Effect of β-cyclodextrin on the hydrolysis of trifluoroacetate esters

Article abstract of DOI:10.1021/jo001691k

The hydrolysis of p-F, p-Cl, and m-Cl phenyl trifluoracetates was studied in the presence of β-cyclodextrin (β-CD). The reactions are inhibited by β-CD at pH 6 while they are catalyzed in alkaline solution. MM3 calculations reproduce some of the experimen

Full text of DOI:10.1021/jo001691k

J . Org. Chem. 2001, 66, 4399-4404
4399
Effect of â-Cyclod extr in on th e Hyd r olysis of Tr iflu or oa ceta te
Ester s
Mariana A. Fern a´ ndez and Rita H. de Rossi*
Instituto de Investigaciones en F ı´ sico Qu ı´ mica de C o´ rdoba (INFIQC), Facultad de Ciencias Qu ´ı micas,
Departamento de Qu ı´ mica Org a´ nica, Universidad Nacional de C o´ rdoba, Ciudad Universitaria,
5
000 C o´ rdoba, Argentina
Enric Cervell o´ and Carlos J aime
Departament de Qu ı´ mica, Facultat de Ci e` ncies, Universitat Aut o` noma de Barcelona,
0
8193 Bellaterra, Spain
ritah@dqo.fcq.unc.edu.ar
Received December 1, 2000
The hydrolysis of p-F, p-Cl, and m-Cl phenyl trifluoracetates was studied in the presence of
â-cyclodextrin (â-CD). The reactions are inhibited by â-CD at pH 6 while they are catalyzed in
alkaline solution. MM3 calculations reproduce some of the experimental results. The substrates
form inclusion complexes with â-CD which are of similar stability as those of the corresponding
acetates; however, the association of the transition state is less favorable in these reactions than
in those of the acetates, and consequently less stronger catalysis is observed.
Cyclodextrins (CD) are cyclic oligomers of R-D-glucose,
which are produced by enzymatic degradation of starch.
Compounds with six, seven, or eight glucose units,
sampling in modeling structural reorganization of cyclo-
dextrin along the hydrolysis reaction path.
In previous work we reported important differences in
the behavior of phenyl and p-methyl phenyl trifluoroac-
etate esters when compared with the corresponding
1
respectively, are called R-, â-, and γ-CD. They are good
models for hydrolytic enzymes, and many studies have
been done on CD-catalyzed hydrolysis of esters.2
Important differences were found when the leaving group
,3,4,5,6
10
acetate esters which we attributed to a different mode
of inclusion. In this paper, we report a kinetic study of
6
was changed to poorer leaving groups. When the reaction
the hydrolysis of trifluoroacetate esters 1-3 that bear
1
0
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 because the orientation of the
former within the CD cavity has geometry more suitable
better leaving groups than those previously studied, and
also one of them, 3, has a meta substituent. It is known
that substituents in meta position favor the orientation
of the substrate in a position appropriate for the reaction,
which results in stronger catalysis. For instance, the
ratios of the catalyzed (k
constants for p- and m-chlorophenyl acetate are 13 and
5, respectively.11 In contrast, no significant differences
c u
) and uncatalyzed (k ) rate
3
,4,5
for acyl transfer.
3
The hydrolysis of phenyl acetate in the absence and
of the ratio are observed for substrates 2 and 3. We also
report here some molecular mechanics calculations which
were done to aid in the interpretation of the results.
in the presence of â-CD has been studied computation-
7
8
ally by means of semiempirical MO calculations (AM1)
and considering the effect of solvent by the Langevin
9
dipole solvent model. This work provides an important
insight into the role of the macrocycle cavity in catalysis
and to the necessity of including thermal conformational
(1) Bender, M. L.; Komiyama, M. Cyclodextrin Chemistry; Springer-
Verlag: New York, 1977. (b) Saenger, W. Angew. Chem., Int. Ed. Engl.
