Kinetic and theoretical studies on the mechanism of intramolecular catalysis in phenyl ester hydrolysis

Article abstract of DOI:10.1021/jo061165e

(Chemical Equation Presented) The kinetic study of the hydrolysis reaction of Z-substituted phenyl hydrogen maleates (Z = H, m-CH₃, p-CH ₃, m-Cl, p-Cl and m-CN) was carried out in aqueous solution, and the results were complemented with theoretical studies. Under some experimental conditions, two kinetic processes were observed. One of them was ascribed to maleic anhydride formation and the other to the anhydride hydrolysis. The Broensted-type plot for the leaving-group dependence was linear with slope β_lg = -1. The experimental results are consistent with a mechanism that involves significant bond breaking in the rate-limiting transition state (α_lg = 0.64). Theoretical results for the reaction in the gas phase showed an excellent Broensted-type dependence with a β_lg of -1.03. A tetrahedral intermediate (TI) could not be found through DFT gas-phase studies (B3LYP/6-311+G*). Calculations carried out within a continuous solvation model or with discrete water molecules failed to find a stable TI. With both models, a flat region on the potential-energy surface is found and a tight optimization of the structures led back to starting materials. The theoretical results do not discard the possible existence of an unstable intermediate on the free-energy surface, but the analysis of the whole body of results compared with other acyl transfer reactions lead us to suggest that an enforced concerted mechanism is the most appropriate to describe these reactions.

Full text of DOI:10.1021/jo061165e

Kinetic and Theoretical Studies on the Mechanism of
Intramolecular Catalysis in Phenyl Ester Hydrolysis
Gabriel O. Andre´s, Adriana B. Pierini,* and Rita H. de Rossi*
Instituto de InVestigaciones en F´ısico Qu´ımica de Co´rdoba (INFIQC), Facultad de Ciencias Qu´ımicas
Departamento de Qu´ımica Orga´nica, UniVersidad Nacional de Co´rdoba, Ciudad UniVersitaria,
5000 Co´rdoba, Argentina
adriana@mail.fcq.unc.edu.ar; ritah@fcq.unc.edu.ar
ReceiVed June 7, 2006
The kinetic study of the hydrolysis reaction of Z-substituted phenyl hydrogen maleates (Z ) H, m-CH3,
p-CH3, m-Cl, p-Cl and m-CN) was carried out in aqueous solution, and the results were complemented
with theoretical studies. Under some experimental conditions, two kinetic processes were observed. One
of them was ascribed to maleic anhydride formation and the other to the anhydride hydrolysis. The
Bro¨nsted-type plot for the leaving-group dependence was linear with slope âlg ) -1. The experimental
results are consistent with a mechanism that involves significant bond breaking in the rate-limiting transition
state (Rlg ) 0.64). Theoretical results for the reaction in the gas phase showed an excellent Bro¨nsted-
type dependence with a âlg of -1.03. A tetrahedral intermediate (TI) could not be found through DFT
gas-phase studies (B3LYP/6-311+G*). Calculations carried out within a continuous solvation model or
with discrete water molecules failed to find a stable TI. With both models, a flat region on the potential-
energy surface is found and a tight optimization of the structures led back to starting materials. The
theoretical results do not discard the possible existence of an unstable intermediate on the free-energy
surface, but the analysis of the whole body of results compared with other acyl transfer reactions lead us
to suggest that an enforced concerted mechanism is the most appropriate to describe these reactions.
Introduction
computational studies that show that the rate of an intramolecular
reaction is proportional to the time that the catalytic group and
the reaction center reside at a critical distance.10-13 These
calculations are in good agreement with Menger’s “spatiotem-
poral” hypothesis14 and shed light on different questionable
aspects regarding the mechanism of enzymatic catalysis.
Ester hydrolysis is an important type of reaction that has
received a great deal of attention in both organic chemistry and
biochemistry,andithasbeensubjectedtomanyinvestigations.15-19
The study of enzymatic hydrolysis is of great interest because
the rate enhancement can be quite dramatic.1,2 Intramolecular
catalysis has been used as a model system that gives important
information about enzyme mechanisms.3-7 The efficiency of
the reactions is very much dependent on the relative position
of the reacting groups8 and the time they spend at the proper
distance for reaction.9 The last point was elegantly proved by
(1) Jencks, W. P. Catalysis in Chemistry and Enzymology; Dover: U.S.A.,
1969.
(9) Menger, F. M.; Fei, Z. X. Angew. Chem., Int. Ed. Engl. 1994, 33,
346.
(2) Wolfenden, R.; Zinder, M. J. Acc. Chem. Res. 2001, 34, 938.
(3) Kirby, A. J.; Dutta-Roy, N.; da Silva, D.; Goodman, J. M.; Lima,
M. F.; Roussev, C. D.; Nome, F. J. Am. Chem. Soc. 2005, 127, 7033.
(4) Fife, T. H.; Singh, R.; Bembi, R. J. Org. Chem. 2002, 67, 3179.
