Microwave role in the thermally induced SRN1 reaction for α-arylation of ketones

Article abstract of DOI:10.1039/c4ra17055e

The coupling between iodobenzene and the enolate anion of acetophenone is accelerated by microwave irradiation. This increase in reaction rate is only ascribed to thermal effects. The coupling reaction gave the corresponding substitution product 1,2-di-phenylethanone in a 50% yield when microwave irradiation was applied between 15-60 s according to the intensity of the pulse. Moreover, this reaction is effective in a temperature window of 70-120 °C. The presence of ionic and dipolar species is not involved in the initiation process as molecular radiators. The excess of tBuOK in the reaction medium may also act as an electron donor helping to generate radicals when the solution temperature increases to 70 °C. This journal is

Full text of DOI:10.1039/c4ra17055e

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Microwave role in the thermally induced SRN1
reaction for a-arylation of ketones†
Cite this: RSC Adv., 2015, 5, 20058
*
*
Daniel A. Caminos, Alexis D. Garro, Silvia M. Soria-Castro and Alicia B. Penenory
˜´˜
The coupling between iodobenzene and the enolate anion of acetophenone is accelerated by microwave
irradiation. This increase in reaction rate is only ascribed to thermal effects. The coupling reaction gave the
corresponding substitution product 1,2-di-phenylethanone in a 50% yield when microwave irradiation was
applied between 15–60 s according to the intensity of the pulse. Moreover, this reaction is effective in a
temperature window of 70–120 ꢀC. The presence of ionic and dipolar species is not involved in the
initiation process as molecular radiators. The excess of tBuOK in the reaction medium may also act as an
electron donor helping to generate radicals when the solution temperature increases to 70 ꢀC.
Received 26th December 2014
Accepted 10th February 2015
DOI: 10.1039/c4ra17055e
www.rsc.org/advances
reduces the effective concentration of the nucleophile and
hinders the purication process. In addition, this methodology
Introduction
provides a simple way to achieve heterocycles such as 1-methyl-
3-phenylindolin-2-one (5) and 2-phenylindol (6) by intra or
intermolecular SRN1 reactions, respectively, in a very fast reac-
tion (Scheme 1B and C). The mechanistic assays showed that
these reactions proceed by an SRN1 mechanism and are ther-
mally induced.4
Under microwave irradiation, two phenomena are respon-
sible for the energy transfer from the electromagnetic micro-
wave to the internal energy of the molecules by rotations and
collisions. These phenomena involve ionic conduction and
dipolar polarization. In the former, the ions move in the
The use of modern microwave heating devices proves valuable
in pharmaceutical and ne chemistry industries offering a
faster and safer synthetic methodology than conventional
heating procedures.1 Thus, the combination of microwave
heating with a process that involves an electron-transfer (ET)
step to generate radical anions and radicals to achieve new C–C
bonds, such as the unimolecular radical nucleophilic substi-
tution or SRN1, is particularly attractive.2 The SRN1 mechanism
is an important route for the synthesis of carbocycles and
heterocycles by ring-closure reactions, such as indol derivatives
with interesting pharmacological properties, and for a signi-
cant number of natural products.3
Recently we report the use of microwave irradiation for the
formation of new C–C bond in the a-arylation of aromatic
ketones and acetamides by the SRN1 mechanism (Scheme 1).4
This was the rst report of microwave-induced SRN1 reaction in
the aromatic system. The microwave-induced reaction showed
as many advantages as those related to simplicity, shorter times
(10 min of microwave irradiation compared with 120 min of
photoirradiation), compatibility with substituents such as CN,
F, OCH3, and a better performance in the intramolecular
formation of 2-oxindol derivatives as compared to photoin-
duced reactions. Accordingly, this process allows the synthesis
of 2-aryl-1-phenyletanones (3) by a-arylation of the enolate
anion of acetophenones (2) with different haloarenes (1)
(Scheme 1A). The main problem under these reaction condi-
tions concerns the enolate/ketone aldol condensation that
´
´
INFIQC, Facultad de Ciencias Quımicas, Universidad Nacional de Cordoba, Ciudad
´
Universitaria, X5000HUA Cordoba, Argentina. E-mail: penenory@fcq.unc.edu.ar;
Web: http://www.fcq.unc.edu.ar/inqc
† Electronic supplementary information (ESI) available: Benzyne mechanism
evaluation by GC-MS and 1H and 13C-NMR spectra of 3f. Yield and temperature
proles at different microwave pulses. See DOI: 10.1039/c4ra17055e
Scheme 1 Microwave induced a-arylation of ketones and acetamides.
