Safe, selective, and high-yielding synthesis of acryloyl chloride in a continuous-flow system

Article abstract of DOI:10.1002/cssc.201600348

Acid chlorides are an important class of compounds and their high reactivity and instability has prompted us to develop a straightforward procedure for their synthesis with ondemand and on-site synthesis possibilities. The focus of this report is acryloyl chloride, mainly important for the acrylate and polymer industry. A continuous-flow methodology was developed for the fast and selective synthesis of the otherwise highly unstable acryloyl chloride. Three routes were investigated in a microreactor setup and all three can potentially be used for its production. The methodology was further expanded to the synthesis of other unstable acid chlorides by both the thionyl chloride and the oxalyl chloride mediated processes. The most sustainable method was the oxalyl chloride mediated procedure under solvent-free conditions, in which nearequimolar amounts of carboxylic acid and oxalyl chloride were used in the presence of catalytic amounts of DMF at room temperature. Within 1 to 3 min, nearly full conversions into the acid chlorides were achieved.

Full text of DOI:10.1002/cssc.201600348

DOI: 10.1002/cssc.201600348
Full Papers
Safe, Selective, and High-Yielding Synthesis of Acryloyl
Chloride in a Continuous-Flow System
Marine Movsisyan,[a] Thomas S. A. Heugebaert,[a] Rudy Dams,*[b] and Christian V. Stevens*[a]
Acid chlorides are an important class of compounds and their
high reactivity and instability has prompted us to develop
a straightforward procedure for their synthesis with on-
demand and on-site synthesis possibilities. The focus of this
report is acryloyl chloride, mainly important for the acrylate
and polymer industry. A continuous-flow methodology was de-
veloped for the fast and selective synthesis of the otherwise
highly unstable acryloyl chloride. Three routes were investigat-
ed in a microreactor setup and all three can potentially be
used for its production. The methodology was further expand-
ed to the synthesis of other unstable acid chlorides by both
the thionyl chloride and the oxalyl chloride mediated process-
es. The most sustainable method was the oxalyl chloride medi-
ated procedure under solvent-free conditions, in which near-
equimolar amounts of carboxylic acid and oxalyl chloride were
used in the presence of catalytic amounts of DMF at room
temperature. Within 1 to 3 min, nearly full conversions into the
acid chlorides were achieved.
Introduction
The broad utility of acid chlorides has drawn tremendous at-
tention over the years. This class of compounds is important
to facilitate numerous synthetic transformations. The focus of
this paper is acryloyl chloride, a chemical compound that has
received significant attention since the late 19th century. This
compound is a highly reactive intermediate used for the pro-
duction of important acrylates and polymers with commercial
applications in absorbents, coating materials, and paints. Its
high instability and sensitivity towards hydrolysis, Michael addi-
tion, and polymerization make this compound unfavorable for
synthesis and storage.[1] As a result of variability in product
quality and availability from commercial sources, the use of
acryloyl chloride in a production process on industrial scale is
unpredictable. Reliable on-site methods that use chlorinating
reagents of steady supply, quality, and price is needed.[2]
cially with PCl3 and SOCl2, from acryloyl chloride by distillation
is very difficult because of the small difference in boiling
points. More recently, a patent was published on the synthesis
of acid chlorides such as methacryloyl chloride with phospho-
rus trichloride.[4] During this process, no polymerization inhibi-
tor was used and a high-quality acryloyl chloride was produced
by the distillation of a liquid reaction mixture that contained
the acid and PCl3 as O2 was blown into the reaction liquid. The
O2 stream, added as a mixture of O2, N2, and air, provided an
effective inhibition for the polymerization of acrylic acid and
acryloyl chloride.
Organic reactants have also been reported for the synthesis
of acryloyl chloride. The use of oxalyl chloride for the transfor-
mation of different carboxylic acids into their corresponding
acid chlorides was reported by Adams and Ulich in 1920.[5]
Benzene as a solvent and an excess of the chlorinating re-
agents (1.5–2.5 equiv.) were necessary to achieve a fast and
almost quantitative conversion. Furthermore, a benzoyl chlo-
ride mediated procedure was first reported by Brown for the
preparation of different types of aliphatic acid chlorides.[3] An
excess of benzoyl chloride (1.5 equiv.) was used at an elevated
temperature, and the acid chloride was separated by simple
distillation. Hoque et al. reported a similar procedure.[6] Acryloyl
chloride was synthesized by the distillation of acrylic acid and
benzoyl chloride in a molar ratio of 1:2 in the presence of hy-
droquinone (68–72% yield). A slightly different molar ratio was
chosen by Chen et al., who reacted benzoyl chloride with
acrylic acid in 1:0.8 molar ratio (yield not reported).[7] Grosius
and Croizy developed a procedure using phenylchloroform to
synthesize acryloyl chloride.[8] The reaction occurred in the
presence of a Lewis acid as a catalyst (ZnO or ZrCl4) and a poly-
merization inhibitor (hydroquinone, hydroquinone methyl
esters, or copper chloride). The reaction and the distillation oc-
Numerous methods have been reported for the synthesis of
acryloyl chloride. The transformation of acrylic acid to the acyl
chloride has been attempted by using different inorganic acid
chlorides, such as PCl3, PCl5, and SOCl2.[1a,3] However, poor re-
sults (maximum 72% yield) were obtained, mainly because of
the occurrence of the aforementioned side reactions. Further-
more, the separation of these inorganic acid chlorides, espe-
[a] M. Movsisyan, Dr. T. S. A. Heugebaert, Prof. Dr. C. V. Stevens
Department of Sustainable Organic Chemistry and Technology
Ghent University
Coupure Links 653, 9000 Ghent (Belgium)
E-mail: Chris.Stevens@UGent.be
[b] Dr. R. Dams
Materials Resource Division
3M Belgium BVBA
Haven 1005, Canadastraat 11, 2070 Zwijndrecht (Belgium)
E-mail: rdams1@mmm.com
Supporting Information and the ORCID identification number(s) for the
author(s) of this article can be found under http://dx.doi.org/10.1002/
cssc.201600348.
