introduction
characterized in condensed media. In contrast to the host-
guest chemistry of R-, β-, and γ-cyclodextrin which has
developed steadily over the past century, the supramolecular
chemistry of cucurbit[6]uril only began to develop in the
1980s and 1990s as a result of the pioneering work of Mock,3
Buschmann and co-workers,4 and Kim and co-workers.5,6
Cyclodextrins1 and cucurbiturils2 are both important
host molecules that have been extensively studied and
*To whom correspondence should be addressed. Fax: þ34-981-595-012.
(1) (a) Bender, M. L.; Komiyama, M. Cyclodextrin Chemistry; Springer-
Verlag: Berlin, Germany, 1978. (b) Szejtli, J. Cyclodextrins; Osa, T., Ed.;
Elsevier: Oxford, UK, 1996; Vol. 3.
(3) Mock, W. L. Top. Curr. Chem. 1995, 175, 1–24.
(4) Hoffmann, R.; Knoche, W.; Fenn, C.; Buschmann, H.-J. J. Chem.
Soc., Faraday Trans. 1994, 90, 1507–1511.
(5) Lee, J. W.; Samal, S.; Selvapalam, N.; Kim, H.-J.; Kim, K. Acc. Chem.
Res. 2003, 36, 621–630.
(6) Kim, K. Chem. Soc. Rev. 2002, 31, 96–107.
€
(2) (a) Mock, W. L. In Comprehensive Supramolecular Chemistry; Vogtle,
F., Ed.; Elsevier: New York, 1996; Vol. 2, pp 477-493. (b) Lagona, J.;
Mukhopadhyay, P.; Chakrabarti, S.; Isaacs, L. Angew. Chem., Int. Ed. 2005,
44, 4844–4870. (c) Kim, J.; Jung, I.-S.; Kim, S.-Y.; Lee, E.; Kang, J.-K.;
Sakamoto, S.; Yamaguchi, K.; Kim, K. J. Am. Chem. Soc. 2000, 122, 540–541.
848 J. Org. Chem. 2010, 75, 848–855
Published on Web 01/08/2010
DOI: 10.1021/jo902398z
r
2010 American Chemical Society

Basilio et al.
JOCArticle
SCHEME 1
SCHEME 2
showing a 105 times acceleration that is attributed to bound-
substrate destabilization. CB7 and CB8 have been employed to
catalyze different types of photocycloaddition reactions.14 Very
recently Nau15 and co-workers have shown that the supramo-
lecular complexation by CB7 affords a highly efficient inhibi-
tion on the activity of proteases, which can be analyzed by a
host-substrate complexation model.
A number of host-guest studies have been carried out by
using the cooperative effect of simultaneous addition of
cyclodextrins and cucurbiturils. Cucurbiturils mainly bind
cationic guests instead of cyclodextrins distinguishing be-
tween guests based on hydrophobic size rather than charge.
Formation of ternary complexes has been reported.16 The
pH-responsive movement of the cucurbituril units in the
host-guest complexes suggests its application as a basis for
stimuli-responsive reconfigurable systems.17
The main objective of the present work is to show the
differences and similarities between the CB7 and β-CD
cavities by using not only the equilibrium constant values
for the formation of the host guest complexes, but also the
specific interactions that can occur inside the cavities. To this
end we have studied two kinds of solvolytic reactions in the
presence of CB7 and β-CD because these reactions have
extreme sensibility to the physical properties of the reaction
medium. We have studied the solvolysis of 1-bromoadaman-
tane, whose solvolytic reaction takes place via an SN1 reac-
tion mechanism without the possibility of nucleophilic
solvent assistance.18 Moreover we have studied the solvolysis
of substituted benzoyl chlorides (Scheme 2). Because these
reactions in question exhibit no acid catalysis,19 any changes
in reactivity must be directly related to changes in the
physical properties of the environment of the host cavity.
This point is of special relevance because it is well-known
that complexation by cucurbiturils and cyclodextrins
can shift the pKa value of included guests.20 Cucurbituril
Interest in the cucurbit[n]uril family has increased dramati-
cally in the new millennium following the preparation of four
new cucurbit[n]uril homologues (CB5, CB7, CB8, and
CB10 CB5) by the research groups of Kim and Day.2c,7
3
Scheme 1 compares the structures of β-CD (a) and CB7
(b). Although the sizes and shapes of these two hosts are
similar, their structural differences lead to distinct binding
differences. CB7 has a symmetric geometry with two iden-
tical openings that are lined with electronegative carbonyl
groups. However, β-CD has a less symmetric geometry with
one opening to the interior lined with primary hydroxyl
groups and the other lined with secondary hydroxyls. Several
different modes of intermolecular interactions promote the
binding of guest by cucurbiturils. First, as for cyclodextrins,
a hydrophobic effect applies, i.e., a composite effect derived
from an interplay between the release of “high-energy water”
upon complexation of nonpolar organic residues and con-
comitant differential dispersion interactions inside the cavity
and in bulk water.8 Second, ion-dipole interactions of metal
cation4,9 or organic ammonium ions10 with either ureido
carbonyl rim may come into play, while hydrogen-bonding
interactions prevail less frequently.11 As a peculiarity, the
complexation of metal cations at the ureido rims can lead
to ternary supramolecular complexes composed of host,
included guest, and associated metal ion. In fact, it has been
suggested that the cations function as “lids” to seal the portal
and promote binding.12
The confinement imposed by supramolecular inclusion and
the associated variations in substrate reactivity are especially
important in supramolecular catalysis. Mock13 and co-workers
have studied the influence of CB6 on cycloaddition reactions
(7) (a) Day, A. I.; Arnold, A. P.; Blanch, R. J.; Snushall, B. J. Org. Chem.
