The alkaline hydrolysis of aryl (2E)-3-(4′-hydroxyphenylazo)propenoates. A kinetic study

Article abstract of DOI:10.1021/jo015795m

The alkaline hydrolysis of the title esters, possessing three conjugated π units between the internal nucleophile (the hydroxyl group) and the reaction center, follows an E1cB mechanism involving the participation of an "extra extended" p-oxo azoketene type intermediate. For the hydrolysis of the 2,4-dinitrophenyl ester kinetic data, activation parameters and trapping of the intermediate are consistent with a dissociative pathway carrying the reaction flux. The effect of the leaving group variation on reactivity agrees with the proposed mechanism, and the existence of an intermediate is also supported by diode array stopped-flow experiments. The presence of sp² nitrogen atoms in the conjugated backbone is beneficial to the dissociative mechanism.

Full text of DOI:10.1021/jo015795m

J . Org. Chem. 2001, 66, 7685-7690
7685
Th e Alk a lin e Hyd r olysis of Ar yl
(2E)-3-(4′-Hyd r oxyp h en yla zo)p r op en oa tes. A Kin etic Stu d y
Giorgio Cevasco,* Daniele Vigo, and Sergio Thea*
C.N.R., Centro di Studio per la Chimica dei Composti Cicloalifatici ed Aromatici; Dipartimento di
Chimica e Chimica Industriale, Universita` di Genova, Via Dodecaneso 31, I-16146 Genova, Italy
giocev@chimica.unige.it
Received May 25, 2001
The alkaline hydrolysis of the title esters, possessing three conjugated π units between the internal
nucleophile (the hydroxyl group) and the reaction center, follows an E1cB mechanism involving
the participation of an “extra extended” p-oxo azoketene type intermediate. For the hydrolysis of
the 2,4-dinitrophenyl ester kinetic data, activation parameters and trapping of the intermediate
are consistent with a dissociative pathway carrying the reaction flux. The effect of the leaving
group variation on reactivity agrees with the proposed mechanism, and the existence of an
intermediate is also supported by diode array stopped-flow experiments. The presence of sp2 nitrogen
atoms in the conjugated backbone is beneficial to the dissociative mechanism.
Since the pioneering work of Bruice and co-workers,1
the presence of ionizable R-protons in the substrate has
been thought to be a prerequisite for the occurrence of a
unimolecular elimination mechanism, by way of short-
lived ketene intermediates, in the alkaline hydrolysis of
esters.
We have been able to demonstrate that the E1cB
mechanism carries the reaction flux even in the absence
of labile proton on the atom R to the carbonyl function:
we have shown that the alkaline hydrolysis of esters of
the type HO-π-COOAr can occur following the dissocia-
tive mechanism provided that the hydroxyl group, acting
as the internal nucleophile after ionization, is conjugated
with the reaction center. In the simplest case we inves-
tigated, the hydrolysis of aryl 4-hydroxybenzoates,2 the
π-system was an aromatic ring and we showed that esters
having leaving groups with pKa values lower than about
6.5 hydrolyze through the E1cB mechanism with the
participation of the unprecedented p-oxo ketene inter-
mediate 1.
We have subsequently shown that the dissociative
mechanism is followed also when the π-system is formed
by two conjugated π units, as in aryl 4-hydroxycinnama-
tes,3 and we have observed that the interposition of a
vinylene group appears to favor the dissociative pathway
most likely owing to an increased stability of the inter-
mediate 2, which could be related to a larger delocaliza-
tion of π electrons.
In the framework of our research on this topic, we have
recently reported4 a study on the hydrolysis of aryl
(2E,4E)-5-(4′-hydroxyphenyl)pentadienoates. In these sub-
strates, the intervening backbone between the internal
nucleophile and the reaction center is constituted by
three conjugated π units, i.e., one aromatic ring and two
vinylenic groups. We have provided evidence that alka-
line hydrolysis of esters possessing acidic leaving groups
(pKa of the leaving phenol lower than ca. 6) follows the
E1cB pathway with the participation of the elongated
p-oxo ketene intermediate 3. Reactivity comparisons
among esters sharing the same leaving group have shown
that, taking into account differences in internal nucleo-
philicity of the substrates, the presence of additional
vinylenic groups favors the hydrolytic process occurring
via the dissociative pathway.
