Mechanistically optimized intramolecular catalysis in the hydrolysis of esters. Global changes involved in molecular reactivity

Article abstract of DOI:10.1002/(SICI)1099-1395(199706)10:6<461::AID-POC914>3.0.CO;2-7

The hydrolysis of the 2′,2′,2′-trifluoroethyl monoester of 1,8-naphthalic acid (1) proceeds via the monoanion with the intermediate formation of the corresponding anhydride. The rate constant for the formation of 1,8-naphthalic anhydride (2) is ca 2500 times faster than its rate of hydrolysis. The isotope effect in the plateau region and theoretical calculations at the PM3 level suggest that elimination of the alkoxide is the rate-limiting step for the reaction. Accordingly, decomposition of the isopropyl monoester of naphthalic acid proceeds 10⁴ times slower than the spontaneous decomposition of 1. The remarkably high rate of monoester decomposition derives from the special configuration of the substrates and important contributions that arise from relief of torsional strain, which clearly includes electron redistribution due to the decrease in steric hindrance to resonance and the fact that proximity obviates solvation.

Full text of DOI:10.1002/(SICI)1099-1395(199706)10:6<461::AID-POC914>3.0.CO;2-7

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY, VOL. 10, 461–465 (1997)
MECHANISTICALLY OPTIMIZED INTRAMOLECULAR CATALYSIS IN
THE HYDROLYSIS OF ESTERS. GLOBAL CHANGES INVOLVED IN
MOLECULAR REACTIVITY
1
1
2
1
´
SANTIAGO F. YUNES, JOSE C. GESSER, HERNAN CHAIMOVICH AND FARUK NOME *
1
Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil
2
Instituto de Qu ´ı mica, Universidade de S a˜ o Paulo, S a˜ o Paulo, SP, Brazil
The hydrolysis of the 2Ј,2Ј,2Ј-trifluoroethyl monoester of 1,8-naphthalic acid (1) proceeds via the monoanion with the
intermediate formation of the corresponding anhydride. The rate constant for the formation of 1,8-naphthalic
anhydride (2) is ca 2500 times faster than its rate of hydrolysis. The isotope effect in the plateau region and theoretical
calculations at the PM3 level suggest that elimination of the alkoxide is the rate-limiting step for the reaction.
4
Accordingly, decomposition of the isopropyl monoester of naphthalic acid proceeds 10 times slower than the
spontaneous decomposition of 1. The remarkably high rate of monoester decomposition derives from the special
configuration of the substrates and important contributions that arise from relief of torsional strain, which clearly
includes electron redistribution due to the decrease in steric hindrance to resonance and the fact that proximity obviates
solvation. © 1997 by John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 10, 461–465 (1997) No. of Figures: 3 No. of Tables: 0 No. of References: 17
Keywords: mechanistically optimized intramolecular catalysis; ester hydrolysis; molecular reactivity.
Received 11 October 1996; revised 5 February 1997; accepted 12 February 1997
INTRODUCTION
a system which we believe contributes significantly to the
understanding of reactivity in biological systems.
In recent decades, the fascination with enzyme catalysis has
led chemists on a continuing search for simpler models
where the rates and selectivity of biological catalysts are
mimicked. Intramolecular accelerations are classical and
EXPERIMENTAL
Materials. The isopropyl monoester of 1,8-naphthalic
acid was prepared by reacting 1,8-naphthalic anhydride (2)
with sodium isopropoxide in propa-2-nol. The reaction
1–3
simple examples of this type of work.
At present,
however, there is no comprehensive theory, accepted by all
involved, that can explain, or predict, the factors by which
an enzymatic and/or intramolecular reaction will be faster
mixture was treated with HCl, extracted with CHCl and
3
finally the solvent was removed under vacuum. IR (KBr),
4–10
Ϫ1
1
(or slower) than the intermolecular counterpart.
Despite
␯max 3444, 2976, 1703, 1688 cm
; H NMR (CDCl3 ,
complications, quantitative comparisons between intra- and
intermolecular reactions are commonly expressed as effec-
200 MHz), ␦ 8·17–7·26 (m, ArH, 6 H), 5·33 (septuplet, CH,
13
1 H), 1·41 ppm (d, CH3 , 6 H);
C NMR (DMSO,
tive molarities (EM) taken as the ratios of the
200 MHz), ␦ 174·2, 168·5, 134·4, 133·2, 132·2, 130·8,
130·6, 130·1, 128·8, 125·8, 125·5, 125·2, 69·4, 21·9,
21·9 ppm; analysis, calculated for C H O , C 69·76, H
Ϫ1
intramolecular rate constant (k , s ) to the intermolecular
1
Ϫ1 Ϫ1
2
rate constant (k , lmol
s
), i.e. EM=k /k ( ). The wide
M
2
1
2
15 14
4
range of EMs for different types of reactions has generated
descriptive theories where the putative causes of large EMs
range from simple proximity to spatiotemporal descrip-
tions. In this paper, we report and analyze the remarkably
high rate of hydrolysis of monoesters of 1,8-naphthalic acid,
5·46, O 24·78; found, C 69·58, H 5·39, O 25·02%.
The 2Ј,2Ј,2Ј-trifluoroethyl monoester of 1,8-naphthalic
acid (1) was prepared in situ by a procedure identical with
4
–11
Ϫ1
that described above. IR, ␯ 2977, 2946, 1735, 1568 cm ;
max
1
H NMR (CF CH OH, 200 MHz), ␦ 8·15–7·45 (m, ArH,
3
2
13
6
2
1
H), 4·75 ppm (q, CH , 2 H); C NMR (CF CH OH,
2
3
2
00 MHz), ␦ 177·1, 167·8, 135·8, 133·8, 132·8, 130·1,
29·7, 129·2, 128·0, 125·3, 124·5, 124·3, 123·9, 59·7 ppm.
*
Correspondence to: F. Nome.
Contract grant sponsor: CNPq.
Contract grant sponsor: PADCT.
Contract grant sponsor: FINEP.
Methods. Rates of formation of the anhydride products
from monoesters of 1,8-naphthalic acid were followed
©
1997 by John Wiley & Sons, Ltd.
CCC 0894–3230/97/060461–05 $17.50

