Rapid amidic hydrolysis: a competitive reaction pathway under basic conditions for N-(hydroxymethyl)benzamide derivatives bearing electron-donating groups

Article abstract of DOI:10.1016/j.tetlet.2009.10.069

Studies of N-(hydroxymethyl)benzamide derivatives have concluded that the hydroxide-dependent reaction occurs via a specific-base catalyzed deprotonation of the hydroxyl group followed by rate-determining loss of the benzamidate and generation of the aldehyde. The 3-methyl, 4-methyl, and 4-methoxy-N-(hydroxymethyl)benzamide reaction mechanism deviates at higher [HO^-] with amidic hydrolysis becoming competitive and having reaction half-lives of ～17 s, in 1 M KOH, I = 1.0 M (KCl), 25 °C. An intramolecular general-base catalyzed mechanism has been suggested for the amidic hydrolysis reaction.

Full text of DOI:10.1016/j.tetlet.2009.10.069

Tetrahedron Letters 50 (2009) 7358–7361
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Tetrahedron Letters
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Rapid amidic hydrolysis: a competitive reaction pathway under basic
conditions for N-(hydroxymethyl)benzamide derivatives bearing electron-
donating groups
*
John L. Murphy, William J. Tenn III, Joseph J. Labuda, Richard W. Nagorski
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Studies of N-(hydroxymethyl)benzamide derivatives have concluded that the hydroxide-dependent
reaction occurs via a specific-base catalyzed deprotonation of the hydroxyl group followed by rate-
determining loss of the benzamidate and generation of the aldehyde. The 3-methyl, 4-methyl, and
4-methoxy-N-(hydroxymethyl)benzamide reaction mechanism deviates at higher [HOꢀ] with amidic
hydrolysis becoming competitive and having reaction half-lives of ꢁ17 s, in 1 M KOH, I = 1.0 M (KCl),
25 °C. An intramolecular general-base catalyzed mechanism has been suggested for the amidic hydro-
lysis reaction.
Received 10 September 2009
Revised 9 October 2009
Accepted 15 October 2009
Available online 21 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Ka½HOꢀꢂ
Carbinolamides are the seemingly simple combination of an
amide and aldehyde, however, the functionality has a surprisingly
diverse range of roles. They are constituents in a number of mole-
cules of medicinal importance1,2 and have been found as interme-
diates in biological processes with outcomes that are both
positive3,4 and negative5 to those systems. Relatively few studies
have focused on the mechanisms by which this functionality reacts
but, all studies of the hydroxide-dependent breakdown of carbin-
olamides, in water, agree that the reaction occurs via a specific-
base catalyzed deprotonation of the hydroxyl group, followed by
rate-determining breakdown to form the aldehyde and amidate
(see Scheme 1).6–8 This conclusion was supported by a lack of buf-
fer catalysis and hydroxide dependence changing from first order
to zero order on moving from lower to higher [hydroxide].6,7 Also,
the studies of the effect of substituents with increasing electron
demand, on the aromatic ring of N-(hydroxymethyl)benzamide, re-
sulted in increasing apparent second-order rates (k01, see Eqs. 1 and
2) and increased maximal rate constants at high hydroxide (k1).7a,c
Reported here are the rates of the hydroxide-dependent aqueous
reaction of N-(hydroxymethyl)benzamide derivatives bearing elec-
tron-donating groups (1a–c), where the maximal rates appear to
be independent of the aromatic substituent. The kinetic results
coupled with the preliminary product analysis indicate that a rel-
atively fast amidic hydrolysis reaction (half-life of ꢁ40 s) has be-
come competitive with carbinolamide breakdown at high [HOꢀ],
in H2O, I = 1.0 M (KCl) at 25 °C:
kobsd ¼ k
ð1Þ
ð2Þ
1 Kw þ Ka½HOꢀꢂ
Ka½HOꢀꢂ
kobsd ¼ k1
¼ k01½HOꢀꢂ
Kw
In previous studies, the fit of kobsd to the rate expression for the
mechanism shown in Scheme 1 (see Eq. 1) yielded both k1 and Ka of
the hydroxyl group of the carbinolamide.7a,c These studies found
that the aromatic substituents had only a small effect on the Ka
of the hydroxyl group (
q = 0.07), but k1 was more strongly affected
(q
= 0.67).7a,c,8 The only detectable product of these reactions was
the amide of the carbinolamide starting material.7a,c Therefore, it
could be predicted that electron-donating groups would continue
to progressively reduce the maximal rate constant and have only
small effects on the Ka of the hydroxyl group of the carbinolamide.
Figure 1 shows the plot of kobsd versus [HOꢀ] for 1a–c. The gen-
eral appearance of these plots is similar to those seen previously
O
O-
O
OH
Ka
+ H3O+
N
H
N
H
X
X
k1
2a-c
1a-c
O
X
O
O
HOH
1a = 3-CH3
1b = 4-CH3
1c = 4-OCH3
H
N
H
+
+ HO-
N
H
H
H
X
X
* Corresponding author. Tel.: +1 309 438 8978; fax: +1 309 438 5538.
E-mail address: rnagor@ilstu.edu (R.W. Nagorski).
Scheme 1. Accepted mechanism for specific-base catalyzed breakdown of N-
(hydroxymethyl)benzamide derivatives
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.069

