Metal ion promoted transesterifications of carboxylate esters. A structure/activity study of the efficacy of Zn2+ and La3+ to catalyze the methanolysis of some aryl and aliphatic esters

Article abstract of DOI:10.1039/b414763d

The methanolysis of various aryl and aliphatic carboxylate esters promoted by methoxide, 1,5,9-triazacyclododecane: Zn²⁺(^-OCH ₃) and La³⁺(^-OCH₃), were studied and the derived rate constants (k_OCH3, k_cat ^3:Zn(OCH3) and k_cat^La(OCH3)) correlated in various ways. The metal ion catalyzed reactions are very much faster than the background reactions in some cases reaching up to 7 × 10⁶-fold acceleration when present at concentrations of 5 mmol dm^-3. The data for both metals exhibit non-linear Bronsted correlations with the pK _a of the leaving group which are analyzed in terms of a change in rate limiting step from formation to breakdown of a metal-coordinated tetrahedral intermediate as the pK_a increases above values of ～14.7. Plots of the log k_OCH3 reaction vs. the log k _cat, values for each metal ion indicate low sensitivity for aryl esters and a higher sensitivity for the aliphatic esters. A mechanistic rationale for the observations is presented.

Full text of DOI:10.1039/b414763d

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A R T I C L E
Metal ion promoted transesterifications of carboxylate esters. A
structure/activity study of the efficacy of Zn2+ and La3+ to catalyze
the methanolysis of some aryl and aliphatic esters
Alexei A. Neverov, N. E. Sunderland and R. Stan Brown*
Department of Chemistry, Queen’s University, Kingston, Ontario, Canada K7L 3N6.
E-mail: rsbrown@chem.queensu.ca; Fax: 613-533-6669; Tel: 613-533-2400
Received 23rd September 2004, Accepted 26th October 2004
First published as an Advance Article on the web 10th November 2004
The methanolysis of various aryl and aliphatic carboxylate esters promoted by methoxide, 1,5,9-triazacyclododecane :
3:Zn(OCH3)
La(OCH3)
Zn2+(−OCH3) and La3+(−OCH3), were studied and the derived rate constants (kOCH3, kcat
and kcat
)
correlated in various ways. The metal ion catalyzed reactions are very much faster than the background reactions in
some cases reaching up to 7 × 106-fold acceleration when present at concentrations of 5 mmol dm−3. The data for
both metals exhibit non-linear Brønsted correlations with the pKa of the leaving group which are analyzed in terms
of a change in rate limiting step from formation to breakdown of a metal-coordinated tetrahedral intermediate as the
pKa increases above values of ∼14.7. Plots of the log kOCH3 reaction vs. the log kcat values for each metal ion indicate
low sensitivity for aryl esters and a higher sensitivity for the aliphatic esters. A mechanistic rationale for the
observations is presented.
nucleophilicity of the metal-coordinated methoxide to attack the
Introduction
=
transiently associated C O unit. Clearly more work is needed to
Considering their importance to industrial processes and syn-
understand the origins, scope and limitations of Mx+-catalysis
thetic chemistry it is not surprising that considerable attention
of transesterification.
has been devoted to the synthesis of carboxylate esters via acid
The metal catalyzed phosphoryl and acyl transfer reactions
and base promoted pathways.1 Limited information is available
are not limited to lanthanides since we have shown that Zn2+
concerning the mechanisms of action of catalysts developed
and Cu2+, either alone or preferably as complexes with various
to promote transesterification,2 although several examples of
ligands, can promote both methanolysis of phosphate and
metal catalyzed transesterification have been reported3 and some
carboxylate esters.7,8 In a recent study8 we investigated the
important industrial applications are compiled in Parshall and
methanolysis of some phosphate triesters such as paraoxon
Ittel’s authoritative treatise.4
(1a) and fenitrothion (1b) promoted by Zn2+(−OCH3) and
In earlier studies we demonstrated that La3+ 5a and Eu3+,5b
three of its complexes formed by association with phenan-
throline (2a), 2,9-dimethylphenanthroline (2b, DMP) and 1,5,9-
triazacyclododecane (3). Each of these complexes is capable
also of accelerating the methanolysis of p-nitrophenyl acetate
introduced into methanol solution as their triflate or perchlorate
salts along with one equivalent of NaOCH3, greatly accelerated
the transesterification of both activated and non-activated esters.
These metal ions have greatest activity as their monomethoxides,
(PNPA) although the phenanthroline complexes form equilib-
Ln3+(−OCH3)1, and general mechanisms were proposed consis-
rium distributions of inactive dimers (Phen : Zn2+
:
−OCH3)2
tent with the fact that the La3+ system reacts through dimeric
forms (La3+2(−OCH3)2,3,4), while the Eu3+ system apparently
reacts as a monomer (Eu3+(−OCH3)). One important general
aspect of these reactions is revealed through comparison of
which reduce the overall catalytic efficacy relative to the most
active catalyst 3 : Zn2+ −OCH3. A subsequent report9 has
:
noted the problematic dimerization and suggested that Cu2+,
complexed to 2,9-dimethylphenanthroline (DMP) which steri-
cally suppresses the dimerization, is also capable of modestly
promoting the methanolysis of some carboxylate esters. The
Cu2+/DMP combination appears to be an unfortunate choice
for metal promoted methanolysis given the known preference
of that ligand for Cu+ and destabilization of the square-planar
Cu2+.10 DMP does favour binding to the tetrahedral Zn2+ and
the second order rate constants for Ln3+-catalyzed methanolysis
with those for methoxide attack on a given ester (kcatester/kOMe−
)
ester
which shows that the less activated esters are more susceptible
to Ln3+ catalysis than the activated esters. For example, for
the La3+-methoxide system the kcatester/kOMe−ester ratios for phenyl
acetate, phenyl benzoate and ethyl acetate are 21, 8.9 and 2.5
respectively, while that ratio for 2,4-dinitrophenyl acetate is
0.07.5a In the case of Eu3+, the ratio is 4.3 for phenyl acetate,
and 0.2 for p-nitrophenyl acetate.5b A second general aspect of
the Ln3+-catalyzed systems is the rather spectacular rate en-
hancements seen for the methanolysis of esters in general, where
the catalysis is 1–100million-fold relative to the background
reaction in the presence of as little as 5 × 10−3 mol dm−3 of
metal ion at near neutral pH6 and ambient temperature. This
s
s
belies the situation in water where intermolecular metal ion
catalysis of hydrolysis of esters, particularly non-activated ones,
is generally poor or non-existent, as opposed to intramolecular
hydrolysis where the metal ion is held through binding to
=
some group, close to the scissile C O bond. The origins of
the rate enhancements we see in methanol are uncertain but
could include stronger pre-equilibrium binding of the ester
to the metal ion in the reduced polarity medium and greater
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 5 – 7 2
6 5
©

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gives good catalysis as the monomethoxide, but dimerization
is still a problem.8 Building on our previous work on the
methanolysis of phosphate esters promoted by transition metal
ions7,8 we have chosen 3 : Zn2+(−OCH3)11 as a superior catalyst
for the methanolysis of a series of carboxylate esters (4–
15) having alcohol portions of varying leaving group ability.