4
62
S. F. YUNES ET AL.
spectrophotometrically at the wavelength maximum of 2
anhydride (Scheme 1). The pH–rate constant profile for the
hydrolysis of 1 exhibits a plateau around pH 4–6 (Figure 1),
which indicates that the spontaneous decomposition of the
monoester monoanion is the main mechanistic pathway
(Scheme 1).
(340 nm) by using a Hewlett-Packard HP8452A spec-
trophotometer fitted with a thermostated water-jacketed cell
holder. All solutions were prepared using distilled, de-
mineralized water, which was boiled and cooled under
nitrogen to remove dissolved CO . Reaction was initiated
The pH–rate constant profile for the hydrolysis of 1 can
be quantitatively fitted using equation (1), which satisfies
Scheme 1:
2
by injection of 10 ␮l of ca 10 m
M
solutions of substrates
into 3 ml of buffers solution. Absorbance versus time data
were stored directly on a microcomputer using a Micro-
química 16 bit A/D interface board. First-order rate
constants, kobs , were estimated from linear plots of
+
kobs =k /(1+[H ]/K )
(1)
1
a
Treatment of the experimental data with equation (1)
Ϫ1 Ϫ1
ln(AϪA ) against time for at least 90% reaction using an
renders values of k1 =1·49ϫ10
s
and a kinetic
t
iterative least-squares program; correlation coefficients, r,
were >0·999 for all kinetic runs.
pK =3·47. The pK obtained agrees well with that expected
a
a
12
for 1 based on pK =3·67 for 1-naphthoic acid and the
a
expected substituent effect for the electron-withdrawing
8
-substituent. The absence of a kinetic solvent isotope effect
RESULTS AND DISCUSSION
(kH2O /kD2O =1·01 in the plateau region) is consistent with
The velocity of the decomposition of the monoester 1, when
compared with the rate of decomposition of the correspond-
ing anhydride 2, permitted the demonstration of the
formation of the intermediate. The calculated rate constants
for the descending limb of the kinetics shown in Figure 1
either the formation or the decomposition of the tetrahedral
intermediate as the rate-limiting step of the reaction, since
in both cases either a hydrogen atom or a water molecule is
not involved in the route to the transition state.
Despite all the difficulties in comparing bimolecular and
monomolecular reactions, there is general agreement that at
least the reaction pathways of the reactions to be compared
(
inset) are identical with those measured with authentic
,8-naphthalic anhydride. It is clear, therefore, that the
hydrolysis of the 2Ј,2Ј,2Ј-trifluoroethyl monoester of
,8-naphthalic acid occurs with the intermediate formation
1
must be identical. Using the commonly used reference
9
1
phthalic acid monomethyl ester (EM is assumed to be 10
M
of the corresponding anhydride. The rate constant for the
first step, which leads to the formation of naphthoic
anhydride, is ca 2500 times faster than the hydrolysis of 2.
Hence, the rate constant for the trans-acylation reaction can
be obtained without interference from the hydrolysis of the
for all phthalate esters; the reference intermolecular reaction
2
is the nucleophilic attack of acetate on phenylacetate ), the
13
EMs obtained with 1 are in excess of 10 . Indeed, the rate
constant in the plateau region (k ) for the formation of the
1
4
anhydride from the monoester of 1 is 10 times faster than
Figure 1. Effect of pH on the first-order rate constant for the hydrolysis of the 2Ј,2Ј,2Ј-trifluoroethyl monoester of 1,8-naphthalic acid. The
inset shows the absorbance at 340 nm as a function of time
©
1997 by John Wiley & Sons, Ltd.
JOURNAL OF PHYSICAL ORGANIC CHEMISTRY, VOL. 10, 461–465 (1997)

