COMMUNICATION
www.rsc.org/greenchem | Green Chemistry
Ethyl lactate as a tunable solvent for the synthesis of aryl aldimines†
Jacqueline S. Bennett,* Kaitlyn L. Charles, Matthew R. Miner, Caitlin F. Heuberger, Elijah J. Spina,
Michael F. Bartels and Taylor Foreman
Received 3rd October 2008, Accepted 7th January 2009
First published as an Advance Article on the web 14th January 2009
DOI: 10.1039/b817379f
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Ethyl L-lactate can be tuned with a cosolvent to create
polarity conditions ideal for synthesizing aryl aldimines that
crystallize directly out of solution within minutes under
ambient conditions in excellent yields and requiring no
further purification.
with catalyst followed by recrystallization, aqueous suspension
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followed by recrystallization, aqueous suspension with vigorous
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mechanical stirring for ≥2 h, solid phase grinding followed
◦
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by vacuum removal of water at 80 C, and clay-catalyzed
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microwave synthesis followed by dichloromethane extraction.
In most of these syntheses, recrystallization or extraction was
required to further purify or isolate the desired imine. Some
methods also required catalysts or heat and nearly all required
stirring. In contrast, our method required no catalyst, stirring,
or further purification of the product imine. Nor was evidence of
starting materials or solvents apparent in spectroscopic analyses.
The imines prepared are useful in a variety of applica-
Imines (Fig. 1) are intermediates in many reactions of both
enzymatic and pharmaceutical interest. Traditional syntheses
often involve the use of toxic solvents such as methylene
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chloride or refluxing in petroleum-based solvents such as
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toluene as azeotroping agents. Some recent imine syntheses
have successfully used more benign solvents or conditions but
still require recrystallization or other work up procedures, which
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tions. Salicylideneanilines show activity against tuberculosis,
a leading causes of infectious death. Cinnamylidene imines are
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negate some of the benefits of the green synthesis itself. Here,
we describe a greener synthesis of aryl aldimines using ethyl
L-lactate as the solvent. Water was used as a cosolvent to
optimize solvent polarity and induce rapid formation of product.
The imines crystallized directly out of solution in high purity and
yield, requiring no further purification. Ethyl lactate is unusual
in that it is miscible with water as well as nonpolar organic
solvents. Thus, a broad range of solvent polarity is accessible
by simply “tuning” ethyl lactate with a cosolvent to create ideal
conditions for rapid product formation. In addition, ethyl lactate
is approved by the FDA as a food additive, is derived from
renewable resources, and is biodegradable. Polarity adjustment
by using a cosolvent is a standard technique for optimizing
recrystallizations but we could find no instances of this same
logic applied to reaction conditions. “Solvent tuning” is typically
used in reference to supercritical fluids, when cosolvents are
useful intermediates in the preparation of b-lactam antibacte-
rial compounds and have been shown to greatly accelerate
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photodegradation of polyethylene, which could have favorable
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environmental consequences.
To demonstrate the versatility of this solvent tuning technique
for generating aryl aldimines, a variety of aryl aldehydes and aryl
amines containing both activating and deactivating substituents
were examined (Table 1). We found no need for catalysts
or external energy for the reactions except the example with
p-nitrobenzaldehyde (a). The literature data that we used for
comparison are the best sources we could find where yields and
some measure of purity, usually melting point, were reported.
Full spectroscopic characterization of products is included in
the ESI.† Only one example (a) required heat due to solubility
problems with the p-nitrobenzaldehyde, but the reaction was
complete within three minutes, compared to 24 h of continuous
heat in the literature method.
All reactions were first run in pure ethyl L-lactate. Reactions
that took more than ten minutes were tuned with water to
reduce reaction time. The % EL values in Table 1 reflect the
best combination of crystal quality and reaction speed. While
we did not examine the mechanistic aspects of this reaction, we
surmise water exerted its effect by one or both of the following
routes: (1) water stabilized the carbinolamine intermediate,
which accelerated the reaction or (2) the obvious insolubility
of the imine product made it apparent when the reaction was
complete, thus, excess time was not wasted to ensure reaction
completion.
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added to affect parameters like equilibria. As far as we can
find, this communication is the first example of ethyl lactate
polarity tuning under ambient conditions to optimize reaction
purity, yield, and speed.
Fig. 1 General synthesis of aryl aldimines.
Recently, several environmentally friendly syntheses of aryl
aldimines have been reported: the sonication of ethanolic
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solutions containing silica as a catalyst, solventless grinding
The synthesis of cinnamylidine aniline (j) is representative
of the procedure. Briefly, 10 mmol aniline was dissolved in
Department of Chemistry and Biochemistry, State University of New
York, College at Oneonta, Oneonta, NY, USA. E-mail: bennetjs@
oneonta.edu; Fax: +1 607 436 2654; Tel: +1 607 436 3431
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mL 80% ethyl L-lactate in water (v/v) followed by addition
of 10 mmol cinnamaldehyde. The reaction mixture was swirled
until homogeneous and then allowed to sit undisturbed at
room temperature for four minutes, when crystal formation
†
Electronic supplementary information (ESI) available: Spectroscopic
data. See DOI: 10.1039/b817379f
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66 | Green Chem., 2009, 11, 166–168
This journal is © The Royal Society of Chemistry 2009