Efficient and catalyst-free condensation of acid chlorides and alcohols using continuous flow

Article abstract of DOI:10.1039/c2gc35555h

An efficient, catalyst-free continuous flow procedure for the condensation of acid chlorides and alcohols was developed. Different esters could be obtained using this protocol with excellent conversions starting from the corresponding acid chlorides and alcohols in very short reaction times (5-7 min). The reaction was performed solventless for liquid reagents but requires a solvent for solid reagents in order to prevent clogging of the microreactor. Since no catalyst is needed, the purification of the reaction mixture is very straightforward. Scale-up of the reaction to a microreactor with an internal volume of 13.8 ml makes it possible to produce 2.2 g min^-1 of ester with an isolated yield of 98% and recuperation of the formed HCl.

Full text of DOI:10.1039/c2gc35555h

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PAPER
Efficient and catalyst-free condensation of acid chlorides and alcohols using
continuous flow
Frederik E. A. Van Waes,a J. Drabowicz,b A. Cukalovica and Christian V. Stevens*a
Received 13th April 2012, Accepted 7th August 2012
DOI: 10.1039/c2gc35555h
An efficient, catalyst-free continuous flow procedure for the condensation of acid chlorides and alcohols
was developed. Different esters could be obtained using this protocol with excellent conversions starting
from the corresponding acid chlorides and alcohols in very short reaction times (5–7 min). The reaction
was performed solventless for liquid reagents but requires a solvent for solid reagents in order to prevent
clogging of the microreactor. Since no catalyst is needed, the purification of the reaction mixture is very
straightforward. Scale-up of the reaction to a microreactor with an internal volume of 13.8 ml makes it
possible to produce 2.2 g min−1 of ester with an isolated yield of 98% and recuperation of the formed
HCl.
Introduction
The reaction between an acid chloride and an alcohol is a
well-known reaction and is used extensively in organic chem-
istry, for example as a protection strategy for hydroxyl groups.1
Typically, this reaction is performed in the presence of a catalyst.
Among the base catalysts used for this reaction of acid chlorides,
the most common are pyridine, Et3N and 4-dimethylamino-
pyridine (DMAP).1,2a Other bases, such as 1,4-diazabicyclo[2.2.2]-
octane (DABCO),2a,b N,N,N′,N′-tetramethylethylenediamine
Scheme 1 Catalyst-free condensation of acid chlorides and alcohols
using continuous flow.
(TMEDA)2c or NaOH,2d can also be used. Besides these bases,
other catalysts are reported in the literature: LiClO4,3a Al2O3,3b–d
3l
TiO2,3e ZnO,3f–h ZrOCl2·8H2O,3i CeCl3,3j Tl,3k BiCl3 and
BiFeO3.3m However, in view of an increased sustainability there
between 88% and 93%. However, the scale of their reactions
is a continuous search for more straightforward processes and
was limited to 5 mmol and the number of acid chlorides investi-
process intensification. In the framework of our research to use
microreactor technology to develop reactions which really
gated was limited. For example, no aromatic acid chlorides were
included. Moreover, they used as much as 20% excess of acid
chloride and most of their research focussed on the use of acid
anhydrides which makes the method less atom efficient in com-
parison to the use of acid chlorides. This prompted us to evaluate
the catalyst-free condensation of acid chlorides and alcohols
using continuous flow in order to develop an industrially rele-
benefit from continuous processing, we studied the condensation
of acid chlorides with alcohols.4 Most of the catalysts mentioned
above can be used solventless. Strazzolini et al. reported a cata-
lyst-free reaction between acid halides and alcohols in CH2Cl2.5a
However, they describe a competition between alkyl halide and
ester formation. Ranu et al. reported a solvent-free and catalyst-
vant, practical, efficient, fast and green procedure (Scheme 1).
free procedure for the condensation of acid chlorides and alco-
Performing the condensation of acid chlorides and alcohols
hols.5b Different alcohols were reacted with acetyl or propanoyl
under catalyst-free conditions has also an important economical
chloride giving the corresponding esters with an isolated yield
advantage because the costs for the catalyst are eliminated and
the purification becomes almost redundant. Moreover, the use of
microreactor technology is inherently safer than batch technol-
aSynBioC Research Group, Department of Sustainable Organic
ogy because of the small internal volume and excellent heat
Chemistry and Technology, Faculty of Bioscience Engineering, Ghent
transfer associated with the microreactor chip. The excellent heat
University, Coupure Links 653, B-9000 Gent, Belgium.