(5) Menger, F. M.; Ladina, M. J. Am. Chem. Soc. 1988, 110, 6794.
(6) Suh, J.; Chun, K. H. J. Am. Chem. Soc. 1986, 108, 305.
(7) Kirby, A. J.; Lancaster, P. W. J. Chem. Soc., Perkins Trans. 2 1972,
1206.
(10) Lightstone, F. C.; Bruice, T. C. Acc. Chem. Res. 1999, 32, 127.
(11) Lightstone, F. C.; Bruice, T. C. Bioorg. Chem. 1998, 26, 193.
(12) Lightstone, F. C.; Bruice, T. C. J. Am. Chem. Soc. 1997, 119, 9103.
(13) Lightstone, F. C.; Bruice, T. C. J. Am. Chem. Soc. 1996, 118, 2595.
(14) Menger, F. M. Acc. Chem. Res. 1985, 18, 128.
(15) Marlier, J. F. Acc. Chem. Res. 2001, 34, 283.
(16) Um, I.-H.; Back, M.-H.; Han, H.-J. Bull. Korean Chem. Soc. 2003,
24, 1245.
(8) Bond, A. D.; Kirby, A. J.; Rodriguez, E. Chem. Commun. 2001, 2266.
10.1021/jo061165e CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/06/2006
7650
J. Org. Chem. 2006, 71, 7650-7656

Intramolecular Catalysis in Phenyl Ester Hydrolysis
TABLE 1. Rate Constants and Kinetic pKas for the Hydrolysis of
Since the 1950s, it has been widely accepted that the
hydrolysis of alkyl esters occurs via a stepwise addition-
elimination mechanism.20,21 The nucleophilic attack of the
hydroxide ion on the acyl carbon gives as a result a stable
oxyanion tetrahedral intermediate (TI), which in a subsequent
step collapses to form products.22 Indirect experiments20,23 and
theoretical evidence24-26 of TI existence are quite convincing,
and the mechanism of nucleophilic displacement on acyl
derivatives in solution has been explained by the concept of a
stable intermediate. On the other hand, for good leaving groups
such as aryloxide ions, there is reasonably good evidence that
acyl transfer reactions proceed through concerted mechanisms,
where the nucleophilic attack and leaving group departure occur
simultaneously and a TI is not formed along the reaction
coordinate.27-30 All these studies pertain to intermolecular
reactions,27,31,32 but the subject was only seldom discussed for
intramolecular reactions.33
Aryl Hydrogen Maleates 1a
c
c
d
e
kHA
10-2 s-1
kA
kN
Ke
b
Z
pKa
10-2 s-1 104 s-1 M-1
105 M-1
p-CH3 3.03 ( 0.06 0.2 ( 0.1 5.5 ( 0.1
23
42 (46)
20.6
11 (11)
2.4
m-CH3 3.0 ( 0.1
0.3 ( 0.2 8.0 ( 0.2
16.5
10.7
9.6
H
3.10 ( 0.09 0.4 ( 0.2 9.7 ( 0.3
2.68 ( 0.04 0.7 ( 0.6 39.7 ( 0.4
p-Cl
m-Cl
2.66 ( 0.05 2 ( 2
90 ( 9
3.65
0.40 (0.37)
a Ionic strength, 0.5 M; temperature, 25.0 °C; acetonitrile, 3.85%.
b Calculated from the observed rate constant for the anhydride formation
reaction at different pH values. c Rate constant for the anhydride formation
reaction (see Scheme 1). d The values of kN for the phenolysis of maleic
anhydride were taken from ref 34. e Ke ) kN/kA. The values within
parentheses were obtained from an independent method (ref 34).
SCHEME 1
In previous work we have reported that the hydrolysis
reactions of phthalic acid monoesters are strongly sensitive to
the pKa of the phenol leaving group (âlg ) -1.15),33 which
indicates a significant bond breaking in the transition state of
the rate determining step. Besides from a study of the back
reaction, that is, the phenolysis of phthalic and maleic anhydride,
we concluded that the results were consistent with a concerted
or enforced concerted mechanism.34
Although linear-free relationships is one of the most useful
techniques for the study of mechanisms,27 it is not always
enough to distinguish between concerted and stepwise pathways.
Results and Discussion
We report here experimental and theoretical results for the
hydrolysis of aryl hydrogen maleates 1, which are important
for the relevant discussion about the concerted versus the
stepwise mechanism on intramolecularly catalyzed ester hy-
drolysis.
