Intramolecular base catalysed hydrolysis of ortho-hydroxyaryl esters: The anomalous position of methyl 3,5-dinitrosalicylate on the Linear Free Energy Relationship plot

Article abstract of DOI:10.1039/b200741j

The pK_a of the ortho-hydroxy group in methyl 3,5-dinitrosalicylate, HMDNS, is 2.45. Rate constants for the reaction of its conjugate base, MDNS^- with hydroxide anion and water are 5.3 × 10^-2 mol dm^-3 s^-1 and 6.6 × 10^-6 s^-1, respectively at 25°C. The rate constant for the uncatalysed reaction of HMDNS and water is 6.5 × 10^-6 s^-1 and so there is no evidence for intramolecular general base catalysis of the water reaction with MDNS^- by the weakly basic ortho-O^-. By means of Bronsted plots the water reaction of MDNS^- is compared with that of a group of other salicylate esters (β = 0) and also a structurally different group of esters (β = 0.4), both of which undergo intramolecular base catalysed hydrolysis. Although the title ester structurally belongs to the first set of compounds, its anomalous position on the plot clearly corresponds to the trend of the second set. This is explained in terms of differences in resonance stabilisation and hydrogen bonding in the transition state.

Full text of DOI:10.1039/b200741j

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Intramolecular base catalysed hydrolysis of ortho-hydroxyaryl
esters: the anomalous position of methyl 3,5-dinitrosalicylate on
the Linear Free Energy Relationship plot
2
Alexei U. Moozyckinea,b and D. Martin Davies*b
a Department of Chemistry, University of Wales Swansea, Swansea, UK SA2 8PP
b Division of Chemical Sciences, School of Applied and Molecular Sciences,
University of Northumbria at Newcastle, Newcastle upon Tyne, UK NE1 8ST
Received (in Cambridge, UK) 21st January 2002, Accepted 5th March 2002
First published as an Advance Article on the web 17th April 2002
The pKa of the ortho-hydroxy group in methyl 3,5-dinitrosalicylate, HMDNS, is 2.45. Rate constants for the reaction
of its conjugate base, MDNSϪ with hydroxide anion and water are 5.3 × 10Ϫ2 mol dmϪ3 sϪ1 and 6.6 × 10Ϫ6 sϪ1,
respectively at 25 ЊC. The rate constant for the uncatalysed reaction of HMDNS and water is 6.5 × 10Ϫ6 sϪ1 and so
there is no evidence for intramolecular general base catalysis of the water reaction with MDNSϪ by the weakly basic
ortho-OϪ. By means of Brønsted plots the water reaction of MDNSϪ is compared with that of a group of other
salicylate esters (β = 0) and also a structurally different group of esters (β = 0.4), both of which undergo
intramolecular base catalysed hydrolysis. Although the title ester structurally belongs to the first set of compounds,
its anomalous position on the plot clearly corresponds to the trend of the second set. This is explained in terms of
differences in resonance stabilisation and hydrogen bonding in the transition state.
in less acidic salicylic acids, as expected, the proton is part of
the phenolic group.
Introduction
It is generally accepted that the pH-independent hydrolysis of
salicylate esters, SEϪ, and catechol monobenzoate, CMBϪ,
involves the attack of a water molecule on the ester anion cata-
lysed by the neighbouring OϪ.1–3 Bruice has shown that the rate
constants calculated for the intramolecular base catalysed
hydrolysis of a range of phenyl 4- and 6-substituted salicylate
esters are independent of the pKa of the ortho-hydroxy group
and, moreover, are very similar to the rate constants for
similar methyl salicylate esters.4 Thus these rate constants are
Scheme 2
independent of the basicity of the catalytic group and of the
nature of the leaving group. The similarity of rate constants
extends to that of the attack of a water molecule on the tri-
Experimental
arylmethane dye, Green S, D2Ϫ, which also has an OϪ ortho to
Methyl 3,5-dinitrosalicylate (MDNS) 99ϩ% was purchased
the carbon under attack.5 In contrast, literature results show
from Aldrich and used as received. Measurements were carried
that the rate constants for the intramolecular base catalysed
out at 25 0.2 ЊC in aqueous solutions, generally ionic strength
attack of water on catechol esters, CEϪ, and other esters, EIϪ
0.1 mol dmϪ3, using acetate, phosphate or carbonate buffers or
and AHNϪ, are dependent upon the basicity of the catalytic
potassium chloride–hydrochloric acid or sodium hydroxide, as
group.2,6–9 This prompted the present study of the neighbouring
described previously.5 The two hydrochloric acid solutions of
group effect of the ortho-hydroxy substituent on the hydrolysis
lowest pH, however, were above ionic strength 0.1 mol dmϪ3.
reactions of methyl 3,5-dinitrosalicylate, MDNSϪ, and its con-
Solutions of MDNS in distilled water were prepared shortly
jugate acid, HMDNS, shown in Scheme 1. The acid dissociation
before use to avoid a substantial loss of reagent due to
hydrolysis. Measurements of pH and pH titrations were carried
out on a 702 SM Titrino calibrated with Hydrion buffers.
