Catalysis of aminolysis of p-nitrophenyl acetate by 2-pyridones

Article abstract of DOI:10.1002/poc.914

The influence of a series of alkyl-substituted 3-cyano-2-pyridones on the kinetics of the reaction of p-nitrophenyl acetate (10) with n-butylamine (9) was studied. The reactions were monitored under pseudo-first-order conditions using an excess of n-butyl

Full text of DOI:10.1002/poc.914

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2005; 18: 901–907
Published online 21 February 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/poc.914
Catalysis of aminolysis of p-nitrophenyl acetate
by 2-pyridones
Christian B. Fischer, Harald Steininger, David S. Stephenson and Hendrik Zipse*
Department of Chemistry and Biochemistry, LMU M u¨ nchen, Butenandtstrasse 13, D-81377 Munich, Germany
Received 28 September 2004; revised 3 January 2005; accepted 16 January 2005
ABSTRACT: The influence of a series of alkyl-substituted 3-cyano-2-pyridones on the kinetics of the reaction of
p-nitrophenyl acetate (10) with n-butylamine (9) was studied. The reactions were monitored under pseudo-first-order
1
conditions using an excess of n-butylamine by H NMR spectroscopy at 23 C in CDCl . A non-linear dependence of
ꢀ
3
the observed rate constants kobs on the pyridone concentration was observed in all cases. The results were analysed
using two different kinetic models. The first model is based on the amine-catalysed background reaction in
combination with a pyridone-catalysed process, whose efficiency is reduced through dimerization of the pyridone
catalyst to an inactive dimer. The second model also involves the amine-catalysed background process, now in
combination with a catalysed process proceeding through pre-equilibrium complexation of the substrate with a 1:1
amine–pyridone complex and a second (rate-determining) step involving C—N bond formation. In addition to these
kinetic studies, the aggregation behaviour of pyridones 2 and 3 was also studied in pure deuteriochloroform solutions
and mixtures of n-butylamine and deuteriochloroform. While substantial aggregation to dimers occurs for both
pyridones in deuteriochloroform, no such dimerization appears to occur in deuteriochloroform solutions containing
ꢂ3
ꢂ1
2
50 ꢁ 10 mol l n-butylamine. This finding strongly supports kinetic model 2 as the more realistic choice.
Copyright # 2005 John Wiley & Sons, Ltd.
Supplementary electronic material for this paper is available in Wiley Interscience at http://www.interscience.
wiley.com/jpages/0894-3230/suppmat/
KEYWORDS: catalysis; non-linear kinetics; NMR spectroscopy; aggregation behaviour; nitrogen heterocycles; pyridones;
aminolysis
10,11
INTRODUCTION
hydroxypyridine (1b) (Scheme 1).
Both of these
tautomers can, of course, act as ‘bifunctional’ catalysts.
Tautomers 1a and 1b are known to aggregate readily,
especially in apolar solution, the symmetric dimer I and
the chain motive II being two conceivable association
patterns (Scheme 1). The aggregation behaviour in solu-
tion has been studied quantitatively by UV–visible mea-
Ester aminolysis is an important reaction for the synthesis
of amides and peptides and has accordingly been studied
1
for a large variety of systems. Catalysis by acids and
bases is frequently observed, but unattractive for the
construction of sensitive and stereochemically complex
2–4
structures.
10
The catalytic activity of pyridones was
surements in cyclohexane and decane, by IR techniques
13
12
studied early on in simple model systems such as
p-nitrophenyl acetate (10) and n-butylamine (9) and
also more complex systems containing amino acid sub-
in CCl , by vapour pressure osmometry in chloroform,
4
1
and by H NMR spectroscopy in THF-d . All of these
9
8
studies are in clear support of a dimeric structure in the
particular solvent and hence in the liquid phase. Earlier
work on the pyridone-catalysed reaction of p-nitrophenyl
acetate (10) and n-butylamine (9) in chlorobenzene was
limited to a narrow concentration range owing to solubi-
5–8
strates.
