Mechanism of intramolecular catalysis in the hydrolysis of alkyl monoesters of 1,8-naphthalic acid

Article abstract of DOI:10.1039/c1ob05574g

Hydrolysis of alkyl 1,8-naphthalic acid monoesters 1a-d is subject to highly efficient intramolecular nucleophilic catalysis by the neighboring COOH group. The reactivity for the COOH reaction depends on the leaving group pK _a, with values of β_LG of -0.50, consistent with a mechanism involving rate determining breakdown of tetrahedral addition intermediates. The release of the steric strain of the peri-substitiuents in the highly reactive alkyl 1,8-naphthalic acid monoesters is fundamental to understand the observed special reactivity in this intramolecular reaction. DFT calculations show how the proton transfers involved in the cleavage of the neutral ester can be catalyzed by solvent water, thus facilitating the departure of poor alkoxide leaving groups.

Full text of DOI:10.1039/c1ob05574g

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PAPER
Mechanism of intramolecular catalysis in the hydrolysis of alkyl monoesters
of 1,8-naphthalic acid†
Bruno S. Souza, Santiago F. Yunes, Marcelo F. Lima, Jose´ C. Gesser, Marcus M. Sa´, Haidi D. Fiedler and
Faruk Nome*
Received 11th April 2011, Accepted 3rd June 2011
DOI: 10.1039/c1ob05574g
Hydrolysis of alkyl 1,8-naphthalic acid monoesters 1a–d is subject to highly efficient intramolecular
nucleophilic catalysis by the neighboring COOH group. The reactivity for the COOH reaction depends
on the leaving group pKa, with values of bLG of -0.50, consistent with a mechanism involving rate
determining breakdown of tetrahedral addition intermediates. The release of the steric strain of the
peri-substitiuents in the highly reactive alkyl 1,8-naphthalic acid monoesters is fundamental to
understand the observed special reactivity in this intramolecular reaction. DFT calculations show how
the proton transfers involved in the cleavage of the neutral ester can be catalyzed by solvent water, thus
facilitating the departure of poor alkoxide leaving groups.
1. Introduction
Attempts to understand enzyme catalysis at the molecular level
have led chemists to study systems involving medium effects and
intramolecular catalysis in ester and amide hydrolysis, as simple
models for the corresponding enzyme reactions.1 Intramolecular
“models” and enzyme reactions both involve reactions between
Scheme 1 Dissociative mechanism for the hydrolysis of the monoester
8DMNP-.
groups brought together in a single molecule or complex.2 The
early observation of essential carboxyl groups in the catalytic
centers of aspartic acid-based enzymes generated continuing
an efficient intramolecular reaction site. Relative accelerations
interest in the possible roles of these groups in catalyzing hydrolysis
(EMs), obtained by comparisons of second and first order rate
reactions.3
constants, can be as large as 1011 in model systems based upon
As previously discussed, general acid–base catalysis is highly
naphthalic acid derivatives.5 The spontaneous hydrolysis of the
efficient in enzyme active sites, but in only a handful of model
2¢,2¢,2¢-trifluoroethyl monoester of 1,8-naphthalic acid 1a has been
systems. A particularly efficient intramolecular model system is
the phosphate transfer from the 8-dimethylammonium-naphthyl-
1-phosphate monoanion 8DMNP- to water and to a range of
shown to involve the monoanion 1a- reacting via a tetrahedral
intermediate 2a- to form naphthalic anhydride (NA). NA is in
slow equilibrium with naphthalic acid (3) in water, but the rate
constant for its formation at pH 5 is ca. 2500 times faster than
nucleophiles, which shows general acid catalysis by the neighbor-
ing NH+ group, with a strong intramolecular hydrogen bond in the
that for its hydrolysis (Scheme 2).5b
transition state (Scheme 1).4 The substantial acceleration (of the
The remarkably high rate of reaction of the monoester monoan-
ion 1a- derives from the special configuration of the substrate, in
order of 106-fold at 39 ◦C) is achieved by the concerted action of
an internal general acid and an external nucleophile, in a reaction
which group proximity restricts solvation, and there is important
with low sensitivity to the incoming nucleophile.