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curred simultaneously at an elevated temperature (105–1808C)
in approximately 5 h (yield not reported).
lyst has been reported for less reactive or sterically hindered
acids.[1b] Preliminary research conducted on the flow synthesis
of acryloyl chloride in the presence of DMF showed the neces-
sity for a catalyst to obtain a significant conversion enhance-
ment.[12] It is well known that acid chlorides such as thionyl
chloride and oxalyl chloride react readily with DMF to generate
a reactive chloro-iminium intermediate (Vilsmeier–Haack re-
agent) in situ, which is ideal as a halogenating reagent.[13]
A broad screening was conducted to evaluate the effect of
DMF and the reaction conditions on the synthesis of acryloyl
chloride with thionyl chloride, oxalyl chloride, and benzoyl
chloride. For the transformation of acrylic acid into acryloyl
chloride, two separate syringe pumps were used to introduce
a solution of the acid and DMF and a solution of the chlorinat-
Besides the reactivity of acryloyl chloride towards side reac-
tions, its rapid and highly exothermic synthesis is extremely
difficult to control. Problems that concern the purity of acryloyl
chloride and the hazardous nature of the chlorinating reagents
and the byproducts require the development of a straightfor-
ward and selective procedure for the on-demand and on-site
synthesis of acryloyl chloride. We envisioned that microreactor
technology could offer a good alternative to the previous
routes. Continuous-flow systems are emerging as sustainable
and safe technologies. Nowadays, the miniaturization of reac-
tors has become a powerful tool in organic chemistry. The ad-
vantages of this technology have already been documented
extensively.[9] Its benefits are based on the principles of micro-
fluidics, more specifically, an increased surface-to-volume ratio
and fast mass and heat transfer. An enhanced level of control
of the reaction parameters, a high selectivity, and a high effi-
ciency can thus be obtained. These advantages can certainly
be applied to the reaction under study to allow precise tem-
perature control and thus to control the exothermicity of the
reaction. Furthermore, the inherently smaller reactor volume
enhances process safety significantly, an important feature
when dealing with hazardous chemicals.[10] The toxic and cor-
rosive gasses formed during the synthesis of acryloyl chloride
can hence be contained in a closed system, which reduces
safety issues greatly. In the last two decades, many advances
in organic chemistry have been made by implementing micro-
reactor technology in the academic, pharmaceutical, and fine
chemistry sectors.[9c,11] In this report, we present a continuous-
flow system for the synthesis of acryloyl chloride and other
labile acid chlorides.
ing reagent into a capillary flow reactor via
a T-mixer
(Scheme 1). The reaction mixture was collected in a flask in
Scheme 1. Schematic representation of the continuous-flow setup.
Results and Discussion
Different procedures were evaluated to find a method that
meets the industrial requirements with regard to safety, purity,
selectivity, and on-demand and on-site synthesis. A continu-
ous-flow setup was assembled to investigate different chlori-
nating reagents for the transformation of acrylic acid to acrylo-
yl chloride. The most frequently used method for the prepara-
tion of acid chlorides is the use of thionyl chloride and oxalyl
chloride as chlorinating agents. The less aggressive benzoyl
chloride can also be used as an alternative.[1b] A wide screening
of these three chlorinating reagents was performed with the
aim to develop a safe, selective, and efficient procedure with
economic and environmental feasibility.
which the headspace was connected to two additional flasks
for the neutralization of the released gasses with aqueous
NaOH. It was envisioned that, on an industrial scale, the gas-
eous byproducts such as HCl and SO2 could be treated in
a scrubber process with lime milk (Ca(OH)2).[14] The reactions
were all performed under solvent-free conditions (see Support-
ing Information). Furthermore, the isolation of acryloyl chloride
in the three procedures was performed conveniently by dis-
continuous distillation under reduced pressure at room tem-
perature. As expected, dry conditions were crucial.