Furthermore, aiming to increase our knowledge on the
factors that drive the mechanism in ester hydrolysis
(inter alia, stability of the putative unsaturated inter-
mediate), we have also investigated other esters possess-
ing different molecular architecture such as two aromatic
π-systems linked by Z ) Y π-conjugated systems, with Z
and Y being N or CH. In all cases, these substrates react
through the usual associative BAc2 mechanism,5 and this
result could be rationalized invoking an exceedingly large
loss of aromaticity on going from substrate to the transi-
tion state when two p-phenylene units are present in the
π-conjugated bridge.
(1) Holmquist, B.; Bruice, T. C. J . Am. Chem. Soc. 1969, 91, 2993-
3003. Pratt, R. F.; Bruice, T. C. J . Am. Chem. Soc. 1970, 92, 5956-
5964.
(2) Cevasco, G.; Guanti, G.; Hopkins A. R.; Thea, S.; Williams, A. J .
Org. Chem. 1985, 50, 479-484.
(3) Cevasco, G.; Thea, S. J . Org. Chem. 1994, 59, 6274-6278.
(4) Cevasco, G.; Vigo, D.; Thea, S. J . Org. Chem. 2000, 65, 7833-
7838.
(5) Cevasco, G.; Thea, S. J . Org. Chem. 1999, 64, 5422-5426.
10.1021/jo015795m CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/24/2001

7686 J . Org. Chem., Vol. 66, No. 23, 2001
Cevasco et al.
F igu r e 2. pH-rate profiles for the hydrolysis of aryl (2E)-3-
(4′-hydroxyphenylazo)propenoates in 40% (v/v) dioxane/water
at 25 °C and 0.1 M ionic strength made up with KCl. See the
Experimental Section for buffers. Lines are calculated from
eqs 1 or 2; identity is given in Table 1.
F igu r e 1. pH-rate profiles for the hydrolysis of 2,4-dinitro-
phenyl esters 4b (solid circles) and 6 (triangles) in 40% (v/v)
dioxane/water at 25 °C and 0.1 M ionic strength made up with
KCl. Buffers employed to keep pH constant are listed in the
Experimental Section. Lines are calculated from eqs 1 and 3,
respectively.
In this equation, the second-order term kb is related
to the bimolecular attack of hydroxide ion on the ionized
ester and causes an upward curvature, at sufficiently
high pH values, of the pH-rate profiles as depicted in
Figure 2.
In Table 1 are collected experimental conditions and
the values of the kinetic parameters, obtained from
primary kinetic data by iterative nonlinear curve-fitting
performed with the Fig.P program,6 for the hydrolysis of
the substrates 4a -f. This program provides, together
with the rate constants, the Ka values of the substrates.
This is in particular very useful for the more reactive
esters 4a -c since, owing to exceedingly high reactivities,
their pKa values cannot be spectroscopically measured.
Table 2 indicates that kinetic pKa values are in good
agreement with the spectroscopic ones.
In an attempt to improve our understanding of the
effects of structural modifications on the hydrolytic
pathways in the conjugated backbone, we have under-
taken a kinetic study on the hydrolysis of the title esters
4. The substitution of sp2 nitrogen atoms for sp2 carbon
atoms in the conjugated backbone could indeed favor the
dissociative pathway if, as suggested by theoretical and
experimental data (see below), such substitution im-
proves conjugation through the π bridge. We wish now
to report our results on the alkaline hydrolysis of these
esters that strongly support the occurrence of the E1cB
mechanism with the participation of the intermediate 5.
The dependence on pH of the pseudo-first-order rate
constants for the hydrolysis of 2,4-dinitrophenyl (2E)-3-
(4′-methoxyphenylazo)propenoate (6) is also shown in
Figure 1 and indicates, as expected, a simple second-
order rate law in hydroxide ion and ester concentrations
(eq 3).
kobs ) kOH Kw/aH
(3)
Resu lts a n d Discu ssion
In this equation, Kw is the ionic product of water and
a pKw value of 15.00 has been reported7 for the medium
employed in this work The kOH value for BAc2 attack of
hydroxide ion on this ester, in 40% dioxane-water (v/v)
solvent at 25 °C and ionic strength 0.1 M (KCl), is 183 (
The observed pseudo-first-order rate constants for the
alkaline hydrolysis of 2,4-dinitrophenyl (2E)-3-(4′-hy-
droxyphenylazo)propenoate (4b), at 25 °C in 40% diox-
ane-water (v/v) solvent and ionic strength 0.1 M (KCl),
were found to follow eq 1.
2 M-1 s-1
.