J. L. Murphy et al. / Tetrahedron Letters 50 (2009) 7358–7361
7359
0.05
0.04
0.03
0.02
0.01
0.00
0.8
0.6
0.4
0.2
0.0
-0.2
k
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
0.0
0.2
0.4
0.6
[HO-] (M)
0.8
1.0
σ
Figure 2. Hammett plot of the apparent second-order rates (k01) for the hydroxide-
dependent reaction for 3-methyl-N-(hydroxymethyl)-benzamide, 4-methyl-N-
(hydroxymethyl)benzamide, and 4-methoxy-N-(hydroxymethyl)benzamide with
other apparent second-order rate constants for a series of N-(hydroxymethyl)benz-
Figure 1. Observed hydroxide dependence of the rate of reaction (kobsd, sꢀ1) for 3-
methyl-N-(hydroxymethyl)benzamide (1a, e), 4-methyl-N-(hydroxymethyl)benz-
amide (1b, s), and 4-methoxy-N-(hydroxymethyl)-benzamide (1c, h) in H2O,
I = 1.0 M (KCl), at 25 °C; solid line represents the predicted rate for the specific-base
catalyzed breakdown of 1c based upon apparent second-order rate of reaction.
amide compounds from Ref. 7c, in H2O at 25 °C, I = 1.0 M (KCl) versus r.
Extending the conclusion that all compounds discussed react
via the same specific-base catalyzed mechanism at lower [HOꢀ].
It follows that the substituents on compounds 1a–c would lead
to the same small effect on the Ka of the hydroxyl group previously
observed for other N-(hydroxymethyl)benzamide derivatives
for N-(hydroxymethyl)benzamide derivatives bearing electron-
withdrawing groups.6,7a,d However, in contrast to the previous re-
sults, there is no strong dependence between the substituent on
the amide portion of the carbinolamide and k1. In fact, the maximal
rates observed (k1) for 1a–c are similar or larger than that observed
for N-(hydroxymethyl)benzamide (k1 = 0.042 sꢀ1),7a indicating that
electron-donating groups are not extending the previously re-
ported trend.6,7a,c Additionally, 1c, bearing the strongest electron-
donating group, has the highest maximal rate of the three com-
pounds reported here (see Fig. 1), and, such a result, would lead
to a nonlinear Hammett correlation.7a,c This observation indicates
that there has been a change in the rate-limiting step of the reac-
tion or a change in the mechanism of the reaction itself.9 This out-
come was unexpected, as it is in contrast to the results reported
earlier by Bundgaard et al.6e
(q
= 0.07).7c Thus, the pKa’s for 1a–c can be predicted by a simple
extrapolation of the previously reported Hammett correlation
(see Table 1).7c The limiting rate (kc1alc) for the specific-base cata-
lyzed carbinolamide breakdown of 1a–c can then be calculated
using Eq. 2, the experimentally determined apparent second-order
rates (k0 ) and the predicted Ka’s of the hydroxyl group (see Table
1
1). It is apparent that the limiting rates calculated in this manner
are much smaller than the kobsd values seen at high [HOꢀ] in Figure
1. This difference between predicted rates and kobsd is further illus-
trated by inserting the predicted Ka and kcalc into Eq. 1 yielding the
1
expected kobsd values for the specific-base catalyzed carbinolamide
breakdown. The solid line in Figure 1 is the predicted rates for the
specific-base catalyzed breakdown of 4-methoxy-N-(hydroxy-
methyl)-benzamide. At 1 M KOH, kobsd for 1c is 2.1-fold larger than
the predicted rate under the same conditions and the rate differ-
ences for 1a and 1b are 1.6 and 1.7, respectively. This trend in rate