First, thionyl chloride was used for the formation of acryloyl
chloride as it is widely known to transform carboxylic acids to
the corresponding acid chlorides.[1b] The most important indus-
trial production method of thionyl chloride involves the reac-
tion of sulfur trioxide and sulfur dichloride. Its commercial
availability, high quality, and low cost make this activating re-
agent highly important in an industrial setting.[15] In this work,
the stoichiometry of the catalyst and thionyl chloride was eval-
uated along with the reaction conditions such as residence
time and reaction temperature. A selection of the experiments
is shown in Table 1 (see Supporting Information for the full da-
Continuous-flow experiments with the three chlorinating re-
agents under solvent-free conditions showed that no to little
conversion (maximum 30%; see Supporting Information) into
acryloyl chloride was achieved, even at an elevated tempera-
ture (50–1008C) and with an excess of the chlorinating reagent
(1.2–2 equiv.). In this work, the optimization was not deemed
important to evaluate various solvents. As a result of the liquid
nature of the reagents, the possibility of high throughput, and
positive environmental aspects such as atom efficiency, neat
conditions were chosen for the experiments. The use of a cata-
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in a reduced selectivity towards acryloyl chloride (Entries 7–10).
For experiments with 1.2 and 2 equivalents of DMF, a shorter
residence time gave less byproduct formation (Entries 11 and
12, 15 and 16).
Table 1. Results of the thionyl chloride mediated synthesis of acryloyl
chloride with DMF.
With an excess of DMF, the reaction mixture remained ho-
mogeneous throughout the entire reactor. However, with cata-
lytic amounts of DMF a segmented plugflow was observed,
which indicated the presence of HCl and SO2. A backpressure
regulator was not used in the experiments because of the in-
compatibility of the polyether ether ketone (PEEK) material
with the acidic reaction conditions. Additionally, we assumed
that solubilizing HCl would stimulate side reactions. A plugflow
system is hence beneficial for this system as it enhances the re-
action selectivity and avoids HCl addition on the double bond.
The optimization of the thionyl chloride mediated synthesis
of acryloyl chloride resulted in two suitable procedures, which
depend on the amount of DMF. With an excess of DMF and
thionyl chloride, a high selectivity towards acryloyl chloride
(96%) can be achieved at 608C in 30 s (Table 1, Entry 15). A
slightly lower selectivity (92%) was obtained with catalytic
amounts of DMF in 3 min (Table 1, Entry 7).
Entry
DMF
[equiv.]
SOCl2
[equiv.]
T
[8C]
tr
Conv.[b]
[%]
Ratio
2/3
[min]
1
2
3
4
5
6
7
8
0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.2
100
60
60
60
40
20
60
60
60
60
60
60
80
60
60
60
3[a]
3[a]
3[a]
1[a]
1[a]
1[a]
3
1
3
1
3
22
96
97
96
86
91:9
0.05
0.1
0.1
0.1
0.1
0.2
0.2
0.5
0.5
1.2
1.2
1.2
2
90:10
88:12
87:13
86:14
85:15
92:8
84:16
86:14
84:16
88:12
91:9
54
100
100
100
100
100
100
100
100
100
100
9
10
11
12
13
14
15
16
1
1
3
3
83:17
80:20
80:20
96:4
2
2
0.5
[a]Actual retention time (tr) below reported tr because of gas formation.
[b] Determined using H NMR spectroscopy.
The reprotoxicity issues related to DMF make this compound
not the most ideal catalyst in production processes.[16] Other
catalysts were hence screened for the thionyl chloride mediat-
ed acryloyl chloride synthesis. Based on the biphasic acid scav-
enging using ionic liquids (BASIL) process of BASF for the
in situ generation of an ionic liquid for the removal of waste
HCl, 1-methylimidazole and n-butylimidazole were used to
scavenge HCl.[17] It was foreseen that the imidazole would cata-
lyze the reaction and act as a base to form the corresponding
imidazolium chloride salt, an ionic liquid, which thus scavenges
HCl. The experiments conducted with both n-butylimidazole
and 1-methylimidazole led to pumping difficulties because of
the hampering of the flow and/or the clogging of the reactor
tube. The viscosity increase because of the dense and immisci-
ble nature of the imidazolium salts is presumably responsible
for the encountered difficulties.[17] Alternatively, N,N-dimethyla-
cetamide (DMAc) was evaluated as a possible catalyst (Table 2).
An excess of DMAc resulted in the clogging of the reactor.