2001, 66, 8094–8100. (b) Day, A. I.; Blanch, R. J.; Arnold, A. P.; Lorenzo, S.;
Lewis, G. R.; Dance, I. Angew. Chem., Int. Ed. 2002, 41, 275–277.
(8) (a) Schmidtchen, F. P. Chem.;Eur. J. 2002, 8, 3522–3529.
(b) Buschmann, H.-J.; Jansen, K.; Schollmeyer, E. Thermochim. Acta 1998,
317, 95–98.
(15) Henning, A.; Ghale, G.; Nau, W. M. Chem. Commun. 2007, 1614–
1616.
(9) Buschmann, H.-J.; Cleve, E.; Schollmeyer, E. Inorg. Chim. Acta 1992,
193, 93–97.
(10) (a) Mock, W. L.; Shih, N. Y. J. Am. Chem. Soc. 1989, 111, 2697–
2699. (b) Mock, W. L.; Shih, N. Y. J. Am. Chem. Soc. 1988, 110, 4706–4710.
(11) Buschmann, H.-J.; Jansen, K.; Schollmeyer, E. Thermochim. Acta
2000, 346, 33–36.
(12) (a) Jeon, Y. M.; Kim, J.; Whang, D.; Kim, K. J. Am. Chem. Soc.
1996, 118, 9790–9791. (b) Whang, D.; Heo, J.; Park, J. H.; Kim, K. Angew.
Chem., Int. Ed. 1998, 37, 78–80.
(13) (a) Mock, W. L.; Irra, T. A.; Wepsiec, J. P.; Adhya, M. J. Org. Chem.
1989, 54, 5302–5308. (b) Mock, W. L.; Irra, T. A.; Wepsiec, J. P.; Manimaran,
T. L. J. Org. Chem. 1983, 48, 3619–3620.
(14) (a) Jon, S. Y.; Ko, Y. H.; Park, S. H.; Kim, H.-J.; Kim, K. Chem.
Commun. 2001, 1938–1939. (b) Maddipatla, M. V. S. N.; Kaanumalle, L. S.;
Natarajan, A.; Pattabiraman, M.; Ramamurthy, V. Langmuir 2007, 23,
7545–7554. (c) Pattabiraman, M.; Natarajan, A.; Kaanumalle, L. S.;
Ramamurthy, V. Org. Lett. 2005, 7, 529–532. (d) Wang, R.; Yuan, L.;
Macartney, D. H. J. Org. Chem. 2006, 71, 1237–1239.
(16) (a) Rekharsky, M. V.; Yamamura, H.; Kawai, M.; Osaka, I.;
Arakawa, R.; Sato, A.; Ko, Y. H.; Selvapalam, N.; Kim, K.; Inoue, Y.
Org. Lett. 2006, 8, 815–818. (b) Zou, D.; Andersson, S.; Zhang, R.; Sun, S.;
Akermark, B.; Sun, L. Chem. Commun. 2007, 4734–4736.
(17) (a) Chakrabarti, S.; Mukhopadhyay, P.; Lin, S.; Isaacs, L. Org. Lett.
2007, 9, 2349–2352. (b) Ooya, T.; Inoue, D.; Choi, H. S.; Kobayashi, Y.;
Loethen, S.; Thompson, D. H.; Ko, Y. H.; Kim, K.; Yui, N. Org. Lett. 2006,
8, 3159–3162.
(18) (a) Raber, D. J.; Bingham, R. C.; Harris, J. M.; Fry, J. L.; Schleyer,
P. v. R. J. Am. Chem. Soc. 1970, 92, 5977–5981. (b) Bentley, T. W.; Carter,
G. E. J. Am. Chem. Soc. 1982, 104, 5741–5747.
(19) Motie, R. E.; Satchell, D. P. N.; Wassef, W. N. J. Chem. Soc., Perkin
Trans. 2 1993, 1087–1090.
(20) (a) Bakirci, H.; Koner, A. L.; Schwarzlose, T.; Nau, W. M. Chem.;
Eur. J. 2006, 12, 4799–4807. (b) Saleh, N.; Koner, A. L.; Nau, W. M. Angew.
Chem., Int. Ed. 2008, 47, 5398–5401. (c) Wang, R.; Macartney, D. H. Org.
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Org. Lett. 2009, 11, 2595–2598.
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FIGURE 1. Influence of CB7 (left) and β-CD (right) concentration upon the observed rate constant for solvolysis of 1-bromoadamantane
at 25.0 °C.
complexation leads to an increase in pKa (AHþ as guest)
whereas cyclodextrin complexation leads instead to a de-
crease in pKa. Thereby complexation may result in either
catalysis or inhibition of hydrolysis of acid-labile substrates.
