Practical separation of alcohol-ester mixtures using Deep-Eutectic-Solvents

Article abstract of DOI:10.1016/j.tetlet.2012.10.044

Deep-Eutectic-Solvents (DES) were assessed for the separation of alcohol-ester mixtures, for example those typically obtained from catalytic kinetic resolutions of racemic alcohols. DES can efficiently dissolve molecules containing hydrogen-bond-donors (alcohols), whereas esters remain as second phase. By using this concept, tedious separation chromatographic steps may be easily overcome with bio-based non-hazardous solvents.

Full text of DOI:10.1016/j.tetlet.2012.10.044

Tetrahedron Letters 53 (2012) 6968–6971
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Practical separation of alcohol–ester mixtures using Deep-Eutectic-Solvents
Zaira Maugeri a, Walter Leitner a,b, Pablo Domínguez de María a,
⇑
a Institut für Technische und Makromolekulare Chemie (ITMC), RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany
b Max-Planck-Institut für Kohlenforschung, 45470 Mülheim an der Ruhr, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Deep-Eutectic-Solvents (DES) were assessed for the separation of alcohol–ester mixtures, for example
those typically obtained from catalytic kinetic resolutions of racemic alcohols. DES can efficiently dissolve
molecules containing hydrogen-bond-donors (alcohols), whereas esters remain as second phase. By using
this concept, tedious separation chromatographic steps may be easily overcome with bio-based non-
hazardous solvents.
Received 2 August 2012
Revised 4 October 2012
Accepted 9 October 2012
Available online 16 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Deep-Eutectic-Solvents
Separations
Alcohols
Esters
Kinetic resolutions
During the course of chemical reactions the desired synthetic
targets are often generated in mixtures containing different by-
products, non-reacted components, etc. As a consequence, a
work-up to purify the desired product until on-spec levels is always
required. This may represent a challenge for many synthetic reac-
tions, and typically involve tedious and time-consuming separation
procedures (e.g. chromatographic separations) that may even ham-
per the industrial use of a certain reaction/process. An example may
be the (catalytic) kinetic resolution of racemic alcohols (via enan-
tioselective acylation) to afford optically active compounds. Once
an efficient process is set-up (e.g. using enzymes), the separation
of both enantiomers—reacted and unreacted—needs to be accom-
plished. That separation in many cases is challenging, for example
involving time-consuming chromatographic steps. Several alterna-
tives have been reported, for example using polymer-supported
substrates,1–6 fluorous-phase solvents,7–9 ionic liquids, and
mixtures of them with scCO2,10–13 membrane approaches,14–16
in situ further derivatization of products,17 or the use of anhydrides
as acyl donors.18,19 Albeit these approaches are successful, there is
still the need for generalizable and easy-to-handle strategies for
such purposes.
wardly formed by gently mixing a quaternary ammonium salt
(e.g. cheap and non-toxic choline chloride) together with a hydro-
gen-bond-donor (e.g. cheap and non-toxic urea, glycerol, sugars,
carboxylic acids, etc.), with increasing use in organic synthesis, elec-
trochemistry, bio- and organocatalysis, and in material science.20–26
The mixture of these two components in appropriate molar propor-
tion generates a sink in the melting point, affording liquid mixtures
at room temperature. DES are able to dissolvehydrogen-bond-donor
molecules (e.g. alcohols), whereas other non-hydrogen-bond-donor
molecules (e.g. esters, ketones, etc.) remain as a second phase in con-
tact with DES. Based on this property, herein it is shown that such
difficult-to-separate mixtures of alcohol–esters (e.g. those coming
from kinetic resolutions of racemates), can be in fact separated in
an efficient, clean, and rapid way (Scheme 1).
Thus, an ester–alcohol mixture (e.g. as those coming from en-
zyme-catalyzed kinetic resolution of alcohols) is mixed with DES,
and the sample decanted. The upper phase will mainly contain es-
ter (not soluble in DES), whereas the alcohol will dissolve in DES.
The upper phase may be subjected to further extractions until
on-spec purities are reached. Subsequently, the DES-phase can be
extracted (e.g. with an organic solvent or with supercritical fluids),
to obtain the alcohol and the remnant ester. Despite the potential
of DES for such extractive approaches, so far only the biodiesel
purification (by removing glycerol),27–29 or the DES-based extrac-
tion of natural products have been reported.30,31 Very recently
the separation of phenol from oils based on DES was reported as
well.32
In this Letter a simple and efficient novel approach for the
separation of alcohols and esters (e.g. mixtures typically obtained
from enzymatically-resolved racemates) is reported. The strategy
is based on the use of Deep-Eutectic-Solvents (DES) as separating
agents. DES are a new type of ionic solvents that are straightfor-
To validate the principle, the kinetic resolution of (R,S)-1-
phenylethanol catalyzed by immobilized Candida antarctica lipase
B (CAL-B) under solvent-free conditions (vinyl acetate–alcohol,
⇑
Corresponding author. Tel.: +49 241 8020468; fax: +49 241 8022177.
E-mail address: dominguez@itmc.rwth-aachen.de (P. Domínguez de María).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.044