transfer also allows rapid heating or cooling of the reaction
mixture. Although there are a few examples of the formation of
esters using microreactor technology, to the best of our knowl-
edge, this is the first procedure reported starting from acid
chlorides using a catalyst-free procedure. Known esterification
E-mail: chris.stevens@ugent.be; Fax: +32 9 264 62 21;
Tel: +32 9 264 59 57
bCenter of Molecular and Macromolecular Studies, Department of
Heteroatom Chemistry, Polish Academy of Science, Sienkiewicza 112,
90-363 Lødz, Poland. E-mail: draj@bilbo.cbmm.lodz.pl;
Fax: +48 42684; Tel: +48 42680 3234
2776 | Green Chem., 2012, 14, 2776–2779
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Table 1 Condensation of benzoyl chloride with MeOH, EtOH or
iPrOH: GC-conversion (%)
reactions in the literature using continuous flow include Fischer-
type esterifications,6a–c the use of lipases6d–f and other types of
esterification reactions.6g–i
Alcohol (equiv.)
T (°C)
RTa (s)
1
1.1
1.2
1.3
1.5
2
Results and discussion
MeOH
80
80
80
90
100
EtOH
80
100
110
130
130
140
140
iPrOH
80
100
200
300
300
300
—
—
95
95
—
—
—
—
—
99
—
96
99
—
—
—
—
100
—
—
98
—
—
—
97
97
—
—
—
In preliminary batch experiments, the condensation of equimolar
amounts of benzoyl chloride with ethanol was carried out at
room temperature in diethyl ether. Only a trace of ethyl benzoate
was detected after 21 h. However, this benzoate was isolated in
quantitative yield when benzoyl chloride was reacted with a
10 molar excess of ethanol for 200 min. A similar condensation
of benzoyl chloride with a 10 molar excess of methanol gave
quantitatively methyl benzoate after 15 min.
To evaluate the condensation of acid chlorides and alcohols
under continuous flow, the reaction between benzoyl chloride
and methanol was chosen as the generic reaction. All reactions
were performed solventless (unless the starting material was a
solid) in a microreactor with an internal volume of 10 μl
(Labrix® Start microreactor from Chemtrix).
—
300
300
300
300
400
300
400
—
—
—
—
—
—
—
—
—
95
99
99
99
99
—
—
—
—
—
—
—
88
99
100
—
—
—
—
93
—
—
—
—
—
—
98
—
—
—
—
—
—
300
300
300
300
—
—
—
—
—
—
—
—
—
—
—
—
—
92
99
—
95
100
—
61
—
—
—
100
110
120
100
a RT = residence time.
In a first series of experiments, the optimal conditions for the
microreactor procedure were developed. The reaction tempera-
ture, the residence time and the stoichiometric ratio of both
reagents were varied and the results were evaluated using IR
obtained for a stoichiometric ratio EtOH/BnCl of 1.1 when the
reaction temperature was raised (130 °C or 140 °C).
(νCvO
= 1770 cm−1; νCvO
=
methyl benzoate
benzoyl chloride
1720 cm−1). From these experiments, it was clear that the reac-
tion temperature is preferable above the atmospheric boiling
point of methanol (Tb = 65 °C). Good conversions were obtained
with a reaction temperature of 80 °C whereas the conversion was
limited at 50 °C. In order to prevent the formation of gas
bubbles in the microreactor chip (HCl is formed during the reac-
tion and the reaction mixture is heated above the atmospheric
boiling point of the alcohol), a back pressure regulator (BPR) of
10 bar was used. The most important experiments were then
reconfirmed in order to determine the conversion by GC
(Table 1).
Full conversion of benzoyl chloride with methanol into
methyl benzoate was obtained with a residence time of 300 s, a
reaction temperature of 80 °C and as little as 1.3 equiv. of
MeOH. In order to determine the isolated yield, the microreactor
was run for 5.6 h. The work-up of the reaction mixture was very
straightforward: pure methyl benzoate was obtained with a yield
of 90% after evaporation of the excess MeOH. At lower resi-
dence times, traces of benzoyl chloride were detected in the reac-
tion mixture, even if the ratio MeOH/BnCl was increased. In
attempts to achieve full conversion with a stoichiometric ratio
beneath 1.3, the reaction temperature was increased but without
success. However, 99% conversion was obtained with a reaction
temperature of 100 °C and 1.1 equiv. of MeOH.
When benzoyl chloride was reacted with iPrOH instead of
EtOH, the conversion was poor at a reaction temperature of
80 °C, even with 2 equiv. of iPrOH. Raising the reaction temp-
erature allowed again good conversions. For the condensation of
benzoyl chloride and iPrOH, the optimised conditions were a
reaction temperature of 120 °C, a residence time of 300 s and
1.3 equiv. of iPrOH.
Using the optimised conditions for the different alcohols,
other acid chlorides were converted into their corresponding
esters (Table 2).