1
980, 19, 344. (c) Tabushi, I.; Kuroda, Y. Adv. Catal. 1983, 32, 417.
2) Breslow, R.; Trainor, G.; Ueno, A. J . Am. Chem. Soc. 1983, 105,
739.
3) Van Etten, R. L.; Sebastian, J . F.; Clowes, G. A.; Bender, M. L.
J . Am. Chem. Soc. 1967, 89, 3242.
(
2
(
Resu lts
(
(
4) Komiyama, M.; Bender, M. L. J . Am. Chem. Soc. 1978, 100, 4576.
5) (a) Tee, O. S.; Takasaki, B. K. Can. J . Chem. 1985, 63, 3540. (b)
The hydrolysis rates of substrates 1-3 were measured
at pH 6.00 and 9.02 in the presence of several concentra-
tions of â-cyclodextrin (â-CD). At each concentration of
the macrocycle at least four concentrations of buffer were
Tee, O. S.; Mazza, C.; Du X- X. J . Org. Chem. 1990, 55, 3603.
(6) Menger, F. M.; Ladika, M. J . Am. Chem. Soc. 1987, 109, 3145.
(7) Luzhkov, V. B.; Venanzi, C. A. J . Phys. Chem., 1995, 99, 2312.
(8) Dewar, M. J . S.; Zoebish, E. G.; Healy, E. F.; Stewart, J . J . P. J .
Am. Chem. Soc. 1985, 107, 3902.
9) (a) Warshel, A. Computer Modelling of Chemical Reactions in
12
used (Table S1-S3). The observed rate constant at each
(
Enzymes and Solutions; J ohn Wiley & Sons: New York, 1991. (b)
Warshel, A.; Russel, S. Q. Rev. Biophys. 1984, 17, 283. (c) Lee, F.; Chu,
Z. T.; Warshel, A. J . Comput. Chem. 1993, 14, 161. (d) Luzhkov, V.;
Warshel, A. J . Comput. Chem. 1992, 13, 199.
(10) Fernandez, M. A.; de Rossi R. H. J . Org. Chem. 1997, 62, 7554.
(11) Tee, O. S. Adv. Phys. Org. Chem. 1994, 29, 1.
(12) Supporting Information.
1
0.1021/jo001691k CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/12/2001

4
400 J . Org. Chem., Vol. 66, No. 12, 2001
Fern a´ ndez et al.
F igu r e 2. Effect of â-CD on the rate of hydrolysis of 1-3 at
pH 9.02. Rate constants were extrapolated to zero buffer
concentration. Temperature 25 °C. Solvent 3.8% ACN. The
lines were calculated using eq 8 and the parameters shown in
Table 3.
F igu r e 1. Effect of â-CD on the rate of hydrolysis of 1-3 at
pH 6. Rate constants were extrapolated to zero buffer concen-
tration. Temperature: 25 °C. Solvent 3.8% ACN. The lines
were calculated using eq 9 and the parameters shown in Table
in the presence of â-CD 0.012 M and in its absence is
6.7, while in this case it is 1.4. We note that the catalysis
observed for the acetate contrasts with the inhibition
found for the perfluorinated esters.
3
.
pH and each buffer concentration was plotted against
â-CD concentration, and the plots were fitted by using
eq 1
c + a[â-CD]
kobsd
)
(1)
1
+ b[â-CD]
where a and b are adjustable parameters, c is the
observed rate constant in the absence of â-CD, and [â-CD]
represents the molar concentration of â-CD.
Using the parameters a and b calculated at each buffer
concentration, the values of the rate constants were
calculated for the same concentration of â-CD. These
values were then plotted against buffer, and from the
intercept of the plots, the rate constants extrapolated to
zero buffer concentration were obtained. At pH 6 the rate
decreases whereas at pH 9 it increases with â-CD
concentration, showing in all cases a saturation effect
Th eor etica l Ca lcu la tion s. The inclusion of phenyl
acetate, 4H, and phenyl trifluoroacetate, 4F , into the
â-CD cavity was emulated following previously described
methodology13 using Allinger’s MM3 force field.