With equimolar amounts of DMAc and 1.2 equivalents of thio-
nyl chloride, acrylic acid was converted completely, and a selec-
1
taset). The presence of the catalyst had a big influence on the
reaction. It was observed that small amounts of DMF were suf-
ficient to enhance the conversion significantly. With only
0.05 equivalents of DMF and 1.5 equivalents of thionyl chlo-
ride, the conversion of acrylic acid was increased from 22 to
96% in neat conditions at 608C in 3 min with a selectivity of
90% for acryloyl chloride (Entry 1 vs. 2). However, the double
bond is prone to HCl addition, and under these conditions
a small amount of 3-chloropropionyl chloride (3) was formed.
Furthermore, 4% of acrylic acid was still present in the reaction
mixture. A higher amount of DMF resulted in the complete
conversion of acrylic acid into either acryloyl chloride (2) and/
or 3 (Entries 3, 7, 9, and 11 vs. 14). With 0.2 equivalents of DMF,
100% conversion of acrylic acid was achieved with a slightly
enhanced selectivity towards acryloyl chloride (92%) at 608C
in 3 min (Entry 7). With 2 equivalents of DMF and 1.2 equiva-
lents of thionyl chloride, 96% conversion into the desired com-
pound was achieved in only 30 s (Entry 15). Additionally, the
influence of the temperature was evaluated for reactions with
0.1 and 1.2 equivalents of DMF (Entries 4–6, 12 and 13). In the
first case, a decreased conversion of acrylic acid was observed
when the temperature was decreased. At 608C, 96% of the
starting material was converted, whereas a 208C decrease re-
sulted in 86% conversion of acrylic acid (Entry 5). An additional
208C decrease led to a decreased conversion of 54% (Entry 6).
However, for the experiments with 1.2 equivalents of DMF,
a temperature increase from 60 to 808C enhanced the HCl ad-
dition to result in a doubling of the amount of byproduct 3
(Entry 12 vs. 13). For selectivity reasons, 608C was chosen as
the optimum temperature.
Table 2. Results of the thionyl chloride mediated synthesis of acryloyl
chloride with DMAc.
Entry
DMAc
[equiv.]
SOCl2
[equiv.]
T
[8C]
tr
Conv.[a]
[%]
Ratio
2/3
[min]
1
2
3
4
5
6
1
1
1
1
1
1
1.2
1.2
1.2
1.5
1.5
1.5
60
60
60
60
60
60
3
1
0.5
3
1
100
100
100
100
100
100
89:11
89:11
90:10
85:15
90:10
84:16
After evaluating the temperature effect, the influence of the
residence time was screened. It was observed that up to
0.5 equivalents of DMF, decreasing the residence time, resulted
0.5
1
[a] Determined by using H NMR spectroscopy.
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tivity of up to 90% towards acryloyl chloride at 608C was
reached in 30 s. The remaining 10% was the byproduct 3
formed by HCl addition on the double bond (Entry 3).
Table 3. Results of the oxalyl chloride mediated synthesis of acryloyl
chloride with DMF.
Next, the use of N-formylmorpholine (NFM) was evaluated in
the same flow setup. Different amounts of NFM (catalytic, equi-
molar, and an excess) were used, but each experiment was
stopped because of clogging issues. Overall, it can be conclud-
ed that the procedure with thionyl chloride is a fast and effi-
cient method for the synthesis of acryloyl chloride. Catalytic
amounts of DMF were enough to achieve the full conversion
of acrylic acid with 92% selectivity towards acryloyl chloride
(Table 1, Entry 7). An excess of DMF leads to an increased selec-
tivity towards the desired acid chloride up to 96% (Table 1,
Entry 13). We also observed that DMF acted as a HCl scaveng-
er, which reduced the formation of 3-chloropropionyl chloride
and enhanced the selectivity. DMAc is an alternative catalyst
for the synthesis of acryloyl chloride.
Entry
DMF
[equiv.]
(COCl)2
[equiv.]
