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Herein, we describe the solvent-free ball milling Tishchenko reaction. Using high speed ball
milling and a sodium hydride catalyst, the Tishchenko reaction was performed for aryl aldehydes
in high yields in 0.5 hours. The reaction is not affected by the type of ball bearing used and can be
successful when conducted in a liquid nitrogen environment.
This journal is © The Royal Society of Chemistry 2009 Green Chem., 2009, 11, 79–82 | 79
Table 1 Tishchenko reaction of aryl aldehydes using 10% sodium Table 1 (Contd.)
hydride catalyst
Time
Time Entry Substrate (hrs) % Conversion % Yield TOF
Entry Substrate (hrs) % Conversion % Yield TOF
13 2 >99 93 2.5
1 2 >99 91 2.5
2 0.5 >99 92 10
14 16 >99 97 1
3 0.5 >99 98 10
80 | Green Chem., 2009, 11, 79–82 This journal is © The Royal Society of Chemistry 2009
conducted with brass and stainless steel balls (~99% conversion). Conclusions
This suggests at least for this particular reaction that the shaking
of the vial has enough energy to make an amorphous mixture of In conclusion, we report an environmentally benign method
the reagents to provide a chemical reaction even without a ball! for the Tishchenko reaction using solvent-free ball milling
On very large scale, ball milled reactions can generate a conditions. We used sodium hydride as the catalyst instead of the
signifigant amount of heat, thus we wanted to conduct these more traditional aluminum catalyst which allowed the reaction
reactions in the Spex Certiprep freezer mill in a liquid nitrogen to procede in high yield and short reaction times. We discovered
environment to determine the feasibility of the reaction under in this particular reaction the type of ball used has little to
low temperature conditions. Using our typical conditions, no affect on the yield or rate of the reaction and the reaction
p-chlorobenzaldehyde and sodium hydride was placed inside a proceeded equally well without the addition of a ball. We also
reaction vial and cooled to -196 ◦ C. The reaction was milled observed the ball milled Tishchenko reaction can take place
for 30 minutes at which point it was allowed to warm to while the vial is immersed in a liquid nitrogen environment.
room temperature. 1 H NMR and GC-MS both confirmed the Currently, we are in the process of creating a magnesium vial
presence of the expected dimeric ester of p-chlorobenzaldehyde that is expected to act as the catalyst as well. Ball milling is a
(~5% yield). This demonstrates the ability to conduct ball milling novel method for conducting organic reactions. With a better
experiments in a low temperature environment which would understanding of how these reactions procede we will be able to
allow this process to be implemented with highly exothermic make significant strides in the development of various solvent-
reactions. free reactions.
In an attempt to avoid handling sodium hydride, we wanted
to generate our catalyst in situ. Sodium formate is known under Experimental
certain condtions to break down to sodium hydride and carbon
All NMR spectra were recorded on a Bruker Avance 400 spe-
dioxide.26,31,32 We thought we could use sodium formate, which is
ctrometer. Deuterated NMR solvents were obtained from
safe and very easy to handle as a direct precusor to the sodium
Cambridge Isotope Laboratories, Inc., Andover MA, and used
hydride catalyst. Unfortunately, after ball milling benzaldehyde
without further purification. p-bromobenzaldehyde, p-chloro-
and sodium formate for 16 hours we saw no evidence of the
benzaldehyde, p-anisaldehyde, benzaldehyde, p-tolualdehyde,
desired dimeric ester. It has been shown that various metal
p-(methylthio)benzaldehyde, m-anisaldehyde, napthaldehyde,
catalyst can facilitate the disproportation of sodium formate
2-thiophenecarboxaldehyde and sodium hydride were purchased
to sodium hydride and carbon dioxide.33–36 We tested whether
from Acros Organics and used without further purification. m-
a combination of catalytic sodium formate (10 mol%) and
Fluorobenzaldehyde, m-tolualdehyde and 1,2-phthalic carbox-
palladium tetrakistriphenylphospine (1 mol%) would lead to
aldehyde were purchased from Sigma-Aldrich and used without
the generation of the sodium hydride catalyst. Using this mixture
further purification. Ball milling was carried out in a 8000M
along with benzaldehyde we were able to generate trace amounts
SpexCertiprep Mixer/Mill. Ball milling under a liquid nitrogen
of benzyl benzoate after milling for 44 hours (Scheme 3).
was carried out in a 6750 SpexCertiprep Freezer/Mill. Ball bear-
ings were purchased from Small Parts incorporated. Custom
made vials were made by the machine shop at the University of
Cincinnati with metal rods purchased from ESPICorp Inc.
Typical procedure
Scheme 3 Generation of sodium hydride catalyst from sodium formate Benzaldehyde (0.22 g, 2.07 mmol), and sodium hydride (0.004 g,
and palladium tetrakistriphenylphosphine. 0.2 mmol) were added to a custom-made 2¢¢ by 1/2¢¢ screw
capped stainless steel vial along with a 1/8¢¢ inch stainless steel
ball bearing. The vial was placed in an 8000M Spex Certiprep
In addition to sodium hydride, we also investigated other mixer/mill and the contents were ball milled for 0.5 h. The
benign catalysts that could give high yields of the Tishchenko resulting mixture was dissolved in methylene chloride28 (15 mL)
reaction using ball milling conditions. Ball milling benzaldehyde and washed with 10% HCl (15 mL). The organic layer was dried
with catalysts such as lithium bromide and calcium oxide over anhydrous MgSO4 and the solvent was evaporated under
did not provide the desired dimeric ester but rather gave reduced pressure. This afforded benzyl benzoate in > 98% yield.
unreacted starting material. We custom made vials out of nickel
and molybdenum to investgate if these metals would lead to
Tishchenko products, however, neither of these gave the dimeric
Notes and references
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2003.
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82 | Green Chem., 2009, 11, 79–82 This journal is © The Royal Society of Chemistry 2009