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Table 1 Effect of base/nucleophile ratio on 3a yielda
solution by the change in the electric eld orientation; in the
latter, the dipoles try to align through this changing electro-
magnetic eld.5 Both movements and rotations produce an
increase in the collisions of the molecules or ions with their
neighborhood. This increment in the internal energy is located
around the absorbing species (ionic and dipolar) and the focal
point of the microwave. Thus, the so called “Molecular Hot
Spots” could undergo a higher local temperature (high internal
energy) than the pull solution.6 In these radical reactions, the
initiation step is proposed to take place by a thermal microwave-
induced ET.4
Nevertheless other theories imply that initial radical forma-
tion could be generated by the homolytic C–I bond rupture. This
rupture does not come from microwave irradiation itself, but
could be promoted in the “Molecular Hot Spots” or by a selec-
tive heating produced by molecular radiator as ionic species, i.e.
K+, acetophenone enolate anion, tBuOꢁ or the neutral mole-
cules with high dipole moments. With the aim of gaining
insight into the reaction mechanism under microwave irradia-
tion and of eliminating possible controversial issues about the
microwave role in the reaction, we investigate the coupling
reaction between acetophenone enolate anion and PhI at
different microwave irradiation conditions.
Entry
2b
tBuOKb
Base/2
Productc 3a%
Iꢁ (%)d
5
1
2
3
4
5
6
7
3
10
3
3
1.5
3.1
10.1
5
10
5
1.0
1.0
1.7
3.3
3.3
3.0
2.0
55
32
52
40
27
19
25
78
nq
95
87
94
88
76
d
d
nd
d
nd
nd
nd
1
1
3
2
a
Reactions heated to 70 ꢀC by microwave irradiation (150 Wmax) under
N2 atmosphere for 10 min. Nucleophile ¼ acetophenone (2), base ¼
b
tBuOK, and PhI (0.5 mmol) in 2 mL of DMSO. Equivalents relative to
c
d
PhI. Quantied by NMR with internal standard. Determined
potentiometrically using a Ag/Ag(I) electrode. d: detected. nd: no
detected. nq: no quantied.
by further reaction of the phenyl radicals generated in a high
local concentration (Scheme S1, ESI†).7 As mentioned above,
the main reaction side-product 5 derives from the self-
condensation of acetophenone enolate anion.
Deprotonation of acetophenone (pKaDMSO ¼ 24.7)8 by the
tBuOK (pKaDMSO ¼ 32.2)9a is highly favored (K ¼ 5 ꢂ 107); however,
3 equivalents of the base lead to a particularly low amount of
remaining ketone that allows the self aldol condensation process
ꢀ
at temperatures higher than 60 C. In order to avoid this unde-
Results and discussion
sirable side-product, the concentration of tBuOK was increased to
favor equilibrium displacement to anion enolate formation
(Table 1, entries 2 to 5). In the rst attempt, the nucleophile rela-
tion was increased to 10 equivalents, with a similar base/
nucleophile ratio (Table 1, entry 2). A signicant decrease in the
yield of product 3a to 32% was found and side-product 5 was
clearly detected together with traces of unreacted PhI. The best
results were obtained with 5 equivalents of the base (2.5 mmol),
and a base/nucleophile ratio of 1.7 (Table 1, entry 3). In this
condition, side-product 5 was not detected and the nal purica-
tion of the products proves easier than the previous method using
3 equivalents of the base.10 By increasing the concentration of
tBuOK with a base/nucleophile ratio to 3.3, product yield was not
improved (Table 1, entry 4). When acetophenone was reduced to
1.5 eq., but not tBuOK (5 eq.), in a base/nucleophile ratio of 3.3, the
yield of product 3a decreased to 27%; yet, iodide anion reached
94% yield (Table 1, entry 5). A similar behavior was observed for
acetophenone 1 eq. and tBuOK 3 and 2 equivalents with 88 and
76% yield of iodide anion, respectively (Table 1, entries 6 and 7).
These results support the idea of an electron transfer process from
both tBuOꢁ and acetophenone enolate anions.11 Nevertheless,
these anionic species are always present with their cationic counter
ion K+ that could act as an ionic radiator and generate the super-
heated molecular hot spot (see below for a discussion).
Microwave-induced reactions
The reaction between PhI (1a) and the enolate anion of aceto-
phenone (2) was taken as a model to explore the effectiveness of
microwave irradiation as heating method for thermal initiation,
in DMSO (Scheme 2). Table 1 shows the results obtained.