T
[8C]
tr[a]
[min]
Conv.[b]
[%]
Ratio
2/3
1
2
3
4
5
6
7
8
0
1.5
1.5
1.5
1.5
1.5
1.5
1.1
1
1.5
1.1
1.1
1.05
1.05
1
50
60
60
60
40
20
0
3
3
3
1
1
1
3
3
3
5
3
5
3
5
3
5
5
5
5
1
5
1
5
1
11
96
100
96
100
100
97
94
100
98
98
98
94
94
96
98
98
95
98
99
100:0
95:5
92:8
91:9
94:6
96:4
90:10
86:14
87:13
96:4
92:8
97:3
96:4
98:2
93:7
98:2
98:2
97:3
99:1
98:2
98:2
97:3
98:2
98:2
0.05
0.1
0.1
0.1
0.1
0.5
0.5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.5
1.5
1.5
2
0
9
50
20
0
20
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Oxalyl chloride is the second organic chlorinating reagent
suitable to convert a,b-unsaturated carboxylic acids to the cor-
responding acid chlorides. The direct chlorination of anhydrous
oxalic acid with phosphorus pentachloride is the typical com-
mercial-scale procedure for the synthesis of oxalyl chloride.[18]
Experiments were conducted under neat conditions in the
same microreactor setup as for the thionyl chloride procedure
(see Supporting Information). Again, the effect and the stoichi-
ometry of the catalyst and the influence of the reaction condi-
tions on the conversion were screened (Table 3). Catalytic
amounts of DMF were sufficient to achieve up to 96% conver-
sion of acrylic acid with a 95% selectivity towards acryloyl
chloride with 1.5 equivalents of oxalyl chloride at 608C in
3 min (Entry 1 vs. 2). A small amount of 3 (5%) was also
formed during the reaction. The use of double the amount of
DMF did not affect the selectivity of the reaction significantly
but resulted in the full conversion of acrylic acid (Entry 3). The
effect of temperature was further evaluated for experiments
with 0.1 equivalents of DMF and 1.5 equivalents of oxalyl chlo-
ride. A decrease of the reaction temperature from 60 to 40 and
208C had a slight effect on the conversion (Entries 4–6). Under
these reaction conditions, a selectivity increase towards acrylo-
yl chloride was observed. At 208C, the full conversion of acrylic
acid was achieved with 96% selectively into acryloyl chloride
with a residence time of 1 min (Entry 6). The effect of the tem-
perature was also studied with different amounts of DMF and/
or different amounts of oxalyl chloride. Even at 08C, an excel-
lent conversion to acryloyl chloride was achieved (Entries 7, 8,
11, 13, and 15).
20
0
1
1.1
1.05
1
1.1
1.1
1.05
1.05
1
20
20
20
20
20
20
20
20
20
2
2
2
2
97
99
97
91
2
1
[a] Actual tr below reported tr because of gas formation. [b] Determined
by using 1H NMR spectroscopy.
sufficient to reach 98% conversion of acrylic acid with 97% se-
lectivity towards acryloyl chloride (Entry 12). A segmented flow
was observed in each experiment, which showed the forma-
tion of CO, CO2, and HCl clearly. Again, we chose not to use
a backpressure regulator for both selectivity and compatibility
reasons.
Reactions with oxalyl chloride in the presence of other cata-
lysts were also attempted. DMAc and NFM both led to the
clogging of the reactor, regardless of if these reagents were
used in catalytic, equimolar, or excess amounts.
Also, the procedure with oxalyl chloride can be seen as
a suitable method for the synthesis of acryloyl chloride. With
2 equivalents of DMF and 1.1 equivalents of oxalyl chloride,
a conversion of 99% of acrylic acid was achieved at room tem-
perature in 1 min with a selectivity of 98% towards acryloyl
chloride (Table 3, Entry 20). The full conversion of acrylic acid
and excellent selectivity to acryloyl chloride (96%) could also
be obtained with catalytic amounts of DMF (0.1 equiv.; Table 3,
Entry 6).
Next, the residence time was evaluated. A decrease in the
residence time resulted in a slight decrease in the conversion
(4–7%; Entry 3 vs. 4). This was, however, not observed with
higher amounts of DMF and a small excess of oxalyl chloride
(Entries 19 vs. 20 and 21 vs. 22). In the next series of experi-
ments, the effect of oxalyl chloride was evaluated (Entries 9,
10, 12, 14; 16–18; 19–24). A decrease of 1.5 equivalents of
oxalyl chloride to 1.1 to 1.05 equivalents and further to equi-
molar amounts did not influence the conversion. A slight
excess of oxalyl chloride (1.05 equiv.) and 1.2 equivalents of
DMF at room temperature and a residence time of 5 min were
To demonstrate the scale-up possibilities beyond laboratory
scale, the synthesis of acryloyl chloride was conducted for
a prolonged period of time without any alteration of the reac-
tion conditions. A dual syringe pump (Africa system) to pump
the solution of acrylic acid and DMF and a Chemyx syringe
pump to pump oxalyl chloride were used to ensure a continu-
ous system. The reaction was run at ambient temperature with
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a residence time of 1 min (Table 3, Entry 20). After reaching
steady state, the flow process was operated without interrup-
tion for 1 h in a 0.5 mL reactor tube with a throughput of 8.5 g
of acryloyl chloride per hour, which corresponds to approxi-
mately 200 g per day. Over the entire operation time, the con-
version of acrylic acid (97%) and the selectivity (98%) towards
the desired acryloyl chloride remained constant.
product by increasing the amount of the chlorinating reactant
(Entries 10–11). With 3 equivalents of benzoyl chloride, 80% of
the acrylic acid was converted selectively into acryloyl chloride,
in 3 min at 608C (Entry 11). Furthermore, a dependence on the
residence time was observed. A decrease in residence time re-
sulted in a lower conversion (Entries 11–13). Throughout the
entire reactor, the solution mixture remained homogeneous,
and no byproducts were formed in these experiments.
