pH Dependent Effect of β-Cyclodextrin on the Hydrolysis Rate of Trifluoroacetate Esters

Article abstract of DOI:10.1021/jo961627w

The kinetics of the hydrolysis of phenyl trifluoroacetate (1a) and p-methylphenyl trifluoroacetate (1b) is pH independent below pH 6 and shows first order dependence on HO^- concentration above pH 8. The reaction is weakly buffer catalyzed. In the presence of β-cyclodextrin the rate increases in a nonlinear fashion at constant pH above pH 8 but it decreases at pH 6. At pH 9.91 the ratio of rate constants for the reaction in the presence and in the absence of 0.012 M β-cyclodextrin is 11 and 2 for phenyl acetate and phenyl trifluoroacetate, respectively. The different behavior of the two substrates is attributed to different modes of inclusion. It is suggested that the reacting complex in the case of substrates 1a and 1b has the trifluoromethyl group inside the cavity. The inhibition of the reaction in neutral solution is attributed to a microsolvent effect and to protection of the carbonyl group toward water attack.

Full text of DOI:10.1021/jo961627w

7
554
J . Org. Chem. 1997, 62, 7554-7559
Articles
p H Dep en d en t Effect of â-Cyclod extr in on th e Hyd r olysis Ra te of
Tr iflu or oa ceta te Ester s
Mariana A. Fernandez and Rita H. de Rossi*
Instituto de Investigaciones en F ı´ sico Qu ı´ mica de C o´ rdoba, Facultad de Ciencias Qu ı´ micas, Departamento
de Qu ı´ mica Org a´ nica, Universidad Nacional de C o´ rdoba, Ap. Postal 4, CC 61, 5000 C o´ rdoba, Argentina
Received August 20, 1996X
The kinetics of the hydrolysis of phenyl trifluoroacetate (1a ) and p-methylphenyl trifluoroacetate
-
(
1b) is pH independent below pH 6 and shows first order dependence on HO concentration above
pH 8. The reaction is weakly buffer catalyzed. In the presence of â-cyclodextrin the rate increases
in a nonlinear fashion at constant pH above pH 8 but it decreases at pH 6. At pH 9.91 the ratio
of rate constants for the reaction in the presence and in the absence of 0.012 M â-cyclodextrin is 11
and 2 for phenyl acetate and phenyl trifluoroacetate, respectively. The different behavior of the
two substrates is attributed to different modes of inclusion. It is suggested that the reacting complex
in the case of substrates 1a and 1b has the trifluoromethyl group inside the cavity. The inhibition
of the reaction in neutral solution is attributed to a microsolvent effect and to protection of the
carbonyl group toward water attack.
Cyclodextrins are cyclic oligomers of R-D-glucose which
considered it of interest to study the effect of cyclodextrin
on the hydrolysis of perfluoroalkyl esters. We now report
results regarding the hydrolysis of esters 1, to be
compared with those of amides and acetates having the
same leaving group. The reactions were catalyzed at pH
g 9 and inhibited at pH e 6. The results also indicated
that replacing the methyl by a trifluoromethyl group in
aryl esters leads to a less effective catalysis by â-cyclo-
dextrin (â-CD).
are produced by enzymatic degradation of starch. Com-
pounds with six, seven, or eight glucose units are called
R-, â-, and γ-cyclodextrin.1 They have been shown to be
a good model for hydrolytic enzymes, and many studies
have been done in regard to the cyclodextrin catalyzed
2
-6
hydrolysis of esters,
but much less attention has been
given to the effect on the reaction of amides.7
-11
In the hydrolysis of esters important differences were
found when the leaving group was changed to poorer
leaving groups.6 As the reaction takes place within an
inclusion complex in which the phenyl group of the ester
resides in the hydrophobic cavity of CD, the efficiency of
the ester cleavage relative to that by hydroxide ion is
generally greater for meta than for para substituents
since the orientation of the former within the CD cavity
3
-5
has a geometry more suitable for acyl transfer.