UV/vis spectra were obtained using a Pharmacia Biotech
Ultraspec 2000 spectrophotometer with a thermostatic cell-
holder. The hydrolysis was followed at the wavelength of
maximum MDNS absorbance, A, 365 nm using a concentration
of 6 × 10Ϫ5 mol dmϪ3 in most cases. First order rate constants,
kobs, were calculated from the slopes of plots of ln(A∞ Ϫ A) or
ln(A Ϫ A∞) against time using linear regression.
Scheme 1
constant of HMDNS, KHMDNS, is the highest of any salicylic
acid ester whose hydrolysis has been studied and MDNSϪ there-
Results
fore has the least basic catalytic group. Moreover, in the
hydrolysis product, dinitrosalicylate monoanion, HDNSϪ, a
very recent 1H NMR study10 suggests that the proton is biased
toward the carboxylate residue, as shown in Scheme 2, whereas
Fig. 1 shows the spectra of MDNS at various pH values; differ-
ences in the UV region below 250 nm are due to the different
buffer systems used. The drop in absorbance of the band at
1158
J. Chem. Soc., Perkin Trans. 2, 2002, 1158–1161
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b200741j

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Fig. 3 Dependence upon pH of decimal logarithm of the observed
first order rate constant for the hydrolysis of 6.0 × 10Ϫ5 mol dmϪ3
MDNS at 25 ЊC. The circles correspond to pH values where the first
derivative dA/dt at λ = 365 nm was negative, the triangles to pH values
where dA/dt was positive. The curve represents the best fit of eqn. (5) to
the data.
rate constants are shown in Fig. 3 as a function of pH. Compar-
able rate constants were observed at 8 × 10Ϫ6 and 2.5 × 10Ϫ4 mol
dmϪ3 MDNS (results not shown) and at 1.4 × 10Ϫ2 mol dmϪ3
using a pH-stat method at pH 11.5 recording the volume of
0.1 mol dmϪ3 NaOH consumed. The product of MDNS
hydrolysis at pH 11.5 was shown by pH titration with 0.1 mol
dmϪ3 HCl to be a dibasic acid with the higher pKa, 6.8 at
ionic strength 0.1 mol dm3, and the lower pKa below the limit
measurable by this technique. This is consistent with the
product being dinitrosalicylate whose pKa values (pKH2DNS and
pKHDNS respectively, Scheme 2) at minimal ionic strength using
a spectrophotometric method are 7.36 and 0.13.10
365 nm and the increase at lower wavelengths with an isosbestic
point at 320 nm correspond to the formation of the colourless
HMDNS species from the bright yellow MDNSϪ as shown in
Scheme 1. Fig. 2 shows the pH dependence of the absorbance of
The results shown in Fig. 3 are consistent with the reaction
scheme shown in eqns. (1) to (4). Following a data treatment
(1)
(2)
(3)
Fig. 1 Absorption spectra of 9.0 × 10Ϫ5 mol dmϪ3 MDNS at 25 ЊC at
the following pH values, in order of decreasing absorbance of the band
at 365 nm: 10.04, 3.87, 2.76, 2.31, 1.52, 0.81.
(4)
described previously,5 taking the overall rate equation corre-
sponding to this reaction scheme, the equation for KHMDNS
,
corresponding to the acid dissociation shown in Scheme 1,
the mass balance equation for MDNS, and the ionic product of
water, KW, leads to eqn. (5) for the observed rate constant for
the hydrolysis of MDNS, where k0obs, k1obs and k2obs are
defined in eqns. (6) to (8). The value of KHMDNS is substituted
into eqn. (5) and the best fit values of the kinetic parameters
and their standard deviations shown in Table 1 are obtained
using non-linear least squares with proportional weighting to fit
kobs. Calculated values of the individual rate constants, taking
Kw, 1.88 × 10Ϫ14 mol2 dmϪ6, are also shown in Table 1.