14,15
The
optimization was done using the full matrix Newton-
Raphson method. The four orientations shown in Figure
3, A-D, were used for the inclusion emulation (at 1 Å
1
6
(Figures 1 and 2).
intervals). The calculated (MM3) relative steric energies
The hydrolysis of phenyl acetates with different sub-
for the various orientations are collected in Table 1.
stituents on the aromatic ring has been studied at
alkaline pH, but there are very few studies about their
hydrolysis at neutral pH because of their low reactivity.
To compare our results at pH 6 with that of an acetate
derivative, we studied the reaction of p-nitrophenyl
acetate in the same environment. The effect of â-CD on
the hydrolysis of this substrate at pH 6 is significantly
smaller than that observed at pH 10.6 by Bender et al.3
These authors found that the relative rate of the reaction
Orientation A (Figure 1S), where the phenyl ring is inside
the cavity and the CF CO or CH CO portion of the
3 3
molecule is protruding through the smaller rim of the
cyclodextrin cavity, is always computed to be by far the
most stable. On the other hand the energy minimum for
inclusion in orientation D (Figure 3), where the trifluo-
romethyl group is deeply included into the CD cavity, is
about 5 kcal/mol more stable for the trifluoroacetate than
for the acetate (note in Table 1 that the SE is 9.2 and

Effect of â-Cyclodextrin on Trifluoroacetate Hydrolysis
J . Org. Chem., Vol. 66, No. 12, 2001 4401
Ta ble 2. Ster ic En er gy (SE, k ca l/m ol), Hea t of
F or m a tion (∆Hf, k ca l/m ol), F r ee En er gy of F or m a tion
∆Gf, k ca l/m ol), a s Obta in ed by th e MM3 Ca lcu la tion s on
Sp ecies In volved in Mech a n ism s a a n d b (see text)
(
SE
∆Hf
∆Gf
watera
â-CD
4H
0.00
62.70
9.40
55.49
5.47
45.53
61.48
24.96
67.99
13.54
49.94
69.27
-57.85
-1463.54
51.61
-54.69
750.24
74.69
823.54
84.79
830.67
832.31
73.14
817.61
76.5
with H
with F
4
5
5
6
H/â-CDb
-1430.89
H
16.33
H/â-CDb
-1472.33
-1402.46
-64.67
-1550.24
-108.59
-1599.95
-1526.69
H
4F
4
5
5
6
F /â-CDb
F
F /â-CDb
F
816.14
823.40
a
Experimental thermodynamic values obtained from General
Chemistry; Atkins, P. W., Ed.; Scientific Am. Books: New York,
1
989. b Represents the complex of the corresponding compound
with â-CD.
Tetrahedral compounds 5H, 5F , 6H, and 6F were
calculated as models for the transition states for the
hydrolysis reactions. Compounds 6 represent the tetra-
hedral intermediates formed by the attack of one of the
secondary OH groups of â-CD on the carbonyl carbons
of the esters, and they are models for the transition states
in the CD-catalyzed pathways.
The hydrolysis pathways considered were the follow-
ing:
(a) The normal acyl cleavage mechanism of ester
hydrolysis in basic media. MM calculations cannot be
undertaken on the hydroxyl anion because of the absence
of parameters, and we used the protonated species as
suitable reaction models (eq 2).
F igu r e 3. The four substrate orientations considered for the
emulation of the complexation of 4H and 4F by molecular
mechanics (MM3) calculations.
