A study on a primitive artificial esterase model: Reactivity of a calix[4]resorcinarene bearing carboxyl groups

Article abstract of DOI:10.1002/poc.1371

The host molecule octacarboxymethyl calix[4]resorcinarene 1 catalyses the hydrolysis of substituted phenyl N-methylpyridinium-4-carboxylate esters 3a-f by complexation followed by intracomplex reaction via an anhydride intermediate. The reactivity in the

Full text of DOI:10.1002/poc.1371

Research Article
Received: 8 October 2007,
Revised: 3 March 2008,
Accepted: 5 March 2008,
Published online in Wiley InterScience: 2008
(www.interscience.wiley.com) DOI 10.1002/poc.1371
A study on a primitive artificial esterase
model: reactivity of a calix[4]resorcinarene
bearing carboxyl groups
a
a
by
a
*
˘
Giorgio Cevasco , Andrea Galatini , Necmettin Pirinc¸c¸ioglu , Sergio Thea
and Andrew Williamsbz
The host molecule octacarboxymethyl calix[4]resorcinarene 1 catalyses the hydrolysis of substituted phenyl N-
methylpyridinium-4-carboxylate esters 3a–f by complexation followed by intracomplex reaction via an anhydride
intermediate. The reactivity in the presence of 1 is higher than that of the background at low pH; at high pH an
inversion of reactivity occurs, the background becomes predominant since the host inhibits hydrolysis of the
esters. The reactivity of esters 3a–f complexed with the host suffers little change in effective charge on the phenolic
oxygen (ꢀ0.15 units) in contrast with the changes observed in alkaline hydrolysis (ꢀ0.28 units) and in the hydrolysis
of the model monoaryl glutarate esters (-1.02 units). The less negative effective charge in the transition state for host 1
catalysis compared with that in the glutarate case is ascribed to stronger solvation by water molecules in the complex
compared with that due to water molecules in the bulk solvent. Copyright ß 2008 John Wiley & Sons, Ltd.
Keywords: calixresorcinarenes; molecular receptors; catalysis; ester hydrolysis
INTRODUCTION
RESULTS
Carboxylate ions, in aqueous solution, catalyse the hydrolysis of
substituted phenyl esters via an anhydride intermediate or by
general base catalysis (Scheme 1).[1–7]
Kinetics of hydrolysis of the esters nicely fit first-order rate laws up
to 90% of the full reaction. Addition of 1 inhibits the hydrolysis of
both neutral and charged esters at pH 7.05 and above (Fig. 1 and
Fig. 2, respectively).
Since carboxylate ions can be readily incorporated into
macrocycles possessing cavities suitable as hosts, the system
would be interesting to study as a primitive model of an enzyme.
Calix[4]resorcinarenes would be particularly useful because they
have a binding site, and the rim of the macrocycle can be
functionalized easily to possess carboxylate ions which would be
suitable for reaction with aryl esters as in Scheme 1. Previous
work has shown that resorcinarenes bearing aliphatic chains
terminated by (CH3)2N groups at their upper rim can be good
catalysts for ester hydrolysis.[8] In this study, we investigate the
effect of a carboxy containing resorcinarene 1 on the hydrolysis
of some selected substituted phenyl esters.
Esters derived from N-methylpyridinium-4-carboxylic acid are
particularly useful in a preliminary study because they bear a
positive charge and therefore are expected to complex more
efficiently than neutral esters to a host possessing carboxylate
anion groups. Moreover, the reactivity of such esters is higher
than that of corresponding neutral aliphatic esters and the
effective charge characteristics of acyl group transfer reactions
with these positively charged esters have been elucidated
previously.[9,10]
On the other hand, the hydrolysis of the ester 3a at lower pH’s
is catalysed by the addition of 1 (Figure 2). Rate constants (kobs
)
depend on the concentration of the host and follow the rate law
of Eqn (1), derived from Scheme 2, where kb is the background
rate constant, KS is the dissociation constant of the host–guest
complex and kc is the rate constant for the complexed ester.
ðkb ꢁ Ks þ kc ꢁ ½hostꢂÞ
kobs
¼
(1)
ðKs þ ½hostꢂÞ
Rate constants for the hydrolysis of esters 2a–d in the absence
or presence of varying concentrations of host 1 are given in
Table 1.