Herein we report the kinetic studies with the zinc complex
3 : Zn2+(−OCH3) and for comparison purposes those with
(La3+(−OCH3))2.
b. General UV/vis kinetics
Stock solutions (5 mmol dm−3) of each of the aryl esters were
prepared in 99.8% anhydrous acetonitrile (Aldrich). For the
Zn2+-catalyzed reactions, stock solutions of Zn(OTf)2 and ligand
3 were made in anhydrous methanol to 0.05 mol dm−3 and
tetrabutylammonium hydroxide was diluted from 1.0 mol dm−3
(as supplied) to 0.05 mol dm−3 with dry MeOH. For each kinetic
run, the catalyst was formulated in situ by adding known aliquots
of Zn(OTf)2, ligand 3 and NBu4(OH), to methanol solvent such
that the final volume was 2.5 ml. Since the final ratios of ligand,
Zn2+ and −OCH3 were 1 : 1 : 0.5 the solution is self buffered at
sspH = 9.1 corresponding to the spKa of 3 : Zn2+(HOCH3).7,13 The
kinetics were followed by monistoring the change in absorbance
of 2 to 10 × 10−5 mol dm−3 of esters 4–11 at 276.9, 309, 330, 310,
283, 291, 274.6, 280 and 275.9 nm respectively. The Abs. vs. time
data were fit to a standard first order exponential equation to ob-
tain the pseudo-first order rate constants, kobs. The rates of the re-
action were monitored at four to six different catalyst concentra-
tions in duplicate ranging from 2.5 × 10−4 to 5.0 × 10−3 mol dm−3,
and the gradients of the plots of kobs vs. [3 : Zn2+(−OCH3)] were
taken as the second order rate constants (k2obs) for the catalyzed
reaction, these rate constants being given in Table 1.
The La3+-catalyzed reactions were monitored by UV/vis
spectrophotometry under buffered (N-ethylmorpholine,
12 mmol dm−3) conditions at sspH 8.74 in the presence of
0.2 to 2.0 × 10−3 mol dm−3 La(OTf)3 as described in our
earlier publications.5 The rates of methanolysis of 2 to 10 ×
10−5 mol dm−3 solutions of esters 5, 6, 8, and 9 were monitored
at 274.9, 335, 283 and 294 nm respectively to obtain the
kobs pseudo-first order rate constants at each [La3+], and the
gradients for the kobs vs. [La3+] plots were calculated to give the
Experimental
a. Materials
4-Chlorophenol (99+%), 3-nitrophenol (99%), 4-methoxy-
phenol (99%), 2,3,5-trimethylphenol, pentafluorophenol
(99+%), 2,4-dimethylphenol (98%) and 2,6-dimethylphenol,
4-nitrophenol and 2,4-dinitrophenol were all acquired from
Aldrich and used as received for syntheses of the corresponding
esters. Acetic anhydride (98%) from Aldrich and NaOH pellets
(98.8%, Fisher Scientific) were also used as received for the
syntheses. Trifluoroethyl acetate, 97% (Lancaster), phenyl
acetate (Aldrich) and isopropyl acetate, 99% (Aldrich) were
used as received as substrates. Syntheses of the aryl esters
followed the general procedure detailed in the literature,12 and
overall k2 for La3+-catalyzed methanolysis which are given in
obs
Table 1. Also included in Table 1 are the reported rate constants
for methanolysis of esters 4, 7 and 10 computed from kobs vs.
[La3+] total data given in our previous paper.5a
The rates of methanolysis of 20 mmol dm−3◦solutions of esters
13 and 14 in CD3OD were monitored at 25 C by 1H NMR in
the presence of 3 : Zn2+(−OCH3) (for ester 13) or La3+ plus one
equivalent of NaOCH3 (for esters 13 and 14). The rates were de-
termined though observation of both the rate of disappearance
of the starting materials and rate of appearance of products,
the pseudo-first order rate constant being evaluated from the
exponential fits. The second order rate constants for catalysis
were calculated as kobs/[catalyst] and are given in Table 1.
The rates of methanolysis promoted by −OCH3 in the absence
1
in all cases gave products having H NMR and mass spectra
consistent with the structures. Sodium methoxide, 0.5 mol dm−3
(Aldrich), as well as HCl, 0.02 mol dm−3 solution (standardized,
Fisher Scientific), 1,5,9-triazacyclododecane, 97% (Aldrich)
(12-3N), zinc triflate (Zn(OTf)2, 98%, Strem Chemicals) and
La(OTf)3, 99.999% (Aldrich) were used as supplied.
1
of any metal ion were determined by UV/vis or H NMR as
Table 1 Second order rate constants for the methanolysis of esters 4–15 promoted by methoxide, 3 : Zn2+(−OCH3) and La3+(−OCH3) at 25 ◦C
Ester
pKa of ArOH in MeOH
k
OCH3/dm3 mol−1 s−1
kcat3:Zn(OCH3)/dm3 mol−1 s−1h
kcatLa(OCH3)/dm3 mol−1 s−1i
4
7.83b
8.84a
484.8
73.3
49.7
190e
43.6
23.8
39.8
19.2
16.7
8.6
13.9
4.28
4.30
3.00
0.042
0.006
31
5
14.6
21.9
38.6g
27.7
18.0
29.33g
—
4.33
10.0
0.071g
0.004g
6
12.41b
11.30b
13.59b
14.7c
7
8
7.04
9
1.58
2.01(2.66)f
0.63
10
14.33b
15.04b
15.36b
15.78d
18.42d
19.79d
18.13
11
12
0.49
13
12.64
0.057g
0.007g
0.17e
14
15
Methyl acetate
a Determined as the sspH at half neutralization, this work. b From refs. 15,16,14. pKa for 12 calculated according to the method provided in ref. 14;
MeOH
H2O
MeOH
H2O
pKa
= 1.12pKa
+ 3.56. c R. L. Schowen and K. S. Lathan, J. Am. Chem. Soc., 1967, 89, 4677. d Computed from pKa
= 0.748pKa
+
6.53, see text. e From ref. 9. f From C. G. Milton, M. Gresser and R. L. Schowen, J. Am. Chem. Soc., 1969, 91, 2047. g Data from ref. 5a for methoxide
and lanthanum reactions; lanthanum reactions determined at sspH = 8.86 for 7 and 10; values are computed from the gradient of the plot of kobs vs.