It has been proposed that the catalytic effi-
ciency of 2-pyridones is based on the property of
simultaneously donating and accepting a hydrogen
9
bond. Most of the studies have concentrated on parent
7
system 1, which is known to equilibrate, depending on
the polarity of the surrounding solvent, between the
two known tautomeric forms 2-pyridone (1a) and 2-
lity problems of the pyridone catalysts. We have now
synthesized a series of alkyl-substituted 2-pyridones (2–8)
(Scheme 2), which are likely to display improved solubi-
14
lity in apolar media. For selected candidates of this
series, we first studied the aggregation behaviour in a low-
polarity solvent such as CDCl , and subsequently the
*Correspondence to: H. Zipse, Department of Chemistry and Bio-
chemistry, LMU M u¨ nchen, Butenandtstrasse 13, D-81377 Munich,
Germany.
E-mail: zipse@cup.uni-muenchen.de
3
catalytic activity of 1–8 in the reaction of p-nitrophenyl
acetate (10) with n-butylamine (9).
Contact/grant sponsor: DFG; Contact/grant number: Zi 436/4-2.
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 901–907

9
02
C. B. FISCHER ET AL.
Scheme 1
1
Figure 1. Concentration dependence of selected H NMR
data for 2 (CDCl , 300 K)
3
1
Following the procedure of Chen and co-workers and
7
18
Horman and Dreux, the experimental data were fitted to
a simple dimerization model described through Eqns (1)
and (2) (for further details see the supplementary mate-
rial, available in Wiley Interscience):
Scheme 2
ꢀ
ꢁ
ꢀ
ꢁ
1=2
1=2
jꢀ ꢂ ꢀ j
jꢀobs ꢂ ꢀ j
D
M
M
RESULTS AND DISCUSSION
ꢀobs ¼ ꢀD ꢂ
ð1Þ
ð2Þ
2
K
½Mꢃ
a
0
Association behaviour of 2-pyridones
ꢀobs ¼ ꢀ þ f ðꢀ ꢂ ꢀ Þ
M
D
D
M
The aggregation behaviour of pyridones 2 and 3 was
studied in detail in deuteriochloroform solution. Pyridone
The observed shift (ꢀobs) is expressed in terms of the
monomer shift (ꢀ ), the dimer shift (ꢀ ), the total
concentration of the pyridone 2([M] ), the dimerization
constant (K ) and the mole fraction of the dimer ( f ). The
a
variable parameters in the fitting process are K , ꢀM and
a
2
was chosen owing to its remarkably short hydrogen
M
D
1
4
bonds formed in the solid state. Pyridone 3 is closely
related to 2 in structural terms, but shows significantly
0
D
ꢂ3
ꢂ1
better solubility in CDCl at 298 K (2, 40 ꢁ 10 mol l ;
3
ꢂ3
ꢂ1
ꢀD (Table 1). The values of ꢀ (2) ¼ 6.44 ꢄ 0.07 ppm and
M
3
, 120 ꢁ 10 mol l ). In particular when compared with
ꢂ3
ꢂ1
ꢀD(2) ¼ 14.04 ꢄ 0.01 ppm obtained from these measure-
simpler derivatives such as 5 (0.9 ꢁ 10 mol l ), the
ments are in close agreement with those obtained pre-
aggregation behaviour of 2 can conveniently be studied
1
viously in low-temperature H NMR studies (Table 1).