Finally, the less aggressive chlorinating reagent benzoyl chlo-
ride was screened for the synthesis of acryloyl chloride. Benzo-
yl chloride is made commercially through the partial hydrolysis
of benzotrichloride, which is produced by the chlorination of
toluene. Alternatively, benzoyl chloride can be produced by
the reaction of benzoic acid with thionyl chloride, phosgene,
or phosphorus pentachloride.[19] In the continuous-flow experi-
ments with benzoyl chloride, the stoichiometry of DMF and
benzoyl chloride was evaluated along with reaction conditions
such as residence time and reaction temperature (see Support-
ing Information). We observed that the reaction of acrylic acid
and benzoyl chloride yielded the desired acryloyl chloride se-
lectively (Table 4). However, small amounts of DMF were insuf-
Based on these results, it can be concluded that the rate of
the reaction was increased by the addition of DMF to the reac-
tion mixture and thus a catalytic effect was observed. It has
been reported that benzoyl chloride in the presence of DMF
does not form a Vilsmeier–Haack intermediate, in contrast to
thionyl chloride and oxalyl chloride.[20] The formation of other
N,N-dimethylamides and formyl chloride has been suggested.
However, neither N,N-dimethylbenzamide nor N,N-dimethyla-
crylamide was detected in this study. As such, whether or not
the Vilsmeier–Haack intermediate was formed from DMF and
benzoyl chloride is still subject to discussion.
The best procedure for a mild, controllable, and completely
selective synthesis of acryloyl chloride (80%) was the use of an
excess of DMF (2 equiv.) and benzoyl chloride (3 equiv.) with
a residence time of 3 min at 608C (Table 4, Entry 11).
Table 4. Results of the benzoyl chloride mediated synthesis of acryloyl
chloride with DMF.
Again, other catalysts were screened for the benzoyl chlo-
ride mediated synthesis of acryloyl chloride (see Supporting In-
formation). When triethylamine was used, a tube-plugging
problem was encountered immediately after the mixing of the
solutions. This is probably because of the formation of the in-
soluble triethylammonium hydrochloride salt. The effect of
DMAc was also evaluated. An excess of DMAc resulted in the
clogging of the reactor. With equimolar amounts of DMAc,
a maximum conversion of 21% of acrylic acid into acryloyl
chloride was reached. The experiments showed clearly that an
increase of either the residence time or the temperature result-
ed in a higher conversion into the acid chloride. Next, NFM
was screened for the reaction (Table 5). With an excess of ben-
zoyl chloride, increased amounts of NFM resulted in an en-
hanced conversion (Entries 1–3, 6). The conversion, however,
stagnated with equimolar amounts of NFM (Entries 3 vs. 6).
Under equimolar conditions of NFM and 1.5 equivalents of
benzoyl chloride, a maximum conversion of 64% was reached
at 808C in 3 min (Entry 3). The use of double the amount of
benzoyl chloride induced a slightly higher conversion (72%;
Entry 5). A positive correlation between the conversion and
both the residence time (Entries 7–9, 10–12) and temperature
(Entries 7 and 10, 8 and 11, 9 and 12) was observed.
Entry
DMF
[equiv.]
PhCOCl
[equiv.]
T
[8C]
tr
Conv.[a]
[%]
Ratio
2/3
[min]
1
2
3
4
5
6
7
8
0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2
70
60
60
60
40
20
60
40
20
60
60
60
60
60
2
3
3
3
3
3
3
3
3
3
3
1
0.5
3
0
37
62
67
65
67
65
66
66
73
80
78
72
65
0:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
0.2
0.5
1.2
1.2
1.2
2
2
2
2
2
9
10
11
12
13
14
3
3
3
1.5
2
2
3
1
[a] Determined by using H NMR spectroscopy.
ficient to achieve a high conversion of the acrylic acid into
acryloyl chloride (Entries 1–3). Excess amounts of DMF
(1.2 equiv.) and benzoyl chloride (1.5 equiv.) enabled us to con-
vert 67% of the acrylic acid selectively into acryloyl chloride at
608C in a residence time of only 3 min (Entry 4). The experi-
ments were also conducted at lower temperatures (40 and
208C) and the same conversions were reached, which indicates
that temperature is not a determining parameter (Entries 4–6
and 7–9). At 608C, an increase of the amount of DMF to
2 equivalents did not affect the conversion (Entry 7). Neither
did a further increase to 3 equivalents of DMF give rise to
a higher conversion (Entry 14). Presumably, the presence of
benzoic acid in the mixture restricts this equilibrium reaction.
The equilibrium can, however, be shifted towards the desired
The procedure with benzoyl chloride can be seen as a mild
and selective method for the synthesis of acryloyl chloride. The
equimolar presence of the catalyst (DMF/NFM) was necessary
to obtain good conversions into the acid chloride. The highest
conversion of acrylic acid into acryloyl chloride (80%) was
reached with 2 equivalents of DMF and 3 equivalents of benzo-
yl chloride within 3 min at 608C (Table 4, Entry 11). Overall, we
observed a high dependence of the conversion on the temper-
ature and residence time.