`
Dipartimento di Chimica e Chimica Industriale dell’Universita di Genova, Via
*
Dodecaneso 31, 16146 Genova, Italy.
E-mail: sergio.thea@chimica.unige.it
a G. Cevasco, A. Galatini, S. Thea
Dipartimento di Chimica e Chimica Industriale dell’Universita di Genova,
`
The purpose of this work is to investigate the selectivity and
influence of the host molecule 1 on the reactivity of some
carboxylic acid esters, either neutral (2a–c) and positively
charged (2d and 3a–f), as shown in Chart 1. Linear free energy
relationships giving rise to effective charge distributions[11–13] will
also provide information about the micro-environment of the
guest ester (substituted phenyl N-methylpyridium-4-carboxylate
tosylate salts 3) in the complex with resorcinarene derivative 1.
C.N.R., Consiglio Nazionale delle Ricerche, Via Dodecaneso 31,16146 Genova,
Italy
˘
b N. Pirinc¸c¸ioglu, A. Williams
University Chemical Laboratory, Canterbury, Kent CT2 7NH, UK
y
Present address: Department of Chemistry, Faculty of Science, Dicle University,
21280 Diyarbakır, Turkey.
z
Deceased on 13th January 2007.
J. Phys. Org. Chem. 2008, 21 498–504
Copyright ß 2008 John Wiley & Sons, Ltd.

REACTIVITY OF CALIX[4]RESORCINARENE
Scheme 1. Mechanisms for the carboxylate ion-catalyzed hydrolysis of esters
Chart 1. Structures of macrocyclic host 1 and carboxylates 2 and 3
Figure 1. Dependence of rate constants on host 1 concentrations for the
hydrolysis of 2a (&, curve A, pH 10.38, 0.02 M borate, F ¼ 102) and 2b (*,
curve B, pH 12.05, 0.10 M phosphate, F ¼ 102), and the ethanolaminolysis
of 2b (&, curve C, pH 8.32, 0.5 M ethanolamine, F ¼ 103) at 25 8C. Data are
from Table 1 and lines are calculated from Eqn (1) using parameters from
Table 1
Figure 2. Dependence on pH of the hydrolysis of ester 3a in the
presence of 5 ꢁ 10ꢀ3 M host 1 (solid line, closed squares) or in its absence
(dashed line) at 25 8C. Data are from Table 3 and the solid line is calculated
from Eqn (2); dashed line is calculated from k ¼ 3.24 ꢁ 104 ꢁ [OHꢀ] (from
Table 4)
The reaction of 4-nitrophenyl benzoate 2b with the nucleo-
phile ethanolamine was also examined to see if the inhibition
could be simply due to electrostatic repulsion between ionized 1,
which is negatively charged, and hydroxide ion (see Fig. 1 and
Table 1). The rate constants for the hydrolysis of the charged
esters 3a–f in the absence and in the presence of increasing
concentrations of the host are recorded in Table 2 together with
the derived kinetic parameters KS (the dissociation constant of
Scheme 2.
J. Phys. Org. Chem. 2008, 21 498–504
Copyright ß 2008 John Wiley & Sons, Ltd.
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G. CEVASCO ET AL.
Table 1. Dependence of the rate constant kobs and the derived constants kb, kc and Ks, on the concentration of host 1 for the
hydrolysis of some 4-nitrophenyl esters at 25 8C in water solventa
102 ꢁ kobs/sꢀ1
[1]/M(ꢁ 103)
2ab
4.42
4.00
3.63
3.08
2.65
2.33
2.02
2bc
3.42
2.82
2.42
1.85
1.45
1.18
1.00
2bd
2ce
0.710
0.645 (0.005)e
0.610 (0.010)e
0.558 (0.020)e
0.540 (0.025)e
0.527 (0.030)e
2df
0.343
0.317
0.267
0.230
0.210
0.192
0.182
0.148
7.05
0.00
1.00
2.00
4.00
6.00
8.00
10.0
20.0
0.420
0.278
0.198
0.137
0.089
0.078
pH
10.38
44.0 ꢃ 0.5
12.05
34.1 ꢃ 0.1
8.32
4.21 ꢃ 0.08
10.95
kb/sꢀ1(ꢁ 103)
kc/sꢀ1(ꢁ 103)
KS/M (ꢁ103)
7.10 ꢃ 0.04
4.51 ꢃ 0.16
3.03 ꢃ 0.47
3.48 ꢃ 0.06
1.01 ꢃ 0.14
4.68 ꢃ 0.80
g
g
g
—
10.8 ꢃ 6.0
—
5.51 ꢃ 0.20
—
5.71 ꢃ 0.84i
a The initial concentration of esters is 1 ꢁ 10ꢀ5 M and the wavelength for kinetics is 400 nm.