Aryl Hydrogen Maleates. The hydrolysis of aryl hydrogen
maleates 1 (Z ) H, p-Cl, m-Cl, p-CH3, m-CH3) were studied
between pH 0.60 and 5.60 (Tables S1-S4, Supporting Informa-
tion). Under some experimental conditions, the kinetics profile
showed two kinetics processes: one of them was associated
with the anhydride formation and the other with the anhydride
hydrolysis (Figure S1). The formation of anhydride as inter-
mediate in these types of reactions is widely known.35,36 At a
pH higher than 5.60, the kinetics were not measured because
the second-order rate constant for the maleic anhydride phe-
nolysis is around 104-105 s-1 M-1 34
so a little fraction of
,
phenoxide formed at the beginning, make the back reaction of
eq 1 quite fast. This complicates the kinetics and, therefore,
the interpretation of the results.
The rate constant for the anhydride formation did not show
an appreciable dependence on the buffer concentration (Tables
S3 and S4). The observed rate constant for the anhydride
formation plotted versus pH gives a sigmoid curve (Figures S2-
S6) similar to that reported in the literature for substituted aryl
hydrogen phthalates.33,37 The kinetic pKas were calculated from
the inflection point of these curves. (Table 1).
The observed rate constants were plotted as a function of
the fraction of substrate in the carboxylate form, XA (plot not
shown). The intercepts at XA ) 0 are named kHA in Table 1,
and they were not zero, although they have a high associated
error (at least 50%). These values represent the reaction of the
neighboring carboxylic group (Scheme 1). This observation
contrasts with the results obtained in the study of the hydrolysis
of aryl hydrogen phthalates, where the intercepts of similar plots
are indistinguishable from zero.34
(17) Fragoso, A.; Cao, R.; Ban˜os, M. Tetrahedron Lett. 2004, 45, 4069.
(18) Hengge, A. C.; Hess, R. A. J. Am. Chem. Soc. 1994, 116, 11256.
(19) Hawins, M. D. J. Chem. Soc., Perkins Trans. 2 1975, 285.
(20) Bender, M. L. J. Am. Chem. Soc. 1951, 73, 1626.
(21) Bender, M. L. Chem. ReV. 1960, 60, 53.
(22) Carroll, F. A. PerspectiVes on Structure and Mechanism in Organic
Chemistry; Brooks/Cole Publishing Company: St. Paul, MN, 1998.
(23) Kellogg, B. A.; Brown, R. S. J. Am. Chem. Soc. 1995, 117, 1731.
(24) Topf, M.; Richards, W. G. J. Am. Chem. Soc. 2004, 126, 14631.
(25) Zhan, C. G.; Landry, D. W. Ornstein, R. L. J. Am. Chem. Soc. 2000,
122, 1522.
(26) Pliego, J. R.; Riveros, J. M. Chem. Eur. J. 2002, 8, 1945.
(27) Williams, A. Free Energy Relationship in Organic and Bio-Organic
Chemistry; The Royal Society of Chemistry: Cambridge, U.K., 2003.
(28) Ba-Saif, S.; Maude, A. B.; Williams, A. J. Chem. Soc., Perkin Trans.
2 1994, 2395.
(29) Stefanidis, D.; Cho, S.; Dhe-Paganon, S.; Jencks, W. P. J. Am. Chem.
Soc. 1993, 115, 1650.
(30) Ba-Saif, S.; Luthra, A. K.; Williams, A. J. Am. Chem. Soc. 1987,
109, 6362.
(31) Castro, E. A.; Pavez, P.; Santos, J. G. J. Org. Chem. 2002, 67, 4494.
(32) Castro, E. A.; Angel, M.; Pavez, P.; Santos, J. G. J. Chem. Soc.,
Perkin Trans. 2 2001, 2351.
(33) Andre´s, G. O.; Granados, A. M.; de Rossi, R. H. J. Org. Chem.
2001, 66, 7653.
(34) Andre´s, G. O.; de Rossi, R. H. J. Org. Chem. 2005, 70, 1445.
(35) Kirby, A. J. AdV. Phys. Org. Chem. 1980, 17, 183.
(36) Bruice, T. C.; Pandit, U. K. J. Am. Chem. Soc. 1960, 82, 5858.
(37) Thanassi, J. W.; Bruice, T. C. J. Am. Chem. Soc. 1966, 88, 747.