We reported that a mixture of 0.5 mmol of 1a, 3 equivalents
of acetophenone and 3.1 equivalents of tBuOK aer microwave
irradiation at 70 ꢀC for 10 min in DMSO afforded the substi-
tution product 2-phenylacetophenone (3a) in 55% yield, with a
conversion of 78% determined by iodide ion quantication
(Table 1, entry 1).4 A similar result was found at 5 and 30 min.
Increase in time to 30 min or rise in temperature to 100 ꢀC did
not show a substantial increase in the yield of substitution
product 3a; however, an increase in the reduction product was
shown by the higher iodide ion yield. Furthermore, product 3a
proved to be stable under the reaction conditions. Thus, GC-MS
analysis did not show any side-product generated by thermal
decomposition at 70–80 ꢀC under microwave heating for
10 min, and 3a was recovered in 84% isolated yield. All attempts
to detect the reduced product benzene were unsuccessful.4 In
ꢀ
addition, when the reaction temperature exceeded 120 C, the
presence of terphenylenes was detected and a lower yield of 3a
was achieved, Scheme 3. Terphenylenes are probably produced
Scheme 2 Microwave-induced a-arylation of acetophenone with Scheme 3 a-Phenylation of acetophenone enolate anion and side-
phenyl iodide in DMSO.
products.
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We have previously established that the reaction follows an
S
RN1 mechanism,4 based on the presence of radical intermedi-
ates in the reaction assessed by the use of a radical clock12 and
by the inhibition of the reaction in the presence of a strong
electron acceptor like m-dinitrobenzene,3 affording 14% yield of
product 3a and 21% conversion yields.
In order to evaluate whether a benzyne mechanism can
compete with SRN1 in the presence of an excess of base, the
reaction was performed using 0.5 mmol of 4-methyl iodo-
benzene (1f) as substrate with 3 equivalents of acetophenone
and 5 equivalents of tBuOK (Scheme 4). A benzyne mechanism
will afford equal amounts of meta and para 1-phenyl-2-(tolyl)
ethanone 3f. A GC-MS analysis of the organic extract of the
reaction crude showed two signals with m/z 210.10 with a rela- Fig. 1 Reactions under N2 atmosphere heated by microwave irradiation
(150 Wmax) for 30, 10, 5, 3 and 1 min after irradiation. Acetophenone (1.5
mmol), tBuOK (2.5 mmol) and PhI (0.5 mmol) in 2 mL of DMSO. In light
tive integration of 99% (tr ¼ 10.4 min) and 1% (tr ¼ 10.3 min).
Aer purication in a short silica gel column and then by
gray squares, yield of product 3a quantified by NMR with internal standard;
identication and quantication by NMR using an internal
standard, only one product was found. NMR reveals a 42% yield
in dark gray triangle % Iꢁ, determined potentiometrically using a Ag/Ag(I)
electrode. Typical power applied to these experiments from the CEM
of 1-phenyl-2-(para-tolyl)ethanone. Taking into account both discover Microwave reactor in solid black line.
assays we can assume that the meta product represents less than
0.4% (see ESI† for more details). These results indicate that the
way it is possible to reduce the reaction time to less than 1 min.
Nevertheless we speculate that all radical reaction could occur
during the ꢃ22 s microwave pulse with a maximum power of
ꢃ100 W, or in other words, under the application of 1300 J to
the 2 mL reaction mix in DMSO.
S
RN1 mechanism is the main mechanism involved in product
formation.
Reaction time
In our previous reports we observed a slight difference between
5, 10 and 30 min of reaction times (49%, 55% and 54% yields
respectively), and 10 min was selected as standard reaction
condition.4 Now we aim at testing the optimized base/
nucleophile ratio of 1.7 vs. reaction time at 70 ꢀC. Aer
several experiments with microwave heating, any appreciable
difference was found in the yields aer 1, 3, 5, 10 or 30 min at
Microwave applied power
Several tests were performed to establish how the microwave
power inuenced the reaction course. In these experiments a
continuous pulse of a xed power for different times was
ꢀ
applied; the sample reached a temperature higher than 70 C.