The level of control offered by the flow setup allowed us to
develop different methods to conduct this fast, exothermic,
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comprise a closed safe system and allow a highly selective and
efficient synthesis of the reactive compound. As acryloyl chlo-
ride is used mainly in the production of polyacrylates, its syn-
thesis can influence downstream reactions. Hence, it was cru-
cial that the generated byproducts did not interfere in the sub-
sequent reactions. The presence of sulfur-containing com-
pounds was reported to be detrimental.[21] The procedure with
oxalyl chloride was hence considered to be superior for the
synthesis of high-quality acryloyl chloride.
Table 5. Results of the benzoyl chloride mediated synthesis of acryloyl
chloride with NFM.
Entry
NFM
[equiv.]
PhCOCl
[equiv.]
T
[8C]
tr
Conv.[a]
[%]
Ratio
2/3
[min]
1
2
3
4
5
6
7
8
0.2
0.5
1
1
1
2
2
2
2
1.5
1.5
1.5
2
3
1.5
2
2
2
2
2
80
80
80
80
80
80
80
80
80
3
3
3
3
3
3
3
1
31
53
64
69
72
61
66
53
43
71
63
55
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
The success with oxalyl chloride and thionyl chloride
prompted us to test the thionyl chloride and oxalyl chloride
mediated procedures for the selective and efficient synthesis
of other acid chlorides and hence screen other substrates for
which the corresponding acid chlorides are difficult to obtain.
The carboxylic acids used as starting materials include unsatu-
rated, saturated, and heterocyclic acids. In many cases, the cor-
responding acid chlorides are unstable and difficult to prepare.
Katritzky et al. developed the benzotriazole method for the
synthesis of N-acylbenzotriazoles as an alternative for acid
chlorides,[22] which can also be produced in flow.[23] In this
study, the scope of both the oxalyl chloride and the thionyl
chloride methods was widened for other substrates. As ob-
served in the previous experiments for the synthesis of acryloyl
chloride, a slight excess of the chlorinating reagent was suffi-
cient to obtain a high conversion. Hence, for the optimization
of the continuous-flow synthesis of various acid chlorides,
1.05 equivalents of the chlorinating reagent was used. As the
reactions with DMF displayed a high conversion, DMF was
chosen as the catalyst. The amount of DMF was varied from
0.1 to 1.2 equivalents to test both the reactivity and the selec-
tivity of the reaction. The experiments were conducted under
solvent-free conditions at room temperature with residence
times of 1–5 min.
9
0.5
3
1
10
11
12
2
2
2
100
100
100
2
0.5
1
[a] Determined by using H NMR spectroscopy.
and gas-generating reaction. Overall, three suitable flow proce-
dures were developed for the synthesis of acryloyl chloride.
The benzoyl chloride mediated method can be considered as
a mild and selective method to achieve a good conversion.
The best result (80%) was obtained by reacting acrylic acid in
the presence of 2 equivalents of DMF with 3 equivalents of
benzoyl chloride at 608C with a residence time of 3 min. A
higher conversion of acrylic acid can, however, be reached
using oxalyl chloride and thionyl chloride as chlorinating re-
agents. For the latter, two possible methods are proposed that
depend on the amount of DMF used. Both catalytic amounts
and an excess of DMF can be used to furnish acryloyl chloride.
If catalytic amounts of DMF (0.2 equiv.) are utilized, the full
conversion of acrylic acid with 92% selectivity towards acryloyl
chloride is reached at 608C in 3 min (Table 1, Entry 7). An even
higher reaction selectivity towards the desired acid chloride
(96%) can be obtained with 2 equivalents of DMF at 608C in
30 s (Table 1, Entry 15). For the oxalyl chloride mediated syn-
thesis, two methods are presented. With 2 equivalents of DMF
and 1.1 equivalents of oxalyl chloride, a conversion of 99% of
acrylic acid was achieved at room temperature in 1 min with
For the procedure with thionyl chloride, excellent conver-
sions into the acid chlorides were achieved (Table 6). The ex-
periments were performed at room temperature in a similar re-
actor setup as the previous experiments. We observed that the
effect of DMF on the reactivity was significant. Catalytic
amounts of DMF were insufficient to achieve a high conversion
(condition A for compounds 4, 6, and 7). A small excess of
DMF, however, provided the acid chlorides in excellent to full
conversion (condition B for compounds 4–7).
a
selectivity of 98% towards acryloyl chloride (Table 3,
To further demonstrate the applicability of oxalyl chloride,
the process optimized previously was used in the presence of
oxalyl chloride (Table 7). The experiments (condition B for com-
pounds 4–7) displayed a full conversion with 1.2 equivalents of
DMF. Catalytic amounts of DMF, however, also resulted in rea-
sonable to excellent conversions (condition A for com-
pounds 4, 6, and 7).