Ta ble 1. Ca lcu la ted (MM3) Rela tive Ster ic En er gy (r el
SE, in k ca l/m ol) for th e Min im ized Str u ctu r es of th e
Com p lexes of 4H a n d 4F w ith â-Cyclod extr in in th e F ou r
Or ien ta tion s Con sid er ed (see F igu r e 3)
(
b) Complexation of 4H or 4F , followed by the forma-
tion of 6H or 6F , respectively, which are finally trans-
formed into the products, eqs 3 and 4.
rel SE (kcal/mol)
orientation
4H
4F
A
B
C
D
0.0
7.5
6.2
9.2
0.0
6.9
6.3
4.1
The computed energies for reactants, complexes and
intermediates involved in each mechanism are shown in
Table 2.
4
.1 for 4H and 4F , respectively), in agreement with the
higher hydrophobicity of the CF group.
Considering mechanism a (eq 2), it is worth noting here
that reactions involving fluorinated compounds are com-
puted to be faster than the corresponding nonfluorinated
compounds in agreement with what has also been
experimentally observed. The ∆∆G value calculated using
the data shown in Table 2 for 4H and 4F reacting
3
(
13) (a) J aime, C.; Redondo, J .; S a´ nchez-Ferrando, F.; Virgili, A. J .
Org. Chem. 1990, 55, 4773-4776. (b) Redondo, J .; J aime, C.; Virgili,
A.; S a´ nchez-Ferrando, F. J . Mol. Struct. 1991, 248, 317-329. (c)
Fotiadu, F.; Fathallah, M.; J aime, C. J . Inclusion Phenom. 1993, 16,
5-62. (d) Fathallah, M.; Fotiadu, F.; J aime, C. J . Org. Chem. 1994,
9, 1288-1293. (e) P e´ rez, F.; J aime, C.; S a´ nchez-Ruiz, X. J . Org. Chem.
995, 60, 3840-3845. (f) Ivanov, P. M.; J aime, C. An. Qu ı´ m., Int. Ed.
996, 92, 13-16. (g) Ivanov, P. M.; J aime, C. J . Mol. Struct. 1996,
77, 137-147. (h) Salvatierra, D.; Ivanov, P. M.; J aime, C. J . Org.
Chem. 1996, 61, 7012-7017. (i) Salvatierra, D.; J aime, C.; Virgili, A.;
S a´ nchez-Ferrando, F. J . Org. Chem. 1996, 61, 9578-9581. (j) Entrena,
A.; J aime, C. J . Org. Chem. 1997, 62, 5923-5927. (k) Cervell o´ , E.;
J aime, C. J . Mol. Struct. (THEOCHEM) 1998, 428, 195-201. (l)
S a´ nchez-Ruiz, X.; Ramos, M.; J aime, C. J . Mol. Struct. (THEOCHEM)
5
5
1
1
3
17
according to eq 2 is 6.8. These data indicate that 4F
should be about 900 times more reactive than 4H. The
-
4
-1
observed differences in reactivity, i.e., 7.34 × 10
s
at
11
-1
pH 10.6 for phenyl acetate and 71.6 s at pH 9.91 for
(15) Parameters for the aryl ester are not available and were
replaced by those of an allyl ester. Parameters used were: 3-75-50
(kb ) 0.770, θ ) 106.8), 1-3-75-50 (V1 ) -2.500, V2 ) 1.390, V3 )
0.000), 7-3-75-50 (V1 ) 0.000, V2 ) 0.000, V3 ) 0.000), 6-1-6-50
(V1 ) 0.000, V2 ) 0.000, V3 ) 0.180), 11-1-3-75 (V1 ) 0.848, V2 )
0.000, V3 ) 0.000).
1
4
998, 442, 93-101. (m) Cervell o´ , E.; J aime, C. An. Qu ı´ m., Int. Ed. 1998,
-5, 244-249. (n) Salvatierra, D.; S a´ nchez-Ruiz, X.; Gardu n˜ o, R.;
Cervell o´ , E.; J aime, C.; Virgili, A.; S a´ nchez-Ferrando, F. Tetrahedron,
2
000, 56, 3035-3041. (o) Cervell o´ , E.; Mazzucchi, F.; J aime, J . Mol.