As will be shown, a different behavior has been observed
when the solvolysis of benzoyl chlorides is studied into the
CB7 or the cyclodextrin cavity. The different behavior can
be explained on the basis of nucleophilic solvent assistance
inside the CB7 cavity. This effect leads to a change in the
mechanism of solvolysis of benzoyl chlorides: in the presence
of cyclodextrins the reaction follows mainly an associa-
tive mechanism, but in the CB7 cavity an SN1 mechanism
prevails.
SCHEME 3
takes place simultaneously in bulk water and inside the host
cavity.
Results and Discussion
Solvolytic displacement reactions can be affected by sol-
vents in several ways, including nucleophilic solvent assis-
tance and electrophilic solvent assistance. Nucleophilic
solvent assistance can be defined as electron donation from
solvent to the developing positive dipole of a reacting C-X
bond, and electrophilic solvent assistance can be defined as
electron acceptance by the solvent from the leaving group.
By comparing the sensitivity of various reactions to ionizing
power and nucleophilicity, it is possible to deduce mecha-
nistic information.
This kinetic scheme takes into consideration the simulta-
neous existence of two well-differentiated environments:
water and host cavity (CB7 or β-CD) between which the
substrates are distributed. By considering that solvolysis can
take place simultaneously in water, kw, and the host cavity,
kCB7 or kCD for CB7 and β-CD, respectively, it is possible to
derive the following rate equation:
kw þ kCB7KCB7½CB7ꢀ
kobs
¼
ð1Þ
1 þ KCB7½CB7ꢀ
1. Solvolysis of 1-Bromoadamantane. Bridgehead caged
systems such as 1-bromoadamantane can be used as a model
for SN1 reactions. There is extensive experimental evidence
consistent with the absence18,21 of kinetically significant
nucleophilic attack in solvolysis of 1-bromoadamantane.
Consequently is an excellent substrate for defining a scale
of solvent ionizing power for bromides.
Figure 1 shows the effect of the presence of CB7 and β-CD
on solvolysis of 1-bromoadamantane. In both cases the
observed rate constant decreases as a consequence of forma-
tion of host-guest complexes.
Kinetic experiments for solvolysis of 1-bromoadamantane
were carried out by using a [1-bromoadamantane]=1.00 ꢁ
10-4 M, so that in the presence of CB7 it is impossible to
confirm whether [1-bromoadamantane] , [CB7], and so in
order to obtain the equilibrium constant it is necessary to
resort to a trial and error method (see the Supporting
Information). The obtained binding constant, KCB7 = (2.0 (
0.2) ꢁ 107 M-1, is in the same order of magnitude as those
reported for other adamantane derivatives.22 The limiting value
of kobs obtained for [CB7] > 0.2 mM allow us to obtain the
solvolytic rate constant inside the CB7 cavity, kCB7 = (7.1 (
0.2) ꢁ 10-6 s-1. This value is approximately 103 times slower
than that in bulk water.
These results are consistent with a mechanistic scheme
(Scheme 3) considering the formation of a host:guest com-
plex between the 1-bromoadamantane and CB7 or β-CD
(KCB7 or KCD, respectively) where the solvolytic reaction
Solvolysis of 1-bromoadamantane in the presence of
β-CD shows the existence of 1:1 and 2:1 β-CD:adamantane
(21) Bentley, T. W.; Schleyer, P. v. R. Adv. Phys. Org. Chem. 1977, 14,
1–67.
(22) Liu, S.; Ruspic, C.; Mukhopadhyay, P.; Chakrabarti, S.; Zavalij,
P. Y.; Isaacs, L. J. Am. Chem. Soc. 2005, 127, 15959–15967.
850 J. Org. Chem. Vol. 75, No. 3, 2010

Basilio et al.
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FIGURE 2. (Left) Plot of the influence of CB7 concentration on the pseudo-first-order rate constant for solvolysis of 4-NO2 at 25.0 °C. (Right)
Plot of 1/kobs for solvolysis of 4-NO2 in the presence of CB7 according to eq 3.
complexes. Kinetic results can be fitted by eq 2 (curve in
Figure 1, right).
As a representative example of an associative mechanism,
Figure 2 shows the influence of CB7 concentration on
the pseudo-first-order rate constant, kobs, for solvolysis of
4-NO2 (4-H, 3-Cl, 3-NO2, and 4-CF3 should be included in
this category). The obtained results show that kobs decreases
approximately six times when the concentration of CB7
increases up to 6.7 mM.