1
using H NMR spectroscopy (600 MHz) in CDCl . Of
3
The value of the association constant K (2) ¼
particular relevance for these studies performed at 300 K
ꢂ3
a
3
ꢂ1
ꢂ1
(
8.3 ꢄ 0.1) ꢁ 10 M
(CDCl , 300 K) is smaller than
3
and a concentration of 10 ꢁ 10 mol l
is the NH
resonance located in the spectrum at around 13.45 ppm
11c
that obtained by Persico et al. for dipyridone systems
4
ꢂ1
linked by rigid spacers of K ¼ 6 ꢁ 10 M
(CDCl3,
(
typically observed as a broad signal), the resonance for
the aromatic proton located at C-4 of the pyridone ring at
.75 ppm (singlet) and the 7-CH group located in close
a
2
98 K), but larger than that measured for parent com-
3
ꢂ1
pound 1 of K (1) ¼ 2.9 ꢁ 10 M and for the closely
7
a
2
related 3-ethoxycarbonyl-2(1H)-pyridone of K ¼ 1.3 ꢁ
proximity to the NH unit, which can be found as a triplet
at 3.02 ppm (J ¼ 7.5 Hz). On lowering the temperature to
a
3
ꢂ1
19
(CDCl , 296 K). The association constant
1
0 M
3
ꢀ
ꢂ53 C (220 K), we observe splitting of the NH signal to
1
Table 1. Results for H NMR studies of pyridones 2 and 3
performed at various temperatures (T ) and concentrations [c]
provide two new signals at 6.63 and 14.15 ppm. In line
with previous studies of H-bonded systems, we attribute
the signal at 6.63 ppm to the monomeric pyridone 2
Pyridone 2
Pyridone 3
[
ꢀ (2)] and the signal at 14.15 ppm to its dimer
M
Parameter
ꢀM (ppm)
ꢀ (ppm)
Variable T Variable [c]
T ¼ 300 K)
Variable [c]
(T ¼ 300 K)
6.22 ꢄ 0.12
13.57 ꢄ 0.02
7778 ꢄ 163
15
[ꢀD(2)]. In order to characterize the equilibrium be-
(
1
tween these species in a quantitative manner, the H
NMR spectrum was measured at different concentrations
(regular intervals from 1 ꢁ 10 to 15 ꢁ 10 mol l in
deuteriochloroform) at 300 K (Fig. 1).
6.63
14.15
—
6.44 ꢄ 0.07
14.04 ꢄ 0.01
8340 ꢄ 104
ꢂ3
ꢂ3
ꢂ1
D
ꢂ1
K (M
)
16
a
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 901–907

CATALYSIS OF p-NPA AMINOLYSIS BY 2-PYRIDONES
903
determined for 3 using the same approach is similar to
3
ꢂ1
that of 2 at K (3) ¼ (7.8 ꢄ 0.2) ꢁ 10 M (CDCl , 300 K).
a
3
In order to support further the formation of dimers as the
dominant form of aggregation in apolar solution, we
20
follow the procedure described by Quaglia et al. This
procedure involves the correlation of the relative aggre-
gation-induced shifts (Áꢀ ¼ ꢀ ꢂ ꢀmin) of two different
proton positions of 2. A linear dependence should be
observed if only dimers and no higher aggregates exist in
solution. For this type of analysis, we select the signals
corresponding to the amide proton and the protons at C-7.
The C-7 methylene group is best suited for the analysis,
1
because the corresponding H NMR signal shifts signifi-
cantly with changes in concentration.