The apparent second-order rate constant (kapp ) kaKa/
Kw ) ca. 2 × 107 M-1 s-1, Table 1) calculated for the
attack of hydroxide ion on neutral 4b is considerably
larger (>105) than the second-order rate constant related
to the BAc2 attack of hydroxide ion on 6 (a smaller value
could be envisaged from σp values for OH and OMe,
which are -0.37 and -0.27, respectively). The remark-
ably high ratio kapp/kOH strongly suggests that these
esters do not react through the same mechanism, i.e.,
the associative one. Actually, one can calculate the rate
constant (kcalc) for the bimolecular attack of hydroxide ion
kobs ) ka/(1 + aH/Ka)
(1)
The pH-rate profile for the hydrolysis of ester 4b is
illustrated in Figure 1 (b) and similar plots (Figure 2)
were obtained for esters 4a and 4c (identity of substrates
is shown in Table 1). In eq 1, aH is the proton activity, ka
is the pseudo-first-order rate constant in the plateau
region of pH and Ka is the ionization constant of the
hydroxyl group of the ester.
The pH dependence of the pseudo-first-order rate
constants for hydrolysis of esters 4d -f obeys eq 2
(6) Fig.P from Biosoft, Cambridge, U.K., 1991.
(7) Arned, H. S.; Fallon, L. J . Am. Chem. Soc. 1939, 61, 2374-2378.
kobs ) (ka + kb[OH-])/(1 + aH/Ka)
(2)

Hydrolysis of Aryl (2E)-3-(4′-Hydroxyphenylazo)propenoates
J . Org. Chem., Vol. 66, No. 23, 2001 7687
Ta ble 1. Hyd r olysis of Ar yl (2E)-3-(4′-Hyd r oxyp h en yla zo)p r op en oa tes (4a -f) in 40% Dioxa n e a t
25 °C a n d ) 0.1 M (p Kw ) 15.00)
leaving substituted
a
b
subst
phenoxides
pKLG
ka, s-1
kb, M-1 s-1
kapp, M-1 s-1
log kapp
Nc
pHd
4a
4b
4c
4d
4e
4f
2,6-dinitro
2,4-dinitro
2-methyl-4,6-dinitro
2,5-dinitro
2-chloro-4-nitro
4-chloro-2-nitro
3.71e
4.11
4.35e
5.22e
5.45
6.46
(5.19 ( 0.06) × 10-1
(8.18 ( 0.13) × 10-1
(1.66 ( 0.02) × 10-1
(1.29 ( 0.02) × 10-2
(2.87 ( 0.06) × 10-3
(2.48 ( 0.11) × 10-4
-
-
-
1.43 × 107
2.11 × 107
4.37 × 106
3.27 × 105
6.00 × 104
4.21 × 103
7.155
7.324
6.640
5.514
4.778
3.624
10
15
10
11
12
11
6.77-12.99
5.53-12.66
6.75-12.99
6.75-13.99
6.63-13.99
6.98-13.99
3.75 ( 0.09
2.56 ( 0.10
1.07 ( 0.06
a
J encks, W. P.; Regestein, J . In Handbook of Biochemistry and Molecular Biology, 3rd ed.; Fasman, G., Ed.; Chemical Rubber Co.:
Cleveland, 1976. See text; Ka values are taken from Table 2. c Number of data points, not including duplicates. pH range investigated.
Buffers employed are given in the Experimental Section. e Kortum, G.; Vogel, W.; Andrussov, K. Dissociation Constants of Organic Acids
in Aqueous Solution; Butterworths: London, 1961.
b
d
Ta ble 2. Ion iza tion Con sta n ts of Ar yl
(2E)-3-(4′-Hyd r oxyp h en yla zo)p r op en oa tes (4a -f) in
P h osp h a te Bu ffer s, 40% Dioxa n e a t 25 °C a n d ) 0.1 M
Sch em e 1
a
subst
108Ka, M
pKa
pKa
4a
4b
4c
4d
4e
4f
7.55 ( 0.01
7.59 ( 0.01
7.57 ( 0.02
7.59 ( 0.02
7.62 ( 0.02
7.66 ( 0.07
2.62 ( 0.21
2.16 ( 0.13
1.76 ( 0.12
7.58 ( 0.03
7.67 ( 0.03
7.76 ( 0.03
a
Measured from the kinetics.