It is
surprising that in the case of m- and p-nitro-substituted
On the other hand, in this case we only found evidences
of formation of 1:1 contrary to our previous findings with
trifluoroacetanilides the para isomer is more strongly
7
11
catalyzed than the meta isomer by R-CD and â-CD.
amides where 1:1 as well as 1:2 inclusion complexes were
In a previous work we attributed the different behavior
of amides and esters to different rate-determining steps
in the cyclodextrin-catalyzed reaction, and we also found
different degrees of catalysis depending on the pH of the
study. Since the amides were derived of perfluorinated
compounds and esters were hydrocarbon derived, we
formed.1
0,11
The formation of 1:1 and 1:2 inclusion
complexes is highly dependent on the structure of the
substrates involved, and it is well known that small
variations in the substrate structure can lead to consid-
erable variation in the kinetic behavior of cyclodextrin-
catalyzed reactions and in the type of complexes
formed.1
2-14
X
Abstract published in Advance ACS Abstracts, October 1, 1997.
(
1) (a) Bender, M. L.; Komiyama, M. Cyclodextrin chemistry;
Springer-Verlag: New York, 1977. (b) Saenger, W. Angew. Chem., Int.
Ed. Engl. 1980, 19, 344. (c) Tabushi, I.; Kuroda, Y. Adv. Catal. 1983,
Resu lts
3
2, 417.
The hydrolysis of substrates 1 was measured as a
(2) Breslow, R.; Trainor, G.; Ueno, A. J . Am. Chem. Soc. 1983, 105,
2
739.
(
function of pH in the range of pH 6.00 to 9.91 (Tables S1
3) Van Etten, R. L.; Sebastian, J . F.; Clowes, G. A.; Bender, M. L.
J . Am. Chem. Soc. 1967, 89, 3242.
4) Komiyama, M.; Bender M. L. J . Am. Chem. Soc. 1978, 100,
576.
5) (a) Tee, O. S.; Takasaki, B. K. Can. J . Chem. 1985, 63, 3540. (b)
Tee, O. S.; Mazza, C; Du X.-X. J . Org. Chem. 1990, 55, 3603.
15
and S2). For substrate 1a the observed rate constants
were also determined at pH 1.17 (Table S1). At each pH
at least two buffer concentrations were used to determine
whether there was buffer catalysis. The rate barely
(
4
(
(
(
(
6) Menger, F. M.; Ladika, M. J . Am. Chem. Soc. 1987, 109, 3145.
7) Komiyama, M.; Bender, M. L. J . Am. Chem. Soc. 1977, 99, 8021.
8) Mokimoto, S.; Suzuki, K; Yashihiro, T. J . Chem. Soc. J pn. 1984,
(12) Tee, O. S.; Du X.-X. J . Am. Chem. Soc. 1992, 114, 620.
(13) Pistolis, G.; Gegiou, D.; Hadjoudis, E. J . Photochem. Photobiol.
A 1996, 93, 179.
5
7, 175.
(
(
(
9) Komiyama, M.; Bender, M. L. Biorg. Chem. 1977, 6, 323.
10) Granados, A.; de Rossi, R. H. J . Am. Chem. Soc. 1995, 117, 3690.
11) Granados, A.; Rossi R. H. J . Org.Chem. 1993, 58, 1771.
(14) Davies, D. M.; Deary, M. E. J . Chem. Soc., Perkin Trans. 2 1995,
1287.
(15) Supporting Information.
S0022-3263(96)01627-1 CCC: $14.00 © 1997 American Chemical Society

pH Dependent Effect of â-Cyclodextrin
J . Org. Chem., Vol. 62, No. 22, 1997 7555
F igu r e 1. Observed rate constant for the hydrolysis of 1a (b
left and bottom axes) and 1b (9 right and top axes) vs pH.
Temperature 25.1 °C, solvent contains 3.8% ACN. Ionic
strength 0.2 M.
F igu r e 2. Effect of â-CD on the hydrolysis of 1a at pH 9.02.
Reaction conditions as in Figure 1.
Ta ble 1. Effect of Tem p er a tu r e on th e Obser ved Ra te
-
1
a
Con sta n t (s ) for th e Hyd r olysis of 1a
T °C
buffer,
b
M
5.3
15.1
25.2
34.1
44.1
0
0
0
0
0
0
0
.010
.019
2.02 ( 0.03
2.2 ( 0.1
.029 0.78 ( 0.04 1.24 ( 0.07
.034
.048
.071 0.79 ( 0.03 1.31 ( 0.06
.096 0.84 ( 0.06 1.38 ( 0.06 2.30 ( 0.07 3.7 ( 0.2
3.14 ( 0.08 4.6 ( 0.2
2.1 ( 0.1
2.2 ( 0.2
3.4 ( 0.1
5.0 ( 0.3
5.5 (! 0.3
a
µ ) 0.2 M. Solvent water with 3.8% v/v ACN. Each rate
constant is the average of at least ten determinations. Error
represents the average deviation from the mean. Buffer HPO4
HPO4 ; pH 6.00.
b
2-
/
-
increased outside experimental error with buffer concen-
tration. In Figure 1 the observed rate constant extrapo-
lated at zero buffer concentration is plotted vs pH for
compounds 1a and 1b.
