General base-catalyzed hydrolysis and carbonyl-18O exchange of N-(4- nitrobenzoyl)pyrrole

Article abstract of DOI:10.1139/v98-178

Base-promoted hydrolysis kinetics for N-(4-nitrobenzoyl)pyrrole (1) have been measured as a function of buffer concentration at several pH values at 25°C. In addition carbonyl-¹⁸O exchange kinetics have been determined at a single pH value (9.4

Full text of DOI:10.1139/v98-178

1
410
General base-catalyzed hydrolysis and carbonyl-
18
O exchange of N-(4-nitrobenzoyl)pyrrole
Laurence J. Beach, Raymond J. Batchelor, Frederick W.B. Einstein, and
Andrew J. Bennet
Abstract: Base-promoted hydrolysis kinetics for N-(4-nitrobenzoyl)pyrrole (1) have been measured as a function of
1
8
buffer concentration at several pH values at 25°C. In addition carbonyl- O exchange kinetics have been determined at
a single pH value (9.48) as a function of 1,4-diazobicyclo[2.2.2]octane (DABCO) concentration. At zero buffer
concentration the measured ratio of 18O exchange to hydrolysis (k /khyd) is approximately 0.04, and this value
ex
increases and finally levels off at about 0.23 as the DABCO concentration is increased. These observations are
consistent with the buffer acting as a general-base to catalyze both the attack of water to generate an anionic
tetrahedral intermediate (TO
−
) and the breakdown of TO to give hydrolysis products.
−
Key words: amide, hydrolysis, catalysis, general-base, tetrahedral intermediate.
Résumé : Opérant à 25°C, à plusieurs valeurs de pH, on a mesuré la cinétique de l’hydrolyse catalysée par les bases
du N-(4-nitrobenzoyl)pyrrole (1) en fonction de la concentration du tampon. De plus, opérant à une seule valeur de
pH (9,48), on a déterminé la cinétique d’échange du 18O en fonction de la concentration du 1,4-
diazobicyclo[2.2.2]octane (DABCO). À une concentration nulle de tampon, le rapport des vitesses d’échange du 18O et
d’hydrolyse (k /khyd) est approximativement égal à 0,04; lorsqu’on augmente la concentration du DABCO, cette valeur
ec
augmente pour atteindre une valeur limite d’environ 0,23. Ces observations sont en accord avec l’hypothèse selon
laquelle le tampon agit comme une base générale qui catalyse aussi bien l’attaque de l’eau qui génère l’intermédiaire
anionique tétraédrique (TO
Mots clés : amide, hydrolyse, catalyse, basique générale, intermédiaire tétraédrique.
Traduit par la Rédaction] Beach et al. 1417
−
) que la rupture de TO qui conduit aux produits d’hydrolyse.
−
[
amides that contain less basic amines, for example acetan-
ilides (5), formanilides (6), trifluoroacetanilides (7), and N-
acyl pyrroles (8). Furthermore, during the base-promoted
hydrolysis of trifluoro- and trichloroacetanilide general base-
The amide C—N bond is one of the main structural units
in biological chemistry, and as such hydrolysis of this link-
age has been widely studied (1). Scheme 1 shows the gener-
ally accepted mechanism for hydrolysis of amides in basic
nonbuffered solutions. These hydrolysis reactions involve
reversible formation of an anionic tetrahedral intermediate
catalysis has been observed for the breakdown of TO (9).
−
Menger and Donahue (8a) reported that the hydrolysis of
N-(4-nitrobenzoyl)pyrrole (1) was catalyzed by buffers, such
as 1,4-diazobicyclo[2.2.2]octane (DABCO) and trimethyl-
amine (TMA). In contrast, Slebocka-Tilk et al. (2c) reported
(
TO
) followed by subsequent breakdown to generate amine
−
and carboxylate anion.
18
that neither hydrolysis nor O-carbonyl exchange of the
Whether these base-promoted hydrolysis reactions exhibit
a second-order domain in their pH–rate profiles depends on
the basicity of the amine leaving group (2). For example,
simple amides such as benzamides (3) and simple aliphatic
structurally similar amide N-toluoyl pyrrole (2) was cata-
lyzed by added buffers.
–
amides (1c, 4) only show first-order terms in [HO ] during
O
N
O
N
–
hydrolysis (i.e., k >> k [OH ]). In these cases the tetrahe-
O2N
H C
3
2
3
dral intermediate TO
−
(Scheme 1) is sufficiently reactive to
break down to products without the assistance of a second
hydroxide ion. In contrast, hydroxide-catalyzed breakdown
1
2
of TO has been reported to occur during the hydrolysis of
−
Menger and Donahue (8a) analyzed the observed effects
of added buffer on the rate of hydrolysis of 1 as a buffer-
assisted attack of water on the carbonyl group to generate
Received May 22, 1998.
L.J. Beach, R.J. Batchelor, F.W.B. Einstein, and A.J.
1
Bennet. Department of Chemistry, Simon Fraser University,
the anionic tetrahedral intermediate TO
catalysis. However, given that the structurally similar amide
2 undergoes a hydroxide-catalyzed breakdown of TO it is
−
, i.e., general base-
Burnaby, BC V5A 1S6, Canada.
1Author to whom correspondence may be addressed.
Telephone: (604) 291-3532. Fax: (604) 291-3765.
E-mail: bennet@sfu.ca
−
possible that the observed general base-catalyzed hydrolysis
of 1 may involve catalysis of the breakdown rather than (or
Can. J. Chem. 76: 1410–1418 (1998)
© 1998 NRC Canada

Beach et al.
1411
Fig. 2. Plot of kobs versus [DABCO] for 1, T = 25°C, µ = 1.0
Scheme 1.
−
(KCl).
