Catalytic and inhibitory effects of β-cyclodextrin on the hydrolysis of benzoic anhydride

Article abstract of DOI:10.1002/poc.737

The hydrolysis of benzoic anhydride (Bz₂O) in the presence of β-cyclodextrin (β-CD) was studied in aqueous solution as a function of pH, temperature and ionic strength, at 25°C. The experimental rate constant versus pH profiles show that, in the region of spontaneous water reaction (pH 3.0-6.5), β-CD inhibits the reaction and the isotope effect (k _H2O/k_D2O = 4.7) indicates that the rate determining step of the reaction corresponds to the water-catalyzed nucleophilic attack of water on the carbonyl group of Bz₂O. Conversely, whereas inhibition is observed at pH 6.0, catalysis of the hydroxide ion reaction is observed at pH 8.0 and it is found that the activation entropy is responsible for the catalytic phenomena in the basic hydrolysis of benzoic anhydride. Copyright 2004 John Wiley & Sons, Ltd.

Full text of DOI:10.1002/poc.737

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2004; 17: 370–375
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/poc.737
Catalytic and inhibitory effects of b-cyclodextrin
on the hydrolysis of benzoic anhydride
1
2
1
1
1
Tiago A. S. Brand a˜ o, Jacir Dal Magro, Louise D. Chiaradia, Maria da Gra c¸ a Nascimento, Faruk Nome, *
3
1
Jose V. Tato, and Rosendo A. Yunes
1
Departamento de Qu ı´ mica, Universidade Federal de Santa Catarina, 88040-900 Florian o´ polis, SC, Brazil
2
3
Centro de Ci eˆ ncias Agro-ambientais e de Alimentos, Universidade Comunit a´ ria Regional de Chapec o´ , 89809-000 Chapec o´ -SC, Brazil
Departamento de Qu ı´ mica F ı´ sica, Facultad de Ci e´ ncias, Campus Lugo, Universidad de Santiago de Compostela, 27002 Lugo, Spain
Received 8 July 2003; revised 24 October 2003; 21 November 2003
ABSTRACT: The hydrolysis of benzoic anhydride (Bz O) in the presence of ꢀ-cyclodextrin (ꢀ-CD) was studied in
2
epoc
ꢀ
aqueous solution as a function of pH, temperature and ionic strength, at 25 C. The experimental rate constant versus
pH profiles show that, in the region of spontaneous water reaction (pH 3.0–6.5), ꢀ-CD inhibits the reaction and the
isotope effect (kH O=kD O ¼ 4:7) indicates that the rate determining step of the reaction corresponds to the water-
2
2
catalyzed nucleophilic attack of water on the carbonyl group of Bz O. Conversely, whereas inhibition is observed at
2
pH 6.0, catalysis of the hydroxide ion reaction is observed at pH 8.0 and it is found that the activation entropy is
responsible for the catalytic phenomena in the basic hydrolysis of benzoic anhydride. Copyright # 2004 John Wiley
& Sons, Ltd.
Additional material for this paper is available in Wiley Interscience
KEYWORDS: cyclodextrin; benzoic anhydride; hydrolysis; kinetics; salt effect; thermodynamic parameters; isotope effect;
1
H NMR
INTRODUCTION
of an inclusion complex with the substrate, and a variety of
intermolecular interactions are responsible for the stability
12,13
of CD inclusion complexes in aqueous solution.
Cyclodextrins (CDs) have been widely used as models of
artificial enzymes for a variety of reactions and as
3
stabilizing agents and drug carriers. These typical appli-
cations require contrasting behavior, since an enzyme
model needs to show catalytic efficiency and, in the latter
case, stability requirements demand an inhibitory effect
of cyclodextrins on the reactions involving inclusates.
Among the reactions affected by native ꢁ- and ꢀ-CD,
1,2
As far as we know, there have been no studies on the
effect of native ꢀ-CD on the hydrolysis of anhydrides. The
present work was undertaken to study the effect of native
ꢀ-CD on the hydrolysis of benzoic anhydride (Bz O).