Struct. (THEOCHEM) 2000, 530, 155-163.
14) Allinger, N. L.; Yuh, Y. H.; Lii, J . H. J . Am. Chem. Soc. 1989,
11, 8551, 8566, and 8576.
(16) Allinger, N. L. Molecular Mechanics; ACS Monograph 177;
American Chemical Society: Washington, DC, 1982; p 4.
(
(17) These numbers were obtained as follows ∆∆G
f f
) [∆G (5H) -
1
∆G (4H)] - [∆G (5F ) - ∆G (4F )].
f
f
f

4
402 J . Org. Chem., Vol. 66, No. 12, 2001
Fern a´ ndez et al.
F igu r e 4. Schematic representation of the position for the carbonyl carbon (represented by dots) during the MD simulation of
the â-CD inclusion complex. (a) Corresponding to the 4H complexation; (b) Corresponding to the 4F complexation.
trifluorophenyl acetate,10 indicate even higher energy
differences.
is now favored, and a schematic representation of the
position for the carbonyl carbon along the simulation time
is shown in Figure 4. Interestingly, this force field
calculation shows that the carbonyl group prefers to be
near the secondary OH groups, which are the reactive
ones in cyclodextrin-catalyzed reactions.
Concerning the complexation process, inclusion of
fluorinated compounds is favored against inclusion of
nonfluorinated compounds according to the calculated
complexation energies that differ by 3 kcal/mol in ∆H and
by more than 4 kcal/mol in ∆G (Table 2). This difference
is mainly due to the torsional term, dipole-dipole inter-
actions, and the long-range van der Waals interactions.
The experimental values of the complexation constants
for compounds 4H and 4F are about the same, namely
The accelerating effect of â-CD on the acyl cleavage
reaction is reproduced by calculations because the activa-
tion energies in the absence of â-CD are always greater
than the values obtained in the presence of â-CD. Using
the data shown in Table 2, we calculated the ∆∆G values
for the reactions catalyzed by â-CD as shown in eqs 5-7.
It can be seen in eq 7 that the ∆∆G values for the overall
reaction of 4H and 4F in the presence of â-CD are
significantly lower than the corresponding values for eq
2. In this case, the differences in free energy of formation
between tetrahedral intermediates 5H (5F ) and the
substrates 4H(4F ) are 10.1(3.36) kcal/mol. These results
are consistent with the observation of catalysis by cyclo-
dextrin.
-
1 11
-1 10
1
39 M
and 120 M
,
respectively. The absence of
solvent in our calculations, the use of nonrepresentative
structures or the use of nonproper parameters for the
fluorine atom may be responsible for this discrepancy.
Molecular dynamics (MD) simulations (1000 ps, 300 K)
in water were carried out to solve the first two points.
Computations were performed using the most stable
structures for orientations A and B obtained in the MM3
1
8
calculations. The AMBER* force field and the GB/SA
1
9
solvation model were used in the MacroModel pack-
age.20 The obtained results show the same tendency as
the previous ones and indicate higher stability of 4F /â-
CD than 4H/â-CD. Thus an inadequate set of parameters
for the fluorine atom is probably the reason for this
disagreement.