O
O
−
k1
2 3
k + k [OH ]
−
Ar
+
OH
Ar
NR2
Products
k−1
NR2
OH
TO−
Fig. 1. Plot of kobs versus [TMA] for 1, T = 25°C, µ = 1.0
KCl). Lines drawn through the points are the best linear fits to
(
the data.
Fig. 3. Plot of kBT versus fraction of base (Χ ) for DABCO-
B
catalyzed hydrolysis of 1, T = 25°C, µ = 1.0 (KCl). Line drawn
through the points is the best linear fit to the data.
in addition to) the formation of the anionic tetrahedral inter-
mediate.
The present report contains the details of a kinetic study
1
8
on the rates of carbonyl- O exchange and hydrolysis for N-
4-nitrobenzoyl)pyrrole (1) as a function of buffer concen-
(
tration with the aim of elucidating the mechanism of general
catalysis. In addition, the measured solvent deuterium ki-
netic isotope effect (SDKIE) on the hydroxide-promoted rate
of hydrolysis is included in this report, as is the solid state
structure of N-(4-nitrobenzoyl)pyrrole (1).
X
The experimental conditions employed in the present
study to elucidate the mechanism of buffer-catalyzed hydro-
lysis of 1 were modified from those used by Menger and
Donahue (8a) so that ionic strength was kept constant. Ta-
bles S1 and S2 (supplementary material) list the complete
rate constant data (khyd) measured for the hydrolysis of 1 at
various pH values and buffer concentrations (µ = 1.0, KCl; T =
Rate constants for the hydroxide-promoted hydrolysis of
1, at low pH values, were determined by extrapolating the
measured rate constants in the presence of buffers to zero
buffer concentration. The derived values (kcalc) are compiled
in Table 1. Using the data from Table 1, for pH values <10,
the calculated second-order rate constant for the hydroxide-
2
–
1
–1
promoted hydrolysis of 1 is 31.5 ± 2.7 M s .
2
5°C). The corresponding plots of khyd versus buffer concen-
At high pH values (12–14) the rate of hydrolysis of 1 at
–
–
tration are shown in Figs. 1 and 2. To determine the active
component of the buffer, second-order rate constants (kBT)
for the TMA-catalyzed reaction were calculated using a lin-
varying [OH ] and [OD ] was measured directly, and the ob-
tained pseudo-first-order rate constants are listed in Table 2.
The second-order rate constant for hydroxide- and deuter-
oxide-promoted hydrolysis of 1 at high pH were calculated
3
ear fit of the data from Table S1.
–
1
–1
Figure 3 illustrates the calculated second-order rate con-
to be 35.2 ± 1.5 and 39.4 ± 1.4 M s , respectively. Thus,
stants (k ) versus the fraction of base (Χ ) for the TMA-
catalyzed hydrolysis of 1, also included in the plot is the
the SDKIE (k ͞k ) for this base-promoted hydrolysis
BT
B
H O D O
2
2
reaction is 0.89 ± 0.05 (25°C). To determine partitioning of
best linear fit to this data.
tetrahedral intermediates formed during the hydrolysis of 1
2
Supplementary material may be purchased from: The Depository of Unpublished Data, Document Delivery, CISTI, National Research
Council Canada, Ottawa, Canada, K1A 0S2. Tables of atomic coordinates have also been deposited with the Cambridge Crystallographic
Data Centre and can be obtained on request from: The Director, Cambridge Crystallographic Data Centre, University Chemical Laboratory,
1
2 Union Road, Cambridge, CB2 1EZ, U.K.
3
Only the data with [TMA] ≤ 0.138 M were used in the linear fit.
©
1998 NRC Canada

1
412
Table 1. Calculated pseudo-first-order rate constants for
Can. J. Chem. Vol. 76, 1998
Table 3. Observed pseudo-first-order rate constants for carbonyl-
O exchange and hydrolysis of 1 in the presence of added
DABCO, pH = 9.48, T = 25°C, µ = 1.00 (KCl).
1
8
the hydrolysis of 1 at zero buffer concentration versus pH;
T = 25°C, µ = 1.00 (KCl).a
4
–1
× 104
× 104
Buffer
pH
9.04
9.11
9.41
9.42
9.59
9.76
10.18
10.55
kcalc × 10 (s )
k
k
ex
–
hyd
–1 b
c
1 a
k /k
ex hyd
DABCO (M)
(s )
(s )
DABCO
TMA
TMA
DABCO
DABCO
TMA
TMA
TMA
a
3.78 ± 0.07
3.58 ± 0.03
8.20 ± 0.02
8.24 ± 0.09
11.4 ± 0.2
19.7 ± 0.7
51.8 ± 1.4
113.7 ± 0.6
0.50
0.40
0.30
0.20
0.10
0.08
0.06
0.04
0.02
5.08 ± 0.41
4.76 ± 0.31
4.44 ± 0.54
3.65 ± 0.19
2.55 ± 0.15
1.98 ± 0.25
1.77 ± 0.34
1.75 ± 0.25
1.58 ± 0.23
0.36 ± 0.19d
22.4 ± 0.1
21.3 ± 0.6
19.1 ± 0.6
16.0 ± 0.2
12.7 ± 0.3
12.1 ± 0.8
11.6 ± 0.3
10.7 ± 0.2
10.4 ± 0.4
9.7 ± 0.2
0.227 ± 0.018
0.223 ± 0.016
0.232 ± 0.029
0.228 ± 0.012
0.201 ± 0.013
0.164 ± 0.023
0.153 ± 0.037
0.164 ± 0.024
0.152 ± 0.023
0.037 ± 0.020
Extrapolated from the data given in Tables S1 and S2 where
buffer]total < 0.14 M.