relief of torsional (eclipsing) strain on formation of the fused
In an attempt to detect catalysis by the carboxyl group in the
tricyclic system.5b In this work we examine the remarkably rapid
hydrolysis of unactivated esters rather than p-nitrophenyl phos-
hydrolysis of a series of simple alkyl monoesters of 1,8-naphthalic
acid 1a–d (Scheme 2), where participation of a neighboring
phate esters, we used the naphthalene ring as a template to build
COOH group is fundamental and the results contribute to our
understanding of reactivity in biological systems.
Departamento de Qu´ımica, Universidade Federal de Santa Catarina, Flo-
riano´polis-SC, Brazil. E-mail: faruk@qmc.ufsc.br; Fax: +55-48 3721-6850;
Tel: +55-48 3721-6849
† Electronic supplementary information (ESI) available: Spectra for acid
hydrolysis, Eyring plot for hydrolysis of the alkyl esters, UV-vis titration
of the methyl ester and Cartesian coordinates of the B3LYP optimized
structures together with relevant calculated information. HPLC analyses
of the kinetic samples. See DOI: 10.1039/c1ob05574g
2. Results and discussion
Rates of decomposition of 1,8-naphthalic monoalkyl esters 1a–
d were followed by monitoring UV-vis spectral changes in the
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Scheme 2 Decomposition of alkyl monoesters (1) of 1,8-naphthalic acid (3).
range of 280 to 380 nm. An example of the similar changes
observed in the UV spectra during the hydrolysis of all four
monoalkylesters 1a–d is given in Fig. S1 in the Supporting
Information.†The absorption maxima at 298 and 340 nm have
been attributed to the monoalkyl esters of naphthalic acid and
to 1,8-naphthalic anhydride 3, respectively.5 UV spectral changes
show that the reaction proceeds with formation of 1,8-naphthalic
anhydride (NA), which subsequently equilibrates with naphthalic
acid following previously described pH-dependent decomposi-
tion kinetics. Nevertheless, rate constants for the intramolecular
transacylation can be obtained without interference from the
anhydride hydrolysis reaction.5
Building on our experience in reaction mechanism studies using
MS techniques,6 we applied ESI-MS to monitor the course of the
hydrolysis of some of the slower reactions in aqueous solution and
Fig. 1 shows the results obtained with the monoalkylester 1c. In
the ESI-MS process used here, solvated ions are “fished” directly
from solution and transferred to the gas phase. The data provide
snapshots of the ions present in the reaction solution, which have
been shown in numerous cases to reflect accurately the actual
ionic composition.6a At pH 5.8 and 50 ◦C, samples of reaction
solution, containing all reagents, intermediates, and products,
were transferred directly to the gas phase and characterized
by ESI( )-MS/MS. Initially, ESI-MS-(/MS) hydrolysis of 1c
showed the deprotonated form of the reactant 1c of m/z 229
which reacts forming neutral 1,8-naphthalic anhydride (NA)
and the monoanion of naphthalic acid of m/z 215. Fig. 1B,
shows the decrease in concentration of 1c as a function of time
calculated from the ESI(-)-MS experiments and the results yield
rate constants basically identical to those obtained by UV-vis
spectroscopy (Fig. 2).