Ta ble 3. Activa tion P a r a m eter s for th e Hyd r olysis of
2,4-Din itr op h en yl Ester s in Ca r bon a te Bu ffer , 40%
Dioxa n e, µ ) 0.1 M
∆Hq,
kcal/mol
∆Sq,b
cal/mol K
ester
T range, °C
pH
na
4b
6
9.9-29.8
16.5-41.4
11.50
10.95
5
4
23.2 ( 0.3
16.3 ( 0.2
19.0 ( 1.1
-12.0 ( 0.5
a
b
Number of data points, not including duplicates. Calculated
at 25 °C.
on neutral 4b from the Hammett relationship log k/k0 )
1.97Σσ for the alkaline hydrolysis of substituted 2,4-
dinitrophenyl benzoates.1 If the attenuation factor of 0.54
related to both the vinylene8 and azo9 groups is taken
into account (incidentally the same attenuation factor has
been reported for these groups), since the overall attenu-
ation factor is roughly given by the product of those of
the intervening groups,10 the relationship becomes log
k/k0 ) 0.57Σσ and is thus valid for the BAc2 hydrolysis of
substituted 2,4-dinitrophenyl (2E)-3-(X-phenylazo)pro-
penoates. Now, employing the σp values for the hydroxy
and methoxy groups (-0.37 and -0.27, respectively),
from the kOH value for 6 we finally obtain kcalc ) 160 M-1
s-1. The apparent second-order rate constant (kaKa/Kw,
ca. 2 × 107 M-1 s-1) for 4b is therefore in excess of
calculated kcalc by about 125000-fold, thus confirming the
suggestion that the mechanism for the ka term cannot
be the associative one, and the simplest hypothesis is that
an E1cB process involving the participation of the p-oxo
azoketene type intermediate 5 occurs.
the presence of 0.03 M p-toluidine, which has no effect
on reaction rate, ca. 37% of N-(4-methylphenyl) (2E)-3-
(4′-hydroxyphenylazo)propenamide (7) was found in the
reaction products. This result clearly agrees with the
proposed dissociative mechanism: the intermediate 5 is
trapped by the added nucleophile after the rate-deter-
mining departure of the leaving group, as shown in the
Scheme 1.
The effect of the leaving group variation on reactivity
was also assessed. The plot of the logarithms of the
apparent second-order rate constants (kapp ) kaKa/Kw)
against the pKa of the leaving substituted phenoxide
(pKLG) is shown in Figure 3 (data taken from Table
1) and gives rise to a satisfactory Brønsted relationship
(eq 4).
log (kaKa/Kw) ) (12.73 ( 0.65) - (1.41 ( 0.13)pKLG
(4)
The determination of activation entropy of the reac-
tions (Table 3) provides further evidence that the hy-
drolysis of these two esters follows different pathways.
For the hydrolysis of 4b the value of ∆Sq for the ka term
(measured at pH 11.50) is large and positive as expected
for a unimolecular reaction, whereas the negative value
of ∆Sq for the hydrolysis of 6 (at pH 10.95) is consistent
with an associative process.11
(8) Williams, A. In Chemistry of Enzyme Action; Page, M. I., Ed.;
Elsevier: Amsterdam, 1984; p 145.
(9) Hegarty, A. F.; Tuohey, P. J . Chem. Soc., Perkin Trans. 2 1980,
1238-1243
(10) Page, M.; Williams, A. Organic and Bioorganic Mechanisms;
Addison-Wesley Longman: Harlow, 1997; p 57.
(11) Schaleger, L. L.; Long, F. A. Adv. Phys. Org. Chem. 1963, 1, 1.
J encks, W. P. Catalysis in Chemistry and Enzymology; McGraw-
Hill: New York, 1969. Douglas, K. T. Prog. Bioorg. Chem. 1976, 4,
194. Vlasak, P.; Mindl, J . J . Chem. Soc., Perkin Trans. 2 1997, 1401-
1403. Safraoui, A.; Calmon, M.; Calmon, J .-P. J . Chem. Soc., Perkin
Trans. 2 1991, 1349-1352. Broxton, T. J . Aust. J . Chem. 1985, 38,
77-83.
The dissociative nature of the mechanism driving the
hydrolysis of 4b is fully confirmed by trapping experi-
ments carried out with added nitrogen nucleophile. In

7688 J . Org. Chem., Vol. 66, No. 23, 2001
Cevasco et al.
F igu r e 4. Best fit of concentration vs time courses from DASF
experiments. Hydrolysis of 2,4-dinitrophenyl (2E)-3-(4′-hy-
droxyphenylazo)propenoate (4b) in KOH 5 × 10-3 M (50%
dioxane): (A) 4b; (B) intermediate 5; (C) 2,4-dinitrophenol; (D)
acid.