[
e,f
g
0
.00
Table 2. Observed pseudo-first-order rate constants for the
hydrolysis of 1 in the absence of added buffer versus –log [OL ];
T = 25°C, µ = 1.00 (KCl).
a
Exchange rate constant calculated according to ref. 10, p. 150, from
–
the data given in Tables S4–S6.
b
Mean value of three independent kinetic runs; quoted error = σn–1
.
c
log [OH–]
–1 a
–log [OD–]
–1 a
Errors calculated according to ref. 10.
–
khyd (H O) (s )
khyd (D O) (s )
2
2
d
Additional estimate for the pseudo-first-order rate constant k using
ex
–
4
–1
0
0
1
1
2
.31
.62
.01
.62
.01
a
18.2 ± 0.5
8.5 ± 0.3
3.38 ± 0.06
0.85 ± 0.02
0.33 ± 0.01
0.29
0.59
0.99
1.99
21.2 ± 0.2
10.0 ± 0.5
4.1 ± 0.1
0.39 ± 0.02
data from Table S6 is 0.55 ± 0.25 × 10 s .
e
Extrapolated value from data with [DABCO] ≤ 0.1 M.
f
–4 –1
Value interpolated from the data given in Table 1 is 9.55 × 10 s .
g
Additional estimate using data from Table S6 is k /k = 0.057 ±
ex hyd
0.026.
Mean value of seven or eight independent kinetic runs; quoted error =
σn–1
.
1
8
Given in Table S3 are the measured values for O (per-
Fig. 4. Plot of k /k versus [DABCO] for reaction of 1 at a
pH value of 9.48, T = 25°C, µ = 1.0 (KCl). Line drawn through
the points is the best nonlinear fit to eq. [6].
t
ex hyd
1
8
centage O at time = t1/2hyd) and the calculated rate constant
ratios k /khyd. This tabulated data suggests that the ratio
k /k varies as a function of buffer concentration however,
the reproducibility of the measured O values was gener-
ex
ex hyd
1
8
t
ally worse at higher buffer concentrations, a possible conse-
quence of the required acid quench. Therefore, it was
1
8
decided to follow carbonyl- O exchange and hydrolysis at a
higher pH value using a flow system where the rapid acid
quenching of large volumes of DABCO buffers could be
avoided (see experimental section).
1
8
The measured rate constants for hydrolysis, carbonyl- O
exchange and their ratio (k /khyd) at a pH of 9.48 using the
ex
flow system are given in Table 3 (10), and the corresponding
plot of k /k
versus buffer concentration is shown in
ex hyd
1
6
18
Fig. 4. In addition, the measured O: O ratios for reiso-
lated 1 are given in Tables S4, S5, and S6 (supplementary
2
material).
A single crystal diffraction study was undertaken on 1 to
examine possible structural differences between 1 and 2.
Crystallographic details are summarized in Table 4. The fi-
nal fractional atomic coordinates for the non-hydrogen at-
1
8
the ratio of carbonyl- O exchange to hydrolysis was mea-
sured as a function of buffer concentration at a single
pH value. In an initial set of experiments (pH = 9.0) car-
2
oms are listed in Table S7 (supplementary material). The
observed bond lengths and those calculated after a rigid
body analysis (see experimental section) for 1 are included
in Table 5, and the important bond angles are given in Ta-
ble 6. Figure 5 presents an ORTEP diagram of the so ob-
tained structure for amide 1.
1
8
bonyl- O labelled amide was subjected to the hydrolysis
conditions for one half-time of hydrolysis. After reisolation
of the labelled amide remaining and determination of the
percentage of O present estimates for the ratio k /k
were made using eq. [1].
1
8
ex hyd
Given in Table 7 is a comparison of the C—N and C—O
amide bond lengths for amides 1 and 2 (11). Also included
in Table 7 are the calculated Dunitz parameters (χ and χ )
1
8
18
kex
ln ( O / Ot)
0
[
1]
=
C
N
khyd
ln(2)
for these two amides (12).
©
1998 NRC Canada

Beach et al.
Table 4. Crystallographic data for the structure determination of 1 at 205 K.
1413
Formula
C H O N
2
Crystal system
Monoclinic
1
1
8
3
fw
216.19
Space group
P2 /c
1.456
0.7093
1.0
1
a
–3
a (Å)
b (Å)
c (Å)
b (°)
V (Å )
Z
6.027(3)
21.832(5)
7.580(3)
98.63(3)
986.1
4
205
0.034
ρ (g cm )
c
λ(Mo K ) (Å)
α1
–
1
µ(Mo K ) (cm )
α
min–max 2θ (°)
4–48
3
b
Crystal dim. (mm)
0.18 × 0.27 × 0.32
0.21 × 0.24 × 0.32
2.15
c
Crystal dim. (mm)
d
Temperature (K)
RF
GoF
RwFf
e
0.041
a
Cell dimensions were determined from 22 reflections (36° ≤ 2θ ≤ 41°).
b
c
First crystal: measured complete quadrant shell (±h, k, l; 4° ≤ 2θ ≤ 45°) and incomplete quadrant shell (±h, k, l; 45° ≤ 2θ ≤ 48°).
= 0.027 for ~100 reflections measured on both crystals.
Second crystal: complete quadrant shell (±h, k, l; 45° ≤ 2θ ≤ 48°). R
merge
d
e
2
1/2
GoF = [Σ(w(F – F ) )/degrees of freedom]
.
o
c
RF = Σ|(|F | – |F |)|/Σ|F | for 1142 data (I ≥ 2.5σ(I )).
o
c
o
o
o
f
2
2
1/2
2
2 –1
RwF = [Σ(w(|F | – |F |) )/Σ(wF )] for 1142 data (I ≥ 2.5σ(I )); w = [σ(F ) + 0.0001F ] .
o
c
o
o
o
o
o
Table 5. Selected bond distances (Å) for 1 at 205 K.
