An environmentally benign solvent-free Tishchenko reaction

Article abstract of 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.

Full text of DOI:10.1039/b810714a

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www.rsc.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.
aldehydes.24 Catalysts such as lithium bromide and lanthanide
Introduction
catalysts undergo the Tishchenko reaction with aryl aldehydes
in high yield, but long reaction times (2–3 days) are required.25
One of the simplest and cheapest catalysts that has been used for
the generation of benzyl benzoate from benzaldehyde has been
sodium hydride. Although sodium hydride is generally thought
of as a non-nucleophilic base,26 Swamer and Hauser demon-
strated in refluxing benzene that benzaldehyde can be converted
to benzyl benzoate in moderate yield.27 Since benzaldehyde was
the lone example in this report, the scope and limitations of
the Tishchenko reaction using sodium hydride as the catalyst
are still absent from the literature. Further, the use of benzene
as the solvent under these conditions signifigantly increases the
health risk, especially on large scale. We thought the use of high
speed ball milling under solvent-free conditions would afford
us the possibility of using sodium hydride as the catalyst, while
avoiding the use of benzene. Further, we predicted that under
HSBM conditions catalytic activity would be very high due to
the high concentration of materials in the reaction vials.
Environmental concerns about solvent-based chemistry have
stimulated a renewed interest in the study of chemical reactions
under solvent-free conditions.1–3 Although most of the research
conducted in this area has been performed by using a mortar and
pestle, high speed ball milling (HSBM) is an attractive solvent-
free method that has started to gain attention. In the HSBM
method, a ball bearing is placed inside a vessel that is shaken at
high speeds.4,5 The high speed attained by the ball-bearing has
enough force to make an amorphous mixture of the reagents
that subsequently facilitate a chemical reaction.
The use of commericial ball mills have allowed these reactions
to be scaled up to industrial levels, therefore understanding
organic reactions using this methodology can signifigantly
reduce solvent waste.4,6–9 We recently reported that the rate of the
Baylis–Hillman reaction is increased under HSBM conditions
and we developed a safe solvent-free method for the reduction
of esters.10,11 In this work, we describe the Tishchenko reaction
under these novel conditions.
The conversion of aldehydes to their dimeric esters, better
known as the Tishchenko reaction (Scheme 1) has been known
for more than a hundred years.12 This reaction is heavily used
in industry,13 and it is inherently environmentally benign since
it utilizes catalytic conditions and is 100% atom economic.
Over the years, chemists have looked to develop new reagents
that are more efficient than the aluminum based catalysts
traditionally used. Metal catalysts such as alkali metals,14–17
alkali metal oxides, lanthanides,18–22 and many others have been
developed towards the improvement of Tishchenko chemistry.
Unfortunately, many of these catalysts react sluggishly with
aromatic aldehydes or provide the ester product in low yield.23–25
It was demonstrated that catalytic diisobutylaluminum hydride
(DIBAL-H) reacts with aliphatic aldehydes to give the dimeric
ester but it does not give the Tishchenko product with aryl
Results and discussion
Our results are summarized in Table 1. We started our process
by reacting various aryl aldehydes in the presence of a catalytic
amount of sodium hydride. We attempted 1% and 2% mol
catalyst but found the reaction was most effective with 10%
sodium hydride. Typically, the reactions were conducted in a
custom made 1/2¢¢ ¥ 2¢¢ inch screw-capped stainless steel vial
and milled with a 1/8¢¢ inch stainless steel ball-bearing in a
Spex certiprep mixer/mill 8000M open to the atomosphere
for 30 minutes (Scheme 2). At the conclusion of the reaction
the products were recrystallized with 95% ethanol and dried
over a Hirsch funnel. Liquid products were isolated from
extraction with the minimal amount of methylene chloride.28
Upon isolation 1H NMR,13C 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;
Tel: +1 513 556 9249
Scheme 2 Conducting the Tishchenko reaction under solvent-free ball
milling conditions.
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Table 1 Tishchenko reaction of aryl aldehydes using 10% sodium
hydride catalyst
Table 1 (Contd.)
Time
(hrs) % Conversion % Yield TOF
Time
Entry Substrate
13
Entry Substrate
1
(hrs) % Conversion % Yield TOF
2
>99
93
2.5
2
>99
91
2.5
2
3
0.5 >99
92
10
14
16
>99
97
1
0.5 >99
98
10
10
as 30 minutes under HSBM conditions compared to 5 hrs in
solution.27 The turnover frequencies (TOF’s) were determined
from complete conversion.29
4
5
0.5
2
86
94
80
86
Our success with aryl aldehydes led us to investigate the
Tishchenko reaction of aliphatic and a,b unsaturated alde-
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
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
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
but instead of obtaining ethyl acetate under these conditions the
reaction resulted in the formation of a polymer.30
2.5
6
7
2
>99
93
91
2.5
0.5 >99
10
8
9
2
2
>99
97
69
2.5
2.5
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
material on the Tishchenko reaction under HSBM conditions.