Discu ssion
The hydrolysis reactions of the esters 1-3 show
catalysis by CD at pH > 9. They are also buffer catalyzed,
and this effect takes place in the presence and absence
of â-CD (Table S1).12 The buffer-catalyzed reactions have
The MD simulations for the inclusion complexes be-
tween â-CD and 4H and 4F can also be used to estimate
the geometry for the inclusion complexes. Orientation B

Effect of â-Cyclodextrin on Trifluoroacetate Hydrolysis
J . Org. Chem., Vol. 66, No. 12, 2001 4403
Sch em e 1
Ta ble 3. Exp er im en ta lly Deter m in ed P a r a m eter s for th e
Hyd r olysis of Ar yl Tr iflu or oa ceta tes 1-3 a n d Ar yl
Aceta tesa
TS
KCDOH,
M
KCD
M
,
1 a
kcb
-1
-1
substrate
pH
ko, s-
3.23
13.1
p-F (1)
6.00
0.915
61.2
99 ( 1
28
9
1
.02
145 ( 29 677
0.6a 1.2 × 10
-3
2.0 × 10
-2
-2
-3
128
2174
p-Cl(2)
m-Cl(3)
6.00
4.45
20.4
1.65
198 ( 13 73
9
1
.02
73.9
219 ( 17 793
0.6a 1.6 × 10
-3
-4
2.2 × 10
0.579
88.1
7.0 × 10
312
4166
17
808
12820
6.00
5.99
22.9
176 ( 1
210 ( 1
370
9
1
.00
0.6a 2.0 × 10
a
b
Data for the corresponding aryl acetate taken from ref 11. kc
is Kb′k1 for the reactions at pH 9.02 and k3 for those at pH 6.00.
been discussed in a previous work.21 For reactions medi-
ated by CD, the buffer effects are difficult to interpret
because buffers significantly affect the association equi-
librium constants with different guests22 and should also
affect the interaction of the transition state with CD.
Besides, it has been shown that the nucleophilic reaction
of CD with esters is general base catalyzed by imidazole,23
so it may be possible that the buffers used in this study
could act as general base catalysts of the cyclodextrin-
mediated reaction. Therefore, we have extrapolated the
rate constants to zero buffer concentration in all cases.
At pH 6 the reactions are inhibited by CD and catalyzed
by buffers, thus for the reasons indicated above, all the
data used was extrapolated to zero buffer concentration.
Figures 1 and 2 show the dependence of the extrapolated
values of the observed rate constant with â-CD concen-
tration.
25
The value of K
b
) K
a
/K
w
is ∼100, and k
0
is the pseudo-
first-order rate constant for the reaction in the absence
of â-CD. The formation of a â-CD-substrate complex
cannot be corroborated using other means such as NMR
26
spectroscopy because the substrates react very fast with
water.
The observed rate constant for the reactions at pH 9
after some simplifications is given by eq 8,
27
-
k + K K
K [â-CD] [HO ]
o
b
CDO
1
o
kobsd
)
)
1
+ KCDOH[â-CD]o
k + K ′K
-
k [â-CD] [HO ]
o
b
CDOH
1
o
(8)
1
+ KCDOH[â-CD]o
where K
b
′ is the ionization constant of â-CD in the
complex divided by K . On the other hand, at pH 6 the
observed rate constant is given by eq 9. Under these
conditions only the part of the scheme that is inside the
dotted line square is considered.
The mechanism of catalysis of the hydrolysis of esters
by CDs has been explained in terms of nucleophilic
catalysis by the ionized secondary OH group at the CD
rim, which leads to the acylated CD. Also, general base
catalysis of water addition has been postulated for the
catalysis of some esters hydrolysis.24
w
k + k KCDOH[â-CD]o
o
3
Under conditions where only part of the â-CD is in its
kobsd
)
(9)
1
+ KCDOH[â-CD]o
ionized form,25 inclusion complex formation should take
place with the ionized and the un-ionized â-CD. There-
fore, a minimum mechanism for the hydrolysis reaction
in the presence of â-CD may be represented by Scheme
Both equations have the mathematical form of eq 1.
The value of K ′k can be calculated from the parameter
a obtained for the reactions in basic solutions. In all
b
1
1
.
previous studies of hydrolysis of esters catalyzed by
In Scheme 1, S represents the substrate, CDOH and
1
1
cyclodextrins, the value of K
the catalyzed rate constant. In Table 3 the values of k
determined in the absence of CD and those of k , K ′k
and KCDOH obtained by fitting the experimental data
b 1 c
′ k is usually given as k ,
-
CDO are the neutral and ionized â-CD, and S‚CDOH
-
o
and S‚CDO are their respective inclusion complexes
3
b
1
)
with association equilibrium constants named KCDOH and
k
c
K
CDO. The rate constants k
the reaction of water and HO with the complexed
substrate, and k represents the rate constant for the
nucleophilic reaction of â-CD with the included substrate.