2
RESULTS
4–6
7
cleavage of carboxylic esters, amides and phosphoric
8,9
esters in basic media have been studied the most. In
general, the mechanism involves nucleophilic attack of
the ionized secondary hydroxyl group of CD on the car-
bonyl or phosphoryl group, but in some cases it also
Benzoic anhydride is hydrolyzed in moderately acidic,
neutral and basic aqueous solutions to form two molec-
ules of benzoic acid (or benzoate). Figure 1 shows the pH
dependence of the first-order rate constants for the hydro-
10,11
involves general base catalysis.
Because of this parti-
lysis reaction of Bz O with and without 0.01 M ꢀ-CD.
2
cular mechanistic behavior, they have been highlighted as
models for serine proteases, owing to the nucleophilic
attack of the ionized secondary hydroxyl group, which is
similar to the first step in the deacylation of esters in
this type of enzyme.
CDs show many features characteristic of enzymatic
reactions such as saturation, stereospecificity and formation
The reaction carried out in water between pH 3.0 and
10.0 shows a pH-independent region typical of the
spontaneous water reaction between pH 3.0 and 6.5 and
a first-order dependence on hydroxide ion concentration,
which denotes specific base catalysis, between pH 6.5
and 10.0. In the presence of ꢀ-CD, there is a decrease in
the rate constant of the reaction in the region of
spontaneous reaction and an increase in the rate in the
region of the hydroxide ion-catalyzed reaction.
1,2
*
Correspondence to: F. Nome, Departamento de Qu ´ı mica, Universidade
Federal de Santa Catarina, Campus Universit a´ rio–Trindade, 88040-900,
Florian o´ polis-SC, Brazil. E-mail: faruk@qmc.ufsc.br
Contract/grant sponsors: CNPq; CAPES; CYTED.
The effect of ꢀ-CD concentration on the observed rate
constant for the hydrolysis of Bz O can be seen in Fig. 2.
2
Copyright # 2004 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2004; 17: 370–375

EFFECTS OF ꢀ-CD ON THE HYDROLYSIS OF BENZOIC ANHYDRIDE
371
In Scheme 1, k is the first-order rate constant for the
0
spontaneous hydrolysis and kOH is the second-order rate
constant for the hydroxide ion-catalyzed hydrolysis of
CD
0
Bz O in the aqueous phase. The rate constants k and
k
2
CD
OH
ꢂ
correspond to the reaction of water and HO with the
fraction of Bz O incorporated into the CD cavity. The
2
dissociation constant (Kdiss) between Bz O and ꢀ-CD is
2
given by k /k . At any given pH value, the observed rate
ꢂ1
constant corresponds to contributions from the reaction
1
in water (k ) and in ꢀ-CD (k ).
un
c
The reaction in the aqueous phase, in the absence of
-CD, is given by
ꢀ
kun ¼ k þ k ½OHꢂꢃ
w
0
w
OH
ð1Þ
and the rate constant k for the reaction of Bz O, fully
2
incorporated into ꢀ-CD, is given by
c
Figure 1. pH dependence of the logarithm of the first-order
rate constant for the hydrolysis reaction of Bz O in water (ꢄ)
2
ꢀ
and in the presence of 0.01 M ꢀ-CD (&) at 25 C and ionic
strength 0.5 (NaCl). The lines represent theoretical agree-
ment with Eqn. (4) and the parameters are shown in Table 1
kc ¼ k0 þ k ½OHꢂꢃ
CD
CD
OH
ð2Þ
It follows that, under conditions where the substrate dis-
tributes rapidly between the free and complexed forms,
the hydrolysis of Bz O according to Scheme 1 is describ-
2
ed by means of
w
ꢀꢂCD
kobs ¼ k ꢂ
þ k ꢂ
ð3Þ
un Bz O
c
Bz O
2
2
Expressing the mole fractions of substrate in water and
in ꢀ-CD in terms of Kdiss and the corresponding mass
balance equations, it is possible to derive the equation
½
CDꢃ
kobs ¼ k þ ðk ꢂ k Þ
ð4Þ
un
c
un
Kdiss þ ½CDꢃ
1
which can be used in the Lineweaver–Burk form to
4
calculate the dissociation constant between Bz O and
2
ꢀ
-CD (Table 1).