F igu r e 3. Brønsted plot for the hydrolysis of aryl (2E)-3-(4′-
hydroxyphenylazo)propenoates. The line is calculated from eq
4; for the dashed line see text; the identity of the points is
given in Table 1.
The remarkably high âLG value (-1.41) is consistent
with the dissociative pathway,12 thus indicating that such
esters hydrolyze through intermediate 5, and is in good
agreement with those we previously found for the E1cB
hydrolysis of related substrates.2-4
Unfortunately, we were not allowed to extend our
study to esters possessing leaving phenoxides with pKLG
higher than 6.5 owing to the great trouble we met in their
synthesis, and therefore, we cannot establish whether in
the present system, as we previously observed for related
substrates, a break in linearity in the Brønsted plot with
upward curvature occurs as the nucleofugality of the
leaving group decreases, suggesting a change in mech-
anism from E1cB to BAc2.
It is well-known that associative processes in acyl
group transfer reactions involving carboxylic acid deriva-
tives have âLG values restricted in a narrow range
(-0.20 to -0.25). Now, if a line with a slope of -0.25 is
drawn (dashed line in Figure 4) through the point
indicated as f, which represents the calculated value of
the second-order rate constant (kcalc ) 160 M-1 s-1, see
above) for the BAc2-type attack of hydroxide ion on
the neutral 2,4-dinitrophenyl ester 4b, it will go across
the experimental line at pKLG ca. 8 (changeover point).
It is noteworthy that this value is considerably higher
than those previously found for related systems (i.e.,
6.2 for 4-hydroxybenzoates,2 6.7 for 4-hydroxycinnama-
tes,3 and 6.2 for (2E,4E)-5-(4′-hydroxyphenyl)pentadi-
enoates).4
Finally, the use of a diode array stopped-flow (DASF)
technique has provided further evidence of the participa-
tion of an intermediate in the hydrolysis of 4b. Repetitive
scan of the UV spectrum of this ester in KOH 5 × 10-3
M (50% aqueous dioxane; the choice of this solvent
composition was imposed by the use of the stopped-flow
machine) was recorded in the range 390-540 nm, overall
time 3 s. Experimental data were fitted using Specfit/32
global analysis system13 with a nonlinear regression
modeling by the Marquardt-Levenberg algorithm to the
following equations (identity is given in the caption of
Figure 4):
A f B + C
B f D
Analysis with a fixed C (2,4-dinitrophenoxide ion)
spectrum adequately fit all data affording, in whole
agreement with the proposed mechanism, the changes
of concentration with time shown for illustrative purposes
in Figure 4.
Furthermore, the rate constant calculated from these
data (4.3 ( 0.4 s-1) shows good correspondence (taking
into account the different solvent composition employed)
with the value reported in Table 1 for this ester.
Comparison of the present results with those obtained
in our previous studies2-4 on the hydrolysis of related
esters of the type HO-π-COOAr indicates that several
pieces of evidence suggest an increasing efficiency of the
dissociative mechanism on going from aryl 4-hydroxy-
benzoates to 4-hydroxycinnamates, 5-(4′-hydroxyphenyl)-
pentadienoates, and 3-(4′-hydroxyphenylazo)propenoates.
Among these, we underline that the ratio kapp/kOH for the
2,4-dinitrophenyl derivatives is exceptionally high for
ester 4 (105, this work) compared with those of the other
substrates (ranging from 200 to 2400). Also, the yield of
the amide formed follows this trend. Moreover, the
breakpoint in the Brønsted plots, which indicates where
the BAc2 mechanism gives way to the E1cB one, is
evaluated to occur at an higher pKLG in the present case
(see above).
In conclusion, all evidence presented in this work
points to the fact that the hydrolysis of title esters takes
place following a E1cB mechanism, and it is further
corroborated from the observation that the efficiency of
such mechanism in the hydrolysis of esters of the type
HO-π-COOAr is enhanced by the presence of additional
π units (provided that only one p-phenylene unit is
present in the conjugating bridge) owing to extra stabi-
lization of the intermediate due to a more extended
delocalization of π electrons. Interestingly, our findings
show that esters 4 hydrolyze through the dissociative
pathway more readily than 5-(4′-hydroxyphenyl)penta-
dienoates, although these are iso-π-electronic molecules.