1
The excellent linear dependence between the two H
NMR shifts with a correlation factor of 0.996 over the
whole concentration range (Fig. 2) supports symmetric
dimers as the main form of aggregation in apolar sol-
vents. Following the same procedure as described already
for the amide proton signal (NH), the concentration-
dependent signals for the C-7 protons can be fitted to a
dimerization model with the same result for
3
ꢂ1
K (2) ¼ 8.3 ꢁ 10 M . The reactivity studies (see below)
a
1
were performed in CDCl containing significant concen-
3
Figure 3. Concentration dependence of the 7-CH2 H NMR
trations of the reactants. Of these, the amine n-butyl-
amine (9) may be the most likely to raise the overall
polarity of the reaction medium. The concentration-
signal in the presence (open squares) and the absence
ꢂ3
ꢂ1
)
(closed diamonds) of n-butylamine (250 ꢁ 10 mol l
1
1
we use here the H NMR shifts (ꢀobs) relative to those
measured at the lowest concentration of 1.5 ꢁ
dependent H NMR spectra of pyridone 2 were therefore
ꢂ3
ꢂ1
reinvestigated in the presence of 250 ꢁ 10 mol l of
amine 9 (Fig. 3). This concentration corresponds to that
used in the reactivity studies. Owing to the interference of
signals belonging to the various NH groups present in
solution, we must limit ourselves now to the analysis of
the C-7 proton signals of 2 for concentrations above
ꢂ3 ꢂ1
mol l (ꢀ ). In contrast to the situation in pure
1.5
10
CDCl , there is hardly any concentration-induced varia-
3
tion of the signal for the C-7 protons in this case. This
ꢂ3
ꢂ1
suggests that addition of 250 ꢁ 10 mol l of amine 9
to chloroform solutions of pyridone 2 leads to complete
disruption of its hydrogen-bonded dimers. This effect can
most readily be rationalized by assuming the formation of
ꢂ3
ꢂ1
1
tration, the C-7 proton signal is located at 2.72 ppm in the
.5 ꢁ 10 mol l (Fig. 3). At this low pyridone concen-
1:1 (or higher order) complexes of 2 with amine 9.
presence of amine 9 (open squares in Fig. 3) and at
2.98 ppm in pure CDCl (closed diamonds in Fig. 3). In
3
order to facilitate the comparison of the two sets of data,
Reactivity studies
The catalytic activity of pyridones 1–8 was studied for the
reaction of n-butylamine (9) with p-nitrophenyl acetate
(10) in CDCl at ambient temperature (Scheme 3).
3
The reaction rate was studied under pseudo-first-order
conditions using amine 9 in large excess (250 ꢁ
ꢂ3 ꢂ1
mol l ). Under these conditions, the turnover of
ester 10 can be expressed as a first-order process follow-
10
ing the simple rate law in Eqn (3):
½
esterꢃ ¼ ½esterꢃ expðꢂkobstÞ
ð3Þ
ð4Þ
0
2
kobs ¼ k ½amineꢃ þ k ½amineꢃ½catꢃ
A
cat
Figure 2. Correlation of the association-induced shifts of
the NH proton vs the 7-CH protons
Scheme 3
J. Phys. Org. Chem. 2005; 18: 901–907
2
Copyright # 2005 John Wiley & Sons, Ltd.

9
04
C. B. FISCHER ET AL.
Table 2. Rate constants k and dimerization constants Ka
Based on earlier studies of the same reaction in
chlorobenzene, we expect that the pseudo-first-order
cat
a
for kinetic model 1
rate constant k is composed of at least two components
obs
[
2
ꢂ2 ꢂ1
ꢂ1
Compound
kcat (l mol
s
)
K (l mol
a
)
7
Eqn (4)]. The first component is second order in amine
ꢂ1
ꢂ2
ꢂ1
ꢂ2
ꢂ2
ꢂ1
ꢂ2
ꢂ3
ꢂ1
and describes the self-catalysed process in the absence of
any added catalyst. The second term is first order in
amine and describes the (pyridone) catalysed process.
Additional terms (e.g. those for the uncatalysed process
being first order in amine) are not significant at the
reaction conditions chosen here and are therefore ne-
1
2
3
4
5
6
7
8
7.8 ꢁ 10 ꢄ 2 ꢁ 10
230 ꢄ 15
1
1.3 ꢁ 10 ꢄ 2 ꢁ 10
244 000 ꢄ 6900
750 ꢄ 32
0
1.1 ꢁ 10 ꢄ 2 ꢁ 10
ꢂ1
4.2 ꢁ 10 ꢄ 1 ꢁ 10
136 ꢄ 10
1
1.2 ꢁ 10 ꢄ 3 ꢁ 10
315 000 ꢄ 15 000
444 ꢄ 61
ꢂ1
3.8 ꢁ 10 ꢄ 2 ꢁ 10
ꢂ1
2.5 ꢁ 10 ꢄ 9 ꢁ 10
455 ꢄ 40
0
5,21
glected.