F igu r e 3. Effect of â-CD on the hydrolysis of 1a at pH 9.91.
Reaction conditions as in Figure 1.
The observed pseudo-first-order rate constant can be
represented by an equation of the form of eq 1
q
∆
H
increases as the water content of the solvent
1
8
increases.
k ) k + k [HO-]
(1)
o
w
HO
Effect of â-Cyclod extr in . The hydrolysis rate of
substrates 1 was measured at pH 6, 9.02, and 9.91 in
the presence of several concentrations of â-cyclodextrin,
and at each concentration of â-CD at least two buffer
concentrations were used (Tables S3 and S4). In the case
of substrate 1a the effect of â-CD was also determined
at pH 1.17 to show that the effect is similar to that at
pH 6. The effect of the buffer is about the same for the
two substrates in the reaction with and without cyclo-
dextrin, and in all cases the increase in rate with buffer
concentration is less than 10%. The observed rate
constant at each pH and buffer concentration was
subtracted from the observed rate constant at the same
pH and buffer concentration, but with â-CD these values
were plotted as a function of â-CD concentration (Figures
2 and 3 are representatives).19 It can be seen that at pH
For 1a the rate of the pH independent zone was
determined at various temperatures (Table 1). The plot
not shown) of log k vs 1/T gives a good straight line from
o
(
which the activation energy was calculated. The value
‡
of ∆S (in calories per degree per mole) was calculated
using eq 2.16
q
∆
4
S
Ea
)
log - 10.753 - log T +
(2)
o
.576
4.576T
The calculated values are 7.3 kcal/mol and -32.6 eu
q
q
for ∆H and ∆S , respectively. These values compare well
with those determined by Moffat and Hunt17 which are
6
.26 kcal/mol and -45.9 eu in 30% aqueous acetone.
The thermodynamic parameters have also been deter-
mined in acetonitrile-water of various molar fractions,
6
the rate decreases whereas at pH 9 and 9.91 it increases
q
and it was shown that the ∆S becomes less negative and
with cyclodextrin concentration, showing in all cases a
saturation effect. The effect of â-CD on the hydrolysis
(
16) March, J . Advanced Organic Chemistry. Reactions, mechanisms
and structure, 4th ed.; J ohn Wiley and Sons, Inc.: New York, 1992; p
25.
17) Moffat, A.; Hunt, H. J . Am. Chem. Soc. 1959, 81, 2082.
2
(
(18) Neuvonen, H. J . Chem. Soc., Perkin Trans 2 1986, 1141.

7
556 J . Org. Chem., Vol. 62, No. 22, 1997
Fernandez et al.
Ta ble 2. Effect of r, â, a n d γ-Cyclod extr in on th e
a
Hyd r olysis of 1a in Wa ter Solu tion
kobx, s-
1
cyclodextrinb
pH ) 6.00
pH ) 9.91
none
R-CD
â-CD
γ-CD
2.30 ( 0.07
2.09 ( 0.07
1.01 ( 0.07
1.98 ( 0.05
81 ( 4
101 ( 7
143 ( 14
138 ( 14
a
T ) 25.1 ( 0.1 °C. Solvent contains 3.8% v/v ACN. µ ) 0.2 M.
b
-2
[
buffer] ) 0.1 M [CD] ∼ 1.15 × 10 M.