Bond
Distance
Correcteda
1.22
Bond
Distance
Correcteda
O(1)—C(10)
O(2)—N(2)
O(3)—N(2)
N(1)—C(2)
N(1)—C(5)
N(1)—C(10)
N(2)—C(14)
C(2)—C(3)
C(3)—C(4)
a
1.216(3)
1.220(3)
1.214(3)
1.398(3)
1.395(3)
1.386(3)
1.470(3)
1.344(3)
1.426(4)
C(4)—C(5)
1.334(4)
1.491(3)
1.389(3)
1.398(3)
1.380(3)
1.383(3)
1.371(3)
1.381(3)
1.337
1.493
1.392
1.401
1.382
1.387
1.374
1.383
b
1.249
C(10)—C(11)
C(11)—C(12)
C(11)—C(16)
C(12)—C(13)
C(13)—C(14)
C(14)—C(15)
C(15)—C(16)
1.243b
1.402
1.398
1.388
1.472
1.346
1.429
Bond distances corrected for rigid-body thermal motion.
b
Correction includes a contribution for internal libration of the NO group about the N(2)—C(14) bond.
2
Table 6. Selected bond angles (°) for 1 at 205 K.
Bond
Angle
Bond
Angle
C(2)-N(1)-C(5)
C(2)-N(1)-C(10)
C(5)-N(1)-C(10)
O(2)-N(2)-O(3)
O(2)-N(2)-C(14)
O(3)-N(2)-C(14)
N(1)-C(2)-C(3)
C(2)-C(3)-C(4)
C(3)-C(4)-C(5)
N(1)-C(5)-C(4)
O(1)-C(10)-N(1)
O(1)-C(10)-C(11)
107.15(19)
129.33(18)
123.51(19)
122.95(21)
118.35(21)
118.70(22)
108.39(20)
107.70(22)
108.05(22)
108.71(22)
120.26(19)
120.38(19)
N(1)-C(10)-C(11)
C(10)-C(11)-C(12)
C(10)-C(11)-C(16)
C(12)-C(11)-C(16)
C(11)-C(12)-C(13)
C(12)-C(13)-C(14)
N(2)-C(14)-C(13)
N(2)-C(14)-C(15)
C(13)-C(14)-C(15)
C(14)-C(15)-C(16)
C(11)-C(16)-C(15)
119.36(18)
117.45(19)
122.53(19)
119.75(20)
120.54(21)
118.27(21)
118.31(21)
119.08(21)
122.61(21)
118.86(21)
119.95(21)
are given by eqs. [2]–[4] where k ′ = k /k and k ′ = k /k .
2
2
–1
3
3
–1
The factor of two in eqs. [3] and [4] arises from the neces-
sary assumption that one-half of T reversal to regenerate
O−
1
8
(
i) Hydrolysis of 1 in the absence of buffers
The reported hydrolysis mechanism for N-toluoylpyrrole
2) includes a hydroxide-catalyzed term for breakdown of
amide leads to carbonyl- O exchange, i.e., the two oxygen
atoms in the tetrahedral intermediate are protonically equili-
(
brated. This assumption has been shown to be valid for TO
−
the anionic tetrahedral intermediate (TO
−
) to generate car-
formed during the hydrolysis of 2 (2c).
boxylate and pyrrole anions (2c). The derived expressions of
−
−
k [OH ](k ′+ k ′[OH ])
1
2
3
the rate constants for hydrolysis (khyd), exchange (k ), and
[2]
khyd =
ex
−
1
+ k ′ + k ′[OH ]
2 3
their ratio (k /khyd) from the mechanism shown in Scheme 1
ex
©
1998 NRC Canada

1
414
Can. J. Chem. Vol. 76, 1998
Fig. 5. Molecular structure for amide 1, 50% enclosure ellipsoids are shown.
reduction in the kinetic barrier (k ) for product formation
Table 7. Comparison of the structural parameters for
the amides 1 and 2.
2
from amide 1 compared to amide 2 of approximately 3–4 kJ
–
1
mol . The anionic intermediate T formed during the reac-
O−
Parameter
1a
2
tions of 1 will be more stable than the corresponding inter-
mediate formed from 2 because of the electron-withdrawing
nitro group. Therefore, it can be safely assumed that the two
r(C—O) (Å)
r(C—N) (Å)
χ C (°)
1.220
1.388
1.1
1.211
1.409
0.0
oxygens in the intermediate (T ) formed from 1 are pro-
O−
tonically equilibrated and that the change in the k /k ra-
χ N (°)
1.0
10.1
ex hyd
tio, in the absence of buffer, indicates a greater tendency for
the unimolecular ejection of the pyrrole anion, relative to
hydroxide ion, from the more stable tetrahedral intermediate.
The origin of this effect could be the formation of a hydro-
gen bond, at the transition state for pyrrole anion ejection,
between the anionic tetrahedral intermediate’s O–H group
and a solvating water molecule.
a
Bond distances corrected for rigid-body thermal motion
see Table 5).
(
−
k [OH ]
1
[
[
3]
4]
kex =
−
2
(1 + k ′+ k ′[OH ])
2 3
kex
1
=
−
khyd
2(k ′+ k ′[OH ])
2 3
(ii) Mechanism of buffer catalysis
The intercept with the y-axis (Χ = 0, Fig. 3) for the sec-
B
An indication that a similar pathway exists for the hydro-
ond-order rate constants for buffer-catalyzed hydrolysis of 1
is, within experimental error, zero. Therefore, the basic form
of the buffer is the active species for the general-catalyzed
hydrolysis of 1. Shown in Scheme 2 is the modified mecha-
nism for hydrolysis of 1, where the basic form of the buffer
lysis of 1 in the absence of buffers is shown by the differ-
ence in the calculated second-order rate constants at high
and low pH values in the absence of added buffers (2c). In
–
–
the low pH domain, k ′[OH ] << k ′, the value for k /[OH ]
3
2
hyd
–
1
–1
of 31.5 ± 2.7 M
s
is equal to k k ′/(1 + k ′), while in the
high pH domain, k ′[OH ] >> k ′, the value for k /[OH ] of
1 2 2
can catalyze the formation (k ) and (or) the breakdown
–
–
BF
3
2
hyd
(k ) of T . The principal of microscopic reversibility re-
−
–
1
–1
BP
O
3
5.2 ± 1.5 M
s
is equal to k . Using these two values an
1
quires that if general base-catalysis for the formation of T
O−
occurs then reversal to generate starting material must also
occur with general acid-catalysis.