9.1 ꢁ 10 ꢄ 9 ꢁ 10
143 000 ꢄ 29 000
The catalytic rate constant kcat reflecting
a
the catalytic potential of pyridones 1–8 can be deter-
mined by measuring the rate constant kobs as a function of
the catalyst concentration. However, the results shown in
Fig. 4 for pyridone 2 are clearly not in line with Eqn (4),
since the rate constant kobs depends on the concentration
of catalyst 2 in a decidedly non-linear fashion.
All results were obtained by assuming a rate constant for the background
ꢂ2
2
l
ꢂ2 ꢂ1 ꢂ1
(296 K, 0.25 mol l n-butyl-
reaction of k
amine).
A
¼ 1.066 ꢁ 10
mol
s
yield a new expression for the dependence of the ob-
served rate constant kobs on the total pyridone concentra-
This has in the past been understood as a reflection of
the propensity of pyridones to form (catalytically inac-
tive) dimers in apolar solution. In quantitative terms,
the equilibrium between monomeric pyridones (such as
tion [M] [Eqn (6)]. This will in the following be referred
0
to as kinetic model 1. Equation (6) can be used to
reproduce the change in kobs with the total catalyst
concentration [M] in a non-linear fitting procedure,
5,7
0
1
a and 1b in Scheme 1) and pyridone dimers (such as I in
giving access to the rate constants kcat and k and the
A
Scheme 1) can be described using Eqn (5). The monomer
concentration [M] is given here as a function of the total
pyridone concentration [M] and the dimerization con-
dimerization constant K . In order to reduce the number
a
of unknown parameters, the rate constant k was deter-
A
mined in the absence of any catalyst as k ¼
0
A
ꢂ2 2
ꢂ2 ꢂ1
stant Ka.
1.066 ꢁ 10 l mol
s
at 296 K. Using catalyst con-
ꢂ3
ꢂ1
centrations of up to 20 ꢁ 10 mol l , the rate data for
pyridones 1–8 given in Table 2 were then obtained.
The results obtained for pyridones 2 and 3 are in
surprising contrast to those of the H NMR studies.
Whereas the latter predict practically no dimerization in
À
Á
1
=2
8
K ½Mꢃ þ 1
ꢂ1
a
0
½Mꢃ ¼
ð5Þ
4
K
a
1
À
Á
1=2
chloroform–n-butylamine solutions, the K value ob-
a
kobs
8Ka½Mꢃ þ 1
ꢂ1
0
tained for 2 from kinetic model 1 is much larger than
that determined for pure chloroform solutions (244 000
¼
kA½amineꢃ þ kcat
ð6Þ
½
amineꢃ
4K
a
ꢂ1
vs 8340 M ). Moreover, the K values determined for 2
a
Assuming that only the pyridone monomers are cata-
lytically active, the expression for the monomer concen-
tration [M] in Eqn (5) can be combined with Eqn (4) to
and 3 (having rather similar structures) using kinetic
model 1 are vastly different, whereas no such difference
1
is apparent from the H NMR results. Also, the associa-
tion constants determined from kinetic model 1 for
pyridones 5–8 are difficult to explain with the structural
characteristics of these compounds. It is particularly
irritating to see that the association constants are much
larger for the tert-butyl substituted pyridone 8 than for
the ethyl- and isopropyl-substituted compounds 6 and 7.
Taken together, the association constants predicted
from kinetic model 1 seem unreliable, despite the fact
that Eqn (6) can be used to fit the non-linear de-
pendence of the observed rate constant kobs on the total
pyridone concentration in a satisfactory manner. The
same must, unfortunately, also be said of the catalytic
rate constants k , whose values are determined simulta-
cat
neously with Ka.