Ta ble 3. Effect of ACN on th e Hyd r olysis Ra te of 1a a
kobx, s-
1
kobs/[H2O], s-1 M-1
formation and rupture from the intermediate. The
tetrahedral intermediate from substrate 1 is expected to
be more stable due to the effect of the trifluoromethyl
group.23 However, by using the data for the two com-
pounds, a value of âLG of -0.2524 is calculated at pH > 8,
and this is remarkably similar to the value of âLG for
phenyl acetates, namely -0.32.25 This result may indi-
cate that the degree of bond rupture in the transition
state is similar for both reactions. Similar calculations
for the water reaction give -0.6124 for substrates 1,
indicating a more advanced transition state for the
pH
4% ACNb
2.15
71.6
25% ACN
4% ACN
0.04
25% ACN
0.0084
7
9
.00
.91
0.35
17.0
a
T ) 25.1 ( 0.1 °C. µ ) 0.2 M. b Values extrapolated at zero
buffer concentration.
of 1a at pH 9.91 is significantly smaller than the catalysis
observed for the reaction of phenyl acetate, but different
buffer and pH were used in this and in the reported
study. It might be that the effect of â-CD for substrate
3
-
1
is underestimated due to competition of the buffer and
neutral than for the HO -catalyzed reaction.
The hydrolysis of p-nitrophenyl trifluorocetate was
substrate for the cavity; therefore, we measured the rate
of hydrolysis of phenyl acetate at pH 9.91 in solutions
with and without 0.012 M â-CD. The relative rate of the
reaction in the presence of â-CD 0.012 M and in its
absence is 11 which is in good agreement with literature
values, namely, 8 at pH 10.6.3 Under the same condi-
tions this ratio is 2 for 1a . The R- and γ-cyclodextrin
produced effects in the same direction of â-CD but smaller
in magnitude (Table 2).
shown to be general base catalyzed with imidazole and
2
6
pyridine as bases in 0.56 M water in acetonitrile. The
reactions reported here are only very weakly catalyzed
by buffers. This result may be due in part to the change
in solvent and to the fact that the transition state with
some degree of positive charge development due to the
addition of water is relatively more stable than with a
2
7
much better leaving group as the p-nitrophenol.
The effect of decreasing the polarity of the solvent was
determined for the water as well as for the HO -catalyzed
Effect of Cyclod extr in . For the reactions in the
presence of cyclodextrin, catalysis is observed at pH > 8
and inhibition at pH < 6.
-
reaction in order to determine if the change in solvent
polarity affected the rate in different ways. The data in
Table 3 show that the decrease in polarity of the solvent
due to the addition of acetonitrile produces a decrease
in rate at pH 7 as well as at pH 9.91. These results are
in agreement with a previous study on the effect of
increasing acetonitrile in the neutral hydrolysis of phenyl
The mechanism of catalysis of the hydrolysis of esters
by cyclodextrins has been interpreted in terms of nucleo-
philic catalysis by the ionized OH group at the rim of
the cyclodextrin which leads to the acylated cyclodextrin
(Scheme 1). Also, general base catalysis of water addition
has been postulated for the catalysis of some esters
trifluoroacetate.1
8
hydrolysis,28
but the fact that the reactions reported here
are only weakly affected by general bases suggests that
the mechanism of catalysis is nucleophilic.
Discu ssion
Under conditions where only part of the cyclodextrin
is in its ionized form,29 inclusion complex formation
should take place with the ionized and the unionized
cyclodextrin because it is known that ionization does not
change significantly the association equilibrium con-
stants, and, therefore, a minimum mechanism for the
hydrolysis reaction in the presence of â-CD may be
represented by Scheme 2.
Mech a n ism of Hyd r olysis. The mechanism of hy-
drolysis of esters is usually considered to involve the
formation of a tetrahedral intermediate, eq 3,20 with the
rate-determining step depending on the leaving group.
However, recently William et. al.21 have postulated a
concerted mechanism for the reactions of phenyl esters
a
with phenolate ions when the pK of the leaving group
is within 2 and 11. Guthrie, based22 on literature results
and thermodynamic calculations of the stability of the
intermediates involved, suggested that in general the aryl
acetate reactions occur without intermediates of signifi-
cant life time due to very small barriers for the bond
In this scheme, S represents the substrate, CDOH and
-
CDO are the neutral and ionized â-CD, and S.CDOH
(23) Manion Schilling, M. L.; Roth, H. D.; Herndon, W. C. J . Am.
Chem. Soc. 1980, 102, 4272.
(24) Unpublished results from our laboratory with esters containing
p-Cl, m-Cl, and p-F substituent groups together with the data reported
here give -0.3 and -0.5 for âLG for the HO- and water reaction,
respectively.
(25) Kirsch, J . F.; J encks, W. P. J . Am. Chem. Soc. 1964, 86, 837.
(26) Neuvonen, H. J . Chem. Soc., Perkin Trans 2 1987, 159.
(27) Unpublished results from our laboratory indicate that for a
compound with a better leaving group as p-chlorophenol, there is
significant general base catalysis.