J. Org. Chem, Vol. 71, No. 20, 2006 7651

Andre´s et al.
a
SCHEME 2
SCHEME 3
The equilibrium constants (K) for the formation of ph-
thalic38,39 and maleic40 anhydride from the corresponding diacid
(Scheme 2) are 5 × 10-3 and 0.01, respectively. The value of
k-1[H2O] (Scheme 2) determined for phthalic anhydride33 and
maleic anhydride41 are 9.2 × 10-3 s-1 and 2.5 × 10-2 s-1
,
respectively. From these data, the values of k1 can be calculated
as 4.6 × 10-5 s-1 and 2.5 × 10-4 s-1 for phthalic and maleic
acid, respectively. The ratio of the two rate constants indicates
that the carboxylic group of maleic acid is about 5.4 times more
reactive than that of phthalic acid. This difference in reactivity
may be responsible for the fact that the catalysis by the
carboxylic neighboring group was not observed in the hydrolysis
of aryl hydrogen phthalates, but it was detected for the maleic
derivatives.
a Key: (a) transition state for the nucleophilic attack of the carboxylate
group on the carbonyl ester of aryl hydrogen maleates; (b) transition state
for the nucleophilic attack of substituted phenols on acetic anhydride, ref
28; (c) transition state for the reaction of nucleophiles with aryl acetates,
ref 29; (d) transition state for the nucleophilic attack of substituted phenols
on phthalic anhydride, ref 34; (e) transition state for the hydrolysis of aryl
trifluoroacetates, calculated from data in ref 45; and (f) transition state for
the hydroxyl attack on aryl esters, ref 27.
SCHEME 4
The rate constants for the catalysis of neighboring carboxylate
group (kA) as well as the equilibrium constant for the reaction
(Ke) collected in Table 1 give linear Bro¨nsted-type plots42 with
reasonable correlation.
The âlg for the anhydride formation was -1.00 ( 0.06, which
implies an important C-O bond breaking in the rate-limiting
transition state.43 Similar âlg values were found for intramo-
lecular catalysis of substituted phenyl hydrogen phthalates (âlg
) -1.15),33 the aminolysis of 2-substituted benzoates esters (âlg
) -1),44 and for the carbonate catalysis in the hydrolysis of
aryl trifluoroacetates (âlg ) -1.15).45
The âEq value calculated from the plot of log Ke versus pKa
of the leaving group was 1.57 ( 0.09. This value is the same
within experimental error as the value previously reported (âEq
) 1.69), determined by an independent method,34 and it is also
similar to that reported for acyl transfer reactions (âEq ) 1.7).46
The change in effective charge obtained from the values of
â may be used to position the transition state in the reaction
map. This can be done by comparing the effective charge for
each of the two atoms that take part in bonding changes in the
transition state with that of the product; this ratio, R, is called
the Leffler index (R ) â/âEq).27 The R parameter was estimated
from Rlg ) âlg/âEq ) -0.64. If this value is used as a transition
state index (relative to the structure of the reactants and product
states), then the value of 0.64, measured from the variation of
the phenyl substituents, is consistent with 64% bond rupture
going from the ester to the anhydride. A value of R ) 0.62 was
obtained in the formation of 2-phenyloxazolin-5-one from aryl
benzoyl glycinates, which reacts through a concerted mecha-
nism.47
Taking into account the values of âEq, âlg, and âNuc, and
assuming that the changes in effective charge are conserved,
we have estimated the charge on the oxygen in the rate-limiting
transition state as -0.46 ( 0.10 ((a) in Scheme 3). Similar
effective charges were observed in transition states where a
concerted or enforced concerted mechanism was proposed. For
example, phenolysis of acetic anhydride ((b) in Scheme 3),
which is the back reaction for the acetate nucleophilic attack
on aryl acetate esters to form acetic anhydride, nucleophilic
attack on aryl acetate esters ((c) in Scheme 3), hydrolysis of
aryl trifluoroacetate esters ((e) in Scheme 3), and hydrolysis of
aryl acetate esters ((f) in Scheme 3). The charge on oxygen
estimated for the intramolecular catalysis on aryl hydrogen
maleates and phthalates ((a) and (d) in Scheme 3) are very
similar, and also, similarities were found among the values of
â. Therefore, it is reasonable to think that the mechanisms are
alike and the structure of the transition state for both esters
should not be too different.
Linearity of a free-energy plot is not evidence of a mechanism
with a single transition state; it indicates that the transition state
has a constant structure over the range of substituted phenols
employed. A change in the rate-limiting step for the putative
stepwise process (Scheme 4) would be expected for a phenol
of pKa < 3,48 however, this would be very difficult to measure
for two main reasons: (i) the value of kA would be too high to
measure by stopped-flow technique49 and (ii) it would be very
difficult to synthesize and work with an ester of this type.50
(38) Hawkins, M. D. J. Chem. Soc., Perkin Trans. 2 1975, 282.
(39) Hawkins, M. D. J. Chem. Soc., Perkin Trans. 2 1975, 285.
(40) Eberson, L.; Welinder, H. J. Am. Chem. Soc. 1971, 93, 5821.
(41) Andre´s, G. O.; Silva, O. F.; de Rossi, R. H. Can. J. Chem. 2005,
83, 1281.
(42) This is not formally a Bro¨nsted plot, and the slope values are not
related to general base catalysis. The interaction coefficient (âNuc, âlg, and
â
Eq) can be useful for characterizing a reaction mechanism when the change
in slope represents a change in the structure of a single transition state.