[La3+]t. h Computed from the gradient of kobs vs. [3 : Zn2+(−OCH3)] plots at sspH 9.1 under self buffered conditions. i Computed from the gradient of
kobs vs. [La3+] plots at sspH 8.74 under buffered conditions.
6 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 5 – 7 2

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appropriate for a given ester: for the aryl esters the pseudo-
first order rate constant for methanolysis were determined in
duplicate at four different [−OCH3] ranging from 2.5 × 10−4 to
3.0 × 10−2 mol dm−3, lower [−OCH3] being used for the more
reactive esters and higher [−OCH3] being used for the less reactive
esters. The second order rate constants for these (kOCH3) were
computed as the gradients of the kobs vs. [−OCH3] plots and are
given in Table 1.
Results
3:Zn(OCH3)
Given in Table 1 are the second order rate constants for
the transesterification reactions of esters 4–15 promoted by
methoxide, 3 : Zn2+(−OCH3) and La3+(−OCH3). In all cases
these were determined from the gradients of the plots of the
pseudo-first order rate constants for methanolysis as a function
of [methoxide] or [metal containing catalyst]. In the case of
catalysis by 3 : Zn2+(−OCH3) the solutions were self-buffered
at sspH 9.1 by adding half as much methoxide as the total added
[3 : Zn2+], converting half of the latter to the active species.
The La3+(−OCH3) reactions were buffered with 12 mmol dm−3
Fig. 2 A Brønsted plot of log pKa phenol in methanol vs. log kcat
for methanolysis of aryl acetates promoted by 3 : Zn2+(OCH3), T =
25 ◦C. Dashed line corresponds to NLLSQ fit of data to eqn. (3)
encompassing all esters with b1 = −0.023 0.03 and b2 = −0.690
ROH
0.005 with a breakpoint of pKa
= 14.8 (see text).
s
N-ethyl morpholine at pH 8.74. Also included in Table 1 are
s
s
s
the pKa values for the phenols from the literature or from
measurements of the pH at half neutralization. While pKa
s
s
s
s
values for most of the phenols are available14,15 or can be
calculated from the methods given in references 14 and 16, the
sspKa values for the aliphatic alcohols corresponding to esters
13–15 are not available, to our knowledge. We may calculate the
values based on a linear regression approach similar to that used
by Bosch et al. for correlating the acidities of carboxylic acids,
phenols and ammonium ions in water and methanol.14 From the
autoprotolysis constant of methanol (10−16.77 (mol dm−3)2)14,16 its
sspKa can be computed as 18.13 on the mol dm−3 scale. As far
as we know, the only other aliphatic alcohol for which a spKa in
La(OCH3)
Fig. 3 A Brønsted plot of log pKa phenol in methanol vs. log kcat
for methanolysis of aryl acetates promoted by La3+(−OCH3), T =
25 ◦C. Dashed line corresponds to NLLSQ fit of data to eqn. (3)
encompasses all esters with values of b1 = 0.03
0.005 and b2
=
−0.715 0.005 with a breakpoint of pKa = 14.7 (see text).
−0.821
0.044. Admittedly this correlation is somewhat
methanol is available is hexafluoroisopropanol (sspKa = s13.4917
contrived since it is based on sspKa values calculated from a linear
regression of only two experimental data points. Nevertheless,
it is consistent with the observation that the Brønsted plot for
alkaline hydrolysis for aryl acetates vs. other acetate esters fits
a similar two-line profile.19 The plots of the metal catalyzed
reactions shown in Figs. 2 and 3 show definite evidence of a
break where the rate constants are quite sensitive to phenols or
alcohols with high sspKa values, but far less sensitive to the nature
of the ROH groups with low sspKa values. In these cases there is
no obvious discrepancy between aliphatic and aryl esters, so all
esters are used for the subsequent treatment.
vs. pKa
= 9.318), so that a linear regression (admittedly only
H2O
s
s
on two data points) gives pKa (MeOH) = 0.75pKa(H2O) +
s
s
6.53. The pKa values for the aliphatic alcohols corresponding
to 13–15 were computed from this regression line.
In order to aid in visualizing trends in the data, Brønsted plots
of the sspKa of phenols in methanol vs. the log second order rate
constants for the methoxide, 3 : Zn2+(−OCH3) and La3+(−OCH3)
catalyzed methanolysis of the esters are shown in Figs. 1, 2 and
3 respectively.
To compute the Brønsted dependences we assume that
the overall metal-catalyzed processes follow eqns. (1) and (2)
describing a fast pre-equilibrium binding followed by reversible
creation of an intermediate, the formation and breakdown of
which can be rate limiting depending on the nature of the leaving
group. Steady state treatment gives the general relationship in
eqn. (3) where the exponent pKa refers to the sspKa of the ROH
or ArOH leaving group in methanol and the b terms correspond
to the various binding and kinetic steps. Eqns. (4) and (5)
correspond to limiting cases where formation and breakdown of
the tetrahedral addition intermediate (CH3O-To- : Mx+) is rate
limiting.
Fig. 1 Brønsted plots of pKa for phenol in methanol vs. log kOCH3 for
the methoxide promoted methanolysis of aryl and aliphatic acetates,
T = 25 ◦C. Dashed line of slope b = −0.656 0.021 encompasses esters
6–12, while excluded data points (from the left) correspond to esters 4
and 5 respectively. Dotted line of slope b = −0.821 0.044 corresponds
to the three aliphatic esters 13–15 and methyl acetate.