Thus, using the data in Figs 1 and 2 and Eqns (1)–(4),
Figure 2. Effect of ꢀ-CD on the hydrolysis rate of Bz O at
2
ꢀ
pH 6.0 (ꢄ) and 8.0 (&) at 25 C and ionic strength 0.5 (NaCl).
we can calculate the individual rate and equilibrium con-
stants. At pH 6.0, in the absence and presence of ꢀ-CD,
we can clearly see that the spontaneous water reaction is
The lines were calculated using Eqn. (4) and the parameters
are shown in Table 1
w
0
the only reaction in solution; therefore, k ¼ k in the
un
CD
absence of ꢀ-CD and k ¼ k in the presence of high
Whereas the hydrolysis reaction is inhibited at pH 6.0, it
is slightly catalyzed at pH 8.0.
c
0
ꢀ-CD concentration. Thus, Eqn. (4) and the data in Fig. 2
Our results are fully consistent with Scheme 1. In the
presence of ꢀ-CD, the reaction goes through an anhy-
dride–CD complex (Bz O ꢁ ꢀ-CD), which corresponds to
2
Table 1. Calculated parameters for Bz O hydrolysis in the
absence and presence of ꢀ-CD at 25 C and ionic strength
2
ꢀ
a 1:1 inclusion complex between ꢀ-CD and Bz O.
2
0.5 (NaCl)
Rate constant
Value
w
0
ꢂ1
ꢂ4
ꢂ5
k (s
)
(3.4 ꢅ 0.2) ꢆ 10
515 ꢅ 30
w
OH
ꢂ1 ꢂ1
k
k
k
(M
(s
(M
s )
CD ꢂ1
)
(8.2 ꢅ 0.5 ) ꢆ 10
2530 ꢅ 68
0
CD
OH
ꢂ1 ꢂ1
s )
ꢂ3
Kdiss (M)
(2.0 ꢅ 0.4) ꢆ 10
Scheme 1
Copyright # 2004 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2004; 17: 370–375

˜
T. A. S. BRANDAO ET AL.
3
72
CD
permit the calculation of Kdiss and k0 (values are given
in Table 1).
Using the experimental data at pH 8.0 (Fig. 2) and
Eqns (2) and (4), it was possible to calculate values of
ꢂ3
CD
K
¼ (2.0 ꢅ 0.4) ꢆ 10
w
OH
M
and k ¼ (2.53 ꢅ 0.68) ꢆ
diss
ꢂ3 ꢂ1
c
10
of k , which was calculated from the slope of a plot of
s
and thus the value of k in Table 1. The value
OH
kobs versus the hydroxide ion concentration, is also given
in Table 1.
When the hydrolysis reaction of Bz O in the absence
2
of ꢀ-CD was carried out in dioxane–water mixtures, it
was observed that the rate constant decreased as the
concentration of dioxane increased. The observed rate
constants for the reaction at pH 6.0 in dioxane–water
mixtures with 10 and 20% (v/v) organic solvent content
ꢂ4
ꢂ5 ꢂ1
1
were 1.9 ꢆ 10 and 7.6 ꢆ 10 s , respectively.
Figure 3. Job plot for H NMR shifts of H-5 of ꢀ-CD (&) and
of Bz O (*) at 300 MHz in D O–MeOD (1:1)
H
meta
All models in this work are consistent with a 1:1 sto-
ichiometry between ꢀ-CD and Bz O. In order to confirm
2
2
2
the stoichiometry and the formation of the inclusion com-
plex, the chemical shifts of H-3, H-5, and H-6 of ꢀ-CD
as shown in Fig. 4 suggest that Bz O is deeply embedded
2
in the CD cavity.
and H-ortho, -meta and -para of Bz O were measured by
2
The effect of the ionic strength was studied by the addi-
tion of different NaCl concentrations and the results are
shown in Fig. 5. Surprisingly, the increase in the ionic
1
H NMR spectroscopy (300 MHz). Upon inclusion com-
plex formation, the chemical shift is the average of
that for free (CD) and complexed (CDS) cyclodextrin
strength decreased the rate constants for Bz O hydrolysis
2
(
or substrate):
with and without ꢀ-CD at pH 6.0, but increased the rate
constants in both cases at pH 8.0. The values of the activ-
z
z
ation parameters ÁH and ÁS for Bz O hydrolysis in the
2
ꢃobs ¼ ꢃCDꢂCD þ ꢃCDSꢂCDS
ð5Þ
presence and absence of ꢀ-CD at pH 6.0 and 8.0 were
calculated following standard procedures and are given
15
Equation (5) can be used to derive Eqn. (6), where Áꢃobs
z
in Table 2. The results show that the values of ÁH and
z
represents the difference ꢃobs–ꢃCD and Áꢃ the difference
m
ꢃCDS–ꢃCD
ÁS , at pH 6.0 and 8.0, are greater in the presence of
:
ꢀ
-CD than in aqueous solution.