(12) Williams, A.; Douglas, K. T. Chem. Rev. 1975, 75, 627-649.
Gordon, I. M.; Maskill, H.; Ruasse, M. F. Chem. Soc. Rev. 1989, 18,
123-151. Thatcher, G. R. J .; Kluger, R. Adv. Phys. Org. Chem. 1989,
25, 99-265.
(13) SPECFIT 32 (version 3.0) for Window systems, 2000 Spectrum
Software Associates, Marlborough, MA.

Hydrolysis of Aryl (2E)-3-(4′-Hydroxyphenylazo)propenoates
J . Org. Chem., Vol. 66, No. 23, 2001 7689
2.00 Hz), 8.25 (d, 1, J ) 13.80 Hz), 7.88 (d, 2, J ) 8.80 Hz),
7.04 (d, 1, J ) 14.00 Hz), 6.96 (d, 2, J ) 9.20 Hz), 5.64 (bs, 1),
2.47 (s, 3). Anal. Calcd for C16H12N4O7: C, 51.6; H, 3.3; N, 15.0.
Found: C, 52.1; H, 3.5; N, 14.3. 2,5-Din itr op h en yl (2E)-3-
(4′-h yd r oxyp h en yla zo)p r op en oa te (4d ): mp 132-3 °C;
CDCl3 δ 8.29 (s, 2), 8.25 (d, 1, J ) 13.80 Hz), 7.89 (d, 2, J )
8.80 Hz), 7.00 (m, 3), 5.71 (bs, 1). Anal. Calcd for C15H10N4O7:
C, 50.3; H, 2.8; N, 15.6. Found: C, 50.7; H, 3.0; N, 16.0.
2-Ch lor o-4-n it r op h en yl (2E)-3-(4′-h yd r oxyp h en yla zo)-
p r op en oa te (4e): mp 126-7 °C; CDCl3 δ 8.41 (d, 1, J ) 2.40
Hz), 8.25 (m, 2), 7.88 (d, 2, J ) 9.16 Hz), 7.49 (d, 1, 8.80 Hz),
7.00 (m, 3), 5.75 (bs, 1). Anal. Calcd for C15H10N3O5Cl: C, 51.8;
H, 2.9; N, 12.1. Found: C, 52.3; H, 3.0; N, 12.0. 4-Ch lor o-2-
n it r op h en yl (2E)-3-(4′-h yd r oxyp h en yla zo)p r op en oa t e
(4f): mp 131-2 °C; CDCl3 δ 8.22 (d, 1, J ) 13.92 Hz) 8.14 (d,
1, J ) 2.56 Hz) 7.87 (d, 2, J ) 9.16 Hz), 7.67 (dd, 1, J ) 2.60
Hz; 8.80 Hz), 7.32 (d, 1, J ) 8.79 Hz), 6.99 (m, 3), 5.70 (bs, 1).
Anal. Calcd for C15H10N3O5Cl: C, 51.8; H, 2.9; N, 12.1.
Found: C, 52.1; H, 3.1; N, 12.0. 2,4-Din itr op h en yl (2E)-3-
(4′-m et h oxyp h en yla zo)p r op en oa t e (6): mp 126-7 °C;
CDCl3 δ 9.01 (d, 1, J ) 2.60 Hz), 8.58 (dd, 1, J ) 3.00 Hz; 9.20
Hz), 8.25 (d, 1, J ) 14.00 Hz), 7.93 (d, 2, J ) 9.20 Hz), 7.62 (d,
1, J ) 8.80 Hz), 7.01 (m, 3), 3.93 (s, 3). Anal. Calcd for
This different behavior most likely reflects a superior
conjugative ability of the azo group with respect to the
vinylenic group, as inferred from the reported data on
the hyperpolarizability of azobenzene and stilbene de-
rivatives.14
Exp er im en ta l Section
Gen er a l Meth od s. Starting reagents and solvents were
purified and/or distilled before use. Buffer materials were of
analytical reagent grade. Water was double distilled and
preboiled to free it from dissolved carbon dioxide. Dioxane was
purged of peroxides by passage of the analytical-grade product
through an activated alumina column under nitrogen; the
absence of peroxides was checked by the KI test. The 1H NMR
spectra were recorded with a 200 MHz spectrometer and TMS
as internal standard.