K
b
Mx+ − (−OCH3) + RCO2Rꢀ ꢀ Mx+ − (−OCH3) : RCO2Rꢀ
(1)
k
k
1
Mx+ − (−OCH ) : RCO Rꢀ CH O − T − : Mx+ →P
(2)
ꢀ
3
2
3
o
k
−1
The center part of the methoxide plot in Fig. 1 comprises seven
phenols with sspKa values ranging from 11.17 to 15.04 providing
a very good linear correlation with b = −0.656 0.021, while the
two left points for the pentafluoro and 2,4-dinitrophenyl acetates
deviate markedly. The data for the aliphatic esters including
methyl acetate for which the kOCH3 is reported elsewhere,9 appear
k2obs = Kbk1k2/(k−1 + k2) =
(bb + b1 + b2)pK
a
CbC1C210
/(C−110b − 1pKa + C210b2pKa)
(3)
(4)
(5)
k2obs = Kbk1 = CbC110
(bb + b1)pK
a
ko2bs = Kbk1k2/k−1 = (CbC1C2/C−1)10
(bb + b1 − b−1 + b2)pK
a
to define a different line, the gradient of which is baliphatic
=
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 5 – 7 2
6 7

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The dashed lines in Figs. 2 and 3 are computed from the
NLLSQ fits of all the data to eqn. (3): in Fig. 2, (bb + b1) =
−0.023 and (bb + b1 − b−1 + b2) = −0.710 with a breakpoint at
have determined that the actual catalytic species are dimers
(La3+)2(−OCH3)2,3,4 the relative importance of which depend on
s
the pH and the [dimer].20 The data in Table 1 reveal some
s
sspKa = 14.8; in Fig. 3 (bb + b1) = −0.02 and (bb + b1 − b−1
b2) = −0.710 with a breakpoint at pKa = 14.7.
+
interesting trends in the reactivities of the metal methoxides
relative to methoxide itself. Within the aryl or aliphatic series
the most activated esters toward methoxide attack, as expected,
Alternative presentations of the kinetic data are given in
s
Figs. 4 and 5 which comprise two plots of log kOCH3 vs. log
contain leaving groups with the lowest pKa values for their
kcat
and log kcat
respectively. Following Kirsch
corresponding alcohols, and in these casess(esters 4–7 of the aryl
series and 13 of the aliphatic series) the kcat3:Zn(OCH3)/kOCH3 and
kcatLa(OCH3)/kOCH3 ratios are generally less than 1. However, for
the less activated esters one sees that the kcat3:Zn(OCH3)/kOCH3 and
kcatLa(OCH3)/kOCH3 ratios are generally greater than unity. Although
one normally anticipates that simple Brønsted considerations
would make a metal-coordinated methoxide less nucleophilic
than methoxide itself, in analogous hydrolyses catalyzed by
metal ions this is generally interpreted to arise from a dual role
for the metal ion in providing Lewis acid catalysis and delivering
the Mx+-coordinated OH or OR nucleophile.21
3:Zn(OCH3)
La(OCH3)
and Jencks19 we assume that the mechanism of methoxide
promoted methanolysis is similar enough for all the esters that
the rate constant, kOCH3, can be used as an empirical measure
of the composite effects of structural changes that incorporate
both electronic and steric effects rather than using Hammett
parameters or pKa values. This allows us to make a more
common comparison of the effects of structural changes on
the rates of methoxide and metal-promoted methoxide attack.
For Zn2+, the Fig. 4 plot comprising all data fits a rather poor
linear dependence (not shown) with slope = 0.73 0.13 (r2 =
0.7865). Better linear relationships are drawn through the data
representing the subset of aliphatic esters and aryl esters, and
although there are only three aliphatic esters (13–15), the line
for these is steeper than for the aryl esters (0.82 vs. 0.31). The
La3+(−OCH3) vs. methoxide plot shown in Fig. 5 has a general
appearance similar to that of the 3 : Zn2+(−OCH3) vs. methoxide
data in Fig. 4, with an overall slope of 0.706 0.117 (r2 = 0.820).
While the overall correlation is not good, breaking the data
into the aliphatic (esters 13–15) and aryl (esters 4–12) subsets
gives two lines of quite different slopes, the aliphatic slope being
greater than the aryl one by a factor of ∼5–6.
a. Uncatalyzed attack of methoxide
The plot of the log kOCH3 for methoxide-promoted methanolysis
s
s
of the esters vs. the pKa values shown in Fig. 1 provides a
good linear correlation for the aryl esters except for the strongly
electron withdrawing 2,4-dinitrophenyl and pentafluorophenyl
derivatives which are less reactive than predicted on the basis of
s
s
the pKa data. Non-linear Hammett and Brønsted behaviours
have been observed for the hydroxide-catalyzed hydrolysis
of substituted aryl benzoates22 and acetates.23 Schowen24 has
observed that the “DG‡ for methoxide promoted methanolysis of
aryl acetates and carbonates in methanol are not linearly related
to the DG◦ values for ionization of the corresponding phenols,”
noting that “the rate process becomes less sensitive to the
substituent as the electron-withdrawing power of the substituent
increases”. The fall-off in the rate results from a greater
importance of the resonance interaction in the equilibrium
ionization processes (on which the Hammett and sspKa values are
based) than in the kinetic processes where decidedly less charge
development may have occurred in the rate-limiting TS.22–25
In the present study linear Brønsted behaviour (b = −0.66
0.02)26 is observed for aryl esters with corresponding phenol
sspKa values between 11 and 15 and for these it is probable
that if the reaction is a two step one, the rate limiting step
involves methoxide attack since expulsion of the leaving aryloxyl
group from the anionic tetrahedral intermediate should be
favoured over expulsion of the methoxide. Utilizing the ‘effective
charge treatment’ described by Jencks et al.27 and Thea and
Williams,28 the Brønsted b value suggests the process shown in
Scheme 1 where the rate-limiting transition state has a nearly
neutral aryloxy oxygen. The data are also consistent with a
concerted mechanism with little cleavage of the OAr bond in
the transition state, such as has been shown by Ba-Saif et al.29
for the displacement of the p-nitrophenoxy group from ester 7
by phenoxy nucleophiles.
3:Zn(OCH3)
Fig. 4 Plot of log kOCH3 vs. log kcat
for the methoxide and
3 : Zn2+(−OCH3) catalyzed methanolysis of all acetyl esters, T =
25 ◦C. Lower dotted line comprises the aliphatic esters 13–15 with
slope = 0.821 0.030 (r2 = 0.9987), and upper dotted line comprises
aryl esters 4–12, slope = 0.314 0.055 (r2 = 0.8447).
La(OCH3)
Fig. 5 Plot of log kOCH3 vs. log kcat
for the methanolysis of all
esters promoted by methoxide and La3+(−OCH3). Lower dashed line
comprises aliphatic esters 13–15, slope = 0.914 0.125 (r2 = 0.9817),
while upper dotted line comprises aryl esters 4–12, slope = 0.16 0.09
(r2 = 0.3607).