An alternative model for the non-linear dependence of
the observed rate on the total catalyst concentration is
based on the assumption of the pre-equilibrium com-
plexation of the ester substrate with the pyridone catalyst
(Scheme 4). At the high amine concentrations used in the
Figure 4. Dependence of the ratio kobs/[amine] on the
concentration of pyridone 2. The curve corresponds to
that predicted by Eqn (6)
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 901–907

CATALYSIS OF p-NPA AMINOLYSIS BY 2-PYRIDONES
905
Scheme 4
experiment, the catalyst will most likely be present as a
:1 amine–pyridone complex (The amine concentration
exceeds that of the catalyst by at least 12.5-fold even at
1
22
the highest catalyst concentrations used in this study).
This assumption is also in line with the influence of added
butylamine on the NMR spectroscopic properties of
pyridone 2 as described in Fig. 3. The catalyst–amine
complex will in the following be designated with the
‘
sumed to be identical with the total pyridone concentra-
tion [cat] . Formation of the catalyst–substrate complex
0
cat*’ symbol. The concentration of this species is as-
Figure 5. Dependence of the pseudo-first-order rate con-
stant kobs on the concentration of pyridone 2. The curve
corresponds to that predicted by Eqn (7)
proceeds with equilibrium constant K and can be ex-
C
pected to be rapid as compared with the following (rate-
determining) step, in which formation of the amide bond
occurs. In parallel with this catalysed process (I), we must
The rate constant kA was again held constant at its
independently determined value of k ¼ 1.066 ꢁ
A
ꢂ2 2
ꢂ2 ꢂ1
(
as in kinetic model 1) also expect the self-catalysed
10 l mol
s
at 296 K. The experimentally mea-
aminolysis (II) to occur at substantial rates and consider
the decrease of ester concentration. This completes the
definition of kinetic model 2, which has in the past been
used to rationalize the methylimidazole-catalysed hydro-
lysis of p-nitrophenyl carboxylate esters, the aminolysis
of sulfamate esters in chloroform and metal ion-assisted
sured values for pyridone 2 and the curve predicted by
Eqn (7) are shown in Fig. 5. The results obtained for
pyridones 1–8 are given in Table 3.
The substrate–catalyst association constants K pre-
C
dicted by kinetic model 2 are small and depend much less
on the structural characteristics of catalysts 1–8 than the
effective dimerization constant K (Table 2). Variations in
23–25
1
methanolysis of acetylimidazoles.
In line with the H
a
NMR experiments performed in the presence of amine 9,
kinetic model 2 does not assume any self-association of
the pyridone catalysts, but quantitative formation of
pyridone–amine complexes. The formation of pyri-
done–ester complexes is, of course, equally possible.
the catalytic rate constant kcat are also much smaller than
predicted by kinetic model 1 and again show little
variation with the catalyst structure. The catalytic activity
of pyridones 1–8 can best be characterized by the ratio of
the rate constant for the pyridone-catalysed pathway
(k ) and the effective background rate constant (k ) as
1
However, given the changes observed in the H NMR
cat
0
spectrum of 2 on addition of butylamine and the lack of
such an effect on addition of ester 10, we prefer the
assumption of predominant pyridone–amine complex
formation.
contained in Eqn (7) for the observed rate constant kobs.