Thus over the pulse application, the temperature reached
ꢃ110 ꢀC for the 100 W pulse and ꢃ90 ꢀC for 50 W pulse. When
the microwave pulse ended, the cooling device started and the
temperature slowly decreased to 50 ꢀC (the safe release
temperature from device). This process took approximately 1.3
min, and the reaction lasted 1 min up to 70 ꢀC (Fig. 2), the
temperature set for the reaction to take place.4
ꢀ
70 C (Fig. 1). In these cases, the microwave reactor was set at
ꢀ
150 W maximum, 70 C and the corresponding selected time.
Hence, in the “dynamic mode”, the equipment applies a pulse
to reach the setting temperature. Once the reaction reaches
70 ꢀC, the timer starts countdown and then, sometimes, ꢃ1 W is
applied to maintain temperature at 70 ꢀC. Fig. 1 shows the
typical power curve (black solid line) applied for reactions at 1,
3, 5, 10 and 30 min. Notice that similar yields of 3a (light grey)
and iodide anion (dark gray) were achieved in all cases. In this
A proportional relation between power and temperature
increase was obtained using 30 second pulses (Fig. 3, red dots
Scheme 4 Test for benzyne mechanism using 4-methyl iodobenzene
(1f). The benzyne mechanism affords equals amounts of meta and para Fig. 2 Comparison of temperature (red) and power (black) profiles for
products 3f, while SRN1 mechanism gives ipso-substitution, with dynamic mode heating (solid) and experiments at fixed power at 50 W
formation of only 3f-para product.
(dash) and 100 W (dots).
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line). When we applied more than 50 W by 30 seconds, or
1500 J to 2 mL DMSO, temperature increased but the yield of
product 3a, decreased, probably due to thermal decomposi-
ꢀ
tion at more than 140 C. In these conditions terphenylenes
were also found. On the other hand, the dehalogenation was
near to quantitative at 1500 J for 2 mL reaction. At 25 W the
temperature reached almost 50 ꢀC, and a low yield for 3a and
Iꢁ was found.
With the aim of determining whether the yield of coupling
product 3a was related to temperature or power applied, the
model reaction was tested with xed pulses of 100, 50, 25 and
10 W, by different times (Fig. 4, and S2 in the ESI†). It is
noteworthy that 3a yield is always near ꢃ50% when the
microwave energy applied is 1500 J, similar to the ꢃ1300 J
applied in the xed 70 ꢀC experiments. In each case when the
reaction temperature exceeded 120 ꢀC, the yield of 3a
decreased; however if the reaction did not reach 70 ꢀC, the
yield was much lower than 50%. These results suggest that
the reaction conversion depends more on the temperature
reached than in the microwave pulse intensity. It should also
not exceed 120 ꢀC to avoid thermal decomposition of the
product and side reactions.
The model reaction was then studied by varying the micro-
wave irradiation method in order to establish a relation between
the energy and the yield of 3 (Table 2). A comparison between
the different irradiation methods did not show a clear relation
with the energy applied. It should be noted that total energy
refers to the emitted pulse by the reactor, and not to the accu-
rate microwave energy absorbed. The total energy applied to
reach 70 ꢀC depends on the reaction volume used. As
mentioned before, in the dynamic mode, all samples received
between 1000–1859 J; yet, this did not depend on the full reac-
tion time. The total energy was commanded by the IR temper-
ature sensor to modulate the microwave power applied.
However, in all cases 70 ꢀC were achieved and the yields of
product 3a and Iꢁ were similar (Table 2, entries 1–4).
Fig. 4 Yield and temperature profiles in the coupling reaction of 0.5
mmol PhI, 1.5 mmol acetophenone and 2.5 mmol tBuOK heated by
microwave with pulses of 50 W vs. time. Blue squares (-), product 3%
yield, quantified by NMR with internal standard, % Iꢁ determined
potentiometrically with Ag/Ag+ in green :, and temperature by IR
sensor inside the CEM Discover reactor in red C, doted lines indicate
1500 J point.
reproducible assays was selected. Using similar microwave
energy of 1500 J, independent of intensity and time pulse irra-
diation, the reaction gave the same global results (Table 2,
entries 5–8).