b 0.02 M borate.
c 0.1 M K2HPO4.
d Reaction of ester 2b with 0.10 M ethanolamine.
e Borate (0.02 M); the numbers within the brackets show the concentration of the host.
f K2HPO4 (0.05 M) and the host concentration is in the range of 0–10ꢀ3 M.
g Zero within experimental errors.
Table 2. Dependence of rate constants on the concentration of host 1 for the hydrolysis of tosyl salts of substituted phenyl
N-methylpyridinium-4-carboxylates at pH 7.05 (0.05 M KH2PO4) and 25 8Ca
102 ꢁ kobs/sꢀ1
[1]/M (ꢁ103)
3a
1.54
1.12
0.850
0.770
0.671
0.641
0.515
7.14
3b
0.790
0.530
0.410
0.376
0.327
0.319
0.259
8.35
3c
3d
1.44
0.891
0.681
0.582
0.511
0.473
0.366
7.75
3e
1.57
1.08
0.821
0.729
0.630
0.601
0.449
7.26
3f
3.28
2.00
1.45
1.24
1.04
0.972
0.709
6.36c
0.00
0.20
0.40
0.60
0.80
1.00
2.00
0.466
0.305
0.241
0.225
0.206
0.201
0.182
9.19
b
pKa
kb/sꢀ1 (ꢁ103)d
kc/sꢀ1 (ꢁ103)e
KS/M (ꢁ104)f
15.5 ꢃ 0.2
3.33 ꢃ 0.39
3.30 ꢃ 0.37
10.9
7.91 ꢃ 0.09
1.94 ꢃ 0.12
2.47 ꢃ 0.21
7.85
4.67 ꢃ 0.05
1.54 ꢃ 0.06
1.73 ꢃ 0.16
8.9
14.4 ꢃ 0.4
2.41 ꢃ 0.05
2.35 ꢃ 0.04
10.2
10.5 ꢃ 0.2
2.78 ꢃ 0.26
3.11 ꢃ 0.23
8.94
33.0 ꢃ 0.3
3.87 ꢃ 0.34
2.43 ꢃ 0.12
15.9
kc/KS (sꢀ1 Mꢀ1 g
)
a Tosyl salt of substituted phenyl N-methylpyridinium-4-carboxylate. Concentrations of substrates and wavelengths for kinetic
studies: 3a (4 ꢁ 10ꢀ5 M, lmax ¼ 400 nm); 3b (2.5 ꢁ 10ꢀ4 M, lmax ¼ 340 nm); 3c (4 ꢁ 10ꢀ5 M, lmax ¼ 325 nm); 3d (2.5 ꢁ 10ꢀ4 M, lmax
¼
340 nm); 3e (2.5 ꢁ 10ꢀ4 M, lmax ¼ 370 nm) and 3f (4 ꢁ 10ꢀ5 M, lmax ¼ 410 nm).
b The ionizations constants of leaving groups are from Reference[14], unless stated otherwise.
c pKa value from Reference[15]
.
d First-order rate constant for the reaction of esters in the buffer (including buffer and hydroxide ion terms).
e First-order rate constant for the ester complex with host 1.
f Dissociation constant of esters from their complex with host 1.
g Apparent second-order rate constant for the reaction of substituted phenyl N-methylpyridinium-4-carboxylate esters with free host 1.
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Copyright ß 2008 John Wiley & Sons, Ltd.