To extend the scope of the reaction, the continuous flow pro-
cedure was evaluated for solid acid chlorides and alcohols in
solution.
In a first attempt, a solution of a solid acid chloride (4-bromo-
benzoyl chloride) was reacted with neat MeOH. Different con-
centrations of the acid chloride in different solvents (dioxane,
CH2Cl2 or CH3CN) were evaluated. These experiments were
conducted at a reaction temperature of 80 °C and a residence
time of 300 s. In the first trials, high concentrations of 4-bromo-
benzoyl chloride were used in order to establish a good ratio
between the flows of both reagents. However, using CH2Cl2
(5 M) or dioxane (4 M) resulted in clogging of the microreactor
channels (width = 300 μm, depth = 60 μm). Lowering the con-
centration to 3.25 M in dioxane or CH3CN resulted in less than
5% conversion (GC), even if up to 3 equiv. of MeOH were used.
Subsequently, the concentration of the CH3CN-solution was
lowered to 0.5 M in order to overcome possible mixing problems
due to the viscosity of the 4-bromobenzoyl chloride solution.
However, the conversion of the acid chloride was limited to
10% (GC).
In a next series of experiments, the optimised conditions for
the condensation of benzoyl chloride and methanol were used
for the condensation of benzoyl chloride and ethanol. However
at a temperature of 80 °C, the stoichiometric ratio EtOH/BnCl
had to be above 1.3 in order to obtain good conversions. Prob-
ably, this is due to the fact that a reaction temperature of 80 °C is
close to the atmospheric boiling point of EtOH (Tb = 78 °C).
Increasing the reaction temperature to 110 °C led to full conver-
sion with 1.3 equiv. of EtOH. Excellent conversions (99%) were
Subsequently, a solid alcohol (p-cresol) in solution was
reacted with neat benzoyl chloride (Table 2, entry 11). The
alcohol was dissolved in dioxane or CH3CN with a concentration
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Green Chem., 2012, 14, 2776–2779 | 2777

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Table 2 Condensation of acid chlorides with alcohols under catalyst-free continuous flow conditions
Entry
Acid chloridea (M)
Alcohola (M)
RTb (s)
Tb (°C)
Alcohol (equiv.)
Conversion (%)
1
2
3
4
5
6
7
8
C6H5COCl
C6H5COCl
C6H5COCl
MeOH
EtOH
iPrOH
MeOH
EtOH
iPrOH
MeOH
EtOH
iPrOH
MeOH
p-Cresol (2 M)
p-Cresol (2 M)
p-Cresol (1.5 M)
300
300
300
300
300
300
300
300
300
300
400
400
400
80
110
120
80
110
120
80
110
120
80
140
140
140
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
2
100c
100
100
100
100
100
91
97
100
10
CH3(CH2)2COCl
CH3(CH2)2COCl
CH3(CH2)2COCl
CH3OCH2COCl
CH3OCH2COCl
CH3OCH2COCl
4-BrC6H4COCl (0.5 M)
C6H5COCl
9
10
11
12
13
2
2
2
98
99
79
CH3(CH2)2COCl
4-BrC6H4COCl (1.5 M)
a When the starting material was solid, the compound was dissolved in CH3CN. b RT = residence time, T = temperature. c Isolated yield after running
the microreactor for 5.6 h: 90%.
Table 3 Conversion and yield for the condensation of benzoyl
chloride and MeOH during the course of the operation (KiloFlow®
microreactor)
of 2 M. Initial experiments were conducted at a reaction tempera-
ture of 80 °C, a residence time of 300 s and 1.3 equiv. of
p-cresol in CH3CN. However, these conditions resulted in a
limited conversion of only 25% (GC). The conversion increased
(78% (GC)) by raising the temperature to 120 °C. A further
increase of the reaction temperature (140 °C) in combination
with a residence time of 400 s and 2 equiv. of p-cresol led to a
conversion of 98% (GC). When these reactions were performed
in dioxane, lower conversions were obtained. The optimised con-
ditions were also applied on the condensation of butyryl chloride
with p-cresol (Table 2, entry 12).
Time
Conversiona (%)
Yield (%)
t0 = 0 h
t1 = 1 h
t2 = 3 h
t3 = 4 h
92
80
87
88
90
80
86
87
a GC-conversion.
At last, the condensation of a solid acid chloride (4-
BrC6H4COCl) with a solid alcohol (p-cresol) was evaluated
when both reagents were dissolved in CH3CN. The reactions
were performed at a temperature of 140 °C and a residence time
of 400 s. Initial experiments revealed that 2 equiv. of p-cresol are
needed in order to obtain reasonable conversions. Varying the
concentration of both solutions finally led to the optimal con-
ditions in which both reagents were dissolved in CH3CN with a
concentration of 1.5 M. A conversion of 79% (GC) could be
obtained (Table 2, entry 13).