Jencks, W. P. Chem. ReV. 1985, 85, 511.
(43) A referee has pointed out that it is important to consider that âlg do
not measure only C-O bond cleavage. Addition to a carbonyl group is
very sensitive to substituent effects, so one must expect that a change in
aryloxide leaving group will also change the equilibrium constant for
addition to the carbonyl forming the TI. This will show up as a nonzero âlg
without any bond breaking.
(47) Curran, T. C.; Farrar, C. R.; Niazy, O.; Williams, A. J. Am. Chem.
Soc. 1980, 102, 6828
(44) Fiffe, T. H.; Chauffe, L. J. Org. Chem. 2000, 65, 3579.
(45) Fernandez, M. A.; de Rossi, R. H. J. Org. Chem. 1999, 64, 6000.
(46) Williams, A. Acc. Chem. Res. 1984, 17, 425.
(48) Williams, A. Chem. Soc. ReV. 1994, 94, 93.
(49) Using the value of âlg, we can calculate kA in the order of 9.4 ×
106 s-1 for a leaving group of pKa of 2.
7652 J. Org. Chem., Vol. 71, No. 20, 2006

Intramolecular Catalysis in Phenyl Ester Hydrolysis
SCHEME 5
Cross correlations can be used to get a better understanding
of the intramolecular mechanism, but for the reactions reported
here, it is not possible to change the pKa of the nucleophile, so
cross correlations cannot be determined in the usual way. The
âlg for esters of substituted phenols that react with nucleophiles
by a concerted mechanism change to a more positive value as
the pKa of the nucleophile increases (Figure S8). It is known
that the âlg values show a lineal dependence with the pKa of
the nucleophile.29,51,52 The existence of this cross correlation is
a good indication that there is coupling between the bond-
forming and bond-breaking reactions, consistent with a con-
certed mechanism.
SCHEME 6
From the cross correlations for intermolecular reactions
(Figure S8), a âlg lower than -1 is expected for a nucleophile
with pKa ≈ 3,53 which is in the range of the experimental value
obtained in this work (see above). This result may indicate that
the intramolecular reaction is concerted, although this conclusion
must be taken with caution because it relies on the assumption
that cross correlations from intermolecular reactions are valid
for intramolecular ones.
Theoretical Results. To get more insight into the mechanism
of the intramolecular reaction, eq 1, we carried out theoretical
calculations using ab initio HF and density functional theory
methods,54 the latter with the hybrid B3LYP functional.55 First,
the calculations were done for the reactions in the gas phase,
and then we inspected the effect on the reaction coordinate of
a continuum medium and the addition of discrete water
molecules. The semiempirical AM1 procedure was used for a
preliminary conformational reactant search. The B3LYP func-
tional was chosen due to its good performance in accounting
for electron correlation effects and, therefore, being expected
to afford a more appropriate description of the reaction barrier.
HF and B3LYP calculations were performed with the 6-311+G*
basis set or 6-31+G* when discrete water molecules were used.
The inclusion of diffuse functions in the calculations is necessary
because of the involvement of anionic species.
Lightstone and Bruice10-13 had determined the importance
of the ground-state conformation of the substrate on the rate
constant for reactions of several monophenyl esters of carboxylic
diacids such as succinic and glutaric. They introduced the term
“near attack conformation” (NAC) to define the required
conformation for juxtaposed reactants to enter a transition state.
The reacting groups of the substrates discussed here belong to
the same kind of compounds, but the numbers of starting
conformations are more limited and, therefore, the determination
of the NAC12 is much simpler. Using the AM1 method, we
explored the different possible conformations that aryl hydrogen
maleate esters can adopt. This was carried out by changing the
dihedral angle formed between carbons 4, 7, and 8 and the
oxygen 10 (Scheme 5). The other relevant dihedrals, O9C8O10CAr,
C8O10CArCAr-ortho, and O2C3C4C7 were also inspected.
The most stable conformation found has the neighboring
carboxylate group in a plane perpendicular to that of the
carbonyl ester and in the same plane as the double bond. This
structure is also a minimum at the HF/6-311+G* and B3LYP/
6-311+G* level of theory. It is well-known that the rate of an
intramolecular organic reaction is dependent upon the distance
between reacting atoms in the starting materials.56 The appropri-
ated distances for the intramolecular carboxylate attack of phenyl
succinic esters are between 2.8 and 3.2 Å,13 for phenyl phthalate
ester is 2.7 Å,57 and the values calculated in this work for
Z-substituted phenyl maleates are 2.55, 2.57, 2.60, and 2.61 Å
for Z ) m-Cl, p-Cl, H, and p-CH3, respectively (Figure S9).
The rate constants for the intramolecular reactions are 1.42 ×
10-3 s-1, 4.43 × 10-2 s-1, and 9.7 × 10-2 s-1 for phenyl
hydrogen succinate,35 phthalate,33 and maleate esters, respec-
tively.
