Solvent-free microwave-assisted aromatic nucleophilic substitution - Synthesis of aromatic ethers

Article abstract of DOI:10.1002/1099-0690(200204)2002:7<1278::AID-EJOC1278>3.0.CO;2-B

Specific (not purely thermal) microwave effects are shown to be highly dependent on the nature of the nucleophilic ion pairs and on the substituents and leaving groups on the aromatic substrates. This can be interpreted in terms of a polarity enhancement during the progress of the reaction and a shift of the position of the transition state along the reaction coordinates. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200204)2002:7<1278::AID-EJOC1278>3.0.CO;2-B

FULL PAPER
Solvent-Free Microwave-Assisted Aromatic Nucleophilic Substitution ؊
Synthesis of Aromatic Ethers
[a]
[a]
[a]
[a]
´
Mehdi Chaouchi, Andre Loupy,* Sylvain Marque, and Alain Petit
Keywords: Aromatic ethers / Aromatic nucleophilic substitutions / Microwave irradiation / Phase-transfer catalysis /
Solvent-free reactions / Specific microwave effects
Specific (not purely thermal) microwave effects are shown to
shift of the position of the transition state along the reaction
be highly dependent on the nature of the nucleophilic ion coordinates.
pairs and on the substituents and leaving groups on the aro-
matic substrates. This can be interpreted in terms of a polar-
ity enhancement during the progress of the reaction and a
(
Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Industrially important aromatic nucleophilic substitutions
(SNAr) generally afford only moderate yields under harsh
conditions.[1] They are most commonly carried out on activ-
ated aromatic substrates bearing electron-withdrawing
groups.
In this study, we developed some SNAr reactions invol-
ving different alkoxide anions (ROϪ with R ϭ alkyl,
phenyl) by combining two complementary technologies:
solvent-free PTC conditions and microwave activation, with
noticeable effectiveness.[10,11] The aim of these experiments
was twofold: i) improvement over classical reaction condi-
tions, and ii) explanation of microwave effects in terms of
substituents, halides and nucleophiles.
A considerable improvement was achieved through the
use of solvent-free solid/liquid phase-transfer catalysis
(PTC) conditions, which gave promising results but often at
elevated temperatures with rather long reaction times.[2,3]
A
In order to check for a possible specific (not purely ther-
mal) microwave effect, a monomode reactor involving fo-
cused waves and accurate temperature measurement by IR
detection was used in preference over a multimode domestic
oven.[12] Comparisons between microwave activation and
conventional heating (∆) could thus be made under similar
conditions of time, temperature, pressure etc., and with
identical temperature rise profiles.
new case of solvent-free PTC, for instance, has recently
been published, demonstrating N-arylation of pyrrolidino-
fullerene at 150 °C with K2CO3 in the presence of nBu4NBr
as phase-transfer agent.[4]
Also recently, a few publications exploiting microwave ac-
tivation for SNAr reactions with activated aromatic halides
have appeared. The authors described the use of polar sol-
vents in several reactions:
a) Ethoxylation of o-chlorophenol or p-nitrochloroben-
Regarding the goal of a general interpretation of specific
microwave effects, we can assume that these will be favour-
able if the polarity of the transition state is increased during
the reaction (microwaveϪmaterials interactions are en-
hanced with polarity).[13] This should therefore be the case
for reactions in which the transition state (TS) is more polar
than the ground state (GS) (Figure 1).[24a]
zene in ethanol[5,6]
b) Reactions with tert-butoxide and p-fluorobenzal-
dehyde in DMSO[7]
c) Coupling of amino acids with 2,4-dinitrofluoroben-
zene in water in the presence of sodium bicarbonate.[8]
Only one case of solvent-free SNAr on basic alumina as
support has been described; for reactions between cyclic
amines and activated (p-CHO, p-NO2) chlorobenzenes. Un-
fortunately, however, there was deficient temperature con-
trol and no comparison with conventional heating.[9]
[a]
´
´
Laboratoire des Reactions Selectives sur Supports, UMR 8615,
´
Universite Paris-Sud,
ˆ
Batiment 410, 91405 Orsay Cedex, France
Figure 1. Relative stabilization of transition state (TS) and ground
state (GS) by dipoleϪdipole interactions with electromagnetic field
if TS is more polar than GS
Fax: (internat.) ϩ 33-1/69154679
E-mail: aloupy@icmo.u-psud.fr
1278
WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0407Ϫ1278 $ 17.50ϩ.50/0 Eur. J. Org. Chem. 2002, 1278Ϫ1283