Syn th esis. Esters 4a -f and 6 and the amide 7 were pre-
pared starting from the corresponding acids. The hydroxy acid
was prepared through condensation15 of p-benzoyloxyphenyl-
hydrazine (prepared by reduction16 with SnCl2 of the corre-
sponding diazonium chloride) with methyl 2-chloro-3-oxopro-
pionate (obtained by reaction17 of methyl formate and methyl
chloroacetate in the presence of sodium ethoxide) in ethanol
with solid sodium acetate; the instantaneous dehydrohaloge-
nation of the so obtained arylhydrazone gave methyl ester in
C
16H12N4O7: C, 51.6; H, 3.3; N, 15.1. Found: C, 51.8; H, 3.3;
N, 15.0. N-(4-Met h ylp h en yl) (2E)-3-(4′-h yd r oxyp h en yl-
a zo)p r op en a m id e (7): mp 148-9 °C (from ethanol); Acetone-
d6 δ 9.62 (bs, 1), 9.34 (bs, 1), 8.03 (d, 1, J ) 13.20 Hz), 7.80 (d,
2, 8.80 Hz), 7.68 (d, 2, J ) 8.40 Hz), 7.16 (m, 3), 7.01 (d, 2,
8.60 Hz), 2.30 (s,1). Anal. Calcd for C16H15N3O2: C, 68.3; H,
5.4; N, 14.9. Found: C, 68.2; H, 5.3; N, 15.0.
Meth od s. P r od u ct An a lysis. The products of ester hy-
drolyses were identified as phenol and acid by comparison of
the UV-vis spectra after completion of the reactions with
authentic samples of these compounds under the same condi-
tions.
1
the required 2E form, as confirmed by H NMR spectroscopy.
Benzoyl protecting group was removed by alkaline hydrolysis
with a stoichiometric amount of KOH in cold methanol and
the acid was successively liberated by treatment with bis-
(tributyltin)oxide (BBTO) as described.18 The methoxy acid was
analogously prepared starting from commercial p-methoxy-
phenylhydrazine. Esters and amide were finally prepared from
the acids by condensation with the appropriate phenol or
amine in the presence of DCC. As stated above, we were unable
to prepare esters with leaving group having pKLG higher than
about 6.5. The DCC coupling reaction of the acid with such
phenols failed as well as the alternative route through the acid
chloride, that we have successfully employed in the synthesis
of related esters.4 Several attempts to transform the acid into
the corresponding chloride, accomplished with different types
of protection of the phenolic hydroxyl group of the acid,
invariably led to decomposition of the latter with breakage of
the π skeleton.
The characteristics of the new compounds, purified through
column chromatography and recrystallized from toluene (un-
less otherwise stated), were as follows; mp is given together
with analytical data. All these products were stored in a
refrigerator to avoid decomposition. The stock solutions were
prepared immediately prior to use and stored in the dark.
2,6-Din itr op h en yl (2E)-3-(4′-h yd r oxyp h en yla zo)p r op e-
n oa te (4a ): mp 52-3 °C; CDCl3 δ 8.35 (d, 2, J ) 8.60 Hz),
8.23 (d, 1, J ) 13.80 Hz), 7.87 (d, 2, J ) 9.60 Hz), 7.63 (t, 1, J
) 8.20 Hz), 7.03 (d, 1, J ) 13.4 Hz), 6.96 (d, 2, J ) 9.60 Hz),
6.05 (bs, 1). Anal. Calcd for C15H10N4O7: C, 50.3; H, 2.8; N,
15.6. Found: C, 50.8; H, 2.7; N, 15.8. 2,4-Din itr op h en yl (2E)-
3-(4′-h yd r oxyp h en yla zo)p r op en oa te (4b): mp 135-6 °C;
acetone-d6 δ 9.01 (d, 1, J ) 2.56 Hz), 8.77 (dd, 1, J ) 2.56 Hz;
8.79 Hz), 8.22 (d, 1, J ) 13.92 Hz), 7.98 (d, 1, J ) 8.79 Hz),
7.92 (d, 2, J ) 8.79 Hz), 7.08 (d, 1, J ) 13.56 Hz), 7.08 (d, 2,
J ) 8.79 Hz). Anal. Calcd for C15H10N4O7: C, 50.3; H, 2.8; N,
15.6. Found: C, 51.0; H, 2.9; N, 15.3. 2-Meth yl-4,6-d in itr o-
ph en yl (2E)-3-(4′-h ydr oxyph en ylazo)pr open oate (4c): mp
136-7 °C; CDCl3 δ 8.83 (d, 1, J ) 2.20 Hz), 8.45 (d, 1, J )
Kin etics. The hydrolyses of esters 4a -f and 6 in 40% v/v
dioxane-water solvent were followed spectrophotometrical-
ly: the choice of the appropriate wavelength was dictated by
the pH of the buffers employed in the particular kinetic run
since the ionization of the hydroxyl group of both substrates
and liberated acid in alkaline solutions causes large shift in