3 2
and k involve, respectively,
to eqs 8 and 9 are collected. The values of KCDOH obtained
in basic and acid solutions are in fair agreement which
gives support to the proposed mechanism.
-
1
Following Kurz28 treatment which was applied to CD-
2
9
catalyzed (or inhibited) reactions by Tee, the ratio
and k can be regarded as the
(18) Cornell, W. D.; Cieplak, P.; Bayly, C. I.; Gould, I. R.; Merz, K.
k
1
K
b
′KCDOH/k
o
3 o
KCDOH/k
M., J r; Ferguson. D. M.; Spellmeyer, D. C.; Fox, T.; Caldwell, J . W.;
Kollman, P. A. J . Am. Chem. Soc. 1995, 268, 1144.
TS
association constant of the transition state, KCD . There-
fore its variation with structure gives information re-
garding the nature of the transition state of the CD-
mediated reaction. The changes in rate are determined
by the strength of binding of the transition state relative
(
19) Still, W. C.; Tempczyk, A.; Hawley, R. C.; Hendrickson, T. J . J .
Am. Chem. Soc. 1990, 112, 6127.
20) Mohamadi, F.; Richards, N. G. J .; Guida, W. C.; Liskamp, R.;
Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J . Comput. Chem.
(
1
990, 11, 440.
(21) Fernandez, M. A.; de Rossi R. H. J . Org. Chem. 1999, 64, 6000.
22) (a)Yi, Z. P.; Huang, Z. Z.; Yu, J . S.; Chen, H. L.. Chem Lett.
(
1
998, 1161-2. (b) Ghosh, M.; Zhang, R.; Lawler, R. G.; Seto, C. T. J
(26) Connors, K. A. Binding Constants: The measurement of mo-
Org Chem. 2000, 65, 735.
23) Akiyama, M.; Ohmachi, T.; Ihjima, M. J . Chem Soc. Perkin
Trans. 2 1982, 1511.
lecular complex stability; J ohn Wiley and Sons: New York, 1987.
-
(
(27) Equation 9 is obtained considering that k
3
and k
2
[HO ] are
1
negligible compared with k (see ref 10) and also assuming that
Kb′[HO- , 1 which is true if Kb′ ≈ K
]
(
(
24) Komiyama, M.; Inoue, S. Bull. Chem. Soc. J pn. 1980, 53, 3334.
b
.
25) The pK of â-CD is 12.1 Van Etten, R. L.; Sebastian, J . F.;
a
(28) Kurz, J . L. J . Am. Chem. Soc. 1963, 85, 987.
(29) Tee, O. S. Carbohydr. Res. 1989, 192, 181.
Clowes, G. A.; Bender, M. L. J . Am. Chem. Soc. 1967, 89, 3253.

4
404 J . Org. Chem., Vol. 66, No. 12, 2001
Fern a´ ndez et al.
Exp er im en ta l Section
to that of the substrate. When binding of the substrate
is stronger than binding of the transition state, inhibition
is observed. In the reactions of aryl acetates due to the
partial covalent interaction between the ester substrate
and CD in the transition state, KCDTS usually shows
strong dependence on the position and size of the sub-
stituents.11 In Table 3 we can see that for the reactions
in basic solutions, there are no significant differences
between the values of the association constant for the
Aqueous solutions were made up from water purified in a
Millipore apparatus. Acetonitrile Merck HPLC grade was used
as received. The pH measurements were done in a pH meter
Orion 720A at controlled temperature and calibrated with
32
buffers prepared in the laboratory according to the literature.