Solvent-Free Microwave-Assisted Aromatic Nucleophilic Substitution
FULL PAPER
borderline in nucleophilic substitutions, with possible
competition between electron transfer and SNAr path-
ways.[15,16]
We selected some SNAr cases in which it can be assumed
that the mechanism involves an addition/elimination, and
in which the addition is the rate-determining step
(Scheme 1).[1a,14] This must effectively be the case when a
fluorinated compound is more reactive than a chlorinated
one.
Results
Reaction of the Phenoxide Anion with p-Chloronitrobenzene
The effects of several phase-transfer catalysts, including
tetraalkylammonium salts (Bu4NϩBrϪ
ϭ
TBAB and
MeOct3NϩClϪ
TDA-1,[17] were investigated (Table 1).
ϭ Aliquat 336), a crown ether and
(1)
Scheme 1. Addition-elimination SNAr mechanism
Table 1. Synthesis of 4-nitrophenyl phenyl ether (1) by microwave
irradiation (MW) or by conventional heating in an oil bath (∆)
under otherwise identical conditions
Entry Catalyst
Reaction time
[min]
T
Yield (MW) Yield (∆)
Microwave effects may be dependent on the polarity in-
crease between TS and GS, but also on the position of the
TS along the reaction coordinates.[24b] If it is a reactant-
like TS, as in ‘‘easy’’ reactions, microwave effects should
be lessened. If, however, a product-like TS, for ‘‘difficult’’
reactions is involved, they will be more important. They
might be affected by:
a) Ion-pairing between ROϪ and Mϩ: If tight ion pairs
(involving hard anions, such as CH3OϪ) are involved, modi-
fication of ion pairs in the TS (loose ion pairs) will be
accompanied by a large increase in polarity and therefore a
rather large microwave effect. If loose ion pairs (with soft
anions, such as PhOϪ) are involved, modification in polar-
ity up to the TS will be limited, and microwave effects
should consequently be less important.
[°C] (%)
(%)
1
Ϫ
2
3
5
10
2
3
5
7
2
5
2
5
150 38
24
26
40
64
33
40
60
88
37
61
61
86
2
3
43
57
87
4
5
Aliquat
150 49
71
6
7
84
85
8
9
TDA-1
140 83
87
140 83
93
10
11
12
18-crown-6
The positive effect of catalysts was evident after 2 min
b) Halide effects: Fluoro compounds are much more re-
active than the corresponding chloro derivatives, and con-
sequently need less activation energy. The transition state
therefore occurs early along the reaction coordinates (reac-
tant-like), and so microwave effects could be less effective
than chloro compounds.
(Entries 1, 5, 9 and 11). When the reaction time was ex-
tended to 10 min, though, the yields were essentially the
same even in the absence of catalyst. TDA-1 and 18-crown-
6 appeared to be the most efficient catalysts (Entries 1, 9,
11), while Aliquat 336 required extended reaction times to
give equivalent yields (Entry 7).
c) Aromatic substituent: Electron-withdrawing and acti-
vating groups, such as NO2, should induce a more reactant-
like TS than H would. As some model substrates, we se-
lected 4-nitrophenyl halides and α-naphthyl halides, on the
assumption that specific microwave effects might be in-
creased in the latter case.
When, for comparison with microwave activation (Entry
3), similar reactions were performed at 150 °C with a ther-
mostatted oil bath for the same time interval, with similar
temperature rise profiles (Figure 2) and in the absence of a
catalyst, the yields were only 40%. This suggested the inter-
vention of a specific microwave effect, which also seemed to
However, we have to take into account that the reactivity be of similar intensity in the presence of catalysts (Entries 3,
of naphthalene derivatives may sometimes be considered as 7, 10 and 11).
Eur. J. Org. Chem. 2002, 1278Ϫ1283
1279