(
19) The small change in rate with buffer concentration might
indicate general base catalysis of hydrolysis for the reaction in water.
The same relative increase in rate with buffer concentration indicates
that the reaction mediated by â-CD is not affected by buffer as it was
found for other ester hydrolysis reactions. See Breslow, R.; Czarnniecki,
M. F.; Emert, J .; Hamaguchi, H. J . Am.Chem. Soc 1980, 102, 762.
(20) Reference 16, p 378.
(
21) Ba-Saif, S.; Luthra, A. K.; Williams, A. J . Am. Chem. Soc. 1989,
(28) Komiyama, M.; Inoue, S. Bull. Chem. Soc. J pn.1980, 53, 3334.
1
11, 2647.
22) Guthrie, J . P. J . Am. Chem. Soc. 1991, 113, 3941.
(29) The pK
a
of â-CD is 12.1 (see Van Etten, R. L.; Sebastian, J . F.;
(
Clowes, G. A.; Bender, M. L. J . Am. Chem. Soc. 1967, 89, 3253).

pH Dependent Effect of â-Cyclodextrin
J . Org. Chem., Vol. 62, No. 22, 1997 7557
Sch em e 1
Ta ble 4. Ca lcu la ted P a r a m eter s for th e Hyd r olysis of 1a
a n d 1b in th e Rea ction s w ith Cyclod extr in
-
a
-1
ab
bb
pH
ko[HO ], s
1
a
6
9
9
.00
.02
.91
2.06
13.0
71.6
121 ( 1c
120 ( 40
120 ( 20
(1.7 ( 0.3)103
(1.3 ( 0.1)104
Sch em e 2
1
b
6
9
9
.00
.02
.91
1.46
8.40
51.20
-440 ( 40
(2.5 ( 0.2)103
(1.4 ( 0.2)104
320 ( 40
250 ( 40
260 ( 60
a
Value extrapolated to zero buffer concentration. b Parameters
of eq 8 unless otherwise noted. c Represents the ratio of slope and
intercept of a plot according to eq 10.
-
The rate of the reaction involving HO as an external
-
nucleophile with the complexed substrate (k
2
[HO ] in
Scheme 2) is probably slower than the corresponding to
the nucleophilic reaction of one secondary oxygen anion
-
and S.CDO are their respective inclusion complexes with
1
of the cyclodextrin (k in Scheme 2) since the decrease
association equilibrium constants named KCDOH and KCDO
The value of K
first-order rate constant for the reaction in the absence
of cyclodextrin. It should be noticed that the pathway
involving S.CDO is equivalent to Scheme 1. The forma-
.
-
2
9
in polarity of the solvent decreases the rate of the HO -
catalyzed reaction. It can be seen in Table 3 that when
the solvent changes from 4% ACN to 25% ACN the rate
constant decreases by a factor of four. Besides, the
reactions at pH <7 which involve water as an external
nucleophile reacting with the included substrate are
slower than the corresponding one for the free substrate
b
) K
a
/K
w
is ∼100 and k
0
′ is the pseudo-
-
tion of a cyclodextrin-substrate complex cannot be
corroborated using other means30 because the substrates
react very fast with water.
In Scheme 2 the pathway involving the reaction of HO-
with complexed substrate (k
there are plenty of evidence that external nucleophiles
(see below). Then eq 6 can be simplified to eq 7.
-
2
[HO ]) is included because
-
-
K K
k [HO ][â-CD] + k [HO ]
b
CDO
1
o
o
kobs
)
(7)
can react with complexed substrates and in some cases
1
+ KCDOH[â-CD]o
even at higher rate.3
1,32
It should be noticed that the
reaction pathways involving the complexation of the
substrate with ionized cyclodextrin is kinetically equiva-
lent and therefore undistinguishable from that involving
complexation of the substrate with neutral cyclodextrin
followed by ionization of the complex.
The observed rate constant for Scheme 2 is given by
eq 4 where f represents the fraction of ionized â-CD as
defined in eq 5.
