Microwave effects in solvent-free esters aminolysis

Article abstract of DOI:10.1016/S0040-4020(03)00151-0

Solvent-free ester aminolysis was studied under microwave or conventional heating either in the absence of base or induced by KOtBu with or without a phase transfer agent. The specific microwave effects were shown to be dependent on the conditions and discussed in terms of relative polarities of ground and transition states.

Full text of DOI:10.1016/S0040-4020(03)00151-0

Tetrahedron 59 (2003) 2185–2189
Microwave effects in solvent-free esters aminolysis
a
Laurence Perreux, Andr e´ Loupy and Michel Delmotte
a,*
b
a
Laboratoire des R e´ actions S e´ lectives sur Supports, Universit e´ Paris-Sud-ICMMO-UMR 8615 B aˆ timent 410-91405 Orsay cedex, France
Laboratoire de Microstructure et M e´ canique des Mat e´ riaux, UPRESA 8006, ENSAM, 151, bd de l’h oˆ pital, 75013 Paris, France
b
Received 16 July 2002; revised 28 October 2002; accepted 14 November 2002
Abstract—Solvent-free ester aminolysis was studied under microwave or conventional heating either in the absence of base or induced by
KOtBu with or without a phase transfer agent. The specific microwave effects were shown to be dependent on the conditions and discussed in
terms of relative polarities of ground and transition states. q 2003 Elsevier Science Ltd. All rights reserved.
1
. Introduction
(K) using a thermostated oil bath under the same conditions
pressure, time, temperature,…) including similar profiles
of temperature increase using both activation modes (MW
(
Amides are among the most important functions in organic
1
chemistry, naturally occurring or synthetic. The direct
or K).
transformation of carboxylic esters to amides, of potentially
important synthetic interest, is generally carried out under
harsh conditions requiring high temperatures and extended
2. Results
1
reaction times. Earlier reported conditions for such direct
2
ester aminolysis involve strongly basic catalysis [alkoxides,
4b
Ester aminolysis (Eq. (1)) was studied under microwave
irradiation in the absence of base or induced by potassium
tert-butoxide in the presence (or not) of a phase transfer
agent (Aliquat 336) under solvent-free conditions.
3
4
hydrides, amides, alkyllithium ], metallic catalysts
5
6
7
[
high pressure.
Grignard reagents, aluminum or tin complex ] or even
8
9
Within the framework of ‘Green Chemistry’, a noticeable
improvement was provided by the association of solvent-
1
0–12
free techniques and microwave activation (MW).
1
3
Thus, Varma and Naicker described the solid state
synthesis of amides from non-enolizable esters and amines
using potassium tert-butoxide under microwave irradiation
in an unmodified domestic microwave oven. The tempera-
ture was not controlled but was certainly rather high as the
reaction vessel was placed in an alumina bath, most likely
ð1Þ
Reactions were performed at rather high temperature
(1508C) to:
1
4
providing an important external temperature increase.
We decided to further explore such a procedure to control
the possibility of specific (not-purely thermal) microwave
effects using different substituted esters and amines. As
– prevent reaction from reversibility (EtOH removal)
– ensure potassium amide formation (tBuOH removal)
[Eq. (2)]:
1
1
advocated to be the most efficient and reliable conditions,
the reactions were performed under microwave irradiation
with accurate control and power-enslaved temperature, as
1
5
measured by infrared detection throughout the reaction
using a monomode reactor (focused waves) Prolabo
ð2Þ
1
6
Synthewave S402. For the sake of comparison, the
reactions were also performed with conventional heating
We have successively studied:
0
–
the influence of the amine substituent (R ) in its
reaction with ethyl benzoate in the presence of KOtBu
(Table 1)
Keywords: ester aminolysis; microwave irradiation; solvent-free reactions;
dielectric characteristics; phase transfer catalysis.
*
Corresponding author. Tel.: þ33-1-69-15-76-50; fax: þ33-1-69-15-46-
79; e-mail: aloupy@icmo.u-psud.fr, michel.delmotte@paris.ensam.fr.
– the influence of base and phase transfer agent for the
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00151-0