M. Chaouchi, A. Loupy, S. Marque, A. Petit
FULL PAPER
TDA-1 was shown to be the most efficient catalyst (Entry
16), presumably because of its high thermal stability.[17] The
best yield obtained after optimization was 90%, after micro-
wave irradiation for 20 min at 170 °C. With conventional
heating (oil bath), the yield was only 37% under similar
conditions and with broadly matching temperature rise pro-
files (Figure 3).
Figure 2. Temperature rise profiles under microwave or classical
heating conditions for the reaction depicted in Equation (1) in the
absence of catalyst (Entry 2)
Reaction of the Phenoxide Anion with p-Fluoronitrobenzene
The reaction was performed in the absence of any cata-
lyst. At 150 °C, we obtained a 98% yield under microwave
conditions and 73% by conventional heating both within
30 s.
Figure 3. Temperature rise profiles under microwave (MW) or clas-
sical heating (∆) conditions for the reaction of Equation (3); cata-
lyst ϭ TDA-1
Reaction of the Methoxide Anion with p-Fluoronitrobenzene
(2)
This reaction needed to be performed in the absence of
a phase-transfer agent in order to prevent denitration,[18]
which was observed even at room temperature in the pres-
ence of TDA-1.
Reaction of the Methoxide Anion with p-Chloronitrobenzene
The effects of the nature of the catalyst were studied un-
der microwave conditions for reactions at 125 °C over
30 min. The key results are given in Table 2.
(4)
Under microwave irradiation conditions, the presence of
a nonpolar solvent (nonane) was essential for accurate con-
trol and constancy of the temperature. A quantitative yield
was obtained within 3.5 min at 80 °C, against only 81% by
conventional heating under the same conditions.
(3)
Reaction of the Methoxide Anion with 1-Chloronaphthalene
Table 2. Synthesis of p-nitroanisole (2); microwave (MW), 125 °C,
30 min
This reaction was studied under microwave irradiation
conditions over a wide temperature range for purposes of
optimization (Table 3).
Entry
Phase-transfer agent
Yield (MW)
(%)
13
14
15
16
Ϫ
38
58
68
78
(5)
18-crown-6
Aliquat
TDA-1
1280
Eur. J. Org. Chem. 2002, 1278Ϫ1283

Solvent-Free Microwave-Assisted Aromatic Nucleophilic Substitution
FULL PAPER
over previous conditions. In general, highly polar solvents
such as DMF, NMP or HMPA have previously been
used.[20] Although the results were sometimes satisfactory,
the problem here lies in the use, cost, purification and re-
moval of these solvents. Polar solvents can therefore ad-
vantageously be replaced by a solvent-free method and the
use of microwave irradiation.
Another classical method consists of the addition of cop-
per salts or copper oxides[21,22] to aromatic bromo com-
pounds in the Ullmann synthesis of aryl ethers by a radical
process. With solvent-free PTC, noticeable improvements
were observed in comparison of microwave-assisted reac-
tions with classical heating. Comparative results for the re-
actions depicted in Equations (1), (4) and (5) are given in
Table 4.
Table 3. Synthesis of 1-methoxynaphthalene (3) under microwave
(MW) conditions [Equation (5)]
Entry
Reaction time
[min]
T
[°C]
Conversion
(%)
Yield (MW)
(%)
17
18
19
20
21
30
30
30
60
90
170
150
120
100
100
100
98
91
80
86
27
38
52
71
74
The best result was obtained at 100 °C (Entries 20, 21)
with a 74% yield of 3 (conversion 86%) and a reaction time
of 90 min. At higher temperatures, conversions were nearly
quantitative (Entries 17, 18) but yields were rather poor (27,
38 and 52% at 170, 150 and 120 °C, respectively), indicative
of secondary or subsequent reactions. Some by-product
formation was observed under these conditions:
Table 4. Solvent-free PTC SNAr reactions
Ϫ α-naphthol, which resulted from a demethylation of 3,
which has already been reported to be favoured under these
microwave solvent-free conditions[19]
Ϫ naphthalene, presumably originating from a radical
mechanism
The same reaction as in Entry 20 (1 h at 100 °C) was
performed under similar conditions but provided only a
27% yield of 3 under classical heating conditions with iden-
tical temperature rise profiles (conversion 41%). Reaction
times were extended to 12 h at 100 °C in the oil bath. Al-
though the degree of conversion was now 90%, the yield of
3 was limited to 69%. It thus appeared that secondary reac-
tions were slightly suppressed under microwave irradiation
conditions, since differences between conversions and yields
were lessened in this case.
Phase-Tansfer Agent Effect
The addition of a phase-transfer agent is highly beneficial
in the case of reactions involving tight ion pairs (with hard
anions, such as CH3OϪ) (cf. Table 2) because it results in
more dissociated and lipophilic species after cation com-
plexation or ion pair exchange with tetraalkylammonium
salts [Equation (7)].
Reaction of the Methoxide Anion with 1-Fluoronaphthalene
The optimal conditions for this reaction were found to
be at 80 °C for 1 h, (conversion and yield of 3 94%). Under
conventional heating conditions, the conversion was 74%
and the yield of 3 only 52%, with some unidentified by-
products. It was also obvious in this case that microwave
conditions afforded purer products than classical heating,
during which some secondary by-products were formed.
(7)
TDA-1 and 18-crown-6 were shown to be the most effici-
ent phase-transfer agents (Tables 1 and 2). Tetraalkylammo-
nium salts could be used under limited conditions, although
these were less thermally stable due to Hofmann degrada-
tion when subjected to rather high temperatures.[23]
(6)
The enhancement was less significant with the ion pair
PhOϪ,Kϩ. The reaction with activated substrates was able
to go to completion even in the absence of catalyst, the soft
anion PhOϪ and the already loose ion pair PhOϪ,Kϩ being
sufficiently lipophilic and soluble in the organic phase (the
aromatic halide) as to promote the reaction.
Discussion
Improvements in the Experimental Conditions in
Comparison with Classical Procedures
When the less reactive naphthyl halides were used, the
The results that we obtained with a solvent-free/micro- addition of a phase-transfer agent was a necessity, as no
wave procedure clearly constitute a noticeable improvement reaction occurred in its absence.
Eur. J. Org. Chem. 2002, 1278Ϫ1283
1281