estimate of 0.12 ± 0.11 can be computed for the uncatalyzed
partitioning (k /k ) of the anionic tetrahedral intermediate
–
1
2
T
O−
between regeneration (k ) and hydrolysis (k ) of the
–1 2
The derived expressions of the rate constants for hydroly-
sis (khyd), exchange (k ), and their ratio (k /khyd) from the
amide. Although, this calculated partitioning ratio contains a
large associated error, a second estimate of this quantity can
ex
ex
mechanism shown in Scheme 2 are given by eqs. [5]–[7]
1
8
be made from the rate of carbonyl- O exchange (k ) rela-
ex
where k ′ = k /k , k ′ = k /k , and k ′ = k /k .
BF
BF –1
BH
BH –1
BP
BP –1
tive to hydrolysis (khyd). Where in the absence of buffers and
–
−
−
at a pH value of 9.48, assuming k ′[OH ] << k ′, the mea-
3
2
(k [OH ] + k [B])(k ′+ k ′[B] + k ′[OH ])
1
BF
+
2
BP
3
[
[
5]
6]
khyd
=
sured value for k /k
(Table 3) of 0.037 ± 0.02 (repeat
−
ex hyd
1
+ kBH′[BH ] + k ′+ k ′[B] + k ′[OH ]
2
BP
3
value 0.06 ± 0.03) generates an estimated value for k /k of
–
1
2
0
.07 ± 0.04. That the observed value for k /khyd (0.04–0.06)
ex
−
+
(
k [OH ] + k [B])(1 + k ′[BH ])
1
BF
BH
for the base-promoted hydrolysis of 1, at low pH measure-
ments, is less than that reported (k /k = 0.24) for the cor-
kex
=
+
−
ex hyd
2(1 + kBH′[BH ] + k ′+ k ′[B] + k ′[OH ])
2
BP
3
responding reaction of 2 (2c) requires that TO partitioning
−
to products is favoured to a greater extent by the electron-
withdrawing nitro group (1) than by the electron-donating
methyl group (2). This difference corresponds to a relative
1 + kBH′[BH+]
kex
[7]
=
−
khyd 2(k ′+ k ′[B] + k ′[OH ])
2
BP
3
©
1998 NRC Canada

Beach et al.
1415
Scheme 2.
−
−
k [OH ] + kBF[B]
O
−
k2 + kBP[B] + k [OH ]
O
1
3
Ar
Ar
NR2
Products
+
+ kBH[BH ]
k−
1
NR2
OH
T
O−
Scheme 3.
N
O
N
O
+
Ar
+
Ar
Ar
NR2
X
Products
N
N
−
NR2
O
TZW
Three immediate conclusions can be drawn from the data
shown in Figs. 1 and 2, and given in Table 3, namely, (i) the
hydrolysis reactions of 1 are buffer-catalyzed; (ii) since
such as TZW then the ratio of k /k should drop to zero,
ex hyd
1
8
since no carbonyl- O exchange into the starting amide is
possible from TZW. Therefore, if any nucleophilic attack by
DABCO occurred the intermediate TZW must always revert
to starting amide (Scheme 3).
k /k
<< 1, at low pH and in the absence of buffer, the
ex hyd
rate-limiting step for the hydroxide-promoted hydrolysis
must be formation of TO ; and (iii) buffer accelerates the
slow step of the hydrolysis reaction, i.e., TO formation.
−
−
From the above analysis it must be concluded that the ob-
However, if the buffer only catalyzed the formation of the
served DABCO-catalyzed breakdown of TO to give hydroly-
−
tetrahedral intermediate (k ′ = 0, eq. [7]) then at a constant
sis products is an example of general base-catalysis.
Consequently, the ejection of the pyrrole anion from the
anionic tetrahedral intermediate must occur simultaneously
with, and not subsequent to, proton removal. This conclusion
is in contrast to the proposal of Menger and Donahue (8a).
BP
pH value the ratio k /k should increase in a linear fashion
ex hyd
when the buffer concentration is increased. The observation
that the k /k ratio increases with buffer concentration and
ex hyd
levels off at high concentration provides convincing evi-
dence that both the attack of water on the amide to generate
T
O−
O−
and the breakdown of T to generate the hydrolysis
(iii) Solvent deuterium kinetic isotope effect
products are catalyzed by buffer. At high buffer concentra-
tion, i.e., when k ′[B] >> k ′ + k ′[OH ] and k ′[BH ] >> 1,
the derived expression for k /k
eq. [8].
The measured values for the SDKIE of 0.89 ± 0.05 for the
hydroxide attack at the carbonyl carbon is similar to the re-
ported value for 2 (2c) and is consistent with the transition
state for this step involving direct attack of a partially de-
solvated hydroxide ion on the carbonyl carbon (2).
–
+
BP
2
3
BH
(eq. [7]) simplifies to
ex hyd
kBH′[BH+]
kex
[
8]
=
khyd
2k ′[B]
BP
(
iv) Structural comparison of amides 1 and 2
The data reported in Table 7 shows that in the solid state
In DABCO buffer at a pH value of 9.48 where
+
both amide linkages in 1 and 2 have similar structural pa-
rameters. Consequently, no information is obtained that can
explain either the absence of buffer-catalysis during the hy-
drolysis of 2, or the presence of this type of catalysis in the
case of 1.