Discussion
The various rate constants are presented in Table 1 along with
their alcohol spKa values in methanol where these are available
or can be cosmputed by literature methods from correlations
with the aqueous pKa values.14 For the lanthanum methox-
ide promoted methanolysis the second order rate constant
is determined as Dkobs/D[La3+] under buffered conditions at
sspH 8.74 and is thus presented per La3+ ion, even though we
Scheme 1
In the case of the aliphatic esters the Brønsted plot (including
the literature rate constant for the kOCH3 of methyl acetate7) forms
6 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 5 – 7 2

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a reasonably straight line (slope = −0.821 0.044) apparently
Since addition of methoxide to the ester is metal-ion as-
sisted, microscopic reversibility considerations require that the
separate from that for the aryl esters. Since there is only one
s
s
experimental pKa value available for a member of these four
departure of poor leaving groups (with high pKa values for
s
s
s
esters (methanol), we estimate the pKa values from a linear
the corresponding alcohols) such as ethoxy or isopropoxy must
also be metal ion assisted suggesting that the k2 step must be
partially or entirely rate-limiting and eqn. (5) applies. As the
sspKa decreases, eventually the leaving group is sufficiently good
that it departs without metal-ion assistance and the rate-limiting
step for the reaction must change from breakdown to formation
of the intermediate, in both these cases when the sspKa is about
14.7.
It is curious that in the plateau region, where the leaving
groups are good and formation of the intermediate is rate-
limiting, that the computed Brønsted b is ∼0, signifying little or
no dependence on the nature of the leaving group. We rationalize
this observation within the framework of the limiting case of
eqn. (4) where formation of the intermediate depends on the
counterbalancing effects of changes in the leaving group on
both the Kb and k1 steps, i.e. (bb + b1) → 0. This situation
is strongly reminiscent of the known insensitivity of the rates of
acid-catalyzed hydrolysis of esters to changes in the nature of the
leaving group (q = 0) which Taft30 interpreted as resulting from a
counterbalancing of the alkoxy/aryloxy substituent’s electronic
effect on protonation equilibrium and subsequent nucleophilic
regression relating pKa(MeOH) ands pKa(H2O) which is based
s
s
on the only two experimental aliphatic alcohol pKa values in
methanol of which we are aware. The sspKa values presented in
Table 1 are based on this calculation and must be viewed only
as estimates. Although the slope of the Brønsted line for the
aliphatic esters is within experimental error of that for the aryl
esters, it lies an order of magnitude higher suggesting a steric19
and perhaps electronic retardation for the aryl esters.
Methoxide attack on the aliphatic esters must go through
anionic tetrahedral addition intermediates which, with equally
good or poorer leaving groups than methoxide, must revert to
starting materials in competition with breakdown to product,
the relative amounts of which are controlled by the sspKa values
of the ROH and the Brønsted b value for the k−1 and k2 steps.
The Brønsted line for the four aliphatic esters shown in Fig. 1
appears to be a straight line with a slightly greater gradient than
for the aryl esters, which might arise from that fact that the
series encompasses cases where the rate limiting steps is k1 (13),
a symmetrical case (methyl acetate) where the kobs is k1/2, and
the case of isopropyl acetate where kobs = k1k2/(k−1 + k2) which,
in addition to any steric hindrance to the attack of methoxide
on 15, also might steepen the best fit line.
=
step of attack of water on the protonated C O.
The descending wings of Figs. 2 and 3 have strong dependence
on the nature of the leaving group b = −0.71 which, when
analyzed within the framework of eqn. (5), is consistent with
a significant cleavage of the C–OR bond in the TS. Since the net
effect of the substituent ion Kb and k1 steps cancel, this leads
to the conclusion that the sum of (−b−1 + b2) is significantly
negative.
b. Catalysis by 3 : Zn2+(−OCH3) and La3+(−OCH3)
3:Zn(OCH3)
La(OCH3)
Shown in Figs. 2 and 3 are the log kcat
and log kcat
s
vs. pKa data for the methanolysis of the esters promoted by
thestwo metal-methoxide complexes. Overall the leaving group
acidity covers a range of >1011-fold while the kinetic data span a
range of ∼5000-fold and 9000-fold respectively for the two metal
ions. Each plot exhibits a pronounced break suggestive of at least
a two-step process where formation and breakdown of some
intermediate is rate-limiting. In both the cases, the descending
and plateau b values are experimentally the same at −0.71 and
3:Zn(OCH3)
La(OCH3)
c. Comparision of kOCH3 and kcat
or kcat
Presentation of the rate constant data as in Figs. 4 and 5 has
some advantages over the customary Brønsted or Hammett
plots since the latter rely on substituent induced changes to
equilibrium pKa processes which may not be appropriate for
how a substituent influences a particular reaction where the rate-
s
∼0 respectively with the breakpoint occurring at ∼spKa = 14.7
such that he plateau region covers roughly 106-fold change in
acidity of the leaving group with virtually no change in catalyzed
rate constant.
limiting step(s) have little charge development on the departing
The Fig. 2 and 3 data are analyzed according to the processes
given in eqns. (1) and (2) which give rise to the steady state
expression in eqn. (3) which contains both the Mx+ + ester
equilibrium binding constant (Kb) and the various rate constants
for intramolecular formation and breakdown of the tetrahedral
intermediate. Unlike the case where simple methoxide addition
to the esters forms a highly unstable, and perhaps kinetically
unstable (in the case of aryl esters)29 anionic intermediate
(16), the Mx+–−OCH3 catalyzed process forms a Mx+-stabilized
tetrahedral intermediate with a significant lifetime (17-To-
3:Zn(OCH3)
OR. Comparison of log kOCH3 vs. log kcat
vs. log kcat
or log kOCH3
La(OCH3)
allows one to assess how the rates for two
reactions depend both on steric and electronic influences of
the substituents and a break in such a plot requires that
the substituents influence the two reactions in different ways.
An additional benefit is that this treatment does not rely on
s
s
experimental or estimated pKa values for a given substituent
which, if in error, may influence the conclusions based on the
slopes of Brønsted plots.
The plots in Figs. 4 and 5 are visually similar suggesting that
both La and Zn catalysis respond to structural variations in a
similar way relative to the methoxide reaction. Both plots show
a break surrounded by an ascending domain encompassing the
aliphatic alcohols 14 and 15, followed by a less sensitive domain
encompassing the aryl esters. While one could analyze the entire
series within a common relationship, another approach is to
consider that there are two families encompassing the aryl
and aliphatic esters. The dashed lines drawn on the figures
are linear fits for the two classes and for both metal ions
indicate that the aliphatic esters have a greater sensitivity for
the metal-methoxide reactions than do the aryl esters, probably
because the aliphatic line includes two members with poor
leaving groups. The methoxide and metal-methoxide reactions
are related mechanistically in that esters containing poor leaving
groups such as methoxide, ethoxide and isopropoxide must go
through two step processes in each case with reversibly-formed
tetrahedral intermediates (To-) as shown in eqns. (6) and (1), (2)
respectively.