These results are consistent with the formation of an
inclusion complex between the cucurbituril and benzoyl
chlorides, as shown in Scheme 3. The solvolytic reaction will
take place simultaneously in bulk water and the CB7 cavity
(eq 1). In this case, as with other benzoyl chlorides, the
binding constant of the substrate to the CB7 cavity is smaller
than that with 1-bromoadamantane. Thus larger CB7 con-
centrations should be used in such a way that we can neglect
the concentration of the host:guest complex (CB7:benzoyl
chloride) in comparison with the total host concentration. In
this way the host concentration in eq 1 can be considered as
the total host concentration and the iterative fitting proce-
dure shown in the Supporting Information for 1-bromoada-
mantane is not needed.
kw þ kCDKCD1½CDꢀ
1 þ KCD1½CDꢀ þ KCD1KCD2½CDꢀ
kobs
¼
ð2Þ
2
From the fitting procedure we get KCD1=(3.9 ( 0.8) ꢁ 104
M-1; KCD2 =(7 ( 1) ꢁ 103M-1 and kCD = (6 ( 1) ꢁ
10-5 s-1. The binding constant of 1-bromoadamantane to β-CD,
KCD1, is smaller than that to CB7, KCB7. As will be shown latter
this result is in agreement with the polarity of the CB7 cavity
being smaller that the β-CD one. Moreover the solvolytic rate
constant inside the CB7 cavity, kCB7, is smaller than that in
the presence of β-CD, kCD. This result is a consequence of the
smaller ability of the CB7 cavity than the β-CD one to solvate
the transition state.
Because the nucleophilic solvent assistance is negligible for
solvolysis of 1-bromoadamantane, experimental results in-
dicate that the solvation of the leaving group inside the
cavities of CB7 or β-CD is smaller than that in bulk water.
From the results shown in Figure 1 we can conclude that the
leaving group solvation inside the CB7 cavity is similar to
The fit of the kinetic results to eq 1 (line in Figure 2, left)
confirms the inequality of kw . kCB7KCB7 [CB7], thus eq 1
can be rewritten as:
that found on mixtures of 60% ethanol:40% water (kobs
=
5.1 ꢁ 10-6 s-1) and 70% methanol:30% water (kobs =7.3 ꢁ
10-6 s-1). With these results we can estimate that the ioni-
zing power of the cavity of CB7 is between YBr = 1.26 (60%
ethanol) and YBr=1.42 (70% methanol). Experimental results
obtained in the presence of β-CD suggest23 the polarity of the
cavity is close to a mixture of 50% ethanol:water.
1
1
KCB7
kw
¼
þ
½CB7ꢀ
ð3Þ
kobs
kw
Figure 2, right, shows the fit of experimental data according
to eq 3. From the fit we can obtain the value for the com-
plexation equilibrium constant, KCB7=1.7 ꢁ 103 M-1, and a
maximum value of the rate constant for the solvolysis at
cavity, since kCB7 , kw/KCB7[CB7], kCB7 < 7.2 ꢁ 10-4 s-1
for 4-NO2 solvolysis in the CB7 cavity (see Table 1).
We must notice that the rate constant inside the cavity of
CB7 is approximately 102 times smaller than that in bulk
water. This difference should be ascribed to the weak solva-
tion of the transition state inside the CB7 cavity, when
compared to the transition state solvation in bulk water. It
is reported in the literature that CB7 has a very low polari-
zability (P = 0.12) inside its cavity25 being smaller that the
polarizability of the β-cyclodextrin (P = 0.20) cavity and
smaller than that for p-sulfonatocalix[4]arene (P = 0.25).
2. Solvolysis of Benzoyl Chlorides. The mechanism of
solvolysis of benzoyl chlorides is well-known both in water
and in different solvents.24 The goal is to compare the
observed behavior, in the presence of CB7 or in the presence
of the similar β-CD. However, the low solubility of β-CD in
water prevents the experimental conditions at which solvo-
lysis of benzoyl chlorides occurs inside the cavity from being
reached. This problem can be solved by using the DM-β-CD,
since this compound is 20 times more soluble in water than
the β-CD without significant changes in cavity properties.
2.1. Inhibitory Effect of CB7 upon Solvolysis of Benzoyl
Chlorides. Solvolysis of electron-withdrawing substituted
benzoyl chlorides occurs through an associative pathway.24
(23) Garcia-Rio, L.; Hall, R. W.; Mejuto, J. C.; Rodrı
Tetrahedron 2007, 63, 2208–2214.
(24) Song, B. D.; Jencks, W. P. J. Am. Chem. Soc. 1989, 111, 8470–8479.
´
guez-Dafonte, P.
(25) (a) Marquez, C.; Nau, W. M. Angew. Chem., Int. Ed. 2001, 40, 4387–
4390. (b) Koner, A. L.; Nau, W. M. Supramol. Chem. 2007, 19, 55–66.