The same reaction model carried out at 70 ꢀC in sealed tubes
heated by regular oil bath, pre-heated to 70 ꢀC bath, aer 10, 30
and 60 min, revealed for product 3a yield of 23, 33 and 50%
respectively (Table 2, entries 9–11). As observed in our previous
report no pressure effect was noted, because the reaction
carried out at 1 atm gave similar results.4ꢀ
Apparently at temperatures up to 70 C, 50% of product is
the maximum obtained by thermal initiation. Fig. 5 shows a
collection of several experiments running with different
microwave methods. In those cases when temperature reaches
70 ꢀC, the coupling yields are near 50%. Lower temperatures
produce the decrease of product yield and temperatures higher
Considering that some problems with the IR temperature
sensor were previously reported,13 a power x method for more
Table 2 Comparison between the reactions heated in an oil bath at
70 ꢀC and with microwave under different irradiation methodsa
P (W) E (J) tI (s) tR (min) Tmax (ꢀC) 3ac% Iꢁ (%)d
b
Ent Method
1
2
3
4
5
6
7
8
9
Dynamic
Dynamic
Dynamic
Dynamic
Fixed power 100 1500 15
Fixed power 50 1500 30
Fixed power 25 1500 60
Fixed power 10 1200 120
105e 1187 22
100e 1215 21
90e 1000 23
1
3
5
88
84
81
98
110
99
114
100
70f
70f
70f
52
52
45
52
49
48
49
53
23
33
50
87
95
86
95
97
89
87
100
49
58
110e 1859 21 10
1
1
1
1
Oil bath
F
F
F
10
30
60
10 Oil bath
11 Oil bath
100
a
For the coupling reaction of PhI (0.5 mmol) and 3 eq. acetophenone,
5 eq. tBuOK in 2 mL DMSO. P: power. E: energy. tI: irradiation time.
Fig. 3 Reaction yields and temperature variation vs. applied micro-
wave power for 30 seconds. Yield of product 3a (%) in blue squares (-)
quantified by NMR with internal standard, in green (:) % Iꢁ determined
potentiometrically with Ag/Ag+ and in red dots (C), maximum
temperature reaction determined by IR sensor of the CEM Discover
reactor.
b
tR: reaction time. Temperature measured by IR sensor inside the
c
CEM Discover reactor except, unless otherwise indicated. Product
d
3a% yield, quantied by NMR with internal standard.
%
Iꢁ
determined potentiometrically with Ag/Ag+. Maximum power setting
150 W. Temperature determined by standard lab thermometer.
e
f
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As mentioned before, the maximum yield achieved for this
reaction is ꢃ50%, due to a competitive reduction to benzene
of Ph radicals mediated by the solvent.4 Nevertheless, there
were some doubts about whether microwave irradiation itself
could promote radical formation in this kind of reactions. Is
it another case of no-thermal microwave effect? In our
previous work, PhI was thermally stable under 10 min of
microwave irradiation in DMSO at 70 ꢀC (dynamic mode),
neither benzene nor iodide ions were detected in those
conditions (Table 3, entry 1).4 Similar results were observed
with irradiation at 1 min at 100 W by 15 seconds (Table 3,
entry 2). This fact allows concluding that homolytic rupture
of the CPh–I bond (67 kcal molꢁ1
)
is not the radical initia-
15
Fig. 5 Product 3a yield vs. maximum temperature reaction distribution
in the coupling reaction of 0.5 mmol PhI, 1.5 mmol acetophenone and
2.5 mmol tBuOK heated by microwave. Product 3a% yield (-), quan-
tified by NMR with internal standard. The blue rectangle indicates the
70–120 ꢀC temperature window with ꢃ50% yield of 3 and ꢃ90% of Iꢁ.
tion process. Nevertheless, since PhI and the solvent DMSO
have similar dipolar moments (1.8 D), it is possible to
consider that both should have a similar microwave absorp-
tion (in fact it should be necessary to compare tangent loss;6
yet, they are not accessible for all the species involved); in
addition, in this case there are no ions in the solution to
promote the superheated “molecular hot spot”. In the model
reaction there are various species with high dipolar moment
that can act as stronger microwave absorber than DMSO
(Fig. 6). The tBuOꢁ has a dipolar moment of 3.95 D (ref. 16)
and acetophenone enolate anion has an average dipolar
moment of ꢃ8.8 D, considering their resonance forms.
Alternatively, the potassium cation K+ in the solutions could
be a strong absorber (by ionic conduction), generating the
molecular superheated hot spots or receiving a selective
microwave heating in relation to the solvent surround.
Taking this into account, some tests were conducted. The
microwave irradiation of a solution of 0.5 mmol of PhI and 2
mmol of tBuOK in 2 mL of DMSO in the absence of aceto-
phenone aer 1 min produced dehalogenation at ꢃ85%
yield, even when the assay was carried out at 70 or 100 ꢀC
(Table 3, entries 4 and 5). When 2 equivalents of KCl or NaCl
were used, Iꢁ was not found as product by ET dehalogenation
of PhI. Potentiometric titration showed only ꢃ2 equivalents
of Clꢁ with a maximum temperature of 97 ꢀC and 87 ꢀC,
respectively (Table 3, entries 6 and 7). These experiments
suggest that the ionic species K+ (or Na+) and Clꢁ help the
ꢀ
than 120 C affect product yield by thermal decomposition. A
similar correlation of yield vs. energy makes a more disperse
plot (data not shown).