The solvent isotope effect (kH2O=kD2O) on Bz O hydro-
2
½
CDSꢃ
Áꢃm
lysis in the presence of ꢀ-CD at pH 6.0 and 8.0 gave
values of 4.7 and 3.7, respectively. These values are simi-
Áꢃobs
¼
ð6Þ
½
CDꢃ
0
16
lar to those determined by Butler and Gold for the
hydrolysis of Bz O in the absence ꢀ-CD.
A Job plot was used to obtain the stoichiometry of the
inclusion complex between ꢀ-CD and Bz O. We varied
2
2
the amount of guest and CD, maintaining constant the
total amount of CD plus guest ([CD] þ [S] ¼ 8 mM).
0
0
DISCUSSION
Figure 3 shows the results for H-5 of ꢀ-CD and H
the Bz O; for all hydrogens analyzed, there was a maxi-
of
meta
2
It is known that, in the case of enzyme catalysis the for-
mation of a complex between substrate and catalyst
brings the substrate into close contact with the active
site of the enzyme and reactions can be favored owing to
mum at 0.5 in the Job plot, indicating a 1:1 stoichiometry
for the inclusion complex. The K value calculated from
ass
1
ꢂ1
H NMR data in 1:1 D O:MeOD was 317 ꢅ 17 M and
2
1
Figure 4. H NMR shifts of H-3, H-5, and H-6 of ꢀ-CD and Hortho, Hmeta and Hpara of Bz O [300 MHz; ꢀ-CD:Bz O ¼ 1:1;
2
2
D O–MeOD (1:1)]
2
Copyright # 2004 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2004; 17: 370–375

EFFECTS OF ꢀ-CD ON THE HYDROLYSIS OF BENZOIC ANHYDRIDE
373
preferentially revert to reactants as the CD alkoxide ion
is a better leaving group than the alkoxide ion derived
from the ester.
Two mechanisms have been proposed to explain the
base catalysis of anhydride hydrolysis. The first is nucleo-
philic catalysis, which involves the direct attack of the
catalyst on the carbonyl group of the anhydride, forming
an intermediate that decomposes faster than the substrate
in the presence of water. The second mechanism involves
a concerted attack on the carbonyl group of the anhydride
by a water molecule, assisted by the catalyst. In this
second case, the catalyst facilitates the reaction, accele-
rating the rate-limiting step through hydrogen bonding to
2
3
the uncharged water molecule (general base catalysis).
In the hydrolysis of benzoic anhydride in the presence
of carboxylate-type surfactants, it has been well char-
acterized that the reaction proceeds via nucleophilic
Figure 5. Effect of the concentration of NaCl in the absence
squares) and presence (circles) of ꢀ-CD at pH 6.0 (solid
symbols) and 8.0 (open symbols) on the rate of Bz O
(
24
catalysis.