J. Org. Chem. Vol. 75, No. 3, 2010 851

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TABLE 1. Compilation of Binding Constants between Substituted Benzoyl Chlorides and CB7 and DM-β-CD, As Well As Solvolytic Rate Constants in
Bulk Water and Inside the Cavities of CD7 and DM-β-CD
substrate
kw/s-1
KDM-β-CD/M-1
kDM-β-CD/s-1
KCB7/M-1
kCB7/s-1
4-NO2
3-NO2
4-CF3
3-Cl
4-Cl
3-CH3O
4-H
3-CH3
4-CH3
4-CH3O
(8.2 ( 0.3) ꢁ 10-2
(3.8 ( 0.2) ꢁ 10-2
(3.5 ( 0.1) ꢁ 10-2
0.47 ( 0.02
30 ( 3
0.90 ( 0.04
(1.7 ( 0.2) ꢁ 103
e7.2 ꢁ 10-4
(1.2 ( 0.1) ꢁ 10-2
e7.7 ꢁ 10-3
(3.4 ( 0.4) ꢁ 10-2
0.71 ( 0.08
0.83 ( 0.07
0.14 ( 0.03
3.3 ( 0.6
5 ( 2
0.29 ( 0.05
430 ( 60
610 ( 100
345 ( 30
435 ( 10
1120 ( 30
470 ( 30
810 ( 60
1050 ( 25
730 ( 35
(4.1 ( 0.1) ꢁ 10-2
(1.3 ( 0.1) ꢁ 10-2
(4.8 ( 0.2) ꢁ 10-3
(1.4 ( 0.2) ꢁ 10-3
(3 ( 1) ꢁ 10-3
(6 ( 2) ꢁ 10-3
(3 ( 1) ꢁ 10-2
0.37 ( 0.09
68 ( 10
2500 ( 200
1500 ( 200
480 ( 80
0.19 ( 0.01
0.59 ( 0.02
1.14 ( 0.05
680 ( 50
2.51 ( 0.07
4000 ( 1000
1250 ( 150
326 ( 40
6.3 ( 0.2
19 ( 2
46 ( 1
252 ( 30
Data for DM-β-CD were taken from ref 23.
Table 1 reports the rate constants in bulk water and inside
the cavities of CB7 and DM-β-CD, as well as the binding
constants. The binding constant for 4-NO2 with CB7,
KCB7 =1.7 ꢁ 103 M-1, is approximately 50 times greater
than that with DM-β-CD, KDM-β-CD = 30. In general the
stability constants of the cucurbiturils are larger than those
of the corresponding cyclodextrins with the same guest26 as a
consequence of the lower polarity of the cavity.
From the previous study on solvolysis of 1-bromoada-
mantane we have concluded that the solvolytic rate constant
inside the CB7 cavity is very close to those observed for 60%
ethanol or 70% methanol. However, the results obtained27
for 4-NO2, kCB7 < 7.2 ꢁ 10-4 s-1, are 100-200 times smaller
than those obtained in 60% ethanol, kobs = 6.9 ꢁ 10-2 -1
s ,
and 70% methanol, kobs =0.153 s-1. Solvent effects for
solvolysis of 4-NO2 in alcohol:water mixtures are mainly due
to changes in the solvent nucleophilicity. This means that
water nucleophilicity inside the CB7 cavity should be much
smaller than that for alcohol:water mixtures.
FIGURE 3. Influence of DM-β-CD (data taken from ref 23) con-
centration on the pseudo-first-order rate constant for solvolysis of
4-NO2 at 25.0 °C.
the 3-NO2 derivative, the solvolysis rate constant inside CB7
is approximately 20 times smaller than that inside DM-
β-CD, while for 3-Cl and 4-H the rate of solvolysis in the
CB7 cavity is greater than that inside DM-β-CD. The cavities
of CB7 and DM-β-CD show different affinities to 4-NO2,
3-NO2, 4-CF3, 3-Cl, and 4-H, which is related to the mecha-
nism of reaction, as will be discussed later.
Figure 3 shows the influence of [DM-β-CD] on the rate
constants for solvolysis23 of 4-NO2. DM-β-CD shows a clear
catalytic effect on solvolysis of the 4-NO2 derivative; the
observed rate constant increases approximately 10 times as a
consequence of the reaction between the hydroxyl groups of
the cyclodextrin and the included guest.28,29
2.2. Catalytic Effect of CB7 upon the Solvolysis of Benzoyl
Chlorides. As an example of the behavior of electron-donat-
ing substituted benzoyl we consider 4-CH3O. Figure 4, left,
shows the influence of CB7 concentration on the solvolysis of
4-CH3O where a clear catalytic effect is observed. This
experimental behavior is contrary to that observed for
solvolysis of 4-NO2 (Figure 2, left). Solvolysis of 4-CH3,
3-CH3, 3-CH3O, and 4-Cl also shows a catalytic effect
exerted by the CB7 concentration (not shown). These experi-
mental results are unexpected on the basis of the CB7
influence on solvolysis of 1-bromoadamantane (Figure 1,
left). Results in Figure 1 show that the 1-bromoadamantane
solvolytic rate constant inside the CB7 cavity is similar to
those observed for 60% ethanol or 70% methanol. However,
the 4-CH3O solvolytic rate constant inside the CB7 cavity is
close to kobs = 200 s-1. This value is 103 times larger than
those observed30 in 60% ethanol, kobs = 0.19 s-1, and 70%
methanol, kobs=0.32 s-1. As will be shown later the absence
of correlation between solvolysis of 1-bromoadamantane
and 4-CH3O is explained as a consequence of the solvent
nucleophilic assistance in solvolysis of benzoyl chlorides.
The solvolysis of 4-CF3 shows a similar behavior to that
observed in Figure 2, right. On applying eq 3 a maximum
value for the rate constant in the CB7 cavity is obtained. This
value is 5 times smaller than that in DM-β-CD (see Table 1).
