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G. Cravotto, A. Procopio, M. Oliverio, L. Orio, D. Carnaroglio, Green Chemistry, 2011, 13, 2806-2809.
G. Cravotto, A. Procopio, M. Oliverio, L. Orio, D. Carnaroglio, Green Chemistry, 2011, 13, 2806-2809.
G. Cravotto, A. Procopio, M. Oliverio, L. Orio, D. Carnaroglio, Green Chemistry, 2011, 13, 2806-2809.
Green Chemistry
PAPER
www.rsc.org/greenchem
Introduction
The reaction discovered by Victor Grignard at the beginning
of the XXth century still plays a relevant role in organic and
organometallic synthetic chemistry. The activation of magnesium turnings for the preparation of organomagnesium halides
(the Grignard reagent) and the subsequent initiation of the
Grignard reaction still makes for a tricky procedure during
which chemists moderately heat iodine, 1,2-dibromomethane or
TMSCl in freshly distilled ethereal solvents1 or toluene2 under
dry argon or nitrogen. Although several investigations have
tried to replace tetrahydrofuran (THF),3 it remains the solvent
of choice because of its high Mg2+ coordinating capacity and
ability to stabilize the products. Practical limitations and safety
concerns have emerged from its use in industrial applications due
to the large amount of heat released during the initiation step in
low-boiling point media. Traces of impurities can react strongly
with the Grignard reagents, and process control under reux
conditions is difcult to maintain.4 Different metallic magnesium chip sizes and forms have been tested,5 under chemical,5,6
mechanical7 and sonochemical8,9 activation. Hulshof et al. have
studied the inuence of microwave (MW) irradiation on metallic
magnesium,10,11 and showed that this method can produce a
surface which is just as accessible as the one obtained via the
use of an initiator. Mass-transport and kinetics are strongly
favored by MW irradiation at these interfaces between solid and
a
Dipartimento di Scienza e Tecnologia del Farmaco, via P. Giuria 9,
10125, Torino, Italy. E-mail: giancarlo.cravotto@unito.it
b
Dipartimento di Scienze Farmacobiologiche, Viale Europa, Loc.
Germaneto, 88100, Catanzaro, Italy
Scheme 2 One-pot power US-assisted Grignard formation and reaction with benzophenone.
Entry
2 Power US bath
(200 W, 19.6 kHz)
T = 40 C
3 US Cup Horn
(100 W, 20 kHz) T =
45 C
4 US Cup Horn
(200 W, 300 kHz)
T = 45 C
5 Multimode MW
(165 W) T = 65 C
Time
(min)a
Conv
(%)
Yield Time
(%)
(min)a
Conv
(%)
Yield
(%)
Time
(min)a
Conv Yield
(%)
(%)
Time
(min)a
Conv Yield
(%)
(%)
20 (5)
100
100
20 (10)
100
100
20 (10)
100
100
20 (7)
100
100
10 (2)
100
100
240
(120)
285 (45)
240b
90 (30)
30 (10)d
50c
100
15
100
60 (30)
100
100
15 (5)
100
71c
25 (10)
100
100
20 (5)
100
100
20 (5)
100
100
20 (5)
100
100
10 (2)
30 (5)
100
100
80c
95d
180
180
120e , f , g
1c
<1
180
60 (5)
180
180
180
30 (5)e
65
50
10 (5)
100
100
60 (30)
18
17
Total reaction time. Activation time is reported in parentheses. b Reaction carried out at 10 C. c A signicant percentage of Wurtz-tipe side products
were detected. d Reaction carried out in standard conditions (reux) without MW irradiation. e Reaction carried out at 80 C. f Reaction carried out
in solvent-free conditions and in the presence of 2.5 eq of Mg. g Reaction carried out directly in the cup horn cavity.
Product
Time (min)
Conv (%)
Yield (%)
1
2
3
1ba
3b
5b
5
10
10
98
100
92
94
98
84
Conclusions
In this work we have reported the rst comparative study of
Grignard reactions using several physical activation techniques;
high-intensity US using different frequencies and reactors and
MW irradiation.
The reactions were monitored following the formation of
the organomagnesium halides and their subsequent addition
to benzophenone. Under such sonochemical conditions we
optimised yield, reaction times and process reproducibility. The
milder, safer conditions and its ability to be scaled up were the
main advantages of this efcient 300 kHz protocol over the MWassisted procedure.
Acknowledgements
Experimental
Materials
All the chemicals were obtained from commercial sources and
used without further purication. THF was freshly distilled
before each experiment. Reactions were monitored by TLC
on Merck 60 F254 (0.25 mm) plates, which were visualized by
UV inspection and/or staining with 5% H2 SO4 in ethanol and
heating.
MW-promoted reactions were carried out in a professional
oven, Microsynth - Milestone (Italy); this was also used for
combined MW/US irradiation after a probe equipped with a
R horn was inserted into it.
Pyrex
Gas chromatographymass spectrometry (GC-MS) analyses
were carried out with a gas chromatograph Agilent 6890
(Agilent Technologies - USA) tted with a mass detector Agilent
Network 5973, using a 30 m long capillary column, i.d of 0.25
mm and lm thickness 0.25 mm. NMR spectra were performed
on Bruker 300 Advance spectrometer (300 MHz and 75 MHz
for 1 H and 13 C, respectively).
Description of the sonochemical instruments
The high-power US-bath (19.6 kHz)22 and cup horns for
irradiation at 2023 and 300 kHz23 were made by Danacamerini
(Torino) in collaboration with the corresponding authors group
and are commercially available. An Elma TS540 cleaner bath
operating at 35 kHz was used to provide some comparison of
sonication effects.
US 300 kHz general procedure
366 mg (15 mmol, 1.5 eq) of Mg chips, 3 mL of dry THF
and 1 mmol (0.1 eq) of aryl halide were added to a dry,
one neck, round bottom ask. The mixture was sonicated
(water bath temperature: 55 C) under a nitrogen atmosphere
until activation, then another 9 mmol (0.9 eq) of aryl halide
were added and the mixture was sonicated until completion
(reaction monitored by TLC, work up with NH4 Cl/diethyl
ether). For product 3a, bromobenzene was added dropwise to
avoid the formation of Wurz-type side products. A sample of the
solution was quenched with saturated NH4 Cl solution, extracted
with diethyl ether and analyzed by GC-MS. We calculated
the ratio starting material/Grignard reagent on the base of
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