Fig. 2 First order rate constants vs. pH for the hydrolysis of the isopropyl
(1b, ᭡), methyl (1c, ꢀ) and n-butyl (1d, ) monoesters of 1,8-naphthalic
᭺
acid, at 50.0 ◦C (values below zero on the pH axis correspond to the
H0 function). Curves are calculated according to eqn (1), using the rate
constants given in Table 1. The insert shows the pH rate profile for the
hydrolysis of the trifluoroethyl ester 1a at 20 ◦C.
hydroxide ion catalysis is not significant in the pH-range (<6)
under study.5 Between H0 = -2 and pH 1 the reaction shows
behavior typical for specific acid catalysis; while between pH 1
and 6 the first-order rate constants show a plateau between pH
1 and 3 and for higher pH values the rate constants decrease
for compounds 1b, 1c and 1d. This is not normal behavior for
alkyl esters, and is prima facie evidence for neighboring group
participation. Rate constants for the intramolecular reaction of
the monoalkyl esters 1a–d as a function of pH (Fig. 2) show
that the participation of the COOH group is more efficient for
the more basic leaving groups, while the carboxylate anion is the
most reactive species in the reaction of the 2¢,2¢,2¢-trifluoroethyl
monoester of 1,8-naphthalic acid 1a (Scheme 3).5b The decrease in
reactivity of the alkyl monoesters 1b–d at higher pH is certainly
related to the ionization of the carboxylic acid moiety, which is a
less effective catalyst than the protonated form and the more basic
leaving groups seem to be cleaved more efficiently via general acid
catalysis. This issue will be discussed later in the text.
The series of reactions shown in Scheme 3 account satisfactorily
for the kinetic observations shown in Fig. 2 and allow the
derivation of eqn (1), which describes the pH dependence of the
experimental first order rate constant.
k
(kCOOH + kH[H+ ])
(1+ Ka2 /[H+ ])
-
COO
(1)
kobs
=
+
(1+[H+ ]/ Ka2
)
In eqn (1), kCOOH and kCOO- are the rate constants for the reactions
of the neutral and anionic forms of esters 1a–d, respectively, and
Ka represents the acid dissociation constants of 1a–d, kH denotes
the second order rate constant for the hydronium ion catalyzed
reaction. Since the hydroxide reaction is unimportant between pH
1–6, it can be neglected. The solid lines in Fig. 2 were calculated
Fig. 1 (A) Typical mass spectrum for the hydrolysis of the methyl ester 1c
after 7 h of reaction. (B) Decomposition of 1c at pH 5.80, 50 ◦C followed
by ESI-MS.
The pH-rate profiles for these reactions (Fig. 2) exhibit two
distinct regions, below and above pH 1, and the contribution of
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Significantly, the observed solvent kinetic isotope effect (SKIE)
depends markedly on the species present in solution, with a SKIE
kH O/kD = 1.01 reported for compound 1a in the plateau region
O
2
2
above pH 4,5b strongly indicative of nucleophilic attack by the
carboxylate anion. The same ester 1a, at pH 0, shows a SKIE
kH2O/kD2O = 1.47, which indicates proton transfer, but the observed
SKIE may contain contributions of the acid catalysis and the
remaining reactivity of the monoanion. Conversely, the SKIE
observed for the alkyl esters 1b–d, measured in the pl◦ateau region
of the carboxylic acid form at pH 2.0 (pD 2.50 at 50 C11), shows
kH O/kD values in the range between 2.50 and 2.88 and the
O
2
2
magnitude of the SKIE is fully consistent with the involvement
of proton transfer in the rate-determining step.
The rate constants for assistance by the neighboring COOH
groups show a small dependence on the pKa of the leaving
group (Fig. 3). The exceptional level of reactivity observed for
compounds 1a–d is specific to enzymatic and intramolecular
reactions where the reacting groups are held close together; as
they are in 1,8-naphthalene derivatives.12 Our results are consistent
with those reported by Thanassi and Bruice13 for hydrolyses of
monoalkyl esters of phthalic acid, and by Kirby and coworkers9
for hydrolyses of alkyl hydrogen dialkylmaleates. In fact, hydrolysis
of compound 1c shows a significant general base catalysis in
the presence of chloroacetate buffer (Fig. S4†) and this result
is consistent with an addition elimination mechanism, similar
to that proposed for the hydrolysis of methyl hydrogen di-
isopropylmaleates.9
Scheme 3 Possible reaction paths and species involved in the decompo-
sition of alkyl monoesters of 1,8-naphthalic acid.