In the solvolysis of other substituted benzoyl chlorides with
electron withdrawing groups like 3-NO2, 3-Cl, and 4-H an
inhibitory effect resulting from the addiction CB7 is also
observed. In those cases we do not observe the inequality
kw . kCB7KCB7[CB7] and the experimental results should be
fitted to eq 1. The values of the rate constants in the CB7
cavity and the binding constants between the CB7 and
substituted benzoyl chlorides are reported in Table 1. For
(26) Wyman, I. W.; Macartney, D. H. Org. Biomol. Chem. 2008, 6, 1796–
1801.
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1998, 98, 1977–1996. (b) Easton, C. J.; Lincoln, S. F. Modified Cyclodextrins;
Imperial College Press: London, UK, 1999. (c) Saenger, W.; Niemann, C.; Herbst,
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1393.
852 J. Org. Chem. Vol. 75, No. 3, 2010

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FIGURE 4. Influence of CB7 (left) and DM-β-CD (right, data taken from ref 23) concentration upon the observed rate constant for solvolysis
of 4-CH3O at 25.0 °C.
Results obtained in the presence of CB7 are opposite to
those in the presence of DM-β-CD. An increase of kobs up to
300% is observed in the presence of 6 mM CB7 meanwhile
the solvolytic rate constant of 4-CH3O in the presence
of DM-β-CD (Figure 4, right) decreases approximately
450 times when increasing the concentration of DM-β-CD
up to [DM-β-CD] = 0.15 M.
The inhibitory effect exerted by the DM-β-CD upon
solvolysis of 4-CH3O, as occurs with 4-CH3, 3-CH3,
3-CH3O, and 4-Cl, can be easily explained by recourse to
the formation of an inclusion complex between the benzoyl
chloride and the cyclodextrin. The possibility of a reaction
between the complexed benzoyl chloride and the cyclodex-
trin hydroxyl groups can be discarded for those substrates
which undergo solvolysis fundamentally by means of a
dissociative mechanism. Therefore, in this case the reaction
path within the inclusion complex should be the expulsion of
the leaving group inside the cavity of the cyclodextrin. The
solvolytic rate constant inside the cyclodextrin is smaller
than that in bulk water because of the lower polarity of the
cavity.31-38
solvolysis of substituted benzoyl chlorides versus Win-
stein-Grunwal YCl shows considerable scatter even for
solvents with high ionizing power.39 Its interpretation is
based on considerable information available on the expected
trends in SN2-SN1-type solvolytic reactivity in a wide range
of protic solvents.40 As YCl models SN1 reactivity, Bentley
and co-workers39a have concluded that hydrolyses of ben-
zoyl chlorides are not pure SN1 reactions. It appears that
many solvolysis of benzoyl chloride are weakly nucleophili-
cally solvent-assisted (SN2) to about the same extent as
solvolysis of tert-butyl chloride. The high reactivity of
benzoyl chloride in water and in other solvents of high
ionizing power can readily be explained by the relatively
good stabilization of the incipient benzoyl cation, i.e., in an
SN1 or an SN2 pathway via a transition state with high
carbocation character. Independent evidence for nucleophi-
lically assisted solvolysis, obtained form rate-product cor-
relations in the presence of added o-nitroaniline, support the
proposal35 that even solvolyses in relatively polar solvents
are not pure SN1 processes.
When the solvolysis of 4-CH3O is studied in a mixture of
70% methanol:water, in which the value of YCl is similar to
that obtained in the cavity of CB7, an observed rate constant
kobs = 0.316 s-1 is obtained. On this basis we expect the
4-CH3O solvolytic rate constant in the cavity of CB7 to be
150 times lower than the value obtained in bulk water.
Surprisingly, as can be see in Figure 4, left, the rate constant
increases approximately 4 times when the concentration of
CB7 increases. This result suggests that the electrostatic
interaction inside CB7 between the carbonyl groups of
CB7 and the positive charge developed on the carbony group
of the 4-CH3O increases at least 600 times the solvolytic rate
constant. An electrostatic interaction between the positive
charge developed on the carbonyl group of benzoyl chloride
The polarity in the CB7 cavity is smaller than that in the
DM-β-CD, so an inhibitory effect greater than that shown in
Figure 4, right, would be expected. Nevertheless, the experi-
mental results show an important catalytic effect. This result
is a consequence of the reaction mechanism being not a pure
SN1 one. In fact, a plot of the logarithm of rate constants for
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J. Org. Chem. Vol. 75, No. 3, 2010 853

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FIGURE 5. Hammett plot for solvolysis of substituted benzoyl chlorides in bulk water (left) and inside the cavity of DM-β-CD (9, right) or the
CB7 cavity (O, right) at 25.0 °C. Rate constants for solvolysis of 4-NO2 and 4-CF3 inside the CB7 cavity (right) correspond to maximum values.
the transition state for hydrolysis of a benzoyl chloride with
micellar head groups are illustrated in Scheme 4. The transi-
tion state is written as in a concerted SN1-SN2 borderline
mechanism, with a cationoid acyl center.