the UV-vis spectra. The buffered solution (2.5 mL) was
equilibrated to the required temperature ((0.1 °C) in a 1-cm
path-length quartz cell placed in the thermostated cell holder
of an ordinary, bouble beam spectrophotometer. The reaction
was initiated by adding 10 µL of a stock solution of the
substrate ca. 0.01 M in dioxane placed on the flattened tip of
a narrow glass rod to the buffer. A few vertical strokes of the
glass rod effected mixing and automated acquisition of 50-
200 data points for each kinetic run was performed. The rate
constants reported in Table 1 were obtained through the
skillful use of this technique. Reactions were carried out with
potassium hydroxide at different concentrations (in the pH
range 12.7-14), and with succinate (pH 5.5), phthalate (pH
6.4-7.3), phosphate (pH 7.5-8.7), borate (pH 10-10.5), and
carbonate (pH 11.2-11.5) buffers. In all cases, at least three
different buffer concentrations, at constant pH, were em-
ployed: when buffer effects were observed the rate constants
at zero buffer concentration were obtained by extrapolation.
The ionic strength was kept at 0.1 M with KCl. The pH of the
buffered solutions were measured before and after each kinetic
run using a Ross combined electrode, calibrated with standard
buffers. All pH values quoted for the dioxane-water solutions
are relative values measured directly, no further corrections
being applied. The pseudo-first-order rate constants (kobs) were
obtained by NLLSQ fitting of absorbance vs time data and the
values reported are the averages of at least duplicate runs.
Reactions were normally followed over about seven half-lives.
DASF experiments were carried out with a Tri-Tech stopped-
flow instrument equipped with a diode array detector.
Tr a p p in g. The hydrolysis of 2,4-dinitrophenyl (2E)-3-(4′-
hydroxyphenylazo)propenoate in 0.05 M borate buffer (fraction
of base ) 0.5, 40% aqueous dioxane, ionic strength kept at 0.1
M with KCl, pH 10.10) was kinetically investigated at 400 nm
in the presence of variable amounts of added p-toluidine: no
(14) Van Walree, C. A.; Franssen, O.; Marsman, A. W.; Flipse, M.
C.; J enneskens, L. W. J . Chem. Soc., Perkin Trans. 2 1997, 799-807.
Morley, J . O. J . Chem. Soc., Perkin Trans. 2 1995, 731-734. Buncel,
E.; Rajagopal, S. Acc. Chem. Res. 1990, 23, 226-231.
(15) Sticker, R. E. U.S. Patent 3,651,226 (Cl. 424-226; A 01n), 21
Mar 1972; Chem. Abstr. 1972, 77, 19397w.
(16) Lester, M. G.; Petrow, V.; Stephenson, O. Tetrahedron 1965,
21, 1761-1766.
(17) McMillan, I.; Stoodley, R. J . J . Chem. Soc. C 1968, 2533-2537.
(18) Salomon, C. J .; Mata, E. G.; Mascaretti, O. A. Tetrahedron Lett.
1991, 32, 4239-4242.

7690 J . Org. Chem., Vol. 66, No. 23, 2001
Cevasco et al.
effect on the rate of hydrolysis was observed varying the amine
concentration in the range 0-0.03 M at constant pH. The UV-
vis spectra taken at the end of the reactions carried out in the
presence of the amine were significantly different from that
obtained in absence of it, in particular in the range 450-550
nm. The values of the molar extinction coefficients at 500 nm
of the amide, phenol, and acid were determined employing
authentic samples under the same conditions, and the amide
yield (ca. 37%) was calculated from the absorbances measured
at this wavelength at the end of the reaction carried out in
the presence of 0.03 M p-toluidine. The presence of the amide
was also confirmed by TLC analysis.
Ion iza tion Con sta n ts. The determinations of pKa values
were carried out by spectrophotometric titration (at 520 nm)
of the ionizable substrates employing at least seven buffered
solutions for each determination and extrapolating the absorp-
tion to zero time.
Ack n ow led gm en t. We gratefully thank Prof. C.
Chiappe (University of Pisa) for generous and valuable
help in DASF experiments and subsequent fitting of the
data.
J O015795M