using eqn (1) and the apparent kinetic pKa values obtained for
all four compounds are consistent with the value of 3.82 0.03
measured by the spectroscopic titration of compound 1c (at 25 ◦C,
see supplementary information, Fig. S2†) and the reported pKa of
3.5 for the parent 1,8-naphthalic acid (Table 1).5a
Table 1 summarizes the rate and dissociation constants used
for fitting the pH–rate profiles. The rate constants kCOOH show
the individual contributions to the anchimeric assistance of the
carboxylic acid in the transacylation reaction. The carboxylate
anion is efficient when the less basic 2¢,2¢,2¢-trifluoroethoxide is
the leaving group of the naphthalic acid monoester (1a)5b and does
not contribute significantly with compounds 1b–d. Conversely,
the reactivity of the carboxylic acid form is fully functional
even when more basic and, therefore, less efficient leaving groups
are involved (1b–d). The rate constants for the hydronium ion
catalyzed reaction (kH) are of the same order of those reported for
the reaction of aspirin derivatives7 and are consistent with a partial
contribution of the specific acid catalyzed pathway described in
Scheme 3.
Activation parameters for the hydrolysis of esters 1a–d are
shown in Table 2. Enthalpies of activation fall in the range reported
for the related hydrolysis of methyl hydrogen dialkylmaleates.9
However, compounds 1a–d show negative entropies of acti-
vation substantially lower than the corresponding values for
dialkylmaleates9 which is indicative of a reaction involving a
bimolecular process.10
Fig. 3 Linear free-energy relationships between the log of the rate
constant and the pKa of the leaving group for the participation of
neighboring COOH (ꢀ) groups in the hydrolysis of esters 1a–d at 50 ◦C.
The value of bLG = -0.50 for the reaction involving catalysis
by the COOH group indicates that the reaction is sensitive to
the basicity of the leaving group. Nucleophilic catalysis in the
region where the carboxylate anion is the predominant species
becomes important when the nucleophile is more basic than
Table 1 Rate constants for carboxylic and carboxylate catalysis in ester hydrolysis at 50◦
C
kCOOH (10-4 s-1)
kCOO (s-1)
kH (10-4 M-1s-1)
-
Ester
pKa
pKa (LG)
1aa
1b
1c
3.83 0.02a
4.45 0.33
4.37 0.17
4.26 0.16
12.36b
16.60d
15.49d
15.87d
268.7c
1.43 0.25
6.15 0.12
7.57 0.70
0.15 0.01a
—
—
—
1.15 0.02a
1.83 0.01
3.62 0.06
3.27 0.04
1d
a From ref. 5b measured at 20 ◦C. b From ref. 8. c Rate constant given in the Eyring plot in the Supplementary Information.† d From ref. 9.
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Table 2 Activation parameters for hydrolysis of naphthalic acid monoesters in the pH ranges for catalysis by carboxylic acid groups at 50 ◦
C
Ester
pH
DH‡,a kcal mol-1
DS‡,b cal mol-1K-1
DG‡,c kcal mol-1
(kH O/kD
)
2 O
2
1a
1b
1c
1d
0
15.2
16.0
15.9
15.4
-18.9
-26.6
-24.1
-25.3
21.3
24.6
23.7
23.6
1.47d
2.54
2.88
2.50
2.0
2.0
2.0
a Calculated from the Eyring plots shown in Fig. S3.† b Calculated from DS‡ = (DH‡-DG‡)/T, where T is the temperature. c Estimated from DG‡ = RT
ln[kBT/(hkCOOH)], where kB and h are the Boltzmann and Planck constants, respectively. d Measured at 20 ◦C.