SCHEME 4
Nucleophilic solvation of the transition state on solvolysis
of benzoyl chlorides should lead to the catalytic effect of CB7
in the hydrolysis of 4-CH3O and the different behavior
between CB7 and DM-β-CD. Electrostatic effects can play
a crucial role in molecular recognition events in both aqu-
eous and organic solution.44 The electrostatic potential at the
portal and within the cavity of CB7 is significantly more
negative than that for β-CD. This difference in electrostatic
potential has significant consequences for their recognition
behavior: CB7 exhibits a pronounced preference to interact
with cationic guests whereas β-CD prefers to bind to neutral
or anionic guests.2b,5 The recognition of the dissociative
transition state by CB7 could explain the observed catalytic
effect as a consequence of the electrostatic interaction
between the carbocation developed in the transition state
and the electrostatic potential of the CB7 cavity. In the case
of DM-β-CD the absence of this interaction could explain
the different behavior, shown in Figure 4, and the lower
value of kDM-β-CD with respect to rate constant in water, kw.
2.3. CB7 Prevents Mechanistic Changes. Figure 5, left,
shows the results obtained on studying the rate of solvolysis
of substituted benzoyl chlorides in bulk water. In the Ham-
mett plot we can observe the existence of two very different
slopes: one negative (Fþ = -2.6 ( 0.3) and another positive
(Fþ = 1.4 ( 0.5). The first corresponds to substrates which
undergo solvolysis by an eminently dissociative mechanism,
while the behavior exhibited by the benzoyl chlorides with
electron-attracting groups is consistent with an associative
mechanism.
and the cyclodextrin cavity is not possible. In fact, cyclodex-
trins can form inclusion complexes with inorganic anions41
(generally with equilibrium constants on the order of 1 M-1).
This explains why the value of the rate constant in the
cavity of DM-β-CD is kDM-β-CD = 0.37 s-1, approximately
130 times lower than that in water, and similar to that
obtained in 70% methanol:water. This result shows that in
the absence of electrostatic interaction, between the CB7
cavity and positive partial charge developed at the carbonyl
in the transition state, the qualitative effect of CB7 and DM-
β-CD should be the same.
Previous evidence of the electrostatic stabilization of the
positive charge developed on the carbonyl group in the
solvolysis of benzoyl chlorides has been obtained from
kinetic studies in micellar aggregates.42 Hydrolyses of most
acyl derivatives, including carboxylic anhydrides and diaryl
carbonates, are micellar inhibited, except for some nitro
derivatives,43 but reactions are faster in cationic than in
anionic micelles. The pattern is similar for hydrolyses of
substituted benzoyl chlorides in that k /k- > 1 for nitro
þ
derivatives but is <1 for methyl and methoxy derivatives41
(k /k-=18, 4, 3.6,; 0.27, 0.038, and <0.03 for 4-NO2, 4-Cl,
þ
4-Br, 4-H, 4-CH3, and 3-CH3O, respectively). Interactions of
Figure 5, right, shows a similar correlation when the
reaction occurs inside the cavity of DM-β-CD. In this case
the observed slopes (Fþ = -2.6 ( 0.2 and 3.3 ( 0.5) show
that the associative mechanism is more favored than dis-
sociative. In the presence of DM-β-CD the mechanism
changes at the benzoyl chloride, 4-H, while in bulk water
the mechanism change is observed later at the electron-
withdrawing group, 3-CF3. The DM-β-CD cavity has a poor
capacity to contribute in the electrophilic solvation of the
(41) Mochida, K.; Kagita, A.; Matsui, Y.; Date, Y. Bull. Chem. Soc. Jpn.
1973, 46, 3703–3707.
(42) Tascioglu, S. Tetrahedron 1996, 52, 1113–11152.
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Yatsimirsky, A. K. Langmuir 2000, 16, 8595–8603. (b) Bunton, C. A.; Mhala,
M. M.; Moffatt, J. R. J. Org. Chem. 1985, 50, 4921–4924. (c) Buurma, N. J.;
Herranz, A. M.; Engberts, J. B. F. N. J. Chem. Soc., Perkin Trans. 2 1999,
113–119. (d) Possidonio, S.; Siviero, F.; El Seoud, O. A. J. Phys. Org. Chem.
1999, 12, 325–332. (e) Possidonio, S.; El Seoud, O. A. J. Mol. Liq. 1999, 80,
231–251. (f) Al-Lohedan, H.; Bunton, C. A.; Mhala, M. M. J. Am. Chem.
Soc. 1982, 104, 6654–6660. (g) Bunton, C. A.; Ljunggren, S. J. Chem. Soc.,
Perkin Trans. 2 1984, 355–361. (h) Brinchi, L.; Di Profio, P.; Micheli, F.;
Germani, R.; Savelli, G.; Bunton, C. A. Eur. J. Org. Chem. 2001, 1115–1120.
(44) Honig, B.; Nicholls, A. Science 1995, 268, 1144–1149.
854 J. Org. Chem. Vol. 75, No. 3, 2010

Basilio et al.
JOCArticle
leaving group producing a decrease on the dissociative path-
way. Likewise, the participation of the C(6) hydroxyl group
of the DM-β-CD as a nucleophile favors the associative
mechanism.
cyclodextrin cavities can be explained as a consequence of
the participation of the cyclodextrin hydroxyl groups in the
reaction.