2
ꢀ
n
i
hydrolysis at 25 C. k and k are the observed constants
The experimental rate constant versus pH profiles in
Fig. 1 show that, in the region of spontaneous water
reaction (pH 3.0–6.5), the hydroxyl group of ꢀ-CD is not
functioning as a general base type catalyst, a result which
is fully consistent with the fact that, in aqueous solution,
obs
obs
in the absence and presence of NaCl
Table 2. Calculated thermodynamic parameters for the
hydrolysis of Bz O in the absence and presence of 0.01 M
2
Bz O hydrolysis is not subject to efficient general base-
2
type catalysis. Indeed, the mechanism of the Bz O hydro-
2
ꢀ
-CD, ionic strength 0.5 (NaCl)
lysis reaction at neutral pH without ꢀ-CD shows a
pH 6.0
pH 8.0
16
Thermodynamic
parameter
considerable isotope effect, which indicates that the
rate-determining step of the reaction corresponds to the
water-catalyzed nucleophilic attack of water on the car-
Bz O Bz O ꢁ ꢀ-CD Bz O Bz O ꢁ ꢀ-CD
2
2
2
2
z
ÁH
(kcal mol
12.2 ꢅ 0.7 16.6 ꢅ 0.4 15.6 ꢅ 0.4 17.2 ꢅ 0.3
25
ꢂ1
bonyl group of Bz O. The large isotope effect observed
2
)
z
ÁS (e.u.) ꢂ33.5 ꢅ 2.2 ꢂ21.4 ꢅ 1.4 ꢂ20.2 ꢅ 1.5 ꢂ13.2 ꢅ 1.1
in the presence of ꢀ-CD at pH 6.0 (kH2O=kD2O ¼ 4:7) is
z
ÁÁH
(
4.4
1.6
7.0
also consistent with this mechanism.
ꢂ1
kcal mol )
z
ÁÁS (e.u.)
The NMR results are clear, showing that incorpora-
tion of the benzoate moeity into the CD cavity affects the
chemical shifts of H-3, H-5, and H-6 of ꢀ-CD similarly.
12.1
The shifts observed for Bz O follow the order H
2
>
ortho
Hmeta > Hpara, indicating as expected that Hpara is located
deeper into the cavity and Hortho is in a more aqueous
environment. The positioning of one of the carbonyl
groups close to the upper ring of the CD cavity is strongly
suggestive of a decrease in the microscopic polarity of the
reaction site, a situation that is unfavorable in the light
of the observed effect of added dioxane, where addition
of 10 and 20% (v/v) of dioxane resulted in inhibition of
the spontaneous reaction by 44 and 76%, respectively.
Hence it could well be that the observed inhibition of the
spontaneous reaction is mostly due to a decrease in micro-
scopic polarity, a result which is consistent with previous
1
7
stereochemical effects. This has also been suggested in
the case of catalysis by CDs and either general base or
18
nucleophilic catalysis has been reported. Earlier studies
showed that CDs caused either acceleration or inhibition
of the alkaline hydrolysis of various alkyl benzoate esters,
depending on the nature of the complexes formed. Lach
19,20
and co-workers
proposed that compounds which fit
in close proximity to the hydroxyl groups of CD undergo
an acceleration effect, whereas positioning of the car-
bonyl carbon atom further away from the secondary
hydroxyl groups in CD results in a decrease in the rate
21,22
26
constant. However, Bender and co-workers
suggest-
observations in micellar solutions. All the evidence
indicates that the reaction mechanism in the presence of
ed that, in many cases, the unreactivity of the complexed
esters could be attributed to an unfavorable partitioning
of the tetrahedral intermediate. Attack of the alkoxide
ion of CD on the carbonyl carbon atom of the substrate
would lead to the formation of a tetrahedral interme-
diate having both the CD alkoxide ion and the alkoxide
ion derived from the alkyl benzoate ester as potential
leaving groups. The tetrahedral intermediate would
ꢀ-CD can, between pH 3 and pH 6, be considered to be
similar to that postulated by Engbersen and Engberts,
2
5
that is, a classical ‘water reaction’ that involves a water-
catalyzed nucleophilic attack of water on the carbonyl
group of Bz O. This implies the contribution of at least
2
two (or more) water molecules in the ground state and
several water molecules in the transition state. Indeed, the
Copyright # 2004 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2004; 17: 370–375

˜
T. A. S. BRANDAO ET AL.
3
74
z
strongly negative ÁS value (ꢂ33.5 e.u.) for the hydro-
lysis in pure water in the absence of ꢀ-CD indicates that
the transition state is highly hydrated relative to the
ground state. This value is considerably more negative
than that observed in the presence of the CD catalyst
benzoate ion. Hence it is possible that the reaction
proceeds via general base catalysis promoted by the
ionized secondary hydroxyl group of ꢀ-CD (the pK of
a
this OH group is ꢇ12). Alternatively, the attack of the
hydroxide ion on the substrate encapsulated in the CD
could be a competitive route and this particular pathway
(
ꢂ21.4 e.u.). Thus, the reaction slows owing to the
z
ꢂ1
29
increase in ÁH by 4.4 kcal mol (1 kcal ¼ 4.184 kJ),
which more than compensates the increase in activation
entropy. It is important to consider that, in the ꢀ-CD
cavity, there are considerable water-structure effects,
which will appear strongly in the more hydrated structure
of the transition state. Hence the loss of hydration of the
transition state, relative to the ground state, is most prob-
ably promoted by a solvent organization effect in the CD
cavity, which in turn produces a less negative activation
entropy (Table 2).