the leaving group by at least 3–4 pKa units.14 Similarly, in the
hydrolysis of aspirin the neighboring carboxylate anion functions
as a general base, and nucleophilic attack by the carboxylate anion
is only observed for the 3,5-dinitroaspirin derivative, a compound
with a much better leaving group.15 The enforced proximity of
the carboxylate anion in 1,8-naphthalic acid derivatives 1a–d
allows the observation of a significant nucleophilic reaction even
when the pKa of the leaving group is as high as 12.36 (2,2,2-
trifluoroethanol).9 The exceptional reactivities of the COOH
and COO- forms in intramolecular reactions depends on the
orientation and proximity of the reacting groups, which is close
to a maximum in the alkyl monoesters 1 of 1,8-naphthalic acid.
A similar behavior was reported for the hydrolysis of 1AC2NA
anion, where, despite the relatively high basicity of the naphthoate
leaving group, the carboxylate group acts as a nucleophile rather
than a general base (Scheme 4).10
transition states and intermediates we performed computational
calculations at the B3LYP/6-31+g(d) level on the hydrolysis of the
COOH form of the methyl ester 1c, including one explicit water
molecule to help account for the observed isotope effect which
suggests that the mechanism of the COOH-catalyzed reaction is
likely to involve H2O as a reagent.
Fig. 4 shows the calculated structures of the main species
involved in the decomposition of the methyl ester 1c. Starting
from the ester–water complex (1c·H2O) we located TS1, leading
to the tetrahedral intermediate–water complex (IT·H2O), which
is subsequently decomposed to methanol, water and naphthalic
anhydride (NA) through TS2 according to Scheme 5.
The most significant geometrical parameters of the calculated
structures are given in Table 3. The calculated structures shown
in Fig. 4 are consistent with those previously reported for the
trifluoroethyl ester 1b5b and show the expected rigid, highly
strained aromatic system for the reactant. The structure 1c·H2O
(Fig. 4) has the nucleophilic carbonyl oxygen of the COOH group
˚
only 2.75 A from the ester carbonyl carbon, positioned to lie well
within the p*-region of the C O bond, with a near ideal Dunitz
“attack angle” of 105.8◦. The reactant structure shows significant
strain from the eclipsing interaction of the two carboxyl groups,
in the shape of significant distortions from planarity. Thus the
Scheme 4 Nucleophilic attack by the carboxylate group in 1AC2NA.
˚
˚
carbonyl carbons C1 and C5 lie 0.46 A and 0.51 A, respectively,
above and below the mean plane formed by the ring carbons (C2,
C3 and C4 were excluded because of the strong distortion). Not
only are the positions of carbons C1 and C5 distorted: so too is the
dihedral angle C2–C3–C4–C6 of the naphthalene ring-system. At
approximately 7.75◦ this accounts for the large difference in energy
between 1c·H2O and the anhydride NA. The anhydride is planar,
with no repulsions between carbonyl groups, thus providing a
significant driving force for the strong intramolecular catalysis.
Fig. 5A and 5B show the changes in bond lengths involving TS1
and TS2, respectively. As shown in Fig. 5A, proton transfer plays
a fundamental role in the decomposition of the reactant ester and
the attack of O1 on C1 is concerted with proton transfer from O1 to
water, which then donates H2 to O3. Thus, the water molecule acts
as both a general base and a general acid in the intramolecular
In enzymatic systems, decreasing the effective distances between
groups reacting in the active site should enhance the reactivity of
a carboxylate/carboxylic acid system, which could be ultimately
involved in the hydrolysis of a variety of esters and amides. In fact,
many of the aspartic proteinases function as digestive enzymes
with two aspartic acid residues, one acting as a general acid and
the other as a carboxylate anion.1a
2.1 Theoretical calculations
The high level of intramolecular reactivity observed in the cycliza-
tion reactions of the 1,8-naphthalic acid monoesters must certainly
be related to the special structure of the naphthalene derivatives.
To improve our understanding of the structures of reactants,
Scheme 5 Hydrolysis of monoester 1c consistent with the computational results.