The rate data obtained at different pH were fitted to
an equation of the form of eq 8 where a and b are
adjustable parameters and c is the experimentally de-
termined value of the observed pseudo-first-order rate
constant in the absence of â-CD. All the data except
those of 1a at pH 6.00 fit very well to eq 8. The values
of a and b are collected in Table 4. The lines of figures
2
and 3 were drawn with the calculated parameters.
kobs
)
a[â-CD]o
kobs - c )
(8)
-
-
(fk K
+ (1 - f)k K
[HO ])[â-CD] + k [HO ]
1 + b[â-CD]o
1
CDO
2
CDOH
o
o
1
+ (fKCDO + (1 - f)KCDOH)[â-CD]o
Considering the mechanism of Scheme 2 and the
expression for the observed rate constant of eq 7, the
values of a and b at pH > 8 are (K
-
(
4)
-
b
K
CDO
k
1
K [HO ]
b
-
K
CDOH
k
o
)[HO ] and KCDOH, respectively. Consistent with
this interpretation, the value of b is pH independent.
Assuming that KCDOH ≈ KCDO, the value of K can be
calculated. In all previous studies of hydrolysis of esters
catalyzed by cyclodextrin, the value of K is usually
the catalyzed rate constant. Values of ratio
uncatalyzed pseudo-first-order rate constant)
f )
(5)
-
1
+ K [HO ]
b
b 1
k
-
All our studies were done at pH < 10, then [HO ] <
b 1
k
-
4
-
1
6
0
M and f ≈ K
b
[HO ] ,1. Equation 4 simplifies to eq
3
3
named k
/k (k
ranging from lower than 1 to 10 have been obtained,
so it must be noted that only those values higher than
00 indicate that the intrinsic reactivity of the ionized
c
,
provided that KCDO and KCDOH are of the same order of
k
c
u
u
magnitude. Ionization of one hydroxy group of cyclodex-
trin is not expected to change significantly the association
equilibrium constant.
5
34
1
HO at the rim of the cyclodextrin cavity is higher than
that of hydroxide ion in the solution.
-
-
(
K K
k1 + K
k )[HO ][â-CD] + [HO ]
CDOH 2 o
b
CDO
kobs
)
At pH < 8, the reactions are pH independent, indicat-
1
+ KCDOH[â-CD]o
(6)
ing that water is the nucleophile. In Scheme 2, only the
-
upper part can take place, with k
o
) k
w
and k
2
[HO ] )
CD
k
w
. The observed rate constant is given by eq 9.
(
30) Connors, K. A. Binding Constants: The measurement of mo-
lecular complex stability; J ohn Wiley and Sons: New York, 1987.
31) Gadosy, T. A.; Tee, O. S. J . Chem. Soc., Perkin Trans. 2 1994,
15.
32) Barra, M.; de Rossi R. H. Can. J . Chem. 1991, 69, 1124.
(
(33) Tee, O. S. Adv. Phys. Org. Chem. 1994, 29, 1.
(34) Breslow, R.; Czarniecki, F. M.; Emert, J .; Hamaguchi, H. J .
Am. Chem. Soc. 1980, 102, 762.
7
(

7
558 J . Org. Chem., Vol. 62, No. 22, 1997
Fernandez et al.
CD
KCDOH
k
[â-CD] + kw
w o
kobs
)
(9)
1
+ KCDOH[â-CD]o
For compound 1b the data fit very well to an equation
of the form of eq 8 with c ) k but the rate in the cavity
occurs at lower rate than the rate in bulk solution (Figure
w
4
B). The cavity of cyclodextrins are less polar than
3
5,36
water,
and the effect of acetonitrile shows that the
water as well as the hydroxide ion reaction occurs at a
lower rate when the amount of acetonitrile increases in
the solution so at least part of the observed inhibition
may be attributed to a microsolvent effect. Another
factor which may be important is the availability of the
carbonyl group to react with water, since if it is immersed
in the cavity it may be difficult to reach.
In the case of substrate 1a the data could not be fitted
to eq 8 but fits very well to eq 9 with the first term in
the numerator equal to zero (Figure 4A). In this case,
inversion of eq 9 leads to eq 10, and the reciprocal of the
observed rate constant plotted vs â-CD concentration
(Figure 5) gives a straight line from which KCDOH can be
obtained.