Benzaldehyde and 10 mol% sodium hydride was ball milled
80
1
for fifteen minutes and the % conversion was analyzed by H
NMR. The reactions were conducted in dupilcate and run
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
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
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
10
11
2
80
95
70
91
2.5
1
16
12
2
86
69
2.5
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conducted with brass and stainless steel balls (~99% conversion).
This suggests at least for this particular reaction that the shaking
of the vial has enough energy to make an amorphous mixture of
the reagents to provide a chemical reaction even without a ball!
On very large scale, ball milled reactions can generate a
signifigant amount of heat, thus we wanted to conduct these
reactions in the Spex Certiprep freezer mill in a liquid nitrogen
environment to determine the feasibility of the reaction under
low temperature conditions. Using our typical conditions,
p-chlorobenzaldehyde and sodium hydride was placed inside a
reaction vial and cooled to -196 ◦C. The reaction was milled
for 30 minutes at which point it was allowed to warm to
Conclusions
In conclusion, we report an environmentally benign method
for the Tishchenko reaction using solvent-free ball milling
conditions. We used sodium hydride as the catalyst instead of the
more traditional aluminum catalyst which allowed the reaction
to procede in high yield and short reaction times. We discovered
in this particular reaction the type of ball used has little to
no affect on the yield or rate of the reaction and the reaction
proceeded equally well without the addition of a ball. We also
observed the ball milled Tishchenko reaction can take place
while the vial is immersed in a liquid nitrogen environment.
Currently, we are in the process of creating a magnesium vial
that is expected to act as the catalyst as well. Ball milling is a
novel method for conducting organic reactions. With a better
understanding of how these reactions procede we will be able to
make significant strides in the development of various solvent-
free reactions.
1
room temperature. H NMR and GC-MS both confirmed the
presence of the expected dimeric ester of p-chlorobenzaldehyde
(~5% yield). This demonstrates the ability to conduct ball milling
experiments in a low temperature environment which would
allow this process to be implemented with highly exothermic
reactions.
In an attempt to avoid handling sodium hydride, we wanted
to generate our catalyst in situ. Sodium formate is known under
certain condtions to break down to sodium hydride and carbon
dioxide.26,31,32 We thought we could use sodium formate, which is
safe and very easy to handle as a direct precusor to the sodium
hydride catalyst. Unfortunately, after ball milling benzaldehyde
and sodium formate for 16 hours we saw no evidence of the
desired dimeric ester. It has been shown that various metal
catalyst can facilitate the disproportation of sodium formate
to sodium hydride and carbon dioxide.33–36 We tested whether
a combination of catalytic sodium formate (10 mol%) and
palladium tetrakistriphenylphospine (1 mol%) would lead to
the generation of the sodium hydride catalyst. Using this mixture
along with benzaldehyde we were able to generate trace amounts
of benzyl benzoate after milling for 44 hours (Scheme 3).
Experimental
All NMR spectra were recorded on a Bruker Avance 400 spe-
ctrometer. Deuterated NMR solvents were obtained from
Cambridge Isotope Laboratories, Inc., Andover MA, and used
without further purification. p-bromobenzaldehyde, p-chloro-
benzaldehyde, p-anisaldehyde, benzaldehyde, p-tolualdehyde,
p-(methylthio)benzaldehyde, m-anisaldehyde, napthaldehyde,
2-thiophenecarboxaldehyde and sodium hydride were purchased
from Acros Organics and used without further purification. m-
Fluorobenzaldehyde, m-tolualdehyde and 1,2-phthalic carbox-
aldehyde were purchased from Sigma-Aldrich and used without
further purification. Ball milling was carried out in a 8000M
SpexCertiprep Mixer/Mill. Ball milling under a liquid nitrogen
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
and palladium tetrakistriphenylphosphine.
Benzaldehyde (0.22 g, 2.07 mmol), and sodium hydride (0.004 g,
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
mixer/mill and the contents were ball milled for 0.5 h. The
resulting mixture was dissolved in methylene chloride28 (15 mL)
and washed with 10% HCl (15 mL). The organic layer was dried
over anhydrous MgSO4 and the solvent was evaporated under
reduced pressure. This afforded benzyl benzoate in > 98% yield.
In addition to sodium hydride, we also investigated other
benign catalysts that could give high yields of the Tishchenko
reaction using ball milling conditions. Ball milling benzaldehyde
with catalysts such as lithium bromide and calcium oxide
did not provide the desired dimeric ester but rather gave
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
ester product even under long milling times. It was reported
that benzaldehyde can be converted to benzyl benzoate using
magnesium metal as the catalyst in refluxing toluene.37 We
ball milled p-chlorobenzaldehyde along with magnesium metal
and observed >95% yield of expected dimeric ester. We are
in the process of making magnesium vials to determine if the
magnesium vial itself will be a sutiable catalyst under these
conditions.
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