INTRAMOLECULAR CATALYSIS IN ESTER HYDROLYSIS
463
the hydrolysis of 2Ј,2Ј,2Ј-trifluoroethyl hydrogenphtha-
the ester groups in 1 are in the plane of the naphthalene ring
(Figure 2). The distance between the van der Waals radius
of the carboxylate oxygen atom (O-7) and the carbonyl
carbon (C-2) in the ester moiety is 0·17 Å, which is smaller
than the van der Waals radius of water, precluding the
presence of a solvent molecule between the reactive groups.
Also, similarly to the case of 1,8-diaminonaphthalenes,
1
3
late,
150 times faster than the hydrolysis of
14
2
Ј,2Ј,2Ј-trifluoroethyl
hydrogen-3,6-dimethylphthalate
and comparable to the highest rate accelerations obtained
for similar reactions in highly strained or sterically con-
strained systems.
Semi-empirical quantum chemical calculations of the
15
17
intramolecular reaction at the PM3 level, using the
there is a lack of planarity of the naphthalene ring. In the
1
6
MOPAC program package (version 6·0), are highly
informative. In all cases, the PRECISE keyword was used
and full geometry optimization was carried out (Fletcher–
Powell algorithm) without symmetry constraints. The
location of the transition state was done using the Eigenvec-
tor Following method. The characterization of both kinds of
stationary points, minimal and transition states, was carried
out by diagonalizing their Hessian matrices and looking for
zero and one-negative eigenvalues, respectively. Examina-
tion of the contour plots, obtained under the conditions
described above, indicates that neither the carboxylate nor
route to the transition state, as the carboxylate anion
approaches the neighboring carbonyl, the energy increases
and the transition state for the formation of the tetrahedral
intermediate is reached. The calculated enthalpy of activa-
Ϫ1
tion [5·19 kcal mol (1 kcal=4·184 kJ)] is well below the
experimentally
determined
activation
energy
-
Ϫ1
-
(⌬H =14·45 kcal mol and ⌬S =Ϫ12·9 e.u. were experi-
mentally determined for the hydrolysis of 1 in the plateau
region). In the tetrahedral intermediate (TI), formed in the
initial addition reaction, the torsional strain has been
considerably relieved, allowing the positioning of the
Figure 2. Projection of 1 and TI illustrating the lack of planarity of the naphthalene ring. (a) Lateral view and (b) projection in the naphthalene
ring plane. Selected torsional angles are given
©
1997 by John Wiley & Sons, Ltd.
JOURNAL OF PHYSICAL ORGANIC CHEMISTRY, VOL. 10, 461–465 (1997)