1
1
KCDOH[â-CD]o
)
+
(10)
kobs kw
kw
The difference in the catalytic factors for the acetate
and trifluoromethyl derivatives reported here probably
indicates a change in the mode of inclusion, with the
trifluoromethyl inside the cavity (Figure 6A) instead of
the aryl side (Figure 6B). The different mode of inclusion
can be attributed to a combination of effects, such as the
different hydrophobicity of methyl and trifluoromethyl
groups, the shape of the group which makes the lock and
key interaction more favorable, and the dipolar moment
of the molecule. In fact, CPK molecular models show that
the trifluoromethyl group fits very well in the â-CD
cavity. The other complex (Figure 6B) should also be
formed, but the kinetics should reflect the more reactive
species.37 The fact that the catalysis through the complex
with the phenyl group in the cavity (Figure 6B) is less
effective than the corresponding one for phenyl acetate
may be a consequence of the different dipolar moments
of the two compounds which determine the orientation
of the substrate in the cavity.
F igu r e 4. Effect of â-CD on the hydrolysis of 1a (A) and 1b
(B) at pH 6. Reaction conditions as in Figures 1 and 2. The
lines have been calculated with eq 9 for 1b and the reciprocal
of eq 10 for 1a using the parameters reported in Table 4.
Reaction conditions as in Figure 1.
In the reaction of 1b, the substrate in the cavity reacts
whereas 1a does not. It may be that for the former
substrate, due to the presence of the methyl group in the
phenyl ring, there is more complex of type B with the
aryl group inside the cavity.
Following Kurz38 treatment which was applied to
3
9
cyclodextrin-catalyzed (or inhibited) reactions by Tee,
F igu r e 5. Plot according to eq 10 for the hydrolysis of 1a in
the presence of â-CD.
-
1 b o
the ratio k K KCDO/k [HO ] can be regarded as the
TS
association constant of the transition state, KCD ; there-
fore, its variation with substrate structure can give
information regarding the nature of the transition state
of the cyclodextrin-mediated reaction. The change in rate
is determined by the strength of binding of the transition
state relative to that of the substrate. When binding of
the substrate is stronger than binding of the transition
state, inhibition is observed.
Because of the partial covalent interaction between the
TS
ester substrate and cyclodextrin, usually KCD shows
strong dependence on the position and size of the sub-
33
stituents. In Table 5 we can see the ratio of the binding
constants of substrate and transition state for the reac-
tions above pH 8 are about the same whereas the same
ratios in the case of acetate esters give quite different
values for the methyl-substituted and -unsubstituted
ester. This result may indicate that in the case of
(
35) Nigam, S.; Durocher, G. J . Phys. Chem. 1996, 100,
135-7142.
36) Kundu, S.; Chattopadhyay, N. J . Mol. Struct. 1995, 344, 151-
55.
37) Reference 5b.
38) Kurz, J . L. J . Am. Chem. Soc. 1963, 85, 987.
39) Tee, O. S. Carbohydr. Res. 1989, 192, 181.
7
1
(
(
(
(
compound 1 the reactive complex is the one with the CF
3

pH Dependent Effect of â-Cyclodextrin
J . Org. Chem., Vol. 62, No. 22, 1997 7559
The pH measurements were done in a pH meter Orion 720A
at controlled temperature and calibrated with buffers prepared
in the laboratory according to the literature.41
The â-cyclodextrin (Roquette)42 was used as received but the
purity was periodically checked by UV spectroscopy.
The substrates 1a and 1b were prepared by the reaction of
the appropriate phenol with trifluoroacetic anhydride following
literature methods.43 The product was obtained after distil-
lation of the remaining trifluoroacetic anhydride and acid. 1b
was distilled, and the fraction distilling at 160 °C was used
4
4
(
lit. bp 169-170 °C). The purity was controlled by compari-
son of the spectrum of a completely hydrolyzed solution with
a mock solution of the corresponding phenol and by IR
comparing with the literarture. Compounds 1a and 1b have
F igu r e 6. Schematic representation of the inclusion com-
plexes with alkyl (A) and aryl (B) in the cavity of â-CD.
45
∼
5% phenol in excess. In order to determine if this affected
the measured rates, reactions were carried out with the
substrate and 20% of phenol added. No differences in the
measured rates were found.