2
186
L. Perreux et al. / Tetrahedron 59 (2003) 2185–2189
) with several amines 2
Table 1. Reaction of ethylbenzoate (1, R¼C
6
H
5
Table 4. Temperature effect for the reaction of ethyl caproate (1, R¼n-
0
(1.5 equiv.) in the presence of KOtBu (2 equiv.) for 10 min at 1508C
C
(
5
H
2 equiv.) within 2 min
11) with aniline 2 (R ¼C
6
H
5
, 1.5 equiv.) in the presence of KOtBu
0
a
Entry
R
Aliquat 336
Yield 3 (%)
MW
a
Entry
Temperature (8C)
Aliquat (10%)
Yield 3 (%)
K
MW
K
1
2
3
4
5
6
C
C
6
6
H
5
2
þ
2
þ
2
þ
88
90
84
98
80
87
73
83
42
85
22
70
19
20
21
22
23
150
120
90
150
120
90
2
2
2
þ
þ
þ
92
82
79
84
87
74
73
73
53
83
52
45
H
5
CH
2
n-C
8
H
17
2
4
a
Yield in isolated product.
a
Yield in isolated product.
reaction of n-octylamine (which led to the large effects
in Table 1) with several esters (Table 2)
the influence of the ester substituent (R) in its reaction
with aniline (which led to the smaller effects in
Table 1)
Excellent yields were obtained in all cases. The most
important specific microwave effect was observed in the
case of ethyl phenylacetate (entry 16). They were relatively
moderate when the reaction was carried out in the absence
of a phase transfer agent (entries 14 and 17) and decreased
in its presence (entries 15 and 18).
–
–
the influence of temperature in the case of ethyl
caproate (1, R¼n-C H ) with aniline (Table 3), as
5
11
only very weak or no effects were observed at 1508C
(
Table 4).
Both in the presence or absence of Aliquat 336, the
microwave effect was enhanced when the temperature was
decreased from 150 to 908C.
The microwave effects are rather important and noticeably
depend on the nature of amine substituent R : n-C H .
0
C H CH .C H (entries 1, 3, 5). They are shown to be
8
17
6
5
2
6 5
The microwave specific effect shows an increased magni-
tude when the temperature is decreased. This fact,
strongly lowered in the presence of a phase transfer agent
entries 2, 4, 6).
(
17–19
previously described in the literature
is logically
connected to a high temperature level which may lead to
good yields under conventional heating. To show any effect
In the absence of base, an important specific microwave
effect was observed with ethyl phenylacetate (entry
10/MW:K¼63:13). The effect was largely decreased when
KOtBu and Aliquat 336 were involved (entry 11).
(
catalyst, microwave), it is necessary to reduce the
temperature under classical conditions. Those cases can be
revealed by lowering temperature to allow the observation
of the microwave effect.
0
Table 2. Reaction of n-octylamine (2, R ¼n-C
8
H17, 1.5 equiv.) with several
esters 1 for 10 min at 1508C
Entry
R
KOtBu (2 equiv.)
Aliquat (10%)
Yield 3
a
3. Discussion
(
%)
Microwave effects result from material-wave interactions
and, due to the dipolar polarization phenomenon, the greater
the polarity of a molecule (such as the solvent) the more
pronounced the microwave effect when the rise in
MW
K
7
8
9
C
6
6
H
5
5
2
þ
þ
2
þ
2
þ
2
2
þ
2
þ
2
þ
0
0
80
87
63
70
25
83
22
70
13
50
20
70
20
temperature is considered. In terms of reactivity and
10
11
12
13
C
H
CH
2
kinetics, the specific effect has therefore to be considered in
relation to the reaction mechanism, and particularly with
regard as to how the polarity of the system is altered during
the progress of the reaction.
8 17
n-C H
a
Yield in isolated product.
Specific microwave effects can be expected for polar
mechanisms, when the polarity is increased during the
reaction from the ground state towards the transition state
(as more or less implied by Abramovitch in the conclusion
0
Table 3. Reaction of aniline (2, R ¼C
6 5
H , 1.5 equiv.) with several esters 1
in the presence of KOtBu (2 equiv.) at 1508C
Entry
R
Time (min)
Aliquat (10%)
Yield 3
(
a
21
%)
of his review in 1991 ). The outcome is essentially
2
dependent on the medium and the reaction mechanism.
2
MW
K
If stabilization of the transition state (TS) is more
effective than that of the ground state (GS), this results in
an enhancement of reactivity by a decrease in the activation
energy (Scheme 1).
14
15
16
17
18
C
6
6
H
5
5
10
10
2
2
2
2
þ
þ
2
þ
88
90
98
92
84
73
83
33
73
83
C
n-C
H
CH
2
5
H
11
All of these results can be tentatively rationalized consider-
ing the mechanisms involved:
a
Yield in isolated product.