M. Chaouchi, A. Loupy, S. Marque, A. Petit
Table 5. Comparison between classical heating (∆) and microwave activation (MW) according to the reactions
FULL PAPER
expect that the more polar transition state Ϫ the SNAr one
Ϫ would be favoured under microwave conditions.
Microwave-Specific Effects
Some comparisons between microwave and conventional
heating are summarized in Table 5.
The differences in behaviour can be interpreted by con-
sidering the enhancement in polarity of the system during
the progress of the reaction and in terms of the structure of
the reactants. It appears that specific microwave effects and
their magnitude are clearly dependent on:
Experimental Section
Typical Experiment with Potassium Methoxide: 18-Crown-6 (0.5
mmol, 10%) was added to the aromatic substrate (5 mmol) and
potassium alkoxide (7.5 mmol). The mixture was introduced into
a Pyrex vessel adapted to the microwave equipment (Synthewave
402 monomode reactor from Prolabo) fitted with a mechanical stir-
rer. S402 software permitted programming in time and monitoring
of the temperature by modulation of the power from 15 to 300 W.
Irradiation was carried out according to the conditions indicated
in the Tables. At the end of the reaction, the organic products were
extracted into diethyl ether, and filtration through Celite 545 was
carried out. The products were identified (GC-MS, NMR) by com-
parison with authentic samples and analysed by GC (internal
standard ϭ α-naphthol). Under conventional heating conditions
(thermostatted oil bath), the same conditions were reproduced
(time, pressure, glassware, stirring and identical temperature rise
profiles). Under microwave conditions, the temperature was mon-
itored with an infrared detector and calibrated with an optical fibre
thermometer inside the reaction medium. Under conventional
heating conditions, the temperature was measured with an optical
fibre thermometer inside the medium. With nitro aromatic sub-
strates, only 1.2 equiv. of PhOH/KOH was used. GC conditions,
equipment: GC 6000 Carlo Erba; capillary column: 12QC2/BP1,
12 m, film thickness 0.1 µm; programming temperature: 80Ϫ250
°C, 10 °C/min; carrier gas: helium, p ϭ 0.70 bar.
Ϫ the nature of the reactive ion pairs: (i) In the absence
of catalyst (Entry 23) Ϫ that is, when PhOϪ and Kϩ are
involved Ϫ the microwave effect is more important than
when crown ether is present (Entry 24). This is consistent
with the existence of tighter ion pairs in the first case and,
consequently, with an increase in the magnitude of the en-
hancement of the polarity towards the transition state (TS),
which produces looser ion pairs. In the second case, this
effect with PhOK (crown ether) is decreased because of the
polarity, which remains fairly similar between the ground
state and the transition state. (ii) CH3OϪ,Kϩ (involving a
hard anion) is a tighter ion pair than PhOϪ,Kϩ (soft an-
ion). Modification of the polarity up to the transition state
(loose association), and hence specific microwave effects, is
more important (compare Entries 24 and 26).
Ϫ the substituents on aromatic substrates: (i) The nature
of the halide affects the microwave effect, with Cl Ͼ F (Ent-
ries 22 and 25, 28 and 29), consistently with a TS later
along the reaction coordinates with the less reactive com-
pounds. (ii) The aromatic substituent is responsible for a
stronger microwave effect (Entries 28 and 29) in the case of
nonactivated substrates.
Acknowledgments
As to the relative importance of radical and SNAr path-
ways, we have here some indications that microwave irradi-
ation is preferable to SNAr since it minimizes the amount
of by-products. As far as competitive mechanisms are con-
cerned, starting from the same ground state, one might thus
´
We are especially grateful to Professor Marc Gingras (Universite
de Nice) for fruitful discussions.
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