Fig. 2 Dependence upon pH of the absorbance of MDNS, conditions
as for Fig. 1; circles, 365 nm; diamonds, 292 nm.
(5)
MDNS at two different wavelengths. These data were fitted
using non-linear regression, as described previously,5 to yield a
value of the pKa of the ester, pKHMDNS 2.45 0.03.
Changes in absorbance during the hydrolysis of MDNS were
typically only 8% of the initial value and were negative below
the pKa of the ester and positive above it. Observed first order
k0obs = kMDNSKHMDNSKw
(6)
(7)
HO
k1obs = kHMDNSKw ϩ kMDNSKHMDNS
HO
H2O
k2obs = kHMDNS
(8)
H2O
J. Chem. Soc., Perkin Trans. 2, 2002, 1158–1161
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Table 1 Observed rate constants for the hydrolysis of MDNS for pathways involving n protons and the corresponding rate constants calculated
according to eqns. (6) to (8)
n
k
n obs/(dm3 molϪ1
)
nϩ1 sϪ1
kMDNS/dm3 molϪ1 sϪ1
kMDNS/sϪ1
kHMDNS/sϪ1
HO
H2O
H2O
0
1
2
(3.5 0.5) × 10Ϫ18
(2.3 0.2) × 10Ϫ8
(6.5 1.2) × 10Ϫ6
5.3 × 10Ϫ2
6.6 × 10Ϫ6 a
6.5 × 10Ϫ6
a Alternatively, kHMDNS, 1.2 × 106 dm3 molϪ1 sϪ1
.
HO
Table 2 Substrate structures and their pKa values
Ref.
Substrate
X
H
Y
Z
R
pKa
6.02
7.66
8.46
8.63
8.80
9.1
1
5
4
4
11
4
12
4
13
4
p-Nitrophenyl 5-nitrosalicylate
Green S (Lissamine Green B)
Phenyl 6-methoxysalicylate
Phenyl 6-methylsalicylate
Phenyl salicylate
Phenyl 4-methoxysalicylate
Methyl salicylate
Phenyl 4-methylsalicylate
Ethyl salicylate
Phenyl β-resorcylate
NO2
H
p-NO2C6H4
D2Ϫ
H
H
H
OCH3
H
H
H
H
H
H
H
H
H
OCH3
CH3
H
H
H
H
H
H
C6H5
C6H5
C6H5
C6H5
CH3
C6H5
C2H5
C6H5
9.26
9.44
10.1
CH3
H
OϪ
10.76
6
8
2
14
7
9
Ethyl 2-hydroxy-5-nitrophenyl carbonate
Hexachlorophene monoacetate
Catechol monobenzoate
Catechol monocinnamate
Catechol monoacetate
NO2
OC2H5
C6H5
5.48
7.9
8.7
8.9
9.01
9.69
EIϪ
CMBϪ
H
H
H
CH᎐CHC6H5
᎐
CH3
1-Acetoxy-8-hydroxynaphthalene
AHNϪ
nature of the latter. Moreover, all of the cited literature data
show that the rate constant corresponding to the water reaction
involving the ortho-OϪ species is considerably greater than the
upper limit of that involving the unionised reactant, indicating
significant intramolecular base catalysis. Table 2 also gives the
literature values of pKa for the ortho-OH groups, which range
between 5 and 11, and we have extended this range down to
about 2 with MNDS. The lack of effect of pKa on the intra-
molecular base catalysed reaction of the salicylate esters and
the similarity of the corresponding rate constant for Green S,
which also has an OϪ ortho to the electrophilic carbon under
attack, is interesting. (The Brønsted slope is close to zero, ignor-
ing MDNSϪ.) This is particularly so, since the catechol esters,
CEϪ, that undergo intramolecular base hydrolysis in a similar
way to the salicylates, show the expected increase of rate con-
stant for the base catalysed reaction with increasing basicity of
the adjacent OϪ group,2,6,7,14 where the Brønsted slope is ca. 0.4.