L. Perreux et al. / Tetrahedron 59 (2003) 2185–2189
2187
Scheme 1. Relative stabilization of a more polar TS when compared to the GS (polar mechanism).
Scheme 2. Mechanism for base induced ester aminolysis.
(
1) In the presence of base (Scheme 2). The TS for anionic
Alternative reasons for the phenomenon could be possibly
advanced dealing with: -the intervention of microscopic
SN2 reactions involves loose ion pairs as in a charge
delocalized (soft) anion. On the other hand, the GS could
involve a neutral electrophile and either tight or loose ion
pairs depending on:
2
4
localized ‘hot spots’ as yet advocated to justify sono-
chemical effects—enhanced interfacial mass transfer—
enhancement in collision probabilities (pre-exponential
factor in Arrhenius law) due to previous mutual orientation
of dipoles along the electromagnetic field (entropic
–
the anion structure (hard or soft). When the substituent
0
25
R is able to delocalize the negative charge on the
effects).
0
0
2
þ
amine anion (R ¼Ph), the ion pairs R NH , M exist
in a looser association. Consequently, a decrease in
microwave effect is expected as the evolution from the
GS$TS occurs with only a slight modification of
polarity in the ion pairs. Conversely, the microwave
To rationalize the polarity enhancement along the reaction
0
1 ) by the method of reasonant cavity little perturbations
processes, we measure the dielectric characteristics (1 and
26
0
0
and the temperature increase profiles of different mixtures
realized under microwave activation. In fact, this behavior
gave a good indication of the polarity of these systems
characterized by their sensitivity to an electric field. We
chose to study the reaction of n-octylamine with ethyl
phenylacetate under neutral conditions (Table 2). It is first
necessary to study the behavior of each species involved in
the reaction (Fig. 1).
2
þ
effect is optimal with the tighter ion pair (n-OctN , K )
the cationnature. The microwave effect disappears when
–
þ
of the cation and phase transfer is better understood as
a bulky cation (MeN (n-Oct) ) is concerned. The effect
3
0
effect when compared to loose ion pairs R NH ,
2
þ
tight ion pairs R NH , K gave a far more important
0
2
þ
MeN (n-Oct) .
3
2
2
In a parallel study, it was shown that formamide, primary
and secondary amines react with esters in the presence
of potassium tert-butoxide under microwave irradiation.
Substituted amides are formed in yields (generally more
than 70%) much higher than under conventional heating.
All of the reactants were heated under microwave
irradiation. The amide most strongly interacted with the
electromagnetic field. A similar behavior was observed with
(
2) Under neutral conditions (Scheme 3). The case drawn
in Scheme 3 is the most propitious to reveal specific
microwave effects as the polarity is evidently increased
during the reaction from a neutral ground state to a dipolar
transition state which is more prone to microwave
interaction than the neutral GS by dipole–dipole
2
3
interactions.
Figure 1. Temperature increase profiles of reactants under microwave
irradiation (power¼300 W).
Scheme 3. Mechanism for neutral ester aminolysis.

2188
L. Perreux et al. / Tetrahedron 59 (2003) 2185–2189
0
00
Figure 2. Permittivity 1 versus temperature.
Figure 5. Characteristic of absorption 1 versus temperature of several
mixtures.
medium. This is effectively the case when we studied
different mixtures (Figs. 4 and 5).
All of these measurements gave a good indication as to the
evolution of the polarity between the ground and final states.
At the beginning, the reactants are not very polar. When
the amide appears in the medium, a polarity exaltation is
observed and, consequently, an important effect of micro-
wave activation (Table 2).
This approach is quasi consistent with all the results
contained in Tables 1–3. Many rather similar observations
2
2
can be rationalized in the same way. However, there
remains the particular behavior of a benzyl group either on
the ester or the amine. This could eventually be due to
possible p-stacking intervention.
0
0
Figure 3. Characteristic of absorption 1 versus temperature.
the dielectric characteristics during temperature increase
(
4. Experimental
Figs. 2 and 3).
4
.1. General
0
indicated a polarity exaltation in the case of the amide.
00
The increase of the 1 and 1 values with temperature
1H and 13C NMR spectra were recorded on Br u¨ cker AC-250
instruments and IR spectra were recorded on Perkin–Elmer
instruments.
On the contrary, in the case of the reactants, the dielectric
characteristics varied in small extent. Consequently, the
appearance of amide during the reaction promotes a polar
4.1.1. Aminolysis of esters. The synthesis of benzanilide is
representative of the typical procedure employed. Potas-
sium tert-butoxide (2 mmol) was added to a pre-mixed
mixture of aniline (1 mmol) and ethylbenzoate (1.5 mmol)
in a glass test tube which was placed in a monomode
microwave and irradiated for the specified time. The
reaction mixture was extracted with dichloromethane. The
combined extracts were dried over anhydrous magnesium
sulfate and the solvent removed under reduced pressure to
afford a residue which recrystallized from n-pentane: mp
2
1
1
62–1658C; IR 3344, 2924, 1670, 1620, 1545, 745 cm
;
1
13
H NMR (CDCl ) d 7.85–7.15 ppm (m, 11H, ArH),
3
C
NMR (CDCl ) d 165, 139, 137, 131–120 ppm.
3
Acknowledgements
We sincerely thank ‘Electricit e´ de France’ (E.D.F.),
Research and Development Division-77818 Moret sur
0
Figure 4. Permittivity 1 versus temperature of several mixtures.

L. Perreux et al. / Tetrahedron 59 (2003) 2185–2189
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