ratios points to stronger electron-donating groups yielding larger
deviations from the predicted rates at higher [hydroxide].
Previous studies, investigating the apparent second-order rate
constants (k01) for the hydroxide-dependent reaction of a series of
N-(hydroxymethyl)benzamide compounds, found that the Ham-
mett correlation was linear (q = 1.11, in H2O, I = 0.5 M (KCl), at
37 °C) for all compounds studied, which included compound
1c.6e Due to the restricted range in pH over which their kinetic
experiments were performed, these studies were only able to gen-
erate k01, but clearly these results indicate that at low [HOꢀ] all the
compounds reported were reacting via a similar mechanism.6e
In order to explore Bundgaard’s observation, the apparent sec-
ond-order rate constants for 1a–c were determined from the plot
of kobsd versus [HOꢀ] at low [HOꢀ] (see Table 1). A Hammett plot
of the apparent second-order rate constants for 1a–c with the pre-
viously reported rates for compounds bearing electron-withdraw-
Product analysis studies performed by HPLC, for experiments at
pH’s below 10 and quenched at ꢁ50% reaction, showed only the
starting carbinolamide and the amide of the starting material.
However, the same analyses performed at 0.2 M KOH and higher
showed the presence of carbinolamide, amide, and carboxylic acid
derivative of the starting material. Logically, subsequent hydrolysis
of the amide product generated upon breakdown of the carbinol-
amide might be expected as the source of the carboxylic acid prod-
ucts. However, previous amide hydrolysis studies carried out at
100 °C and 1 M hydroxide were shown to have half-lives of
7.7,11a 16,11a 7.6,11a 100,11b and 1011b min for benzamide, N-meth-
ylbenzamide, N,N-dimethyl-benzamide, N-ethyl-4-toluamide, and
N,N-dimethyl-4-toluamide, respectively. Whereas with a kobsd of
ꢁ0.04 sꢀ1, at 1 M KOH (see Fig. 1), in H2O, at 25 °C, for compounds
1a–c, the half-life will be ꢁ17 s. The reactions of 1a–c occur too
quickly for a significant buildup of carboxylic acid due to the sub-
sequent hydrolysis of the amide product of carbinolamide break-
down. Also, parent amide compound, subjected to the same
conditions as the product studies detailed above, did not show
any detectable amounts of carboxylic acid product when analyzed
as described above. The source of the carboxylic acid product must
be associated with the increased rate of reaction for 1a–c versus
previously observed trends.6,7
ing groups,7a,c resulted in a linear correlation with a
q-value of 0.87
(q
= 0.86 previously reported, see Fig. 2).7c,10 As reported by
Bundgaard,6e at low [HOꢀ] all N-(hydroxymethyl)benzamide deriv-
atives studied react by the same mechanism (see Scheme 1) and it
is only at higher [HOꢀ] that the mechanism by which 1a–c react,
apparently deviates.
Table 1
Apparent second-order rates for N-(hydroxymethyl)benzamide derivatives 1a–c with
predicted pKa’s and calculated limiting rates
k01 (Mꢀ1 sꢀ1
)
a
pKparedicted
kc1alc (sꢀ1
)
Compound
1a
1b
1c
0.23
0.22
0.17
13.05
13.06
13.06
0.026
0.025
0.023
a
b
c
Determined in H2O, 25 °C, I = 1.0 M (KCl).
At low [HOꢀ], all substituted N-(hydroxymethyl)benzamide
compounds react by the same mechanism (see Fig. 2). The rate-
Predicted based on pKa data in Ref. 7c having a q-value of 0.07.
Calculated using k01 = ((k1Ka)/Kw) where Kw = 1 ꢃ 10ꢀ14 M2.