4
64
S. F. YUNES ET AL.
Scheme 1
carbonyl group coplanar with the aromatic ring. Also, the
coplanarity of the naphthalene ring is increased con-
siderably. When the decomposition of TI is examined, a
der Waals sum of radii and proceed further to the
equilibrium bonding distance. Certainly, a considerable part
of the rate acceleration stems from putting the reagents at an
appropriate distance for the reaction to occur. It is likely
that, owing to the high amount of energy expended on
desolvation of a carboxylate group, the attack of a
dissociated carboxylic acid on an unactivated ester in water
is essentially forbidden, in aqueous solutions, and no
bimolecular counterpart for this reaction has therefore been
described. In fact, general base catalysis is the natural
mechanistic option in aqueous solutions.
Ϫ1
value of 13·99 kcal mol is obtained for the enthalpy of
activation (calculated enthalpies of activation are generally
smaller than the experimental values), a result which clearly
indicates that the rate-limiting step for the trans-acylation
corresponds to the unimolecular decomposition of TI.
The absence of isotopic effect in the plateau region is
consistent with the theoretical calculations and suggests that
the reaction should depend strongly on the nature of the
leaving group. Indeed, decomposition of the isopropyl
Enzymes and nature do not define proximity in terms of
a definitive number of ångstroms between the amino acid
residue participating in the reaction and the reactive center
in the substrate. In aspartic proteases a single water
1
1
Ϫ4 Ϫ1
monoester of naphthalic acid (k=1·5ϫ10
s
at 50 °C)
4
proceeds 10 times slower than the spontaneous decomposi-
tion of 1.
1
In the present case, the remarkably high rate of monoester
decomposition derives from the very special configuration
of the substrates. Even the simple PM3/MOPAC calcula-
tions described above show that in substrate 1 the steric
crowding of the reaction region is sufficient to exclude
water molecules from part of the reaction region is sufficient
to exclude water molecules from part of the reaction center,
therefore generating a highly reactive carboxylate oxygen.
Although solvent can hydrogen bond both of the reactive
moieties of the substrate, there is not enough space to
position a water molecule between the groups and, there-
fore, the nucleophilic attack becomes facile. Reaching the
tetrahedral intermediate, a considerable part of the torsional
strain is relieved. As a consequence, decomposition of the
tetrahedral intermediate is then rate limiting.
molecule is bridging two aspartic residues, and the
‘proximity’ in this particular case is such that it allows the
nucleophile to become activated, and in a proper spatial
orientation, only on the reaction coordinate leading to the
transition state.
Clearly, the chemistry which actually occurs in aqueous
solutions for the ‘analogous bimolecular reaction’ is
completely different from the chemistry in our model
system, from a mechanistic point of view. What we are
stating here is that enzyme-like catalytic accelerations are
experimentally obtained only when a variety of factors
affect the reaction rate. In this sense, only full comprehen-
sion of the ‘global changes involved in molecular reactivity’
will finally lead to a proper understanding of enzyme
catalysis. Clearly, the rate of any particular reaction cannot
be analyzed in terms of the reactive groups only. Rate
accelerations may be caused by a wide variety of factors
related to structural changes and electron redistribution
processes along the reaction coordinate, involving the
complete molecule and not only the reactive center. In
accord with the essence of the transition-state theory, unless
all the molecular changes involved along the reaction
coordinate are taken into account, we will not understand
The central point here, that has led to much discussion in
trying to define the source of acceleration in intramolecular
catalysis, is that is certainly involves a matter of distance
and time. Here we are not proposing, as Menger clearly
stated, that ‘intramolecular reactions occur at enzyme-like
rates when van der Waals contact distances are imposed for
10
finite times upon reactive groups. Indeed, for any reaction
to occur the reactive partners must initially approach the van
©
1997 by John Wiley & Sons, Ltd.
JOURNAL OF PHYSICAL ORGANIC CHEMISTRY, VOL. 10, 461–465 (1997)

INTRAMOLECULAR CATALYSIS IN ESTER HYDROLYSIS
465
why reagents lead to products at enzyme-like rates. In our
case, important contributions arise from the relief of
torsional strain, which clearly includes electron redistribu-
tion due to the decrease in steric hindrance to resonance,
and the fact that proximity obviates solvation. Clearly,
improvement of our understanding of enzyme catalysis,
through the study of model systems, involves a full
comprehension of the global changes in electronic distribu-
tion on the route to the transition state.
Wilkinson, D. M. Blow, P. Brick, P. Carter, M. M. Y. Waye and
G. Winter, Nature (London) 314, 235 (1985).
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1
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1997 by John Wiley & Sons, Ltd.
JOURNAL OF PHYSICAL ORGANIC CHEMISTRY, VOL. 10, 461–465 (1997)