Reaction initiation
Another important issue involved in the reaction mechanism is
the initial radical formation step (Scheme 5). In the initiation
reaction, a dissociative ET from the present anions tBuOꢁ or the
enolate anion of acetophenone 2 to PhI generates Ph radical
and Iꢁ anions. The radical Ph goes into the chain reaction and
aer coupling with the nucleophile acetophenone enolate
anion, a new C–C bond is generated affording the radical anion
of 2-phenyl-1-phenyletanone. Then, this radical anion species,
by another ET to PhI, gives product 3a and regenerates the Ph
radical to continue the chain reaction.14
ꢀ
heating process of the solution to raise temperature to 97 C
aer 15 s of irradiation at 100 W; however, they are not able to
initiate the reaction. In addition, when PhBr was employed,
the experiment at 70 ꢀC produced 27% yield of Brꢁ,
ꢀ
increasing to 86% at 100 C, (Table 3, entries 8 and 9). With
MeCOSK, a comparable result was found under similar irra-
diation conditions. In this reaction the solution reached a
higher temperature (125 ꢀC) due to the MeCOS-dipole of 4.60
Debye, making it a microwave absorber stronger than tBuOꢁ.
These results are compatible with the general reactivity
pattern of aryl halides in the SRN1 mechanism.3a In this
reaction, the source of initiating electrons could be the
nucleophile itself, which transfers an electron to the PhI to
generate Ph radical and Iꢁ by a dissociative ET.17,18 In these
assays the MeCOSꢁ anion was unable to transfer an electron
like tBuOK,19 and the radical reaction did not take place
because of lack of the initiation step. Any presence of iodide
Scheme 5 Main reaction mechanism. For the inter molecular thermal
SRN1, accelerated by microwave heating.
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Table 3 Dehalogenation under microwave irradiationa
Entry
X
Method
Eq. Base
Time min
Temp ꢀ
C
% Xꢁb
1c
2
I
I
I
I
I
I
I
Br
Br
I
I
I
I
I
I
Dynamic
Fixed power
Dynamic
Dynamic
Dynamic
Fixed power
Fixed power
Dynamic
—
—
10
1
10
1
1
1
1
1
1
1
70
89
70
70
100
97
87
70
100
125
103
65
0
0
3c
4
3.1 tBuOK
2 tBuOK
2 tBuOK
2 KCl
80
82
86
0d
0d
27
86
0e
44f
0
5
6
7
8
2 NaCl
2 tBuOK
2 tBuOK
2 MeCOSK
2 K+, –CH2COCMe3
2 DBU
2 DABCO
2 KCO3
2 KPO3
9
Dynamic
10
11
12
13
14
15
Fixed power
Fixed power
Fixed power
Fixed power
Fixed power
Fixed power
1
1
1
1
67
65
68
0
0
0
1
a
Reaction of 0.5 mmol PhX in 2 mL DMSO with different salts as ionic species in the medium. b Determined potentiometrically using an Ag/Ag(I)
electrode. c From Soria-Castro et al. ref. 4. d 90% of Clꢁ anions. e PhI was detected as the only organic product by GC-MS. f With 21% yield of the
coupling product with enolate anion of pinacolone.
pinacolone (pKa ¼ 27.7)7 to ensure the presence of only
pinacolone enolate anion and tButanol (K ¼ 31.6 ꢂ 103), the ionic
and dipole species helped the heating process (Tmax 103 ꢀC), but
the initiation was poor compared with the reaction being per-
formed by adding an excess of tBuOK.
Other organic bases like DBU and DABCO were employed as
possible electron donors in the initiation step (Table 3, entry 12
and 13). Aer heating at 100 W, the temperature reaches 65 ꢀC
and 67 ꢀC, respectively, without producing any halogen release.
These results are expected if we considered their dipolar
moments of 0.0009 for DABCO, and 3.21 for DBU (Fig. 6). The
last is similar to tBuOꢁ but without the presence of K+ counter
ion that helps to the heating process. It is important to note that
neutral bases like DBU (pKaDMSO 12)9c and DABCO (pKaDMSO
2.97, 8.93),9c are unable to deprotonate the acetophenone to
generate the enolate anion.
Finally, the inorganic bases potassium carbonate and
phosphate were also checked (Table 3, entries 14 and 15,
respectively). In these examples, cations and anions are present
in the reaction mix. In principle, these salts are insoluble in
Fig. 6 Dipolar moment of the present species in the reaction solution.