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Fig. 4 Structures of 1c·H2O, TS1, IT·H2O and TS2 calculated at the B3LYP/6-31+g(d) level for the hydrolysis of the neutral methyl monoester of
1,8-naphthalic acid. Cartesian coordinates are given in the Supporting Information.†
˚
Table 3 Selected distances (A) for the optimized structures in the decomposition of 1c·H2O to MeOH+H2O+NA at the B3LYP/6-31+g(d) level.
Numbering according to Fig. 4
Structure
O1–C1
C1–O2
C1–O3
O3–H2
O1–H1
O2–H1
1c·H2O
IT·H2O
TS1
TS2
NA
2.75
1.44
2.10
1.42
1.39
—
1.35
1.44
1.33
1.75
—
1.21
1.37
1.28
1.28
1.21
—
2.32
—
1.47
2.55
—
3.76
—
3.20
1.31
—
0.99
1.21
1.32
MeOH
—
—
0.97
attack of O1 on C1, activating in turn the carboxylic acid and
the ester carbonyl groups. The formation of IT·H2O via TS1
involves an increase in the O1–H1 distance, with O1–C1 and O3–
Thus the water molecule also plays fundamental roles as both a
general base and a general acid in the reaction via TS2, assisting
the formation of the anhydride carbonyl groups and the loss of
methanol.
Fig. 6 shows the calculated solution free energy (Gsolution) relative
to 1c·H2O involving the structures in Fig. 4 and Scheme 5. The
higher barrier is TS2 and the calculated and experimental values
(27.9 and 23.0 kcal mol-1, respectively) for hydrolysis of 1c are in
good agreement. The product formation is highly exothermic due
to release of the steric strain of the peri-substitiuents in 1c·H2O
˚
˚
˚
H2 distances falling from 2.10 A and 1.21 A in TS1 to 1.44 A and
˚
0.99 A in IT·H2O, respectively (see Table 3).
The variations of bond lengths shown in Fig. 5B also indicate
the essential role of proton transfers as methoxide departure is
assisted by the incipient hydronium ion. In product formation via
TS2, the O2–H1 bond length decreases while those of O3–H2 and
C1–O2 increase, giving methanol, naphthalic anhydride and water.
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Fig. 5 Variation of bond lengths and energies (ꢀ) along the IRC for the hydrolysis of 1c·H2O involving (A) TS1 and (B) TS2.
experimental results and the theoretical calculations are consistent
with a mechanism involving rate determining breakdown of a
tetrahedral addition intermediate. Calculations show that the
cleavage of the neutral ester can be catalyzed by water, which
plays fundamental roles as both a general base and a general acid
in the reaction.
4. Experimental
All chemicals were of reagent grade and were used as received.
ESI analyses were performed with interface, CDL and block
temperatures set at 250, 250 and 200 ◦C, respectively. The detector
was maintained at 1.50 kV, the flow of N2 at 1.5 L min-1 and the
mobile phase was 2 : 8 MeOH/H2O. The ester concentration in the
samples was about 10-5 M. Chemical shifts, d, ppm, are relative to
internal TMS.
Attempts to isolate the individual esters failed due to its reac-
tivity, giving the corresponding anhydride. Thus, all compounds
were characterized in solution as the triethylammonium salt by
mixing 10 mg of AN with 5 eq. of the respective alcohol and 2
eq. of triethylamine in MeOD (for compound 1c) or CD3CN (for
compounds 1b and 1d). Typical HPLC analyses, realized prior to
the kinetic runs, are given in Fig. S5†.
Fig. 6 Gibbs free energy in solution (relative to 1c·H2O reactant)
for the species involved in the hydrolysis of 1c calculated with the
B3LYP/6-31+g(d) method.
going on to the planar aromatic system in AN. The kinetic solvent
isotope effect in the hydrolysis of 1c is consistent with proton
transfer in the reaction through TS2.