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REACTIVITY OF CALIX[4]RESORCINARENE
Table 3. The effect of pH on the hydrolysis of 3a in the presence of host 1 (5 ꢁ 10ꢀ3 M) at 25 8C. The host molecule itself provides
buffering capacity
pH
kobs ꢁ 104/sꢀ1
4.35
3.37
4.47
3.83
4.62
4.45
4.80
4.72
4.80
5.35
5.19
5.93
5.50
7.30
6.05
8.03
6.35
9.07
7.00
8.55
7.96
21.2
the ester–host complex) and kc/KS (the apparent second-order
rate constant for the reaction of N-methylpyridinium
4-carboxylates through the ester–host complex).
assumed as negligible in comparison with kcmax). Rate constants
for the hydrolysis of substituted phenyl N-methyl pyridinium-4-
carboxylates are linearly related to phosphate (HPO24ꢀ) concen-
The pH-dependence of the reactivity of 1 with the ‘charged’
4-nitrophenyl ester 3a was determined for a 5 mM constant
concentration of host (higher concentrations were not attainable
due to insufficient solubility of host 1 at low pH’s); although this
concentration does not completely complex the ester, a
significant part of the reaction flux is via the complex and if
KS is insensitive to pH, the pH-dependence will be a reasonably
good reflection of that for kc. The rate constants possess a plateau
region between pH’s 5 and 7 which falls off at low pH and
increases at higher pH. The rate constants fit Eqn (2) (see Table 3),
where kcmax is the first-order rate constant for the host-mediated
reaction, kOH is the second-order rate constant for alkaline
hydrolysis of the anionic form of the complexed ester, and Ka and
KW are the ionization constants of the host and water,
respectively.
trations (kobs ¼ kHPO ½HPO24ꢀꢂ þ kOH ½OHꢀꢂ) and the derived
4
second-order rate constants for phosphate and hydroxide
catalyzed reactions are shown in Table 4 (it is assumed that
the contribution of water to the overall rate is negligible), where
kHPO and kOH are second-order rate constants for HPO24ꢀ and
4
hydroxide ion catalyzed hydrolysis of 4-nitrophenyl N-methylpyri-
dinium-4-carboxylates. The dependence of the rate and equi-
librium parameters on the pKa of the leaving phenolate ion for
the hydrolysis of substituted phenyl N-methylpyridinium-
4-carboxylate in the absence and in the presence of the host
molecule 1 fit Eqns (3–6).
log kHPO ¼ ꢀð0:42 ꢃ 0:07ÞpKaArOH þ ð2:7 ꢃ 0:5Þ
(3)
4
log kOH ¼ ꢀð0:28 ꢃ 0:03ÞpKaArOH þ ð0:31 ꢃ 0:19Þ
log kcmax ¼ ꢀð0:15 ꢃ 0:01ÞpKaArOH ꢀ ð1:47 ꢃ 0:09Þ
log KS ¼ ꢀð0:068 ꢃ 0:037ÞpKaArOH ꢀ ð3:1 ꢃ 0:3Þ
(4)
(5)
(6)
À
Á
kcmax þ KOH ꢁ KW ꢁ 10pH
ð1 þ 10ꢀpH=KaÞ
(2)
kobs ꢄ kc ¼
The derived parameters in Eqn (2) are as follows: pKa ¼
4.51 ꢃ 0.05, kcmax ¼ (7.96 ꢃ 0.18) ꢁ 10ꢀ4 sꢀ1, kOH ¼ (1.42 ꢃ 0.15) ꢁ
103 Mꢀ1 sꢀ1 with pKW ¼ 14.0. The value of the apparent pKa is
lower than that determined titrimetrically for the host in a
different solvent system (5.95, see Section ‘Experimental’), but
this is not significant as change in the solvent is likely to change
the pKa substantially.
With reference to the reactivity of 3a in the presence of host 1,
the pH (7.05) of the measurements (Table 2) is within the plateau
region as shown in Fig. 2, and hence the parameters kc actually
can be taken as kcmax (in Eqn (2), the term kOH ꢁ KW ꢁ 10pH can be
A small difference is found between the bLG in Eqn (4) (ꢀ0.28)
and that previously reported (ꢀ0.35)[10] for a set of esters bearing
(partly) different substituents. In this work we used the presently
assessed value.