The values reported in Table 3 were obtained for a
ꢂ1
concentration of [9] ¼ 0.250 mol l . In practically all
cases the calculated speedup ratio k /k is modest and
cat
0
The definition of the observed rate constant kobs for
kinetic model 2 is given by the equation
shows little variation with the substitution pattern of the
Table 3. Rate constants k and complexation constants KC
cat
a
ꢅ
for kinetic model 2
k þ k K ½cat ꢃ
0
cat
C
kobs
¼
ð7Þ
ꢅ
ð1 þ K ½cat ꢃÞ
ꢂ1
ꢂ1
K (l mol ) kcat/k0
C
b
C
Compound
kcat (s
)
ꢂ3
ꢂ5
ꢂ5
ꢂ5
ꢂ5
ꢂ5
ꢂ5
ꢂ5
ꢂ5
2
1
2
3
4
5
6
7
8
2.30 ꢁ 10 ꢄ 3 ꢁ 10
85 ꢄ 3
248 ꢄ 18
127 ꢄ 5
87 ꢄ 3
3.45
1.95
2.72
2.51
1.47
1.62
1.50
2.19
The first variable in Eqn (7), k ¼ k [amine] , des-
ꢂ3
0
A
1.30 ꢁ 10 ꢄ 2 ꢁ 10
cribes the self-catalysed process. The second term
describes the pyridone-catalysed pathway with the
catalytic constant k , the complexation constant K
ꢂ3
1.81 ꢁ 10 ꢄ 2 ꢁ 10
ꢂ3
1.67 ꢁ 10 ꢄ 2 ꢁ 10
ꢂ4
9.82 ꢁ 10 ꢄ 1 ꢁ 10
584 ꢄ 40
156 ꢄ 14
118 ꢄ 6
146 ꢄ 27
cat
C
ꢂ3
1.08 ꢁ 10 ꢄ 2 ꢁ 10
and the corresponding concentration of the amine-
complexed catalyst [cat*]. Owing to the nature of the
latter, the amine concentration does not appear expli-
citly in this second term. The K and k values were
ꢂ4
9.99 ꢁ 10 ꢄ 1 ꢁ 10
ꢂ3
1.46 ꢁ 10 ꢄ 7 ꢁ 10
a
All results were obtained by assuming a rate constant for the back-
ꢂ2
C
cat
2
ꢀ
ꢂ2 ꢂ1 ꢂ1
(23 C, 0.25 mol l n-
ground reaction of k
butylamine).
A
¼ 1.066 ꢁ 10 l mol
s
obtained by non-linear least-squares fitting of the
experimentally determined values of kobs to Eqn (7).
b
see text for definition.
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 901–907

9
06
C. B. FISCHER ET AL.
pyridone catalysts. It is particularly interesting to see that
the size of the C-6 substituent does not perturb the
catalytic efficiency of the catalysts. This would be more
in line with a purely supramolecular mechanism of
catalysis, in which the pyridone catalysts provide a
hydrogen bonding environment that is more favourable
for the aminolysis transition state than the substrate
ground state, but cannot rule out alternative mechanisms
results obtained in this study cannot be used to rule out
one of these two mechanistic options. The small varia-
tions in kcat as a function of pyridone structure are,
however, more easy to reconcile with transition structure
15, in which the pyridone is not actively involved in any
bond making/bond breaking processes.
26
including double hydrogen transfer (see below).
EXPERIMENTAL
Materials. Pyridones 2–8 were synthesized and purified
according to the procedures described in Ref. 14. Pyr-
idone 1 was purchased from Aldrich, recrystallized from
acetone, dried in vacuo and stored under nitrogen prior to
use.
CONCLUSIONS
The combination of results obtained from temperature-
1
and concentration-dependent H NMR measurements
with those obtained from kinetic studies of the aminolysis
reaction of p-nitrophenyl acetate in CDCl leaves no
1
General procedure for dimerization studies ( H NMR
3
doubt that the reactivity data for pyridones 1–8 can best
be analysed using kinetic model 2. According to this
model, the pyridone catalysts (present as 1:1 pyridone–
amine complexes) form a weakly bound complex with
the p-nitrophenyl acetate substrate. Unimolecular reac-
tion of this substrate complex to yield the product amide
spectroscopy). All concentration-dependent measure-
ments for 2 and 3 were recorded on a Bruker AMX 600
(600.13 MHz) spectrometer at a constant temperature of
300.00 ꢄ 0.05 K. Before the measurements, all solutions
were freshly prepared by a dilution series from one stock
solution. Deuteriochloroform was stored over CaH and
2
1
1 and p-nitrophenol (12) represents the rate-limiting
distilled under a nitrogen atmosphere prior to use. The
same procedure was applied to prepare the samples for
the low-temperature measurements on a Varian VXR
400 S spectrometer. All measurements were performed
step of this sequence. Comparison of the self-catalysed
background reaction and the pyridone-catalysed pathway
at high catalyst loadings shows that the pyridones 1–8 are
not sufficiently active to accelerate the overall reaction
substantially.