has been confirmed by Breslow et al. The value of the
solvent isotope effect of 3.7 is fully consistent with the
proposed mechanism since the final approximation of the
hydroxide ion to the reacting carbonyl carbon will be
assisted by at least two water molecules. Hence the
observed isotope effect is consistent with the participa-
tion of several water molecules, which stabilize the
transition state of the reaction through hydrogen bonding;
various models which account for this participation have
3
0,31
been proposed.
molecules in the ground state and in the transition state
The contribution of several water
The increase in ionic strength at pH 6.0, in the absence
of ꢀ-CD, caused a small decrease in the rate constant for
the hydrolysis reaction, which could be attributed to un-
specific effects and changes in the structure of the sol-
vent. In the presence of ꢀ-CD, the ionic strength effect at
pH 6.0 is more pronounced, but the observed effect is
complex since it could be the result of the sum of solvent-
structure effects and an important salting-out effect
favoring the equilibrium towards the inclusion complex
Fig. 5).
In order to understand the mechanism of Bz O hydro-
lysis in the region where the hydroxide ion reaction
predominates in aqueous solutions, we examined the re-
action in the presence of ꢀ-CD at pH 8.0, where a cata-
lytic effect is observed (Figs 1 and 2). In this respect, the
z
is consistent with the negative ÁS value (ꢂ20.2 e.u.) for
the hydrolysis in pure water in the absence of ꢀ-CD,
which again indicates higher hydration of the transition
state relative to the ground state. In the presence of the
CD catalyst, the activation entropy is ꢂ13.2 e.u.; there-
fore, the catalytic effect is the result of a large increase in
activation entropy, which compensates the increase in
z
ꢂ1
ÁH of 1.6 kcal mol . As discussed above, the water-
structure effects in the ꢀ-CD cavity appear strongly in the
transition state. It is interesting that in the water reaction,
the activation enthalpy dominates the overall effect,
whereas in the region of pH 8.0, it is the activation
entropy that is responsible for the catalytic phenomenon
(Table 2).
(
2
Bz O hydrolysis reaction is similar to the hydrolysis of
2
In conclusion, it is important to emphasize that the
observed effects of ꢀ-CD on the hydrolysis of Bz O, i.e.
trifluoroacetate and acetate esters, which show inhibition
of the reaction at pH 6 and catalysis at pH 9. The authors
suggested that this fact is related to, and depends on, the
binding strength between the substrate and the CD rela-
tive to the transition state. When the binding of the sub-
strate was stronger than that of the transition state,
2
inhibition of the water reaction and catalysis in the basic
region, are related to the fact that different mechanisms
are operative in these regions. At pH 6.0 an increase in
activation enthalpy is responsible for the observed inhi-
bition of the water reaction, whereas at pH 8.0 the activa-
tion entropy is responsible for the observed catalysis of
the basic hydrolysis of benzoic anhydride.
2
7,28
inhibition was observed.
Clearly, this is not the case
in the hydrolysis of Bz O. In fact, we have two different
2
reactions under the selected pH conditions. Whereas
inhibition of the water reaction is observed at pH 6.0,
catalysis of the hydroxide ion reaction is observed at pH
EXPERIMENTAL
8
.0. Since the reactions are completely different, we con-
Materials. Bz O was prepared and purified as indicated
2
32
tend that the reasons for the observed catalysis and/or
inhibition are mechanistic in nature.
The cleavage of esters has been studied extensively
and, in general, the hydrolysis of aryl esters follows a
mechanism of acyl transfer to an ionized secondary hydr-
in the literature. The ꢀ-CD (Lot C6003-1, MW 1135)
was obtained from Cerestar (USA) with >99% purity and
ꢀ
was dehydrated under vacuum at 100 C for 3 h before use.