In order to investigate the applicability of this reaction on an
industrial scale, the developed mmol procedure was scaled–up.
The optimised conditions for the condensation of benzoyl chlor-
ide and MeOH were tested with a microreactor with an internal
volume of 13.8 ml (KiloFlow® microreactor from Chemtrix).
The use of this system led to a capacity of 2.2 g min−1 methyl
benzoate with an isolated yield of 98%. Moreover, the formed
HCl could be recuperated by purging the reaction mixture with
dry nitrogen gas and subsequently trapping the HCl vapour in
water. The work-up of the reaction mixture was very straightfor-
ward. Pure methyl benzoate was obtained after evaporation of
the excess MeOH. At last, the condensation of benzoyl chloride
and MeOH was run for several hours on the KiloFlow® micro-
reactor in order to monitor the conversion and yield during the
course of the operation (Table 3). After reaching the steady state,
the experiment was run for 4 h and samples were collected at
different times. Initially, a yield of 90% was obtained which is
lower than the yield of 98% in the previous experiment. After
1 h, a drop in the yield was observed after which the yield stabil-
ised on 86–87%.
Conclusions
The developed catalyst-free continuous flow procedure provides
a green alternative for the existing methods of esterification of
acid chlorides. Both aliphatic and phenolic hydroxyl groups
reacted with different acid chlorides with formation of the corres-
ponding esters in excellent conversions and very short reaction
times (5–7 min). The reaction was performed solventless for
liquid reagents but requires a solvent for solid reagents in order
to prevent clogging of the microreactor channels. Upscaling the
reaction resulted in a productivity of 2.2 g min−1 of ester with an
isolated yield of 98% and recuperation of the formed HCl which
makes this reaction industrially relevant.
Experimental
All alcohols and acid chlorides are commercially available.
Liquid reagents were used in neat form and, if necessary, dis-
tilled prior to use. Solid reagents were dissolved in dioxane,
CH2Cl2 or CH3CN.
The small-scale reactions were performed using a Labtrix®
Start system (Chemtrix) (Table 4) fitted with a glass microreactor
chip of 10 μl internal volume and 2 × 1000 μl gas-tight syringes
(SGE). A back pressure regulator (BPR) of 10 bar was used in
order to keep all reagents in solution at elevated temperatures.
Before performing the reaction, the microreactor was rinsed with
the alcohol or solvent under investigation. Subsequently, the
microreactor was primed with the required alcohol and acid
chloride using a total flow rate of 15–20 μl min−1 for 5–6 min.
2778 | Green Chem., 2012, 14, 2776–2779
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Table 4 Technical specifications of the used microreactors
Structural Methusalem Funding by the Flemish Government is
gratefully acknowledged.
Labtrix® Start
KiloFlow®
Channel dimensions
Wetted materials
300 μm × 60 μm
Glass, PEEK,
PTFE, Techtron
T-mixer
1.4 mm × 1 mm
Glass, PEEK, PFA, PPS,
perfluoroelastomer
SOR mixera
Notes and references
Type of mixer
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Finally, both reagents were pumped through the microreactor
with a flow rate corresponding to the desired stoichiometric ratio
and residence time. After a steady state period (50–65 min
depending on the total flow rate, total volume of 100 μl), a
sample was collected to be analyzed by GC. The formed esters
are well known compounds and their spectral data correspond to
the data reported in the literature.
The upscaling of the condensation of benzoyl chloride with
methanol was performed using a KiloFlow® system (Chemtrix)
(Table 4) with an internal reactor volume of 13.8 ml. Both
benzoyl chloride and methanol were sonicated for 15 min before
use. A BPR of 13 bar was used in order to keep all reagents in
the liquid phase. After rinsing the microreactor with methanol,
the reactor was primed with benzoyl chloride and methanol.
Subsequently, both reagents were pumped through the micro-
reactor with a total flow rate of 2.8 ml min−1 (FMeOH
=
0.9 ml min−1, Fbenzoyl chloride = 1.9 ml min−1) and thus a resi-
dence time of 5 min and a ratio MeOH/BnCl of 1.36. After
reaching steady state (30 min), a sample was collected and ana-
lyzed by GC. Formed HCl was recuperated by bubbling dry
nitrogen through the reaction mixture and subsequently trapping
the HCl in water. After evaporating the excess of methanol,
methyl benzoate was obtained with an isolated yield of 98%.
Spectral data are in comparison with the literature.
Acknowledgements
Financial support for this research from the Fund for Scientific
Research Flanders (FWO Vlaanderen) and the Long Term
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 2776–2779 | 2779