The rate constants for hydrolysis of the ester 3a in acetate
buffers at pH 5.85 vary linearly as a function of acetate ion
concentration (0–0.050 M) yielding a second-order rate constant
of 1.09 ꢁ 10ꢀ3
M
ꢀ1 sꢀ1 for attack of acetate ion on 3a.
A trapping experiment was carried out by reacting 1 (5.0 mM)
with 0.02 M tosyl 4-nitrophenyl N-methylpyridinium-4-carbo-
xylate 3a at pH 8.36 in the presence of excess morpholine
Table 4. Effect of phosphate (HPO24ꢀ) and hydroxide ion on the hydrolysis of substituted phenyl N-methylpyridinium-4-carboxylate
esters at pH 7.00 and 25 8Ca,b
Nc
kHPO ꢁ 10ꢀ2/Mꢀ1 sꢀ1d
kOH ꢁ 10ꢀ4 /Mꢀ1 sꢀ1e
pKaArOH
Esters
4
3a
3b
3c
3d
3e
3f
4
4
5
4
4
4
36.7 ꢃ 3.0
11.5 ꢃ 1.0
7.28 ꢃ 0.4
31.4 ꢃ 2.9
26.1 ꢃ 1.0
136 ꢃ 10
7.14
8.35
9.19
7.75
7.26
6.36
3.24 ꢃ 0.2
1.68 ꢃ 0.1
0.90 ꢃ 0.02
3.61 ꢃ 0.15
2.00 ꢃ 0.08
7.79 ꢃ 0.07
a Ester concentration and wavelengths for kinetic studies given in Table 1.
b Concentration range of phosphate buffer between 0.02 and 0.1 M.
c Number of data points not including duplicates.
d Second-order rate constants for HPO24ꢀ-catalyzed hydrolysis of substituted esters calculated from the slope of kobs against [HPO24ꢀ].
e Calculated from the intercept of the plot of kobs against [HPO42ꢀ] assuming Kw ¼ 10ꢀ14
.
J. Phys. Org. Chem. 2008, 21 498–504
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G. CEVASCO ET AL.
(0.4 M). After completion of the reaction (as judged by monitoring
the release of 4-nitrophenol) the solution was brought to pH 2
with dilute HCl and the resultant precipitate was isolated by
filtration and washed with water (to remove the residual
unreacted amine as well as all products derived from the ester
which are soluble in water at acidic pH’s). The 1H NMR spectrum
of the carefully dried residue was analysed, revealing that an
aliquot of the trapping agent had undergone incorporation into
1, consistent with a final mixture of host modified as the
monoamide 1a (as shown in Scheme 3) and the starting material
1 in a ratio of 1:3.
complex and is independent of the accelerative or inhibitory
nature of the system.
Tables 1 and 2 indicate that host 1 complexes with
4-nitrophenyl N-methyl pyridinium-4-carboxylate (KS ¼ 0.33 mM)
better than with 4-nitrophenyl N-methylpyridinium-3-carbo-
xylate (KS ¼ 4.7 mM), possibly due to a more favourable structure
of the ester enabling it to be accommodated within the cavity of
the host. The improved binding (as expressed by 1/KS) of charged
esters compared with that of the neutral ones (Table 1) may be
attributed to favourable electrostatic interactions between
carboxylate and N-methyl residue of the pyridine ring. Electro-
static interactions are often weak in bulk water as charges are
dispersed by solvation. In this system it is likely that the aromatic
rings provide a hydrophobic micro-environment, thus strength-
ening the electrostatic interaction between the carboxylate
groups of the host and the positive charge of the ester. As a result,
the positively charged esters are bound to the host more strongly
than are neutral esters. Benzoate ester associates with the host
twofold better than acetate, which may be attributed to a more
favourable interaction of benzoate within the cavity by means of
p–p interactions between the phenyl component of the
benzoate and the aromatic cavity of 1.