M
x+) which can partition to starting materials and products
depending on the relative transition state energies corresponding
to k−1and k2 (Scheme 2).
Scheme 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 5 – 7 2
6 9

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(6)
Comparison of the steady state analyses of the process in
eqns. (1), (2) and that in eqn. (6) gives eqn. (7),
Fig. 6 A plot of the log kcat3:Zn(OCH3) vs. log kcatLa(OCH3) values for methanol-
ysis of all esters promoted by 3 : Zn2+(−OCH3) and La3+(−OCH3), T =
25 ◦C. Dashed line represents linear regression for all data, slope =
0.997 0.071 (r2 = 0.9529).
ꢀ
ꢁ
K
k
k k
1 2
b
M(OCH
cat
)
log
log
3
log k
+k
−1
2
ꢀ
ꢁ
=
(7)
ꢀ
k
1
ꢀ
k
2
log kOCH
3
ꢀ
ꢀ
k
+k
−1
2
0.071; r2 = 0.9529). The unit slope, with no break, indicates that
the substituents influence both metal-methoxide reactions in the
same way.
for which the two limiting cases of k−1 > k2 and k2 > k−1 can be
derived. The gradients (S) of the extremes in plots in Figs. 4 and
5 are given as eqns. (8) and (9),
ꢀ
ꢁ
K
k k
1 2
b
M(OCH
cat
)
Dlog
D log
3
Dlog k
k
−1
9
Conclusions
ꢀ
ꢁ
=
= S
(8)
ꢀ
ꢀ
k
k
Dlog kOCH
1
2
3
ꢀ
The above study shows that the methanolysis of both aryl and
aliphatic esters is greatly accelerated by the two catalytic systems
described above. In the case of La3+, we have found that the
catalytic entities are dimers with 2, 3 or 4 associated methoxides
which are spontaneously formed in solution at the concen-
trations employed without the requirement of added ligands.
However, transition metal ions such as Zn2+ or Cu2+ require
added ligands to prevent the deleterious formation of dimers and
oligomers, the latter being inactive relative to the monomeric
forms. Our studies show that 1,5,9-triazacyclododecane is an
optimal ligand for use with Zn2+ although phenanthroline
and 2,9-dimethyl phenanthroline (DMP) can also provide
catalytically active complexes despite the partial formation of
dimers under these conditions.7 As little as 5 mmol dm−3 added
La3+ with equimolar methoxide accelerates the methanolysis
of phenyl acetate (10) by 7.8 × 106-fold relative to the back-
ground methoxide reaction at the near neutral of 8.7. The 3 :
Zn2+(−OCH3) catalyst, when present at 5 mmol dm−3, accelerates
the methanolysis of phenyl acetate by 1.6 × 106-fold relative
k
−1
M(OCH
cat
)
3
Dlog k
Dlog(Kbk1)
D log(kꢀ1)
=
= S
(9)
Dlog kOCH
3
which are seen to differ only by the presence of the partitioning
ratios (k2/k−1 and k2 /k−1ꢀ) of the tetrahedral intermediates. This
ꢀ
must be factored into the gradient in the cases of the poor
leaving groups becoming important when the pKa is >∼14
s
s
and thus within the domain described by the ascending wing
in each plot. Although we cannot put quantitative values to
any of these constants, it seems reasonable to suggest that the
larger gradient observed with poorer leaving groups arises from
the substituent changes influencing both the methoxide and the
metal-catalyzed reactions in a similar way, i.e. a gradient closer to
1. Since methoxide is a strong base/nucleophile (sspKa = 18.13)
it is reasonable to conclude that the rate limiting step for its
reaction with most of the esters (with the probable exception of
the isopropyl ester) is attack with breakdown of the intermediate
being fast.31 However the data with the metal catalyzed reactions,
s
to the background methoxide reaction at pH 9.1. We observe
that the best accelerations relative to the bsackground reactions
occur with less activated esters, and in many of these cases, the
kcat3:Zn(OCH3)/kOCH3 or kcatLa(OCH3)/kOCH3 ratios are greater than unity.
It is important to compare the efficacy of our catalytic systems
to those of the Cu2+ : DMP methanolysis system9 and the 3 :
Zn2+(−OH) hydrolytic system.13 The relevant data are presented
in Table 2 in which it is seen that the rate constants exhibited
by the lanthanum and zinc systems for the methanolysis of
phenyl acetate (10) and p-nitrophenyl acetate (7) are between
660 and1400-fold larger than for the Cu2+ : DMP system and
that their catalysis of ethyl acetate methanolysis is at least 100-
fold larger (bearing in mind that for the latter the available
comparison data are for reaction with a more reactive methyl
s
s
where the pKa of the attacking metal associated methoxide is
lowered to ∼9, indicate that there is a change in rate-limiting
step throughout the series. When the leaving groups are good,
s
apparently as is the case with those having a pKa of <14.7,
the rate limiting step for the metal catalyzed reasctions becomes
formation of the tetrahedral intermediate. We propose that the
shallow gradient relating to eqn. (9) results from the fact that
substituent changes tend to counterbalance Kb and k1 such that
their product is relatively constant over the aryl (and probably
trifluoroethyl) series.
A third way of correlating the data is presented in Fig. 6
3:Zn(OCH3)
as a plot of log kcat
vs. log kcatLa(OCH3). In this case, the
data form a straight line with a slope of nearly unity (0.997
Table 2 Comparison of the second order rate constants for methanolysis and hydrolysis processes of given substrates, T = 25 ◦
C
Substrate
=
Phenyl acetate
p-Nitrophenyl acetate
k2/dm3 mol−1 s−1
ROC OCH3
Catalyst
k2/dm3 mol−1 s−1
k2/dm3 mol−1 s−1
La3+(−OCH3)a
29.3
13.9
2.01
38.6
7.1 × 10−2 (R = Et)
4.2 × 10−2 (R = Et)
5.7 × 10−2 (R = Et)
4.2 × 10−4 (R = Me)
∼4 × 10−4 (R = Me)
1.1 × 10−1 (R = Et)e
3 : Zn2+(−OCH3)a
−OCH3 (in methanol)a
Cu2+ : DMPb
19.2
190b
1.6 × 10−2
1.5 × 10−2c
1.26e
2.9 × 10−2
4.9 × 10−2d
9.5e
3 : Zn2+(−OH) (in water)
−OH (in water)
a This work. b Ref. 9. c Computed from data given in ref. 11. d Computed from data given in Ref. 13 for reaction at pH 8.1. e From ref. 19.