It is interesting to note that, consistent with the lower reactivity
of the anionic form of 1c, due to the high energy inherent to
methoxide as leaving group in the gas phase, all attempts to find a
minimum energy in the calculation failed, even with inclusion of
2, 3 and even 4 explicit water molecules hydrogen bonded to the
departing methoxide ion.
4.1 Synthesis
4.1.1 Butyl monoester of 1,8-naphthalic acid (1d). To a so-
lution containing 0.198 g (1.0 mmol) of 1,8-naphthalic acid in
20 mL of butanol at 50 ◦C was added 0.21 mL (1.5 mmol) of
triethylamine, and the reaction was maintained under stirring for
6 h. 1H NMR (400 MHz, CD3CN): d 0.92 (t, J = 7.0 Hz, 3H), 1.02
(t, J = 7.2 Hz, 9H), 1.37 (m, J = 7.0 Hz, 2H), 1.71 (quint, J = 7.0,
2H), 2.55 (q, J = 7.2, 6H), 4.24 (t, J = 7.0, 2H); 7.50 (dd, J = 8.2,
7.1 Hz, 1H), 7.51 (dd, J = 8.2, 7.1 Hz), 7.78 (dd, J = 7.1, 1.4 Hz,
1H); 7.89 (dd, J = 8.2, 1.4 Hz, 1H); 7.94 (dd, J = 7.1, 1.4 Hz, 1H);
8.01 (dd, J = 8.2, 1.4 Hz, 1H). ESI-MS negative-ion mode: m/z
3. Conclusions
The hydrolysis of alkyl 1,8-naphthalic acid monoesters pro-
ceeds with efficient intramolecular catalysis by both neighboring
COOH and carboxylate groups and the reactivity depends on
leaving group pKa, with a bLG value of -0.50 being observed
for the neighboring COOH group. The release of the steric
strain of the peri-substituents in the highly reactive alkyl 1,8-
naphthalic acid monoesters is fundamental to understand the
observed special reactivity in this intramolecular reaction. The
intramolecular efficiency of the observed reaction is comparable
with the fundamental contribution of the carboxylate/carboxylic
acid system in aspartic proteinases, where the aspartic acid residues
act as a general acid and carboxylate anion, respectively.1a The
-
(%): calc for C16H15O4 : 271.10; found: 271.05 (100).
4.1.2 Methyl monoester of 1,8-naphthalic acid (1c). To a
solution containing 0.198 g (1.0 mmol) of 1,8-naphthalic acid in
◦
20 mL of methanol at 25 C was added 0.21 mL (1.5 mmol) of
triethylamine, and the reaction was maintained under stirring for
6 h. 1H NMR (400 MHz, CD3OD): d 1.15 (t, J = 7.3 Hz, 9H), 2.88
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(q, J = 7.3, 6H), 3.88 (s, 3H), 7.51 (t, J = 7.6 Hz, 2H); 7.83 (dd, J =
7.1, 1.3 Hz, 1H); 7.88 (dd, J = 7.1, 1.3 Hz, 1H); 7.91 (dd, J = 8.2,
1.3 Hz, 1H); 8.03 (dd, J = 8.2, 1.3 Hz, 1H). ESI-MS negative-ion
on the energetic results obtained in gas phase were included by
means of the polarizable continuum model (PCM)20 on single
point calculations, with the molecular cavity computed, including
explicit hydrogens, with the UFF radius21 allowing calculation
of the Gibbs solvation free energy (DGsolvation). Using a simplified
model (PCM) to describe solvation effects does not account for
specific solvent–solute interactions (e.g. hydrogen bonds) that are
certainly important in this particular reaction in aqueous solution.