33
The â-cyclodextrin (Roquette) was used as received but the
purity was periodically checked by UV spectroscopy, the pure
compound do not absorb above 230 nm. The substrates were
prepared by the reaction of the appropriate phenol with
substrates when the acetates are compared with trifluo-
3
4
roacetate derivatives; however, the values of KCDTS are
trifluoroacetic anhydride following literature methods. The
product was obtained after distillation of the remaining
trifluoroacetic anhydride and trifluoroacetic acid. The purity
was controlled by comparison of the spectrum of a completely
hydrolyzed solution with a solution of the corresponding phenol
significantly different. Similar results were obtained with
phenyl trifluoroacetate and p-methylphenyl trifluoro-
acetate.10 It is evident that the reason for the small
catalysis for the perfluorinated compounds is due to less
efficient stabilization of the transition state relative to
the ground state for the reactions of these derivatives.
Comparison of the calculated free energy for the rate-
limiting step in mechanism b (eq 6) with that for the
reaction in the absence of cyclodextrin (eq 2), shows that
the difference in free energy for the reaction in water and
3
5
and by IR in comparison with literature data. The kinetic
procedures were described in previous work.10
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 (CONICET), the Agencia Nacional de
Ciencia y Tecnologia (FONCYT) (Argentina), the Con-
sejo Provincial de Investigaciones Cient ´ı ficas y Tecno-
l o´ gicas de C o´ rdoba, (CONICOR) and the Universidad
Nacional de C o´ rdoba. M.F. is a grateful recipient of a
fellowship from CONICET. The Direcci o´ n General de
Ense n˜ anza Superior (DGES) is acknowledged for finan-
cial support through grant PB92-1181, and UAB is also
thanked for a fellowship to one of us (E.C.).
that mediated by CD for 4H compared with 4F is 3.8 kcal/
mol.30 This result is in agreement with the fact that the
catalysis observed is less significant for the perfluori-
nated compounds.
In conclusion, the results presented here indicate that
the less efficient catalysis by â-CD for the reactions of
trifluoroacetate esters compared with acetate esters is
not due to different mode of inclusion of the substrates
1
0
Su p p or tin g In for m a tion Ava ila ble: Table S1-S3, con-
taining the observed rate constant for substrates 1-3 as
function of pH, buffer, and cyclodextrin concentration, and
Figure S1, showing the calculated structure of complex with
orientation A. This material is available free of charge via the
Internet at http://pubs.acs.org.
as we previously suggested but to smaller stabilization
of the transition state for the perfluorinated esters (Table
3
). This effect can be attributed to steric factors because
the CF group has a considerably higher van der Waals
volume than the CH
3
3
1
3
,
and so the transition state for
the reaction with cyclodextrin is more sterically hindered
than that of the corresponding acetate.
J O001691K
(
30) With the data reported in Table 2, ∆∆G values for eq 2 are
(32) Analytical Chemisty. The Working Tools; Strouts, C. R. N.;
Gilgilan, J . H.; Wilson, H. N., Eds.; Oxford University Press: London,
1958; pp 228-233.
6
4.8 and 58 for 4H and 4F . The rate-determining step and the
corresponding energy values for the â-CD-catalyzed reaction is shown
in eq 6, namely 8.77 and 5.79. Then the relative value for 4H and 4F
is calculated as (64.8 - 8.77) - (58 - 5.79) ) 3.8.
(33) Cyclodextrins were a gift from the pharmaceutical company
Ferromet S. A., Buenos Aires, Argentina.
(31) Milioto, S.; Crisantino, R.; Delisi, R.; Inglese, A. Langmuir 1995,
(34) Clark, R. F.; Simons, J . H. J . Am. Chem. Soc. 1953, 75, 6305.
(35) Crower, G. A. J . Fluorine Chem. 1971, 1, 219.
1
1, 718.