7 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 5 – 7 2

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acetate while the La3+ and Zn2+ catalysts refer to the methanol-
ysis of ethyl acetate). A second point of note is that the La3+
and Zn2+ catalysts have second order rate constants comparable
to the rate constant of methoxide attack in methanol, while the
Cu2+ : DMP and 3 : Zn2+(−OH) systems are at least 100-fold
(and several thousand-fold in the case of methanolysis of p-
nitrophenyl acetate) less reactive than methoxide or hydroxide
respectively for a given ester. Interestingly, where a comparison
can be made between the second order rate constants for
hydrolysis and methanolysis promoted by 3 : Zn2+(−OH) or
3 : Zn2+(−OCH3) respectively, the methanolysis reactions are
about 1000-fold faster than the hydrolysis reactions with the aryl
esters, and somewhat less for the aliphatic esters, again bearing
in mind that the hydrolysis data are with methyl acetate and the
methanolysis is with ethyl acetate.
4 G. W. Parshall and S. D. Ittel, Homogeneous Catalysis. The Ap-
plications and Chemistry of Catalysis by Soluble Transition Metal
Complexes, 2nd edn., Wiley-Interscience, New York, 1992, pp. 269–
296.
5 (a) A. A. Neverov, T. McDonald, G. Gibson and R. S. Brown,
Can. J. Chem., 2001, 79, 1704; (b) A. A. Neverov, G. Gibson and
R. S. Brown, Inorg. Chem., 2003, 42, 228.
6 For the designation of pH in non-aqueous solvents we use the recom-
mendations of the IUPAC Compendium of Analytical Nomenclature.
Definitive Rules 1997, 3rd edn., Blackwell, Oxford, UK, 1998. If one
calibrates the measuring electrode with aqueous buffers and then
measures the pH of an aqueous buffer solution, the term wwpH is
used; if the electrode is calibrated in water and the ‘pH’ of the neat
buffered methanol solution then measured, the term swpH is used,
and if the electrode is calibrated in the same solvent and the ‘pH’
reading is made, then the term sspH is used.
7 W. Desloges, A. A. Neverov and R. S. Brown, Inorg. Chem., 2004,
43, 6752.
8 A. A. Neverov and R. S. Brown, Org. Biomol. Chem., 2004, 2, 2245.
9 R. Cacciapaglia, S. Di Stephano, F. Fahrenkrug, U. Lu¨ning and L.
Mandolini, J. Phys. Org. Chem., 2004, 17, 350.
10 (a) S. Kitagawa, M. Munakata and A. Higashie, Inorg. Chim. Acta,
1884, 84, 79; (b) A. Paulovicova, U. El-Ayanan and Y. Fukuda, Inorg.
Chim. Acta, 2001, 321, 56; (c) electrospray MS measurements on
methanolic solutions containing equimolar amounts of CuCl2 and
dimethylphenanthroline (DMP) indicate the presence of monovalent
copper as Cu+ : DMP whereas the electrospray MS of CuCl2 in
the presence of the less sterically encumbered phenanthroline parent
shows only divalent copper complexes, consistent with the well-
known destabilizing effects of DMP on square planar, square pyra-
The fact that La3+ and Zn2+ systems react with many of
the esters faster than does methoxide gives some clue to the
mechanism of reaction. The available data are consistent with a
mechanism of catalysis that involves a pre-equilibrium binding
of the metal-methoxide complex with the ester followed by an
internal delivery of the methoxide via a five-coordinate transition
state to form an anionic tetrahedral addition intermediate
stabilized by a four coordinate Zn2+. This is analogous to
the general mechanism that is widely proposed for metal-ion
catalyzed hydrolyses, but is kinetically equivalent to a process
where an external nucleophilic hydroxide or methoxide attacks
the Mx+-coordinated ester.32 It is particularly interesting that,
where direct comparison can be made with the 3 : Zn2+(−OH)
system in promoting the hydrolysis of these esters in water, the
corresponding methanolysis promoted by 3 : Zn2+(−OCH3) is at
least two to three orders of magnitude larger. The likely origins of
the rate enhancements are an increased pre-equilibrium binding
midal and octahedral coordinate complexes and a stabilizing effect
10a,b
on tetrahedral or pseudo tetrahedral coordination geometries
.
11 The corresponding 3 : Zn2+ −OH species, which was first reported
:
as a model for carbonic anhydrase,13 has been investigated as to its
ability to catalyze the hydrolysis of aryl esters; J. Suh, S. J. Son and
M. P. Suh, Inorg. Chem., 1998, 37, 4872.
12 R. A. Joshi, M. K. Gurjar, N. K. Tripathy and M. S. Chorghade,
Org. Process Res. Dev., 2001, 5, 176.
13 E. Kimura, T. Shiota, T. Kooike, M. M. Shiro and M. Kodama,
J. Am. Chem. Soc., 1990, 112, 5805 report that the pKa for the aquo
form of 4 : Zn2+(H2O) is 8.4.
of the substrate, and a less solvated nucleophile attacking the
2+
=
Zn -coordinated C O unit.
14 F. Rived, M. Rose´s and E. Bosch, Anal. Chim. Acta, 1998, 374,
309.
15 (a) V. A. Palm, Tables of Rate and Equilibrium Constants of Hetero-
cyclic Reactions, Vol. 1 (1), Proizbodstvenno-Izdatelckii Kombinat
Biniti, Moscow, 1975; (b) V. A. Palm, Tables of Rate and Equilibrium
Constants of Heterocyclic Reactions, Suppl. Vol. 1, issue 3, Tartuskii
gosudarsvennii Universitet, Tartu, 1985.
Acknowledgements
The authors gratefully acknowledge the financial assistance
of the Natural Sciences and Engineering Research Council of
Canada, Queen’s University and the United States Department
of the Army, Army Research Office, Grant No. W911NF-04-1-
0057.33 N. E. S. thanks NSERC for the award of a Summer
Student Research Award. Finally, the authors thank Prof.
Andrew Williams and Prof. Elisabeth Bosch for very helpful
discussions concerning various aspects of this work.
16 E. Bosch, F. Rived, M. Rose´s and J. Sales, J. Chem. Soc., Perkin
Trans. 2, 1999, 1953.
17 J. Lu, Ph. D. Dissertation, The University of Western Ontario:
London, Ontario, Canada, 1994, p. 228.