Z. Maugeri et al. / Tetrahedron Letters 53 (2012) 6968–6971
6969
Scheme 1. Concept for the DES-based extraction.
3:1 equiv) was conducted. Full conversions for a kinetic resolution
(50%) were enantiospecifically obtained (ꢀ140 g LÀ1 in 12 h for
each enantiomer) (Scheme 2).
Given the broad versatility to form DES (at low cost and under envi-
ronmentally-friendly conditions), it appears feasible that some
other tailored DES might provide outstanding separations for these
mixtures as well.
Once the reaction was performed and excess of vinyl acetate
removed by distillation, the product mixture (alcohol–ester) was
subjected to DES separation. To validate our idea, an inexpensive
and easy-to-form DES based on choline chloride and glycerol
(1:2 equiv/equiv)21 was used as extractive agent. Equimolar
amounts of 1-phenylethanol and correspondent acetate (Scheme
1) were mixed with DES (Sample:DES 1:5 v/v) and centrifuged.
The upper phase was extracted and analyzed (1H NMR). After several
extraction cycles ester was isolated in the upper phase with high
purity (>99%) and with high efficiency for these non-optimized
extraction conditions (ꢀ70% recovery, Fig. 1A). Likewise, another
assessment was performed in the same extractive conditions for bu-
tyl esters, leading to analogous performances, in this case with even
higher efficiencies (82% of ester of the mixture recovered, Fig. 1B). To
reach a high purity in ester (>99%), four extractive steps were
needed. However, each extractive and separation step can be con-
ducted in a matter of minutes (mixing and centrifugation are imme-
diate), and therefore the efficiency and practicality of the method
can be assured. Therefore, by applying this novel concept, the need
of further chromatographic steps to purify product mixtures would
not be necessary at all—or might be significantly simplified—for
many synthetic applications (not only related to kinetic resolution
of racemates). The broad versatility of DES and their ease of handling
may make this proof-of-concept highly valuable and versatile.
To explore the concept in a wider extent, other alcohol–ester
mixtures, as well as alcohol–ketone and amine–ketone mixtures,
were assessed under the same extractive conditions (Table 1). In
all cases puritiesof 85–99%were achieved in the upper phases, albeit
with less efficiencies for aliphatic alcohols and amines with ketones.
Once the upper phase was removed (ester), the extraction of the
remnant mixture from the DES was assessed. To this end, an equi-
molar solution of 1-phenyl-ethanol/1-phenyl-ethyl-acetate was
mixed with DES (Choline Chloride: Glycerol, 1:2 equiv/equiv) in
the same proportion as before (Sample:DES 1:5, v/v), stirred, and
decanted. The upper phase was removed, with a composition of
ꢀ70% acetate, and 30% alcohol (1st extraction, see also Fig. 1A).
The DES mixture, containing mainly 1-phenyl-ethanol with a part
of 1-phenyl-ethyl-acetate was then extracted using either ethyl-
acetate or ethyl-acetate–water mixtures (Table 2). The remnant
alcohol–acetate could be efficiently extracted from the DES mixture.
Other alternatives like distillation (when possible), or solvents (e.g.
supercritical fluids) or mixtures thereof might also be considered as
extractive agents for further optimized and integrated procedures.
In summary, this Letter has explored the possibility of using DES
as extractive agents for work-up procedures. As an example, mix-
tures of alcohols and esters (e.g. derived from enzyme-catalyzed
kinetic resolutions) can be efficiently separated in a straightforward
and environmentally-benign manner, along with several extractive
cycles, reaching efficiencies of 70–90% in ester, with purities of
>99%. Furthermore, the remnant can be extracted from DES by
means of another solvent, thus allowing the recovery of the chem-
icals and DES recycling. The non-toxic nature and low-cost of DES
components represent a highly promising alternative for many
practical applications with challenging separation steps. Further-
more, the broad versatility in producing DES may obviously be
envisaged as a future tool for tailored extractive solvents in (indus-
trial) synthetic procedures.
O
OH
O
OH
O
Imm. CAL-B
Neat Substrates, 60 °C, 12 h
+
+
O
~ 140 g L-1
~ 140 g L-1
ee > 99 %
ee > 99 %
Scheme 2. CAL-B-catalyzed kinetic resolution of (R,S)-1-phenylethanol under ‘solvent-free’, neat substrates. Reaction conditions: 2.4 mmol of (R,S)-1-phenylethanol;
7.5 mmol of vinyl acetate; enzyme loading 30 mg mLÀ1, temperature 60 °C; 12 h.

6970
Z. Maugeri et al. / Tetrahedron Letters 53 (2012) 6968–6971
Figure 1. Composition of the upper phase during the extraction of a mixture of 1-phenyl-ethanol and a correspondent ester by using DES (ChCl:Glycerol, 1:2 equiv/equiv) as
extractive agents (Sample:DES 1:5 v/v). After vigorous mixing and centrifugation, the upper phase was analyzed by 1H NMR.
Table 1
Extraction of equimolar mixtures alcohol–esters, alcohol–ketones, and amine–ketones with DES (ChCl:Glycerol 1:2, equiv/equiv) as extractive agents (Sample:DES 1:5 v/v). Purity
of upper phase analyzed by 1H NMR
Mixture
Purity of upper phase (Extractions)
99.4% (3 extractions)
Recovery (ester or ketone) (%)
O
OH
OH
83
O
O
99.6% (3 extractions)
86% (4 extractions)
94% (3 extractions)
91
70
40
O
O
OH
O
OH
O
NH2
O
90% (2 extractions)
51

Z. Maugeri et al. / Tetrahedron Letters 53 (2012) 6968–6971
6971
Table 2
Extraction of DES–alcohol–ester mixtures using ethyl acetate or ethyl acetate–water mixtures. Extracted glycerol represents ca. 0.4% of the glycerol content in DES, and therefore
it does not affect the DES properties for reusability
Solv:DES (3 times)
Solvent
Extracted mixture (%)
Efficiency extracted Alc.–Est. (%)
Alc.
Est.
glycerol
ChCl
1:5
0.75:5
EtOAc
H2O:EtOAc 1:2
85
84
9
12
6
4
0.0
0.0
86
89
Experimental
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Acknowledgments
Financial support from DFG training group 1166 ‘BioNoCo’
(‘Biocatalysis in Non-conventional Media’) is gratefully acknowl-
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