On the other hand, based on data reported in the literature,10,58
the approach of the nucleophile had to be within a cone of 30°,
with the axis being approximately 17° off the normal to the
carbonyl plane (Scheme 6), which is in good agreement with
our findings and with the O2C8O9 angle of 106-107°, evaluated
by HF and B3LYP with the indicated basis set.
The potential surface of minimum energy for the intramo-
lecular carboxylate catalysis on the esters hydrolysis was
followed by approaching the oxygen of the neighboring car-
boxylate group to the carbonyl carbon ester in steps of 0.01 Å.
In doing so, a first transition state (TS1) and the TI were
found with HF/6-311+G*. The energy difference between these
two states is at most 0.5 kcal/mol (Table 2). Using TI as starting
point, the leaving group departure was followed by stretching
the bond between the carbonyl carbon of the ester and the
oxygen of the phenoxide leaving group until this bond breaks.
This inspection led to the localization of the transition state
(TS2) whose transition vector corresponds to the departure of
the leaving group. The calculated relative energies are sum-
marized in Table 2.
The procedure described was not satisfactory to obtain TS1
and TI with the B3LYP/6-311+G* functional. Instead, a
different approach was used, and the minimum energy reaction
(50) The rate constant for the carboxylate intramolecular catalysis of
m-cyanophenyl hydrogen maleate was obtained from an indirect measure-
ment (ref 34). A direct rate constant value has not been obtained because
we were unable to synthesize the ester; it is too unstable.
(51) Jencks, W. P. Chem. ReV. 1985, 85, 511.
(54) (a) Hohenberg, P.; Kohn, W. Phys. ReV. 1964, 136, B864. (b) Kohn,
W.; Sham, I. J. Phys. ReV. 1965, 140, A1133.
(55) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785. (b)
Becke, A. D. Phys. ReV. A 1988, 38, 3098. (c) Miehlich, B.; Savin, A.;
Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989, 157, 200.
(56) Scheiner, S. J. Am. Chem. Soc. 1981, 103, 315.
(52) Ba-Saif, S.; Luthra, A. K.; Williams, A. J. Am. Chem. Soc. 1989,
111, 2647.
(53) It should be kept in mind that this statement has implied the
assumption that the shape of the reaction surface in the proximities of the
transition state is independent of the absolute rate of the reactions involved.
(57) Andres, G. O. Ph.D. Thesis, Universidad Nacional de Cordoba,
Argentina, 2004.
(58) Dorigo, A. E.; Houk, K. N. J. Am. Chem. Soc. 1987, 109, 3698.
J. Org. Chem, Vol. 71, No. 20, 2006 7653

Andre´s et al.
TABLE 2. Energy Changes Calculated for the Intramolecular
Catalysis of Z-Substituted Phenyl Maleate Esters in the Gas Phasea
HF/6-311+G*
B3LYP/6-311+G*
c
d
e
e
∆E1
∆E2
∆E3
∆E3
b
Z
pKa
kcal/mol kcal/mol kcal/mol
kcal/mol
p-CH3 10.26
12.29
11.98
11.20
10.85
-0.10
-0.18
-0.45
-0.52
17.53
16.71
14.59
14.15
7.8
7.4
5.7
5.0
H
9.88
9.38
9.03
p-Cl
m-Cl
a Values informed with zero point correction. b Values of the pKa of the
leaving phenol taken from ref 33. c Energy difference between TS1 and
the NAC structure (ETS1 - ENAC). d Energy difference between TI and TS1
(ETI - ETS1). e Energy difference between TS2 and NAC (ETS2 - ENAC).
path toward reactants was followed starting at the geometry of
TS2 by shortening the C8-O10 ester bond distance. By this
inspection, only a shoulder is observed at the TS1 and TI zone.
These results are not surprising considering the small values of
the difference in energy between TS1 and TI, ∆E2, (at most
0.52 kcal/mol) which show that TI is only slightly more stable
than TS1 for all the substrates studied.
FIGURE 1. Bro¨nsted-type plot of the energy for the transition state
of the rate-limiting step vs the pKa of the leaving group. (2) Relationship
between rate constants for the anhydride formation for aryl maleate
esters and the energy for the transition state of the rate-limiting step
(9).