18 B. Blesniewski, Z. Przybyszewski and Z. Paulak, J. Chem. Soc.,
Faraday Trans. 1, 1984, 80, 1769.
19 J. F. Kirsch and W. P. Jencks, J. Am. Chem. Soc., 1964, 86, 837.
20 (a) G. T. T. Gibson, A. A. Neverov and R. S. Brown, Can. J. Chem.,
2003, 81, 495; (b) J. S. Tsang, A. A. Neverov and R. S. Brown, J. Am.
Chem. Soc., 2003, 125, 7602; (c) J. S. W. Tsang, A. A. Neverov and
R. S. Brown, Org. Biomol. Chem., 2004, DOI: 10.1039/b412132e;
(d) we have determined that the maximal activity for the La3+
catalyzed methanolysis of esters and phosphates lies in the sspH
region between 8.7–9.1, where 95% of the activity is attributed to
La3+2(−OCH3)2. Thus, the conditional observed k2La(OCH3) rate
constant reported in Table 1 is ∼1/2 of the k2 of the La3+2(−OCH3)2
active form.
21 The rationale for this is presented in ref. 8 above, and references 3
and 4 of that publication.
22 (a) Z. S. Chaw, A. Fischer and D. A. R. Happer, J. Chem. Soc. (B),
1971, 1818; (b) J. Kirsch, A. Clewell and A. Simon, J. Org. Chem.,
1968, 33, 127; (c) A. A. Humffray and J. J. Ryan, J. Chem. Soc. (B),
1967, 468.
Notes and references
1 (a) J. Koskikallio, in The Chemistry of Carboxylic Acids and Esters,
ed. S. Patai, John Wiley and Sons, New York, 1969, pp. 103–136;
(b) M. A. Ogliaruso and J. A. Wolfe, Synthesis of Carboxylic Acids,
Esters and Their Derivatives, ed. S. Patai and Z. Rappoport, John
Wiley and Sons, Chichester, 1991, pp. 465–476.
2 (a) J. March, Advanced Organic Chemistry: Reactions, Mechanisms
and Structure, 4th edn., John Wiley and Sons, New York, 1992, pp.
397–398 and references therein; (b) M. G. Stanton, C. B. Allen, R. M.
Kissling, A. L. Linclon and M. R. Gagne´, J. Am. Chem. Soc., 1998,
120, 5981 and references therein; (c) R. M. Kissling and M. R. Gagne´,
J. Org. Chem., 2001, 66, 9005.
3 (a) T. Okano, K. Miyamoto and J. Kiji, Chem. Lett., 1995, 246; (b) P.
Dutta, A. Sarkar and B. C. Ranu, J. Org. Chem., 1998, 63, 6027; (c) L.
Baldini, C. Bracchini, R. Cacciapaglia, A. Casnati, L. Mandolini and
R. Ungaro, Chem. Eur. J., 2000, 6, 1322; (d) R. Cacciapaglia, S. Di
Stephano, E. Kelderman and L. Mandolini, Angew. Chem., Int. Ed.,
1999, 38, 349; (e) W. M. Stevels, M. J. K. Ankone´, P. J. Dijkstra
and J. Feijen, Macromolecules, 1996, 29, 8296; (f) N. J. Hinde and
C. D. Hall, J. Chem. Soc., Perkin Trans. 2, 1998, 1249 and references
therein; (g) J. Otton, S. Ratton, V. A. Vasnev, G. D. Markova, K. M.
Nametov, V. I. Bakhmutov, L. I. Komarova, S. V. Vinogradova and
V. V. Ko r s h a k , J. Polym. Sci. Part A Polym. Chem., 1998, 26, 2199;
(h) R. Cacciapaglia, S. Di Stephano and L. Mandolini, J. Org. Chem.,
2001, 66, 5926.
23 (a) J. J. Ryan and A. A. Humffray, J. Chem. Soc. (B), 1966, 842;
(b) T. C. Bruice and M. Mayahi, J. Am. Chem. Soc., 1960, 82, 3067;
(c) J. F. Kirsch and W. P. Jencks, J. Am. Chem. Soc., 1964, 86, 837.
24 C. G. Mitton, R. L. Schowen, M. Gresser and J. Shapley, J. Am.
Chem. Soc., 1969, 91, 2036.
25 We thank Professor Andrew Williams for helpful discussions on this
point.
26 Using the available data23 for the −OH-catalyzed hydrolysis of aryl,
the Brønsted b is computed to be ∼−0.6 for aryl groups which do
not contain strongly withdrawing resonators.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 5 – 7 2
7 1

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27 (a) W. P. Jencks and M. Gilchrist, J. Am. Chem. Soc., 1968, 90,
2622; (b) D. J. Hupe and W. P. Jencks, J. Am. Chem. Soc., 1977, 99,
451; (c) J. M. Sayer and W. P. Jencks, J. Am. Chem. Soc., 1977, 99,
464; (d) M. J. Gresser and W. P. Jencks, J. Am. Chem. Soc., 1977, 99,
6963.
substituent on the k2/k1 partitioning constant in the metal catalyzed
reactions.
32 Suh et al.11 have proposed the 3 : Zn2+ complex promotes the
=
hydrolysis of aryl esters via C O corordination followed by external
attack of methoxide, while Kimura et al.13 have proposed that the
active species is really 3 : Zn2+(−OH). In the present cases, although
we favour the internal delivery mechanism, the available pseudo-
first order rate constants for the primary kinetic data, along with
consideration of reasonable estimates of the pre-equilibrium binding
constant and a diffusion limited rate constant for eternal methoxide
attack of 1010 dm3 mol−1 s−1 do not allow us to rule out external
methoxide attack.
28 (a) S. Thea and A. Williams, Chem. Soc. Rev., 1986, 15, 125; (b) A.
Williams, Acc. Chem. Res., 1984, 17, 425.
29 S. Ba-Saif, A. K. Luthra and A. Williams, J. Am. Chem. Soc., 1987,
109, 6362.
30 (a) R. W. Taft, Jr., J. Am. Chem. Soc., 1952, 74, 2729, 3120; (b) R. W.
Taft, Jr., J. Am. Chem. Soc., 1053, 75, 4231.
31 Given that the rate-limiting step for the methoxide reaction through-
out most, if not all of the series of esters is k1 we can probably replace
the denominator in eqn. (8) with Dlog(kꢀ1). In this case the difference
in the slopes derived by application of eqn. (8) and (9) stems from the
33 The content of the information does not necessarily reflect the
position or the policy of the federal government, and no official
endorsement should be inferred.
7 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 5 – 7 2