When the reaction was carried inside the CB7 cavity a
single Hammett correlation (Figure 5, right) with slope Fþ=
-3.1 ( 0.3 is observed. Because rate constants for solvolysis
of 4-NO2 and 4-CF3 inside the CB7 cavity correspond to
maximum values they were excluded from the set for calcu-
lating Fþ. Inside the CB7 cavity all substituted benzoyl
chlorides undergo solvolysis through a dissociative path.
The Fþ value is equal to that obtained in 97% trifluoro-
ethanol45 (Fþ =-3.1) suggesting the existence of a dissocia-
tive mechanism (SN1 type). However, the results in Figure 5,
right, show that in the reaction an important nucleophilic
assistance must be present. Substituted benzoyl chlorides
with electron-donating groups show a rate constant inside
the CB7 cavity 102 times bigger than that in the DM-β-CD
cavity. Nevertheless the study of solvolysis of 1-bromoada-
mantane shows that the cavities of CB7 and β-CD have
similar electrophilic solvation ability and therefore similar
values of YBr. The fact that reactivity cannot be correlated
only with the solvent ionizing power clearly indicates nu-
cleophilic assistance on solvolysis of substituted benzoyl
chlorides in the CB7 cavity. The nucleophilic assistance
results from the electrostatic interaction between the CB7
cavity and the transition state of the solvolysis reaction.
Experimental Section
CB7 was synthesized by using the procedure described by
Nau et al.,46 and after separation of CB7 from others homo-
logues, the sulfuric acid was exchanged with chlorhydric acid by
dissolving the product in concentrated HCl, diluted with water,
and precipitated with acetone. This procedure was repeated two
times and finally the product was dissolved in water and
precipitated several times with acetone until the pH of the
solution was neutral as seen by indicator paper. Finally the
product was dried on high vacuum at 140 °C for several days.
The pH of a 5 mM solution was checked with a glass electrode
and was found to be 5.7. The product was characterized by
proton nuclear magnetic resonance and electrospray ionization
mass spectrometry based on known literature data.2c
The benzoyl chlorides were commercially available, all of
which had purities between 97% and 98%, and were used
without further purification. Their solutions were prepared in
acetonitrile to prevent it from decomposing too rapidly.
Reaction kinetics was carried out in an Applied Photophysics
stopped flow spectrophotometer with unequal mixing. The
benzoyl chloride dissolved in dry acetonitrile was placed in the
smaller syringe (0.1 mL). The larger syringe (2.5 mL) was filled
with an aqueous solution of the macrocyclic. The total acetoni-
trile concentration was 3.85% (v/v). Solutions of benzoyl chlor-
ides were freshly prepared in dry acetonitrile at the appropriate
concentration in order to obtain a final concentration of 5.0 ꢁ
10-5 M. All experiments were carried out at 25.0 °C. The kinetic
traces were fitted with one exponential equation by using the
software of the SF apparatus. The wavelengths used to monitor
the reactions were 300, 270, 300, 290, 260, 270, 300, 285, 295,
250, and 260 nm for 4-CH3O, 4-CH3, 3-CH3, 4-H, 3-CH3O,
4-Cl, 3-Cl, 3-CF3, 4-CF3, 3-NO2, and 4-NO2, respectively.
Solvolysis of 1-bromoadamantane was followed by conducto-
metry; the kinetic data were treated both by the integral method
and by the initial rate method. All the kinetic experiment could
be reproduced within an error margin of 3%.
Conclusions
Obtained results for solvolytic reactions in the presence of
CB7 and β-CD or DM-β-CD can be explained on the basis of
the different properties of their cavities. Pure SN1 reactions,
1-bromoadamantane, are inhibited by both cucurbituril and
cyclodextrin. In both cases the ability of the cavity to solvate
the Br- leaving group is similar to that of a 70% metha-
nol:30% water mixture. However important discrepancies
have been observed in the solvolysis of substituted benzoyl
chlorides. For electron donating substituted benzoyl chlo-
rides the solvolytic reaction is catalyzed in the cucurbituril
cavity and is inhibited in the cyclodextrin. This behavior is a
consequence of the poor ability of both cavities to solvate the
Cl- leaving group; however, inside the cucurbituril cavity the
interaction between the electrostatic potential at the portal of
the cavity and the acylium cation developed in the transition
state can decrease the energy barrier for the reaction.
Experimental differences for solvolysis of electron with-
drawing substituted benzoyl chlorides between the CB7 or
Acknowledgment. This work was supported by Ministerio
de Ciencia y Tecnologıa (Project CTQ2008-04420/BQU) and
´
Xunta de Galicia (PGIDIT07-PXIB209041PR). N.B. ack-
nowledge FCT for PhD Grant SFRH/BD/29218/2006.
Supporting Information Available: A description of the
fitting procedure for solvolysis of 1-bromoadamantane in the
presence of CB7. This material is available free of charge via
the Internet at http://pubs.acs.org.
(45) Bentley, T. W.; Harris, H. C. J. Chem. Soc., Perkin Trans. 2 1986,
619–624.
(46) Marquez, C.; Huang, F.; Nau, W. M. IEEE Trans. Nanobiosci. 2004,
3, 39–45.
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