(
k /k
)
≈ 0.23 and [B]/[BH ] = 2.13 substitution of
ex hyd limit
these values into eq. [8] gives a ratio for k ′/k ′ of approxi-
BH BP
mately 1 (0.23 × 2 × 2.13 = 0.98).
Since the kinetic expression for buffer-catalyzed hydroly-
sis of 1 contains several variables estimation of the two pa-
rameters kBF and k ′ for the DABCO-catalyzed formation
BP
and breakdown of TO were made using a constrained nonlin-
−
ear least-squares fit of all the DABCO-catalyzed hydrolysis
data (Tables S2 and 3) to eq. [5]. The constraints used in the
In conclusion, replacement of the 4-methyl group in pyr-
role amide 2 with a 4-nitro group (amide 1) activates the
amide linkage sufficiently that general-base-catalyzed attack
of water on the carbonyl group becomes a viable mecha-
nism. In addition, although the nitro group unquestionably
increases the lifetime of the anionic tetrahedral intermediate
–
1
–1
nonlinear fit were as follows: k ′ = k ′, k = 35.2 M s ,
BP
BH
1
–
and k ′[OH ] ≈ 0. The calculated rate constants and standard
3
errors that were derived using the program SYSTAT are k
BF
–
1
–1
–1 –1
=
0.0066 ± 0.0003 M s , k ′ = 29 ± 6 M s , and k ′ =
BP 2
11.2 ± 0.02. Although, the complexity of eq. [5] means that
these derived values are correlated the estimated value for k2′
is consistent with that obtained from the ratio of exchange to
hydrolysis at zero buffer concentration (Table 3), i.e.,
k /k ≈ 1/2k ′. Implicit in the above arguments is that the
buffer acts as a general base rather than as a nucleophile
during the catalytic reaction. If the buffer nucleophilically
attacked the carbonyl carbon to generate an intermediate
(TO
of TO
−
), via inductive withdrawal, the uncatalyzed breakdown
favours ejection of the pyrrole anion over hydroxide
−
ion (k /k = 0.04–0.06) to a greater extent than does the
tetrahedral intermediate formed during the hydrolysis of 2
ex hyd
ex hyd
2
(k /k = 0.24). This effect might be caused by the differ-
ex hyd
ences in acidity of the two respective tetrahedral intermedi-
ates. Thus, in compound 1 the electron-withdrawing nitro
©
1998 NRC Canada

1
416
Can. J. Chem. Vol. 76, 1998
group should result in the development of a stronger hydro-
After this solution had been stirred at ambient temperature
for 24 h the volatile materials were removed under reduced
pressure. To the resulting residue anhydrous toluene
(15 mL) was added, followed by the dropwise addition of
thionyl chloride (1.04 mL, 14.3 mmol), and the reaction
mixture was heated to reflux for 18 h. After the volatile ma-
terials were removed under reduced pressure the resulting 4-
gen bond at the transition state (k ) for product formation.
2
Experimental
The following materials were purchased and used as re-
ceived unless stated otherwise: pyrrole (Aldrich), 4-nitro-
benzoyl chloride (Lancaster), potassium metal and thionyl
1
8
18
18
chloride (Anachemia), H2 O (Isotec, 98.5 atom % O, lot
no. DU2255), trimethylamine hydrochloride (SIGMA,
TMA-HCl), deuterium oxide (Isotec, 99.9 atom % D), and
potassium chloride (BDH). DABCO (1,4-diazabi-
cyclo[2.2.2]octane; Aldrich, 98%) was recrystallized from
nitro-carbonyl- O-benzoyl chloride was purified by vacuum
1
8
distillation (125°C; 5 mTorr). The O-labelled acid chloride
1
8
was used to prepare N-(4-nitro-carbonyl- O-benzol)pyrrole
in an analogous fashion to the preparation of unlabelled 1.
1
8
The overall yield for the synthesis of O-labelled 1 from 4-
nitrobenzoyl chloride was 21%; ir (KBr pellet), ν: 3155 (w),
3107 (w), 1692 (s), 1660 (s), 1601 (m), 1519 (s), 1474 (s),
1409 (s), 1332 (s), 1256 (w), 1189 (w), 1112 (w), 1091 (m),
1075 (m), 1037 (w), 1012 (m), 972 (m), 884 (m), 865 (m),
1
8
pet ether for the O-oxygen exchange experiments. Reagent
grade tetrahydrofuran (BDH, THF) was distilled from its so-
dium benzophenone ketal, and reagent grade toluene (BDH)
was distilled from calcium hydride. NMR spectra were ac-
quired using a Brucker AMX400 NMR spectrophotometer
1
8
+
844 (s), 747 (s), 730 (s) 712 (s); EI–MS, m/z: 218( O-M ,
1
16
+
operating at frequencies of 400.1 and 100.6 MHz for H and
59), 216( O-M , 72), 152(68), 150(100), 122(11), 120(11),
106(21), 104(30), 94(16), 92(17), and 76(44).
1
3
C, respectively. Mass spectra were obtained using a direct
insertion probe and electron impact ionization (70 eV) on a
Hewlett Packard 5985 mass spectrometer. Melting points are
uncorrected.