DISCUSSION
The pH-dependence of the hydrolysis of 4-nitrophenyl N-methyl
pyridinium-4-carboxylates (shown in Figure 2) is consistent with
the involvement of a carboxyl group of the host molecule
(pKaapparent ¼ 4:51 ꢃ 0:05) in the reaction. The second-order rate
constant for the acetate-catalyzed reaction of 4-nitrophenyl
N-methylpyridinium-4-carboxylate is 1.09 ꢁ 10ꢀ3
M
ꢀ1 sꢀ1 and this
Addition of host 1 induces complete inactivation of the
benzoate and acetate esters (kc ¼ 0), whereas esters of hexanoic
acid and of the charged acids retain a significant reactivity.
Chawla and Pathak[16] report that derivatives of calix[n]arenes
(n ¼ 4, 5, 6 and 8) slow down the release of phenol of p- and
m-substituted phenyl benzoates. This is ascribed by these authors
to the encapsulation of the released phenoxide ion into the cavity
of the host during the reaction. Ionic repulsion may not be the
reason for the rate inhibition because reaction of benzoate ester
with ethanolamine (Figure 1 and Table 1) in the presence of the
host molecule also suffers complete inhibition; since at the pH of
the experiment ethanolamine is not negatively charged, it will
not be electrostatically repelled by the host and therefore
hindrance of negatively charged nucleophiles (e.g., buffer and
hydroxide ions) ensuing from electrostatic repulsion may not
simply account for the rate retardation. Thus, it is more likely that
is probably an upper limit because previous studies on
acetate-catalyzed hydrolysis of 4-nitrophenyl esters indicate that
the 4-nitrophenyl esters possess both general base and
nucleophilic components.[1–7] This value can be directly
compared with the value of the parameter kcmax/Ks for 3a
(10.9 Mꢀ1 sꢀ1), which indicates a significant catalytic effect even if
the number of carboxylic groups in 1 is taken into account
ð½kcmax=KSÞ=8ꢂ=knuc ¼ 1250Þ.
Figure 2 shows that the host acts as a catalyst for ester
hydrolysis at low pH’s but as an inhibitor at higher pH’s; this
observation results from the hydroxide ion-catalyzed hydrolysis
of the ester being low at low pH’s but increasing at high pH until it
takes the majority of the reaction flux. This change in reactivity
from catalysis to inhibition is of interest from a practical point of
view; theoretically the value of kc determined under conditions of
inhibition reflects the reactivity of the ester in the ester–host
Scheme 3. The mechanism of action of host 1 for the intramolecular cleavage of 4-nitrophenyl esters
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Copyright ß 2008 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2008, 21 498–504

REACTIVITY OF CALIX[4]RESORCINARENE
benzoate and acetate moieties are located in the cavity so
that their reaction centres are entirely blocked from intermole-
cular attack (buffer, hydroxide and water) or intramolecular
nucleophilic attack by the carboxylate groups of the host.
The parent calix[4]resorcinarene, with all eight phenolic groups
of the host ionized, shows similar saturation kinetics in the
hydrolysis of acetylcholine where a 10-fold rate retardation is
observed.[17]
If carboxylate groups participate intramolecularly in the
reaction via an anhydride (see Scheme 3), the intermediate
could be trapped by an amine to give an amide which could then
be analysed.
rationalized on the basis of the different reactivity of the two
moieties of the asymmetric anhydride, the less reactive one being
that on the side of the host, due to electronic and (possibly) steric
reasons. An additional pathway contributing (in part) to the
formation of amide 1a could be that indicated as pathway (c),
where the ‘internal’ anhydride 5 is formed which then reacts with
morpholine to give host-amide. Since the product analysis shows
that just ca. 25% of the host has been converted to the
host–amide product, the pathways (a) and (b) must lie along the
reaction path, otherwise the host would be converted exclusively
to 1a.
The effective charge map of the reaction of host 1 with esters 3
can be derived from the Brønsted correlations (Eqns 3–6) and is
shown in Scheme 4, compared with those of model reactions. It is
interesting to note that the aryl oxygen of the ester has slightly
more positive effective charge in the complex (þ0.62) than in the
free ester (þ0.55).