DMSO, but under microwave heating, the solubility would be
increased, and the free ions could help to the heating process.
Although, for these experiments any traces of dehalogenation
were observed, indicating that no ET initial step could be
promoted by these bases.
At this point, it is difficult to think of some case of a multi-
photonic process in the initial substrate excitation to promote
radical formation, because the electromagnetic microwave does
not have the necessary energy to break chemical bonds.6 The
required energy jump to break covalent bonds is just so far for
The values were calculated with GAMESS: Compute Properties RHF/3-
21G.
anion was detected and GC-MS analysis also revealed
unreacted PhI as the only species present in the organic layer
aer reaction extraction. Next, the enolate anion of pinaco-
lone was tested as entrainment reactive to initiate the reac-
tion.3a When PhI was irradiated in the presence of 2
equivalent of tBuOK (pKa ¼ 32.2)8 with an excess of
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these microwave photons. Non radiative process must be
involved in the increase of internal energy of the reactive
molecules. Microwave irradiation only accelerates the heating
process efficiently, but no mysterious or magical microwave
effects take place.
This conclusion is in total agreement with that recently
reported by Kappe, considering that several no-thermal micro-
wave effects are related to errors in the temperature measure-
ment in the core reaction, leading to misinterpretation of
results.13
Experimental section
Chemicals
Potassium tert-butoxide (tBuOK), iodobenzene, bromobenzene,
acetophenone, 4-methyl iodobenzene were all high-purity
commercial samples used without further purication.
DMSO absolute grade was used without further purication
and stored over molecular sieves (4 A).
The ketone enolate anion was generated in situ by acid–base
deprotonation using tBuOK.
˚
It is possible to conclude that the increment in tempera-
ture or in the internal energy of the system by the presence in
excess of tBuOꢁ or the nucleophile under microwave irradi-
ation or another heating method could provide the necessary
energy to favor electron transfer from the donors to the ArI.19
Thus, ET from the nucleophile or tBuOꢁ to ArX is produced
by a thermal effect. The microwave is a more efficient heating
method than conventional heating, and the decrease in
reaction time from 60 min to 15 seconds for an oil bath is
remarkable.
General methods
1H and 13C NMR spectra were recorded at 400.16 and 100.62
MHz respectively on a 400 spectrometer, and all spectra were
reported in d (ppm) relative to Me4Si, with CDCl3 as solvent. Gas
chromatographic analyses were performed with a ame-
ionization detector, on 30 m capillary column of a 0.32 mm ꢂ
0.25 mm lm thickness, with a 5% phenylpolysiloxane phase.
GC-MS analyses were performed employing a 25 m ꢂ 0.2 mm ꢂ
0.33 mm with a 5% phenylpolysiloxane phase column. HRMS
spectra were recorded on a GCT Premie orthogonal acceleration
time-of-ight (oa-TOF) GC mass spectrometer. Ionization was
achieved by electronic impact (70 eV) and detection set up
positive mode.
Conclusions
The use of modern microwave heating devices proves valuable
in ne and pharmaceutical chemistry offering a faster and safer
synthetic methodology. In this report we studied the process
leading to new C–C bonds by a-arylation of aromatic ketones
Representative Experimental procedure
and by SRN1 mechanism under microwave irradiation at The reactions were carried out in a 10 mL CEM Discover
moderate temperatures. The initiation step is proposed to take microwave glass vessel, lled with nitrogen and a magnetic
place by a thermal microwave-induced ET.
stirrer. The tube was dried under vacuum, lled with nitrogen,
The main disadvantage of microwave-initiated reaction is and then charged with dried DMSO (2 mL) and degassed. For
the competitive reduction observed for the intermolecular the a-arylation of the haloarene, tBuOK (280 mg, 2.50 mmol),
process. Consequently, the best substitution yields were about acetophenone (1.5 mmol) and aryl halide (0.5 mmol) were then
50%. On the other hand, microwave-induced reaction shows as added to the degassed solvent under nitrogen. The reaction
many advantages as simplicity, particularly shorter times, 15 s tube was subsequently heated by microwave irradiation.