Hydrolysis kinetics
Hydrolysis of 1 was monitored by measuring the change
in absorbance at either 240 nm (trimethylamine buffers) or
–
N-(4-Nitrobenzoyl)pyrrole (1)
278 nm (OH solutions or DABCO buffers) using either a
Under a dry nitrogen atmosphere potassium metal (0.9 g,
3.1 mmol) was added in small portions to a solution con-
Cary-3E UV-vis spectrophotometer equipped with the Cary
six cell Peltier constant temperature accessory or a
DURRUM 110 stopped-flow apparatus thermostatted with a
Lauda RM6 circulating water bath. The slower reactions
were initiated by injection of a stock solution of 1 in DME
(20–50 mL; 18.5 mM) into a equilibrated solvent mixture
(3 mL; 30 min), whereas for the stopped-flow reactions an
2
taining freshly distilled pyrrole (1.6 mL, 23.1 mmol) in an-
hydrous THF (20 mL). After the addition was complete the
resulting solution was heated to reflux until the potassium
had complete reacted. After cooling to ambient temperature
anhydrous toluene (70 mL) was added followed by the
dropwise addition of a solution containing 4-nitrobenzoyl
chloride (4.29 g, 23.1 mmol) in anhydrous toluene
200 mL). The resulting solution was heated to reflux for
4 h, and after cooling to ambient temperature a mixture of
:1 ice-cold water – diethyl ether (total volume 100 mL) was
–4
equal volume of a solution of 1 (0.4 mM) in 10 M HCl (µ =
1, KCl) was mixed with NaOH. Rate constants in deuterated
(
2
1
solvents were measured in an analogous fashion using D O
2
solutions.
added. The diethyl ether layer was separated and washed
with ice-cold water (50 mL). The two aqueous layers were
combined and washed with diethyl ether (50 mL), after the
two layers were separated the organic layers were combined
and volatile materials were removed under reduced pressure.
The resulting black residue was sublimed (100°C; 0.25
mTorr) onto a cold finger, and the resulting product was fur-
ther purified by recrystallization from hexane:2-butanol to
give an analytically pure sample of 1 (1.25 g; 25%): mp
Exchange kinetics
18O-Carbonyl exchange of labelled-1 in the presence of
DABCO buffers was monitored utilizing a fluid flow system
identical to that reported earlier (2c) except that the reaction
was quenched by utilizing a pH-stat assembly consisting of
Radiometer TTT80 titrator, ABU80 autoburette, a PHM82
standard pH meter, and a Broadley–James combination elec-
trode (silver/silver chloride reference) to maintain the
1
8
quenching solution at a pH of 4. The rate of O-carbonyl
exchange in the absence of buffer was measured using the
pH-stat assembly to maintain a constant pH for a time equal
to one or two times the half-time for hydrolysis of 1. The la-
belled-1 remaining in the hydrolysis medium was isolated
by extracting the aqueous solution with freshly distilled
CH Cl (4 × 2 mL), and the combined organic layers were
1
3
1
1
8
28.5–130.0°C (lit. (8) mp 127–128°C); ir (KBr pellet), ν:
155 (w), 3107 (w), 1692 (s), 1601 (m), 1519 (s), 1474 (s),
409 (s), 1332 (s), 1256 (w), 1189 (w), 1112 (w), 1091 (m),
075 (m), 1037 (w), 1012 (m), 972 (m), 884 (m), 865 (m),
1
44 (s), 747 (s), 730 (s) 712 (s); H NMR (400 MHz;
CD COCD ), δ: 6.40 (2H, app dd), 7.29 (2H, app dd), 8.04
3
3
2
2
1
3
(
2H, m), 8.43 (2H, m); C NMR (100 MHz; CD COCD ),
washed with a saturated NaHCO solution (2 × 4 mL) and
water (2 mL). The dichloromethane layer was dried
3
3
3
δ: 166.6, 150.9, 140.0, 124.6, 122.0, 114.5; EI–MS, m/z:
+
2
7
1
16(M , 65), 150(100), 120(20), 104(25), 92(21), and
6(23). Anal. calcd. for C H N O : C 61.11, H 3.73, N
(MgSO ), filtered, and evaporated onto a small dry lint-free
4
11
8
2
3
tissue. The tissue was inserted into a melting point tube and
1
8
2.95; found: C 61.30, H 3.69, N 12.97.
the O-content of the sample was determined by mass spec-
troscopy. In a typical determination 20 separate scans of the
1
8
+
+
N-(4-Nitro-carbonyl- O-benzoyl)pyrrole
M and the M + 2 ions in the mass spectrum were used to
1
8
To a solution of freshly distilled 4-nitrobenzoyl chloride
1.33 g, 7.2 mmol) in anhydrous THF (15 mL) was added
O-water (129 mL, 6.5 mmol) under a nitrogen atmosphere.
estimate the O-content of the sample and its associated
standard error. The rate constant for exchange was calcu-
(
1
8
18
18
lated using eq. [9] where O is the O-content of the start-
0
©
1998 NRC Canada

Beach et al.
1417
ing amide and 18O is the O-content of the amide reisolated
18
thank the referees of this manuscript for their insightful
comments.
t
4
from the reaction medium at time t.
1
8
18
−
ln ( O / O0)
t
[
9]
kex =
t
1
. (a) W.P. Jencks. Catalysis in chemistry and enzymology.
McGraw–Hill Inc., New York. 1969. p. 523; (b) T.H. Lowry
and K.S. Richardson. Mechanism and theory in organic chem-
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(c) C.J. O’Connor. Q. Rev. Chem. Soc. 24, 553 (1970);
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Bennet, and H. Slebocka-Tilk. Acc. Chem. Res. 25, 481
Structure determination
A single colourless needle-shaped crystal of 1, obtained
from the slow evaporation of a solution of 1 in 1:1 v/v 2-
butanol:hexane, was cleaved and fragments of a suitable size
and shape were mounted on glass fibres using epoxy adhe-
sive. Data were recorded at 205 K with an Enraf Nonius
CAD4F diffractometer equipped with an in-house modified
low-temperature attachment and using graphite monochro-
matized Mo K radiation. Two fragments of the same crys-
α
tal, having comparable size and shape, were used because
the first fragment became dislodged during an interruption
of the cooling caused by ice build-up in the low-temperature
apparatus. The same two intensity standard reflections were
measured every hour of exposure time for both crystal frag-
ments and, in either case, fluctuated by ±2.5% during the
course of the measurements. No corrections for absorption
were deemed necessary. Data reduction included corrections
for intensity scale variations and for Lorentz and polariza-
tion effects.
