Tetrahedron Letters
Conducting moisture sensitive reactions under mechanochemical conditions
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Daniel C. Waddell, Tammara D. Clark, James Mack
University of Cincinnati, 301 Clifton court, Cincinnati, OH 45221-0172, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 February 2012
Revised 1 June 2012
Accepted 4 June 2012
Available online 18 June 2012
Dry organic solvents are used for various organic reactions that employ moisture sensitive reagents. The
processes to dry these solvents are hazardous and costly. Setting up reactions in an open atmosphere
while using moisture sensitive reagents has little to no effect on the rate or yield of the reaction under
mechanochemical conditions. We believe this is partly due to the gaseous nature of the water vapor in
the air compared to the dissolved water and oxygen in solution.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Green chemistry
Solvent-free synthesis
Ball milling
Mechanochemistry
Solid state
Introduction
time is costly. According to a study conducted at the University
of California-Santa Barbara, it was concluded that it costs $5053
Reactions that employ moisture and oxygen sensitive reagents
are typically conducted using dry organic solvents in an inert
atmosphere. The inert atmosphere is typically achieved by bub-
in the first year to set up a solvent still and $2487 to maintain that
still in subsequent years. Additionally, they compared these meth-
ods against joining a purification program where solvents are puri-
fied off-site and delivered to the institution. Purification of solvents
using this method has a first year cost of $11,117 and $6050 in sub-
1
bling an inert gas such as nitrogen or argon through a solvent. Gi-
ven the abundance of nitrogen gas in the atmosphere, creating an
oxygen-free reaction environment is routine and can easily be
done at the undergraduate level; obtaining dry organic solvents
however, is not as straight-forward. One popular method for dry-
ing organic solvents is the use of solvent stills. Typically, a solvent
still has a still pot along with a distillation head that is continually
cooled by cold water. The organic solvent is traditionally dried over
an alkali metal (e.g., sodium or potassium) in the presence of ben-
zophenone, which serves as an indicator of the level of dryness of
7
sequent years. Another option is to purchase anhydrous solvents
from a supplier, but these solvents are typically 2–3 times more
expensive than a certified American Chemical Society (ACS) grade
8
solvent.
Through our attempt to uncover the rules of conducting organic
reactions under mechanochemical conditions, we explored the
necessity of conducting mechanochemical reactions in a dry, oxy-
gen-free environment. In a previous report using mechanochemi-
cal conditions, we observed very little difference in the rate or
the yield of the Tishchenko reaction whether setting up reactions
2
,3
the solvent. Over the years there have been major accidents that
have revealed the dangers of this type of set-up. In 2001 at the Uni-
versity of California-Irvine there was a solvent still that exploded,
seriously injuring three students while causing 3.5 million dollars
9
in a dry, inert environment or on the benchtop. Recently, we re-
ported our ability to make kinetic and thermodynamic enolates
4
,5
10
in damages. Because of maintenance and safety concerns, sol-
vent stills are a significant hazard in a laboratory.
under mechanochemical conditions. In this study we used sev-
eral air and water sensitive bases such as sodium hydride and lith-
ium hexamethyldisilazide. Typically, when one uses these types of
reagents in solution, meticulously dried solvents are used and the
reaction is conducted in an oxygen-free environment. Using
1 equiv of lithium hexamethyldisilazide as the base, we conducted
the mechanochemical reaction in a sealed dry box and observed a
21% conversion to the thermodynamic product and 77% conversion
More recently, solvent purification systems have been devel-
oped as a safer alternative to solvent stills. These systems are able
6
to purify solvents to ppm levels of water and oxygen. This type of
system is much safer than a traditional solvent still, though their
use, especially in academia, is limited due to the cost of these sys-
tems (roughly $4000–$5000 per solvent). Regardless of the method
of purification, maintaining dry organic solvents over a period of
1
to the kinetic product based on H NMR data. Similarly, if the reac-
tion is prepared on the benchtop with no other precautions taken,
we observed 27% conversion to the thermodynamic product and
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1
7
2% conversion to the kinetic product based on H NMR data. It