Therefore, in all calculations, we included one water molecule to
begin to account for the kinetic solvent isotope effect observed
experimentally. The total free energy in solution (Gsolution) was
calculated by summing the electronic and thermal free energies
to DGsolvation. For conversion from 1 atm standard state to 1 mol L-1
standard state, DGeq from 1c·H2O to MeOH+H2O+NA shown in
Fig. 6 was corrected22 by adding 3.79 kcal mol-1 to the calculated
value according to an A → B + C + D reaction. For structures
of 1c·H2O and TI·H2O the basis set superposition error (BSSE)
was estimated using the Counterpoise method23 implemented in
Gaussian 03. Theoretical calculations for cyclization involving a
number of explicit water molecules, although possible, were not of
interest for this work.
-
mode: m/z (%): calc for C13H9O4 : 229.05; found: 229.05 (100).
4.1.3 n-Isopropyl monoester of 1,8-naphthalic acid (1b). To a
solution containing 0.198 g (1.0 mmol) of 1,8-naphthalic acid in
20 mL of isopropanol at 50 ◦C was added 0.21 mL (1.5 mmol) of
triethylamine, and the reaction was maintained under stirring for
1
12 h. H NMR (400 MHz, CD3CN): d 1.02 (t, J = 7.2 Hz, 9H),
1.18 (d, J = 6.0 Hz, 3H), 1.36 (d, J = 6.3 Hz, 3H), 2.55 (q, J = 7.2
Hz, 6H), 5.14 (quint, J = 6.2, 1H), 7.50 (dd, J = 8.2, 7.1 Hz, 1H),
7.51 (dd, J = 8.2, 7.1 Hz, 1H), 7.78 (dd, J = 7.1, 1.4 Hz, 1H); 7.89
(dd, J = 8.2, 1.4 Hz, 1H); 7.94 (dd, J = 7.1, 1.4 Hz, 1H); 8.01 (dd, J
= 8.2, 1.4 Hz, 1H). ESI-MS negative-ion mode: m/z (%): calc for
-
C15H13O4 : 257.10; found: 257.00 (100).
4.2 Kinetics
Rates of formation of the anhydrides from monoesters of 1,8-
naphthalic acid were followed on a spectrophotometer coupled
with a thermostated water-jacketed cell holder. All solutions were
prepared with CO2 free distilled, demineralized water which was
boiled and cooled under nitrogen. Reactions were initiated by
injection of 10 mL of ca. 10 mM solutions of substrates into 3
mL of buffer solutions. Absorbance versus time data were stored
Acknowledgements
We are grateful to INCT-Catalise, PRONEX, FAPESC, CNPq,
´
directly on a microcomputer and first-order rate constants (kobs
)
and CAPES for support of this work.
were calculated from linear plots, at the wavelength maximum of
340 nm, of ln(A• - At) against time for at least 90% reaction by
using an iterative least-squares program; correlation coefficients
(r) were > 0.999 for all kinetic runs. At conditions where the rate
constant for NA hydrolysis is similar to its formation, absorbance
vs. time data were fitted with eqn (2), according to Scheme 6,5a
with k1 π k2.
Notes and references
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t
t
2
k1(e−k t −e−k
)
k2e−k t −k1e−k
1
2
1
⎧
⎫
⎪
⎪
−k t
⎪
⎪
⎬
⎪
1
Abs = Ester 1+e
+
+
[
]
⎨
⎪
0
k2 −k1
k1 −k2
⎪
⎩
⎪
⎭
(2)
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Scheme 6
4.3 Computational methods
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Gaussian 03 (Revision D.01)16 program was used for all cal-
culations. The B3LYP17 hybrid functional with the 6-31+G(d)
basis set was employed and the stationary points were verified
by calculating the Hessians matrix, where the minimum energy
structures have no imaginary frequency and transition state
structures have one imaginary frequency. To obtain a deeper
insight into the reaction mechanism, we calculated the intrinsic
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order path,19 starting from the optimized transition-state structure,
with a step length of 0.01 a.m.u.1/2 (Bohr). The solvent effects
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6170 | Org. Biomol. Chem., 2011, 9, 6163–6170
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