All other reagents and solvents were of analytical grade
and freshly prepared distilled water was used throughout.
1,2,4–6
oxyl group of the CD.
In the reaction of benzoic
anhydride, the ionized secondary hydroxyl group of ꢀ-CD
could be reacting as a mechanistic general base-type cata-
lyst or through nucleophilic catalysis. Nucleophilic cata-
lysis can be ruled out because the final absorbance is
consistent with the formation of 2 mol of benzoate. The
benzoylated CD shows a slower rate of hydrolysis and a
much higher molar absorptivity compared with the
Kinetic procedure. The kinetic determinations were car-
ried out in aqueous solution and the temperature and
ionic strength used were varied. Rates of hydrolysis of
benzoic anhydride were followed spectrophotometrically
by monitoring the disappearance of Bz O at 245 nm by
2
using a Hitachi U-2000 UV–visible spectrophotometer
fitted with a thermostated water-jacketed cell holder.
Copyright # 2004 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2004; 17: 370–375

EFFECTS OF ꢀ-CD ON THE HYDROLYSIS OF BENZOIC ANHYDRIDE
375
Reaction was initiated by injection of 10 ml of ꢇ10 mM
temperature in the presence and absence of ꢀ-CD at pH
values of 6.0 and 8.0 are available at http://www.inter
science.wiley.com/jpages/0894-3230/suppmat/.
stock solutions of Bz O in dioxane (stored in a freezer)
2
ꢀ
into 3 ml of aqueous solutions equilibrated at 25.0 C (the
ꢂ5
initial concentration of Bz O was 3.33 ꢆ 10 M and the
2
solutions contained 0.33% dioxane). Absorbance versus
time data were stored directly on a microcomputer using
a Microquimica 12-bit A/D interface board. First-order
rate constants, kobs, were estimated from linear plots of
ln(A ꢂ A ) against time for at least 90% reaction using
REFERENCES
1. Breslow R, Dong ST. Chem. Rev. 1998; 98: 1997–2011.
2
3
4
5
6
7
. Steed JW, Atwood JL. Supramolecular Chemistry. Wiley:
New York, 2000; 641–655.
. Uekama K, Hirayama F, Irie T. Chem. Rev. 1998; 98: 2045–
2076.
. Bonora GM, Fornasier R, Scrimin P, Tonellato U. J. Chem. Soc.,
Perkin Trans. 2 1985; 367–369.
. Tee OS, Mazza C, Du X-X. J. Org. Chem. 1990; 55: 3603–
3609.
. Gadosy TA, Tee OS. J. Chem. Soc., Perkin Trans. 2 1995; 71–76,
and references cited therein.
. Granados A, de Rossi RH. J. Am. Chem. Soc. 1995; 117: 3690–
3696.
1
t
an iterative least-squares program; correlation coeffi-
cients, ꢄ, were >0.999 for all kinetic runs and, between
replicates, the standard deviation for the first-order rate
constants was always <2%. The pH during the reaction
was maintained with the following buffers (0.01 M in all
cases): HCOOH (pH 3–4.5); CH COOH (pH 4–5.5);
3
NaH PO (pH 5.5–7.8); H BO (pH 8–9.5); NaHCO
3
2
4
3
3
(
pH 9.5–11). The solutions were prepared immediately
8
. Hengge AC, Cleland WW. J. Org. Chem. 1991; 56: 1972–1974.
. Moss RA, Gong PK. Langmuir 2000; 16: 8551–8554.
before use, except in the study of the solvent isotope ef-
fect, where the solutions were left to stand for 15 h at
room temperature in order to allow the H/D balances to
be reached. The value of pD was corrected considering
that pD ¼ pH þ 0.4, and the pH measurements were
carried out with a Micronal Model B 374 digital pH-
meter, previously calibrated with standard solutions of
pH 4.00, 7.00 and 10.00 (Carlo Erba).
9
0. Akiyama M, Ohmachi T, Ihjima M. J. Chem. Soc., Perkin Trans. 2
1982; 1511–1515.
1. Komiyama M, Inoue S. Bull. Chem. Soc. Jpn. 1980; 53: 3334–
3337.