The trapping of the intermediate in the hydrolysis reaction of
4-nitrophenyl N-methylpyridinium-4-carboxylate in the presence
of the host 1 with morpholine confirms that the reaction involves
intramolecular nucleophilic attack of carboxylate of the host with
1
the guest ester. The H NMR analysis of the host isolated after
catalysis is consistent with asymmetrical bond cleavage (a and b)
yielding host-amide 1a and N-methylpyridinium-4-carboxamide
4. The preference for the pathway (b) with respect to (a) could be
The transition structure of the reaction exhibits an effective
charge on the ether oxygen of the ester (þ0.47) which is
significantly more positive than that found in the transition state
Scheme 4. Effective charge map[11] for the reaction of host 1 with N-methylpyridinium-4-carboxylate esters compared with those of model reactions
J. Phys. Org. Chem. 2008, 21 498–504
Copyright ß 2008 John Wiley & Sons, Ltd.
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G. CEVASCO ET AL.
carboxylate were synthesized as described previously.[9] The
macrocycle, octacarboxymethyl calix[4]resorcinarene (1) was
prepared from the corresponding octaethyl ester.[8] The octaethyl
ester (5 g, 50 mmol) was dissolved in THF (50 ml) and mixed with
KOH (1 M, 50 ml). The solution was stirred for 24 h, then
evaporated in vacuo, diluted with water (100 ml) and neutralized
with HCl to give a precipitate (1) which was recrystallized from
water/ethanol to yield needles, m. p. > 3008. Found C, 53.62; H,
5.14% Formula C48H48O24ꢅ4H2O requires C, 53.34; H, 5.22%.
1H NMR (200 MHz, DMSO-d6, ppm): d ¼ 6.43 (s, 8H, Ar—H),
4.57–4.55 (q, 4H, J ¼ 7 Hz, —CHCH3), 4.52 (s, 8H, —O—CH2—
CO2H), 4.31 (b, 8H, —O—CH2CO2H) and 1.42–1.39 (d, 12H,
J ¼ 7 Hz —CHCH3). Owing to the low solubility of neutral host 1 in
pure water, the pKa was determined by pH-titration in 40/60 v/v
water/DMF at 258 and is 5.95 ꢃ 0.04, suggesting that no
significant interaction among the carboxy groups is taking place
during ionization. Equivalent weight from the pH-titration: 128.3;
Formula C48H48O24ꢅ4H2O requires: 135.1.
Scheme 5. Cartoon of the transition structure of the intramolecular
reaction of ester with host 1 illustrating the electrophilic interaction
via solvation with water molecules in the host–guest complex
of the reaction with hydroxide ion of the uncomplexed substrate
(þ0.27), and is dramatically more positive than those observed for
nucleophilic catalysis by carboxylate ion in the model reactions
(intramolecular, ꢀ0.32[7] and intermolecular, ꢀ0.09[6]). In both the
latter model reactions, the transition structure is likely to possess
substantial ArO—C bond fission and to reflect a concerted
displacement by the carboxylate anion because the carboxylate
ion is a weak nucleophile. The reaction of carboxylate ion in the
ester complex is unlikely to differ markedly in its fundamental
mechanism from the model; the most plausible explanation of
the substantially more positive effective charge is that there is
solvation of the developing negative charge (on the aryl oxygen)
by groups or solvent molecules residing in the host complex.
There is no electrophilic group in the host’s structure which could
be responsible for such a solvation process but water molecules
present in the host–guest complex (Scheme 5) could solvate the
developing negative charge.
Methods
The kinetic methods employed in this study have been described
previously.[8]
Acknowledgements
The University of Dicle is thanked for a studentship (NP). Financial
support (Grant 2003.1600) from the Compagnia di San Paolo
(Torino, Italy) for the acquisition of a gradient NMR probe is
gratefully acknowledged (GC, AG, ST).
Since the water molecules would not be the part of a water
structure, the solvation interaction could be stronger than that
which occurs in bulk solution. This would have a greater effect on
the developing negative charge in the transition state compared
with that in the bulk solvent where the solvating power of a water
molecule would be reduced by its interaction with other water
molecules. A similar positive effective charge was observed in the
ester hydrolysis catalyzed by the structurally related resorcinar-
ene derivative with eight N,N-dimethylamino functions attached
to its upper rim.[8]
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J. Phys. Org. Chem. 2008, 21 498–504