Ta ble 5. Associa tion Equ ilibr iu m Con sta n t for th e
Su bstr a tes a n d Tr a n sition Sta tes for th e Cyclod extr in
Med ia ted Rea ction s
KCDOH, M-1
KCDTS, M-1
KCDTS/KCDOH
Kin etic P r oced u r es. The reactions were carried out in
an Applied Photophysics SF 17MV apparatus with unequal
mixing. The substrate was dissolved in dry ACN and placed
in the smaller syringe (0.1 mL). The larger syringe (25 mL)
was filled with a water solution containing all the other
ingredients. The total acetonitrile concentration was less than
pH
1
1
a
b
-2
6
.00
120
120
139
,1
246
1886
,10
b
>
1
9
0.60
2.2
a
a
a
14
b
4
%.
b
6
9
0.60
.00
270
270
312
16.6
571
0.06
2.1
b
All reactions were run at 25.1 ( 0.1 °C and at constant ionic
>
1
a
a
a
3030
10
strength 0.2 M using NaCl as compensating electrolyte. The
observed rate constants were determined by following the
appearance of the corresponding phenol (272 nm for 1a and
a
Data for the corresponding acetate taken from reference 3.
Average value of b from Table 4.
b
2
79 nm for 1b). The rates were measured also at other
wavelengths, in order to see if the tetrahedral intermediate
complex could be detected. Under all conditions the same
value of the rate was observed, and a faster process that could
be attributed to the accumulation of the tetrahedral interme-
diate could not be found, although we carefully looked for it.
group inside (Figure 6A). The differences in KCDTS/KCDOH
in the case of the water reaction may indicate that the
more reactive complex is in this case the one with aryl
inclusion (Figure 6B).
The pH of the solutions containing varying concentrations
of cyclodextrin was adjusted by adding a drop of dilute acid or
Con clu sion s
-
2-
2-
3
base. The buffer was PO
4
H
2
/PO
4
H
at pH 6, and CO
/
-
The hydrolysis rate of compounds 1 in water are
weakly base-catalyzed by buffers in basic as well as in
neutral solution. Comparing the values of the observed
rate constants at the same pH for 1a and 1b, we
determined that the sensitivity of the reaction to the
change in leaving group is about the same as the
HCO
2
at pH 9.02 and 9.91.
Ack n ow led gm en t. This research was supported in
part by the Consejo Nacional de Investigaciones Cien-
tificas y T e´ cnicas, Argentina (CONICET), the Consejo
Provincial de Investigaciones Cient ´ı ficas y Tecnol o´ gicas
de C o´ rdoba, Argentina (CONICOR), and the Univer-
sidad Nacional de C o´ rdoba. M. Fern a´ ndez is a grateful
recipient of fellowships from CONICET. We thank Dr.
Alejandro Granados for carrying out some preliminary
experiments.
4
0
sensitivity for the acetates by the âlg
.
This result
indicates that the mechanism are similar for both types
of reactions and probably does not involve the formation
of a tetrahedral intermediate with a finite lifetime.
The reactions are catalyzed by â-CD under conditions
where part of the secondary OH at the rim of the cavity
is ionized. The catalysis is less significant than for the
reactions of the corresponding acetates, and considering
the transition state binding for the catalyzed reaction and
the binding of the substrate, it is concluded that the
reactive complex has the trifluoromethyl group inside the
cavity. The reactions in neutral solution are inhibited
as a consequence of weak binding of the transition state,
and this is even weaker for 1a than for 1b which
indicates that for this reaction the reactive complex is
the one with the aryl inside.
Su p p or tin g In for m a tion Ava ila ble: Table S1 containing
the observed rate constant for the hydrolysis of 1a , and Table
S2 for 1b as a function of pH and buffer concentration. Tables
S3 and S4 containing the observed rate constant for 1a and
1
b, respectively, at different pH, buffer, and â-CD concentra-
tions (4 pages). This material is contained in libraries on
microfiche, inmediately follows this article in the microfilm
version of the journal, and can be ordered from ACS; see any
current masthead page for ordering information.
J O961627W
Exp er im en ta l Section
(
41) “Analytical Chemisty. The Working Tools”; Strouts, C. R. N.,
Gilgilan, J . H.; Wilson, H. N., Ed.; Oxford University Press: London,
958; pp 228-233.
42) Cyclodextrins were a gift from the pharmaceutical company
Ferromet S. A. Buenos Aires, Argentina.
Aqueous solutions were made up from water purified in a
Millipore apparatus. Acetonitrile Merck HPLC grade was
used as received.
1
(
(
(
43) Clark, R. F.; Simons, J . H. J . Am. Chem. Soc. 1953, 75, 6305.
44) Shulgin, A. T. Anal. Chem. 1964, 36, 920.
(40) J encks, D. A.; J encks, W. P. J . Am.Chem. Soc. 1977, 99, 7948.
(45) Crower, G. A. J . Fluorine Chem. 1971, 1, 219.