2. Tabushi I. Acc. Chem. Res. 1982; 15: 66–72.
1
1
1
33
13. Saenger W. Angew. Chem., Int. Ed. Engl. 1980; 19: 344–362.
1
1
4. Connors KA. Binding Constants. Wiley: New York, 1987; 59–65.
5. Maskill H. Structure and Reactivity in Organic Chemistry. Oxford
University Press: New York, 1999; 20–21.
The values of the activation enthalpy and entropy were
calculated from the experimental results (Supplementary
Material, Tables S1 and S2) in the temperature range
16. Butler AR, Gold V. J. Chem. Soc. 1962; 2212–2217.
1
1
1
7. Jencks WP. Catalysis in Chemistry and Enzymology. Dover:
New York, 1987; 615–806.
8. Menger FM. In Nucleophilicity, Harris JM, McManus SP (eds).
American Chemical Society: Washington, DC, 1987; 209–218.
9. Lach JF, Chin T-F. J. Pharm. Sci. 1964; 53: 924–927.
ꢀ
15
2
0–40 C using the equation
ꢀ
ꢁ
ꢂ ꢀ ꢁ
zꢃ
ꢀ ꢁ
z
20. Chin T-F, Chung P-H, Lach JL. J. Pharm. Sci. 1968; 57: 44–48.
k
k
ÁS
ÁH
1
B
2
2
1. Bender ML, Turnquest BW. J. Am. Chem. Soc. 1957; 79: 1656–
662.
2. VanEtten RL, Gloves GA, Sebastian JB, Bender ML. J. Am.
Chem. Soc. 1967; 89: 3253–3262.
23. Johnson SL. Adv. Phys. Org. Chem. 1967; 5: 237–330.
ln
¼ ln
þ
ꢂ
ð7Þ
1
T
ꢀh
R
R
T
1
1
H NMR procedure. H NMR spectra were recorded with
2
4. Marconi DMO, Frescura VLA, Zanette D, Bunton CA, Nome F.
J. Phys. Chem. 1994; 98: 12415–12419.
a Bruker AC spectrometer at 300 MHz, using H O as an
2
internal reference. The Bz O to ꢀ-CD ratio was conti-
2
25. Engbersen JFJ, Engberts JBFN. J. Am. Chem. Soc. 1975; 97:
563–1568.
1
nually varied, maintaining the total concentration at 8 mM
in a 1:1 D O–MeOD mixture.
2
6. Bunton CA, Nome F, Quina FH, Romsted LS. Acc. Chem. Res.
1991; 24: 357–364.
7. Fernandez MA, de Rossi RH. J. Org. Chem. 1997; 62: 7554–
2
2
7
559.
28. Fernandez MA, de Rossi RH, Cervell o´ E, Jaime C. J. Org. Chem.
001; 66: 4399–4404.
Acknowledgements
2
2
9. Breslow R, Czarniecki MF, Emert J, Hamaguchi H. J. Am. Chem.
Soc. 1980; 102: 762–770.
30. Wendhausen R, Zampiron E, Vianna JF, Zucco C, Rezende MC,
We are indebted to CNPq, CAPES and CYTED, Brazil,
for financial support of this work. We are grateful to
Professor Frank Quina for helpful discussions.
Nome F. J. Phys. Org. Chem. 1990; 3: 89–94.
3
3
3
1. Alvarez FJ, Schowen RL. In Isotopes in Organic Chemistry–
Secondary and Solvent Isotope Effects, vol. 7, Buncel E, Lee CC
eds). Elsevier: Amsterdam, 1987; 1–60.
2. Furniss BS, Hamaford AJ, Smith PWG, Tatchell AR (eds).
Vogel’s Textbook of Practical Organic Chemistry (5th edn).
Longman: New York, 1989; 693–694.
3. Schowen KBJ. In Transition States of Biochemical Processes,
Gandour RD, Schowen RL (eds). Plenum Press: New York, 1978;
225–284.
(
Supplementary information
1
Job plots for H NMR shifts of H-3 and H-6 of ꢀ-CD and
of Hortho and Hpara of Bz O at 300 MHz in a 1:1
2
D O–MeOD mixture and rate constants as a function of
2
Copyright # 2004 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2004; 17: 370–375