Entry 20). The full conversion of acrylic acid and a slightly
lower selectivity to acryloyl chloride (96%) could also be ob-
tained with catalytic amounts of DMF (0.1 equiv.; Table 3,
Entry 6).
The choice of the best procedure among the three opti-
mized methods is not that straightforward. Each method has
its own advantages and disadvantages. Different factors play
a role; such as efficacy, selectivity, cost, amount of starting ma-
terial, amount of byproducts, purification, and downstream re-
actions. For the synthesis of acryloyl chloride, the main objec-
tive was to develop a straightforward process that meets the
industrial requirements with regard safety, purity, and selectivi-
ty. Based on these conditions, both the thionyl chloride and
oxalyl chloride mediated flow procedures were suitable as they
Conclusions
The ability of the flow setup to achieve a high conversion in
minutes at room temperature rather than hours at elevated
temperature in batch processes, illustrates the power of micro-
reactor technology. The developed oxalyl chloride mediated
synthesis was superior to the procedures with benzoyl or thio-
&
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Furthermore, the screening of the thionyl chloride and
oxalyl chloride mediated procedures for various substrates
showed the practical, straightforward, and efficient nature of
both methods. Both syntheses enjoy a broad scope, and excel-
lent conversions were reached. The transformation with oxalyl
chloride can be considered to be superior because catalytic
amounts of DMF were sufficient to obtain an excellent conver-
sion, which facilitates product isolation.
Table 6. Scope of the thionyl chloride mediated synthesis of acid chlor-
ides with DMF.
Acid chloride
Condition
DMF [equiv.]
Conv.[a] [%]
A
B
0.1
1.2
51–69
97–100
The simple continuous-flow setup can be used on a laborato-
ry scale and allows a high throughput (200 g per day). The on-
demand and on-site synthesis of acid chlorides was made pos-
sible, which thus eliminates purity and safety issues. Moreover,
this system can be considered as a sustainable method as it
enables a reduction in energy and materials consumption be-
cause of the efficient mass and heat transfer and the high pro-
cess selectivity.
[b]
A
B
C
A
B
0.1
1.2
0.9
0.1
1.2
–
97–100
90–100[c]
98–100
94–99
A
B
0.1
1.2
32–37
99
[a] Determined by using 1H NMR spectroscopy. [b] Clogging occurred.
[c] As a result of solubility issues with crotonic acid, 0.9 equiv. of DMF
were used instead of 0.1 equiv..
Experimental Section
Operating platform: The reagent solutions were pumped through
a perfluoroalkoxy alkanes (PFA) tubular reactor by using a syringe
pump (Chemyx Syringe pump—type Fusion Touch or Fusion Clas-
sic). The connection of the syringes (Hamiltonꢁ syringe 10 mL,
1000 series GASTIGHTꢁ) with an ethylene tetrafluoroethylene
(ETFE) T-connector was performed with an ETFE Luer lock. The
mesoreactor was built of PFA tubing with an internal diameter of
0.020“ (0.50 mm) and an outer diameter of 1/16” with a total
volume of 0.5 mL. The mesoreactor was heated to the desired re-
action temperature in an oil bath. The reaction mixture was collect-
ed in a flask, and the exhaust gasses were quenched in aq NaOH.
Table 7. Scope of the oxalyl chloride mediated synthesis of acid chlorides
with DMF.
Acid chloride
Condition
DMF [equiv.]
Conv.[a,b] [%]
A
B
0.1
1.2
85–92
95–100
[c]
A
B
C
A
B
0.1
1.2
0.9
0.1
1.2
–
100
Acknowledgements
98–100[d]
84–95
97–100
Financial support for this research from 3M Company, the
Agency for Innovation by Science and Technology in Flanders
(IWT), and the Flanders Fund for Scientific Research (FWO) is
gratefully acknowledged.
A
B
0.1
1.2
72–90
99–100
[a]Actual tr below reported tr because of gas formation. [b] Determined
by using 1H NMR spectroscopy. [c] Clogging occurred. [d] As a result of
solubility issues with crotonic acid, 0.9 equiv. of DMF were used instead
of 0.1 equiv.
Keywords: carboxylic acids · acryloyl chloride · microreactors ·
organocatalysis · synthesis design
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Received: March 14, 2016
Revised: April 26, 2016
Published online on && &&, 0000
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FULL PAPERS
The fast and the selective: A continu-
ous-flow methodology is developed for
the fast and selective synthesis of the
otherwise highly unstable acryloyl chlo-
ride. The simple continuous-flow setup
can be used on a laboratory scale and
allows a high throughput (200 g per
day). This system is a sustainable
M. Movsisyan, T. S. A. Heugebaert,
R. Dams,* C. V. Stevens*
&& – &&
Safe, Selective, and High-Yielding
Synthesis of Acryloyl Chloride in
a Continuous-Flow System
method as it enables a reduction in
energy and materials consumption be-
cause of the efficient mass and heat
transfer and the high process selectivity.
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These are not the final page numbers! ÞÞ