The topology of this gas-phase potential surface compares
well with the one obtained for the p-methyl derivative evaluated
with B3LYP/6-311+G* and full geometry optimization within
a continuum solvent model with water as solvent. By this
methodology, the NAC approach geometry was located as a
minimum of the potential surface at an O2-C8 distance of 2.53
Å, with the O2C8O9 angle of 100°. No TI could be found starting
from this NAC by a careful O2-C8 distance approximation scan
search. Instead, the energy continuously raises until an energy
shoulder is reached between 1.676 and 1.576 Å; these points
being 16.98 and 17.11 kcal/mol higher in energy, respectively,
than the NAC structure. An activation energy for p-methylphe-
noxide departure from NAC of 23.01 kcal/mol is evaluated with
this methodology; the TS2 being located at a C8-O10 distance
of 2.117 Å.
value, a computational value59 of âlg of -1.03 can be calculated
in excellent agreement with the experimentally determined value
(see above). In addition, a good linear relationship with slope
of -1.04 (r2 ) 0.994) was obtained between ∆E3 (B3LYP/6-
311+G*) and ln kA (Figure 1), which shows the consistency
between the kinetics and the theoretical results, despite the fact
that the theoretical calculations pertain to the reaction in the
gas phase. This result is not unexpected because the solvent
effect should affect the reaction of the whole series in a
proportional way.
Mulliken natural population analysis on the oxygen atom of
the leaving groups at the transition state (TS2) determined from
the theoretical calculations did not show an appreciable change
for the different substrates because the values are between -0.54
and -0.58 (-0.56 for the p-methyl derivative in a water
continuum; Figure 2). These values are remarkably similar to
the values obtained from linear free-energy relationships,
determined from experimental data (see above).
Further evaluation of the intermediate existence was per-
formed with B3LYP/6-31+G* by inclusion of six discrete water
molecules distributed around relevant centers of negative charge
localization, as determined from the electrostatic potential map
obtained under the continuum solvent model (Figure S10). The
number of water molecules was chosen in such a way as to
assist the negative-charge evolution along the formation and/or
fragmentation of the suspected TI. In doing so, we considered
it adequate to solvate the oxygen negative center of the putative
TI (one water molecule added at this site) and each of the
negative oxygens in the open ester (one water molecule at each
site). Two extra water molecules were added to avoid mutual
electrostatic interactions between the water molecules more
directly involved with the reacting centers along the coordinate.
The sixth water molecule was added to stabilize the oxygen of
the phenoxide group and proved not to be involved along the
inspected coordinate, as it ended up at the carboxylate group.
Under this approach, a flat region on the potential-energy surface
at an O2-C8 distance of 1.63-1.72 Å was found from which
the NAC minimum is reached without energy cost (Figure S11).
Conclusions
The experimental values of âlg and âEq, obtained for the
reaction, are consistent with a mechanism that involves ester
C-O bond breaking in the transition state of the rate-
determining step. This point was successfully correlated with
theoretical results where the bond length was determined in the
range of 1.806-1.829 Å in the transition state in the gas phase
and 2.117 Å in solution.
Moreover, the estimated charge on the oxygen leaving group
in the transition state of the rate-determining step estimated from
experimental data was -0.44 ( 0.10, in excellent agreement
with the theoretical results that yield values between -0.54 and
-0.58. Finally, we would like to remark on the small ∆E
observed between TI and TS1 obtained by HF/6-311+G* as
well as the flatness of the potential energy surface on this region
The gas-phase computational results for the difference in
energy between the TS2 and the NAC structure, ∆E3 (B3LYP/
6-311+G*), were plotted as a function of the pKa of the
substituted phenol leaving group, giving a good linear relation-
ship (Figure 1), with a slope of 2.37 (r2 ) 0.97). From this
(59) This value is calculated dividing the slope of Figure 2 by 2.3, because
the energy is related to the natural logarithm of the rate constant, and the
Bronsted plots are drawn using the logarithm of the rate constant
7654 J. Org. Chem., Vol. 71, No. 20, 2006

Intramolecular Catalysis in Phenyl Ester Hydrolysis
anhydride was sublimed before use.61 The purity of the products
was also checked by comparing the UV-visible absorption
spectrum of a solution of the ester fully hydrolyzed with a mock
solution containing maleic acid and the corresponding phenol.
Aqueous solutions were made up from water purified in a
Millipore apparatus. Acetonitrile HPLC grade was dried on silica
gel 10% p/v, as described in the literature.61 It is very important to
have the solvent dried because, with traces of water, the substrate
hydrolyzes before the solution can be used.
Kinetic Procedures. Most reactions were carried out in a stopped
flow apparatus (SF) with unequal mixing syringes. The appropriate
ester dissolved in dry acetonitrile was placed in the smaller syringe
(0.1 mL). The large syringe (2.5 mL) was filled with water
containing all the other ingredients. The total acetonitrile concentra-
tion was 3.85% v/v. The solution of the substrate for the kinetic
determinations was freshly prepared in dry acetonitrile in the
appropriate concentration to get a final concentration of 1.2 × 10-4
M.