(EIϪ and AHNϪ also appear to belong in this group, despite
their somewhat disparate structures.8,9) The catechol esters and
EIϪ and AHNϪ are not conjugated between the carbonyl site
of attack of water and the adjacent OϪ, unlike the salicylates
and Green S. Hence, for salicylates there appears to be a high
degree of correlation between opposing factors that increase
the basicity of the catalytic OϪ whilst decreasing the electro-
philicity of the carbonyl site of attack. The importance of
resonance effects in intramolecular general acid base catalysis
has been discussed in general terms by Kirby.15 The opposing
factors in the case of salicylates, however, are not exactly
balanced over the widest range of conditions as evidenced by
the lower rate constant with MDNSϪ, which actually falls into
the group of non-conjugated esters in Fig. 4. There must there-
fore be an additional factor in the catalysis that does not come
into effect in the case of MDNSϪ. This factor is related to
hydrogen-bonding. Kirby has given many examples where
intramolecular hydrogen-bonding stabilisation of the product,
manifest as an unusually low pKa of the group in question, is
reflected in the stabilisation of the transition state for intra-
molecular acid base catalysis.15 The present work with MDNSϪ
is the exception that proves that this is also the rule for the other
Discussion
Table 1 shows the rate constants for the uncatalysed reaction
of hydroxide and MDNSϪ; for the reaction involving one
additional proton, which, in line with the accepted
mechanism,1–3 is assumed to be the reaction of MDNSϪ and
water; and for the uncatalysed reaction of HMDNS and water.
It is clear that there is no intramolecular base catalysis in the
case of the MDNSϪ water reaction because the rate constant is
the same as that for the HMDNS water reaction. Clearly, the
ortho-OϪ is simply too weakly basic (pKHMDNS, 2.45) to have
any catalytic activity. Fig. 4 shows Brønsted plots for the water
Fig. 4 Brønsted plots of the dependence of the rate constant for water
reaction on pKa neighbouring hydroxy group: circles, salicylate esters
(SEϪ); triangles, other esters; hexagon, Green S; crossed point, MDNS.
reaction of MDNSϪ and the range of ortho-hydroxyaryl esters
shown in Table 2, together with Green S. The values of the
individual rate constants are deduced from the data given in the
literature for kinetics carried out in the range 25 to 35 ЊC and
in aqueous-based solutions.1,4,6–9,11–13 Rate constants for the
hydrolysis of the 4-nitrophenyl esters of benzoate and ortho-
methoxybenzoate are considerably less than that of 4-nitro-
phenyl salicylate,1 which, notwithstanding the electron
donating character of the OϪ substituent, indicates the catalytic
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salicylate esters, SEϪ, where hydrogen bonding of the ortho-OϪ
and the attacking water in the transition state is followed by the
formation of a salicylic acid HSϪ with a protonated phenol
group, Scheme 3. In HDNSϪ very recent NMR work shows that
the proton is biased to the carboxylate residue,10 and this is
reflected in the fact that the ortho-OϪ confers no energetic
advantage in terms of hydrogen bonding in the transition state,
Scheme 4.
References
1 M. L. Bender, F. J. Kézdy and B. Zerner, J. Am. Chem. Soc., 1963,
85, 3017–3024.
2 B. Capon and B. C. Ghosh, J. Chem. Soc. (B), 1966, 472–478.
3 W. P. Jencks, Catalysis in Chemistry and Enzymology, McGraw-Hill
Book Company, New York, 1969.
4 T. Maugh II and T. C. Bruice, J. Am. Chem. Soc., 1971, 93, 3237–
3248.
5 D. M. Davies and A. U. Moozyckine, J. Chem. Soc., Perkin Trans. 2,
2000, 1495–1503.
6 T. H. Fife and J. E. C. Hutchins, J. Am. Chem. Soc., 1972, 94,
2837–2842.
7 L. E. Eberson and L.-Å. Svensson, J. Am. Chem. Soc., 1971, 93,
3827–3828.
8 T. C. Bruice and I. Oka, J. Am. Chem. Soc., 1974, 96, 4500–4507.
9 F. Hibbert and K. J. Spiers, J. Chem. Soc., Perkin Trans. 2, 1988,
571–574.
10 W. L. Mock and L. A. Morsch, Tetrahedron, 2001, 57, 2957–2964.
11 M. N. Khan, T. O. Olagbemiro and U. Z. Umar, Tetrahedron, 1983,
39, 811–814.
Scheme 3
12 M. N. Khan and T. O. Olagbemiro, J. Org. Chem., 1982, 47,
3695–3699.
13 A. Ågren, U. Hedsten and B. Jonsson, Acta Chem. Scand., 1961, 15,
1532–1544.
14 Y. Shalitin and S. A. Bernhard, J. Am. Chem. Soc., 1964, 86,
2291–2292.
15 A. J. Kirby, in Advances in Physical Organic Chemistry, eds. V. Gold
and D. Bethell, Academic Press, London, 1980, pp. 183–278.
Scheme 4
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