The structure was solved using direct methods. All hydro-
gen atoms were located from an electron density difference
map. All atomic coordinates, anisotropic thermal parameters
for the non-hydrogen atoms and isotropic thermal parame-
ters for the hydrogen atoms were refined.
(
1992); (h) A.J. Bennet and R.S. Brown. In Comprehensive bi-
ological catalysis. Vol. 1. Edited by M.L. Sinnott. Academic
Press, San Diego. 1998. p. 293.
2
3
. (a) H. Slebocka-Tilk, A.J. Bennet, H.J. Hogg, and R.S. Brown.
J. Am. Chem. Soc. 113, 1288 (1991); (b) H. Slebocka-Tilk,
A.J. Bennet, R.S. Brown, J.A. Keillor, J.P. Guthrie, and A.
Johdan. J. Am. Chem. Soc. 112, 8507 (1990); (c) R.S. Brown,
A.J. Bennet, H. Slebocka-Tilk, and A. Johdan. J. Am. Chem.
Soc. 114, 3092 (1992); (d) B. Yao-Liu and R.S. Brown. J. Org.
Chem. 58, 732 (1993).
. (a) M.L. Bender, R.D. Ginger, and J.P. Unik. J. Am. Chem.
Soc. 80, 1044 (1958); (b) C.A. Bunton, B. Nayak, and C.
O’Connor. J. Org. Chem. 33, 572 (1968).
4. M. de Roo and A. Bruylants. Bull. Soc. Chim. Belg. 63, 140
(1954).
An extinction parameter was refined (13). A weighting
5. S.O. Eriksson. Acta Chem. Scand. 22, 892 (1968).
6. R.H. DeWolfe and R.C. Newcomb. J. Org. Chem. 36, 3870 (1971).
scheme, based on counting statistics, was used such that
2
7
8
9
. (a) J.K. Young, S. Pazhanisamy, and R.L. Schowen. J. Org.
Chem. 49, 4148 (1984); (b) R.M. Pollack and T.C. Dumsha. J.
Am. Chem. Soc. 95, 4463 (1973); (c) S.S. Biechler and R.W.
Taft, Jr. J. Am. Chem. Soc. 79, 4927 (1957).
+
w(|F | – |F |) , was near constant as a function of both |F |
o
c
o
and sin θ/λ. Final full matrix least-squares refinement of 178
parameters for 1142 data (I > 2.5σ(I )) converged at R =
o
o
0
.034 with a maximum |shift/error| of 0.001.
The programs used for data reduction, structure solution,
. (a) F.M. Menger and J.A. Donahue. J. Am. Chem. Soc. 95,
4
32 (1973); (b) A. Cipiciani, P. Linda, and G.J. Savelli.
refinement, and plot generation were from the NRCVAX
crystal structure system (14). The programs suite CRYS-
TALS (15) was employed for analysis of structure factors
and thermal parameters. Complex scattering factors for neu-
tral atoms (16) were used in the calculation of structure fac-
tors. Computations were carried out on MicroVAX-II and
0486 computers.
Rigid body analysis (17) of the anisotropic thermal para-
meters of the molecule yielded R = 0.176 for the agreement
Heterocycl. Chem. 16, 673 (1979); (c) A. Cipiciani, P. Linda,
and G.J. Savelli. Heterocycl. Chem. 16, 677 (1979).
. S.O. Eriksson and C. Holst. Acta. Chem. Scand. 20, 1892
(
1966).
1
0. J.R. Taylor. An introduction to error analysis. University Sci-
ence Books, Mill Valley. 1982. p. 57.
1. A.J. Bennet, V. Somayaji, R.S. Brown, and B.D. Santarserio. J.
8
1
Am. Chem. Soc. 113, 7563 (1991).
12. J.D. Dunitz and F.K. Winkler. Acta Crystallogr. Sect. B:
Struct. Crystallogr. Cryst. Chem. B31, 251 (1975).
13. A.C. Larson. In Crystallographic computing. Munksgaard, Co-
penhagen. 1970. p. 293.
14. E.J. Gabe, Y. LePage, J-P. Charland, F.L. Lee, and P.S. White.
J. Appl. Cryst. 22, 384 (1989).
5. D.J. Watkin, J.R. Carruthers, and P.W. Betteridge. CRYS-
TALS. Chemical Crystallography Laboratory, University of
Oxford, Oxford, England. 1984.
between observed and calculated U and an rms discrepancy
ij
2
of 0.0058 Å . In particular the oxygen atoms of the NO -
2
group showed excess motion. Analysis of internal motion of
the molecule in terms of a segmented rigid body (18) in
which the NO2 group was allowed libration about the
C(14)—N(2) bond axis gave R = 0.089 and an rms discrep-
1
2
ancy of 0.0023 Å .
1
1
1
6. International Tables for X-ray Crystallography.Vol. 4. Kynoch
Press, Birmingham, England. 1975. p. 99.
7. V. Shoemaker and K.N. Trueblood. Acta Crystallogr. Sect. B:
Struct. Crystallogr. Cryst. Chem. B24, 63 (1968).
8. K.N. Trueblood. Acta Crystallogr. Sect. A: Cryst. Phys. Diffr.
Theor. Gen. Crystallogr. A34, 950 (1978).
We gratefully acknowledge financial support of this work
from the Natural Sciences and Engineering Research Coun-
cil of Canada and Simon Fraser University. In addition, we
4
Standard errors were calculated according to ref. 10, p. 62.
©
1998 NRC Canada