ꢀ
at a constant temperature of 219.75 ꢄ 0.05 K (ꢂ53.4 C)
in deuteriochloroform in triplicate form.
The low sensitivity of the catalytic rate constant kcat on
the substitution pattern of pyridones 1–8 can best be
rationalized by assuming the stabilization of the amino-
lysis transition state through favourable hydrogen bond-
ing interactions (a supramolecular effect). This is in
contrast to earlier suggestions that, starting from a reac-
tant complex such as 13 (Scheme 5), bifunctional cata-
lysis through pyridones follows a double proton transfer
mechanism through a formally eight-membered ring as
depicted in structure 14. Alternatively, the reaction may
proceed through the same mechanism as in the uncata-
lysed case, in which amine and ester react directly
through a four-membered ring transition state. As re-
flected in transition structure 15, the catalytic effects of
pyridones would then be the result of providing a hydro-
gen bonding environment particularly favourable for the
aminolysis transition state. However, the experimental
1
General procedure for the kinetic studies by H NMR
spectroscopy. All kinetic measurements were recorded at
ꢀ
a constant temperature of 296.15 K (23 C) on a Varian
Mercury 200 (199.98 MHz) spectrometer. The reaction
rate was determined by following the signals for the aryl
protons of p-nitrophenyl acetate and p-nitrophenol. Be-
fore the measurements, the solutions with the required
ꢂ3
ꢂ1
ꢂ1
concentrations of n-butylamine (9) (250 ꢁ 10 mol l ),
ꢂ3
p-nitrophenyl acetate (10) (50 ꢁ 10 mol l ) and the
appropriate catalyst (various concentrations) were freshly
prepared. Deuteriochloroform was stored over CaH and
2
distilled under a nitrogen atmosphere prior to use.
n-Butylamine (9) was purified in the same manner.
2
7
Compound 10 was recrystallized from hexane and,
after confirmation of the correct elemental analysis,
stored under a nitrogen atmosphere prior to use. There
are two basic procedures for the preparation of the
solutions and the reaction mixtures, as follows.
Procedure 1. For catalysts that are sufficiently soluble in
deuteriochloroform (1–4 and 6–8) a stock solution of
known concentration can be prepared directly from the
catalyst and deuteriochloroform. Variation of the catalyst
concentration is achieved through dilution with CDCl3.
The three solutions containing the amine 9, the ester 10
and the catalyst are mixed in equal portions of 180 ml
each in the NMR tube immediately prior to use.
Scheme 5
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 901–907

CATALYSIS OF p-NPA AMINOLYSIS BY 2-PYRIDONES
907
6
. Oie T, Loew GH, Burt SK, Binkley JS, MacElroy RD. J. Am.
Chem. Soc. 1982; 104: 6169–6174.
Procedure 2. Catalyst 5 is less soluble in CDCl but more
3
soluble in n-butylamine–CDCl solution. Hence prepara-
3
tion is achieved by dissolving an exact amount of catalyst
in a well-defined volume of n-butylamine solution in
CDCl . The amine concentration is identical with that
3
used in the measurements. Dilution of the catalyst solu-
tion for varying concentrations is achieved in the same
manner as described in Procedure 1, but now using the n-
butylamine–deuteriochloroform solution. The reaction
mixtures are prepared through addition of 25 ml of 2 M
ester solution to 1 ml of the appropriate n-butylamine–
catalyst solution in the NMR tube.
7. (a) Zipse H, Wang L. Liebigs Ann. 1996; 1501–1509; (b) Zipse H,
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Acknowledgement
We thank the DFG for financial support of this project
(
1
1
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Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 901–907