All reactions were run at 25.0 ( 0.1 °C at constant ionic strength
(0.5 M) using NaCl as the compensating electrolyte. The pH
measurements were done in a pH meter at controlled temperature
and calibrated with buffers prepared according to the literature.62
The observed rate constants were determined by measuring the
change in absorbance at 250 or 265 nm, depending on the ester. In
some of the experiments, the pH of the solution was checked after
the reaction by measuring it in the discarded solution, and the
changes observed were always less than 0.03 pH units. The kinetic
traces were fitted with one exponential equation using the SF
apparatus’s software. The pKas of substituted phenols were taken
from literature.63
Computational Procedures. All calculations were performed
with the Gaussian 98 package of programs.64 The geometry of all
stationary points was fully optimized. The most stable structures
found are in good agreement with the NAC.11 The potential energy
surface from the NAC to the TI and from this intermediate to the
products, formed by the departure of the phenoxide group, were
followed by choosing appropriate distinguished reaction coordinates.
The geometries of the B3LYP/6-311+G* stationary points were
obtained by the full re-optimization of the HF/6-311+G* structures.
The energies obtained within the continuum solvent model were
calculated with full geometry optimization using the Jaguar
program.65 The model solvent used was water (dielectric constant
) 80.370, density ) 0.99823 g/mL) within the continuing model
implemented in Jaguar.66 The B3LYP/6-31+G* calculations,
including six water molecules, were performed with full geometry
FIGURE 2. Optimized structure for the rate-limiting transition state
of aryl maleates intramolecular hydrolysis obtained from DFT (B3LYP/
6-311+G*).
when B3LYP calculations are performed either under a con-
tinuum solvent model or with a discrete number of water
molecules. This theoretical profile seems to indicate that if the
intermediate is formed it will have a considerably short lifetime
due to its low activation energy to revert to reactants. The
theoretical results do not give unequivocal proof for a concerted
or stepwise mechanism, but they rather support a borderline
situation. On the other hand, based on the similarities found in
the behavior of this system when compared with others that
are known to react by concerted mechanisms, we suggest that
an enforced concerted mechanism is the most appropriate to
describe these reactions.
(61) Perrin, D. D.; Armarego, W. L. G. Purification of Laboratory
Chemicals, 3rd ed.; Butterworth-Heinemann, Ltd: Oxford, U.K., 1994.
(62) Handbook of Chemistry and Physics, 72nd edition; Lide, D. R., Ed.;
CRC Press: Boca Raton, FL, 1991-1992; pp 8-30-8-35.
(63) Jencks, W. P.; Regenstein, J. Handbook of Biochemistry and
Molecular Biology, 3rd edition; CRC Press: Cleveland, Ohio, 1977.
(64) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M.
W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.7; Gaussian,
Inc.: Pittsburgh, PA, 1998.
(65) Jaguar version 6.0, Schrodinger, LLC, New York, NY, 2005. See:
http://www.schrodinger.com.
(66) (a) Tannor, D. J.; Marten, B.; Murphy, R.; Friesner, R. A. Sitkoff,
D.; Nicholls, A.; Ringnalda, M.; Goddard, W. A.; Honig, B. J. Am. Chem.
Soc. 1994, 116, 11875. (b) Marten, B.; Kim, K.; Cortis, C.; Friesner, R.
A.; Murphy, R. B.; Ringnalda, M. N.; Sitkoff, D.; Honig, B. J. Phys. Chem.
1996, 100, 11775.
Experimental Section
Materials. The monoaryl hydrogen maleate esters were prepared
from maleic anhydride and the appropriate phenol, adapting the
method described in the literature.60 The products were characterized
by IR and NMR (13C and 1H), as in previous work.41 Maleic
(60) Bojanowska, I.; Jasinski, T. Pol. J. Chem. 1989, 63, 455.
J. Org. Chem, Vol. 71, No. 20, 2006 7655

Andre´s et al.
optimization for each O2-C8 fixed distance. The characterization
of stationary points was done as usual by Hessian matrix calculation,
proving all eigenvalues are positive for a minimum and only one
eigenvalue is negative for a transition state. In the gas phase, the
connectivity between the stationary points was established by
intrinsic reaction coordinate calculations.67
Nacional de Co´rdoba, Argentina. G.O.A. is the grateful recipient
of a fellowship from CONICET.
Supporting Information Available: Rate constants for the
anhydride formation, effect of pH and buffer concentration, B3LYP/
6-311+G* normal frequencies for TS2 and related theoretical data,
absorbance vs time for the p-chlorophenyl hydrogen maleate
Acknowledgment. This research was supported in part by
the Consejo Nacional de Investigaciones Cient´ıficas y Te´cnicas
(CONICET), the Agencia Co´rdoba Ciencia, Agencia Nacional
de Ciencia y Tecnolog´ıa (FONCyT), and the Universidad
-1
hydrolysis, plot of τ1 as a function of pH, and linear free
relationship plots. This material is available free of charge via the
Internet at http://pubs.acs.org.
(67) Gonzalez, C.; Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523.
JO061165E
7656 J. Org. Chem., Vol. 71, No. 20, 2006