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J. L. Murphy et al. / Tetrahedron Letters 50 (2009) 7358–7361
determining step involves breakdown of 2, yielding benzamidate
and formaldehyde. As electron-withdrawing groups are added to
the amide portion of the carbinolamide, the reaction rate increases,
indicating that the nucleofugality of the benzamidate has increase-
d.7a,c From Figure 1, it is only when significant amounts of 2a–c
(based upon Ka’s of other N-(hydroxymethyl)benzamide deriva-
tives, see Scheme 2) are in solution that kobsd deviates from the
previous trends and amidic hydrolysis products are observed. Thus,
the addition of electron-donating groups has decreased the leaving
group ability of the benzamidate, yielding an intermediate (2a–c)
with a longer lifetime and with the potential to undergo other
forms of reactivity.
carbinolamide. In the case of 4-methoxy-N-(hydroxymethyl)benz-
amide, amidic hydrolysis occurs at that same rate as ‘normal’ car-
binolamide breakdown. We have proposed a mechanism that is
second order in hydroxide, wherein the ionized hydroxyl group
of the carbinolamide can act as an intramolecular general base to
deprotonate To2ꢀ , resulting in amidic hydrolysis and release of
aminomethanol anion. This new mechanism of carbinolamide
breakdown may also provide valuable insight into the enzymatic
mechanism for the hydrolysis of amides and other acyl derivatives.
Acknowledgments
It is easy to tie the presence of carboxylic acid product, at higher
[HOꢀ], to the kinetic deviation observed. However, if hydrolysis
were becoming competitive with carbinolamide breakdown, why
is the carboxylic acid product not observed at lower [HOꢀ]? We
are proposing a mechanism that is second order in hydroxide
wherein 2a–c are attacked at the carbonyl carbon by a second
This work was supported by the National Science Foundation
under CHE-051830 and also a MRI grant under CHE-0722385.
Supplementary data
Synthesis and characterization of 1a–c, with experimental
methods, plots of kobsd versus [HOꢀ] for 1a–c with predicted rates
based upon k01 and predicted pKa’s are available. Supplementary
data associated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2009.10.069.
ꢀ
hydroxide molecule to yield To2ꢀ or To which subsequently ion-
ized, leading to To2ꢀ . This is followed by breakdown of To2ꢀ to yield
the benzoic acid derivative and aminomethanol. While it is difficult
to predict an expected rate of hydrolysis due to the unique struc-
ture of To2ꢀ , this hydrolysis reaction occurs much more quickly
than would be anticipated based upon the available data (see
half-lives listed above).11,12 It is generally accepted that amide
hydrolysis occurs with rate-limiting loss of the nitrogen leaving
group and that nitrogen must be protonated or, in the case of very
acidic amines, can depart as an anion.12 Data concerning the Ka of
the nitrogen of aminomethanol are not readily available; however,
it could be safely assumed that the aminomethanol acting as a
leaving group with a negative charge on both the nitrogen and
the oxygen would be energetically unlikely. Alternatively, mecha-
nisms for amide hydrolysis have been investigated wherein the
rate is second order in hydroxide and the second hydroxide ion
deprotonates the hydroxyl group of the tetrahedral intermediate,
leading to product formation.12,13 The deprotonated hydroxyl
group in To2ꢀ could act as an intramolecular general base to
deprotonate the OH group in To2ꢀ (see Scheme 2), with subsequent
loss of the nitrogen leaving group. Intramolecular catalysis and
general catalysis have been observed within a number of sys-
tems.14 It could be further proposed that the anionic nitrogen leav-
ing group could undergo further decomposition with the loss of
hydroxide but no direct evidence for such a mechanism has been
found.
References and notes
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specific-base catalyzed reaction of carbinolamides have arisen. The mechanism
shown in Scheme 1 shows the hydroxyl group being deprotonated followed by
breakdown into the aldehyde and release of the benzamidate. Limited data
concerning the acidity of the protons on the nitrogen of benzamides are
available, but the available data suggest that benzamide has a pKa >19.0 with 4-
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both the nitrogen and the oxygen of carbinolamides will be affected by their
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significantly more acidic than those attached to the nitrogen.; (b) Hine, J.;
Hine, M. J. Am. Chem. Soc 1952, 74, 5266–5271; (c) Homer, R. B.; Johnson, C. D.
The Chemistry of Amides; Interscience: New York, 1970; (d) Wise, W. M.; Brandt,
When differences in structure and reaction conditions are con-
sidered,12,15 the hydrolysis reaction occurs, at least, a 130-fold fas-
ter than normal amide hydrolysis. While the exact nature of the
reaction is currently under further investigation, the results indi-
cate the discovery of a new mechanism for the breakdown of car-
binolamides involving facile amidic hydrolysis whose onset is
dependent on the protonation state of the hydroxyl group of the
O
O
k1
Ka
O-
amide products
N
H
N
H
OH
+ H3O+
X
X
2a-c
1a-c
HO-
OH
HO-
OH
-O
-O
khyd
benzoic acid
products
Ka
O-
N
H
N
H
OH
X
X
To2-
To-
Scheme 2. Proposed amidic hydrolysis route.

J. L. Murphy et al. / Tetrahedron Letters 50 (2009) 7358–7361
7361
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