of microwave irradiation (plus 1 min to release the sample)
compared with 120 min photoirradiation. The ionic and neutral mode instrument equipped with
Microwave-induced reactions were performed in a single
noncontact infrared
a
molecules with high dipolar moment in the reaction media temperature sensor, direct pressure control system for
could allow a faster heating rate in comparison with that in pure measuring the pressure of the reaction vessel contents and a
DMSO solvent under microwave. Yet, neither participates in the cooling system by compressed air. Two methods were used. In
reaction as catalyst or radical generators initiating the SRN1 the rst method a temperature controlled reaction at 70 ꢀC, with
mechanism. The higher yield was obtained in the 70–100 ꢀC a maximum power of 150 W. Although the maximum micro-
temperature window. 70 ꢀC is required to promote the initial ET wave power was set at 150 W, aer the initial heating pulse for
from the nucleophile or tBuOꢁ; however, if temperature exceeds 30 s of maximum 100 W, the average power applied was about 1
ꢀ
120 C, the thermal decomposition of substrates and reactives W to keep the selected temperature. Alternatively, the sample
decrease average yields. The use of lower power does not vessels were irradiated by microwave at different power settings
improve product yield and extends reaction time.
(100, 50, 25, 10 W) and time (10, 15, 20, 30, 60, 75 seconds) as
Nevertheless, the intramolecular reaction accelerated by indicated, and temperature was recorded by the internal IR
microwave irradiation affords good yield and presents a good sensor. Aer the selected irradiation, the device cooled the tube
alternative to photoinduction. The methodology of microwave- to 50 C with compressed air above 1 min (ꢁ0.5 C sꢁ1). The
induced ET could be applicable to other SRN1 examples, average pressure was 1.7 atm in the vessel during the reaction
mainly in the intramolecular ring closure and in other reactions time. Aer completion of the reaction, the vessel was removed
involving radical rearrangement as well as the addition of from the microwave cavity and opened to the atmosphere. The
radicals to neutral molecules and Homolytic Aromatic Substi- reaction was subsequently quenched by addition of water (30
tution (HAS) reactions.20 Comparative study between photoin- mL) and NH4NO3 in excess, and the mixture was extracted with
duction and microwave in different SRN1 ring closure reactions CH2Cl2 (3 ꢂ 20 mL). The combined organic extract was dried
ꢀ
ꢀ
is in progress in our lab.
over anhydrous CaCl2, and the products were quantied by GC
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or NMR by the internal standard method. Water layer was
recovered to quantify halide ions by potentiometric titration
with an AgNO3 standard solution.
D. E. Emmerte Id, Presented at the Richmond meeting of the
American Chemical Society, April, 1928.
8 W. S. Matthews, J. E. Bares, J. E. Bartmess, F. G. Bordwell,
F. J. Cornforth, G. E. Drucker, Z. Margolin, R. J. McCallum,
G. J. McCollum and N. R. Vanier, J. Am. Chem. Soc., 1975,
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328lecture2-evanspka_tables.pdf.
Products characterization
All the products in Table 2 were obtained following the general
procedure, quantied by NMR or GC. Products 3a and 3f are
known compounds and present spectral data as shown in the
literature, in agreement with the structures proposed. 1,2-Di-
phenylethanone (3a);21 1-phenyl-2-(para-tolyl)ethanone (3f).22
10 Surprisingly, with this base/nucleophile ratio, the
equilibrium calculations suggest that the concentration of
free acetophenone in the presence of 5 equivalents of
tBuOK is around 0.749999977 M instead of 0.749999887 M
with 3 equivalents of tBuOK, a difference of 1.2 ꢂ 10ꢁ7 M.
Acknowledgements
This work was supported by Consejo Nacional de Inves-
´
´
tigaciones Cientıcas y Tecnicas (CONICET) and Agencia
´
´
´
Nacional de Promocion Cientıca y Tecnica (ANPCyT), Minis-
˜´˜
¨
11 L. C. Schmidt, J. E. Arguello and A. B. Penenory, J. Org.
´
´
terio de Ciencia y Tecnologıa de la Provincia de Cordoba,
Argentina and SECyT-UNC. A.B.P. and D.A.C. are researchers
from CONICET. S.M.S–C gratefully acknowledges the receipt of
a fellowship from CONICET. Authors thank Fabrizio Politano
for discussion and Willber-Castro-Godoy for assistance.
Chem., 2007, 72, 2936–2944.
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12 J. I. Bardagı, S. E. Vaillard and R. Rossi, Tetrahedron Lett.,
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13 C. O. Kappe, Chem. Soc. Rev., 2013, 42, 4977–4980.
14 For PhI, it was proposed that the ET is concerted with the
fragmentation of the C–I bond generating Ph radical and
iodide anions. See ref. 3.
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RSC Adv., 2015, 5, 20058–20065 | 20065