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org/greenchem | Green Chemistry

An environmentally benign solvent-free Tishchenko reaction


Daniel C. Waddell and James Mack*
Received 24th June 2008, Accepted 7th October 2008
First published as an Advance Article on the web 6th November 2008
DOI: 10.1039/b810714a

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.

Introduction aldehydes.24 Catalysts such as lithium bromide and lanthanide


catalysts undergo the Tishchenko reaction with aryl aldehydes
Environmental concerns about solvent-based chemistry have in high yield, but long reaction times (2–3 days) are required.25
stimulated a renewed interest in the study of chemical reactions One of the simplest and cheapest catalysts that has been used for
under solvent-free conditions.1–3 Although most of the research the generation of benzyl benzoate from benzaldehyde has been
conducted in this area has been performed by using a mortar and sodium hydride. Although sodium hydride is generally thought
pestle, high speed ball milling (HSBM) is an attractive solvent- of as a non-nucleophilic base,26 Swamer and Hauser demon-
free method that has started to gain attention. In the HSBM strated in refluxing benzene that benzaldehyde can be converted
method, a ball bearing is placed inside a vessel that is shaken at to benzyl benzoate in moderate yield.27 Since benzaldehyde was
high speeds.4,5 The high speed attained by the ball-bearing has the lone example in this report, the scope and limitations of
enough force to make an amorphous mixture of the reagents the Tishchenko reaction using sodium hydride as the catalyst
that subsequently facilitate a chemical reaction. are still absent from the literature. Further, the use of benzene
The use of commericial ball mills have allowed these reactions as the solvent under these conditions signifigantly increases the
to be scaled up to industrial levels, therefore understanding health risk, especially on large scale. We thought the use of high
organic reactions using this methodology can signifigantly speed ball milling under solvent-free conditions would afford
reduce solvent waste.4,6–9 We recently reported that the rate of the us the possibility of using sodium hydride as the catalyst, while
Baylis–Hillman reaction is increased under HSBM conditions avoiding the use of benzene. Further, we predicted that under
and we developed a safe solvent-free method for the reduction HSBM conditions catalytic activity would be very high due to
of esters.10,11 In this work, we describe the Tishchenko reaction the high concentration of materials in the reaction vials.
under these novel conditions.
The conversion of aldehydes to their dimeric esters, better
known as the Tishchenko reaction (Scheme 1) has been known Results and discussion
for more than a hundred years.12 This reaction is heavily used
Our results are summarized in Table 1. We started our process
in industry,13 and it is inherently environmentally benign since
by reacting various aryl aldehydes in the presence of a catalytic
it utilizes catalytic conditions and is 100% atom economic.
amount of sodium hydride. We attempted 1% and 2% mol
Over the years, chemists have looked to develop new reagents
catalyst but found the reaction was most effective with 10%
that are more efficient than the aluminum based catalysts
sodium hydride. Typically, the reactions were conducted in a
traditionally used. Metal catalysts such as alkali metals,14–17
custom made 1/2¢¢ ¥ 2¢¢ inch screw-capped stainless steel vial
alkali metal oxides, lanthanides,18–22 and many others have been
and milled with a 1/8¢¢ inch stainless steel ball-bearing in a
developed towards the improvement of Tishchenko chemistry.
Spex certiprep mixer/mill 8000M open to the atomosphere
Unfortunately, many of these catalysts react sluggishly with
for 30 minutes (Scheme 2). At the conclusion of the reaction
aromatic aldehydes or provide the ester product in low yield.23–25
the products were recrystallized with 95% ethanol and dried
It was demonstrated that catalytic diisobutylaluminum hydride
over a Hirsch funnel. Liquid products were isolated from
(DIBAL-H) reacts with aliphatic aldehydes to give the dimeric
extraction with the minimal amount of methylene chloride.28
ester but it does not give the Tishchenko product with aryl
Upon isolation 1 H NMR,13 C NMR and GC-MS were compared
to literature values to confirm product formation. We were
able to convert benzaldehyde to benzyl benzoate in as little

Scheme 1 Tishchenko reaction.

University of Cincinnati, 301 Clifton Court, Cincinnati, OH, USA.


E-mail: james.mack@uc.edu; Fax: +1 513 556 9239; Scheme 2 Conducting the Tishchenko reaction under solvent-free ball
Tel: +1 513 556 9249 milling conditions.

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

as 30 minutes under HSBM conditions compared to 5 hrs in


solution.27 The turnover frequencies (TOF’s) were determined
4 0.5 86 80 10 from complete conversion.29
Our success with aryl aldehydes led us to investigate the
Tishchenko reaction of aliphatic and a,b unsaturated alde-
5 2 94 86 2.5 hydes. Using sodium hydride as the catalyst we attempted
the ball milled Tishchenko reaction with 3-phenylpropional,
pentanal, and 1,2,3,6-tetrahydro-benzaldehyde. Our results
showed that straight chain non-hindered aldehydes such as
3-phenylpropional and pentanal gives only a small amount
of the dimeric ester with these substrates; with the majority
6 2 >99 93 2.5
of the products arising from aldol condensation chemistry.
However, when sterically hindered aldehydes are used, such as
1,2,3,6-tetrahydro-benzaldehyde the dimeric ester is the major
product and we observed no product resulting from the aldol
7 0.5 >99 91 10 condensation. a,b unsaturated systems such as cinnamaldehyde
and 2-butenal gave a mixture of products which included the
expected dimeric ester as well as products which arise from
conjugate additon into the double bond. We also examined the
reaction with acetaldehyde for the preparation of ethyl acetate
8 2 >99 97 2.5 but instead of obtaining ethyl acetate under these conditions the
reaction resulted in the formation of a polymer.30
Since the Tishchenko reaction is catalyzed by various metals,
we wanted to investigate the role of the ball material on this
reaction. Using the dimerization of benzaldehyde to form benzyl
benzoate as the benchmark, we explored the affect of ball
9 2 80 69 2.5
material on the Tishchenko reaction under HSBM conditions.
Benzaldehyde and 10 mol% sodium hydride was ball milled
for fifteen minutes and the % conversion was analyzed by 1 H
NMR. The reactions were conducted in dupilcate and run
10 2 80 70 2.5 with a 1/8¢¢ stainless steel ball, 1/8¢¢ brass ball and in the
absence of a ball. In this particular reaction we saw similar
% conversion irrespective of the ball material used, each giving
~30% conversion. The most surprising result is that we observed
11 16 95 91 1
the reaction was just as sucessful in the absence of a ball
bearing. This suggests the high speed movement of the vial
provides enough energy to cause this reaction. We thought
since benzaldehyde is a liquid, a ball may not be needed in
12 2 86 69 2.5
order create the proper mixing at the molecular level for this
reaction to take place. To test this hypothesis, we ball milled
p-chlorobenzaldehyde, a solid, to determine if the reaction
procedes in the absence of a ball. To our surprise, after 30 minutes
of milling the reaction proceded in similar yield to reactions

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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82 | Green Chem., 2009, 11, 79–82 This journal is © The Royal Society of Chemistry 2009