Hydrogen Chloride Gas in Solvent-Free Continuous Conversion of Alcohols to Chlorides in Microflow

Article abstract of DOI:10.1021/acs.oprd.6b00014

Chlorides represent a class of valuable intermediates that are utilized in the preparation of bulk and fine chemicals. An earlier milestone to convert bulk alcohols to corresponding chlorides was reached when hydrochloric acid was used instead of toxic and wasteful chlorinating agents. This paper presents the development of an intensified solvent-free continuous process by using hydrogen chloride gas only. The handling of corrosive hydrogen chloride became effortless when the operating platform was split into dry and wet zones. The dry zone is used to deliver gas and prevent corrosion, while the wet zone is used to carry out the chemical transformation. The use of gas instead of hydrochloric acid allowed a decrease in hydrogen chloride equivalents from 3 to 1.2. In 20 min residence time, full conversion of benzyl alcohol yielded 96 wt % of benzyl chloride in the product stream. According to green chemistry and engineering principles, the developed process is of an exemplary type due to its truly continuous nature, no use of solvent and formation of water as a sole byproduct.

Full text of DOI:10.1021/acs.oprd.6b00014

Article
pubs.acs.org/OPRD
Hydrogen Chloride Gas in Solvent-Free Continuous Conversion of
Alcohols to Chlorides in Microflow
Svetlana Borukhova, Timothy Noel, and Volker Hessel*
̈
Department of Chemical Engineering and Chemistry, Technische Universiteit Eindhoven, De Rondom 70, 5612 AP Eindhoven, The
Netherlands
S
* Supporting Information
ABSTRACT: Chlorides represent a class of valuable intermediates that are utilized in the preparation of bulk and fine chemicals.
An earlier milestone to convert bulk alcohols to corresponding chlorides was reached when hydrochloric acid was used instead of
toxic and wasteful chlorinating agents. This paper presents the development of an intensified solvent-free continuous process by
using hydrogen chloride gas only. The handling of corrosive hydrogen chloride became effortless when the operating platform
was split into dry and wet zones. The dry zone is used to deliver gas and prevent corrosion, while the wet zone is used to carry
out the chemical transformation. The use of gas instead of hydrochloric acid allowed a decrease in hydrogen chloride equivalents
from 3 to 1.2. In 20 min residence time, full conversion of benzyl alcohol yielded 96 wt % of benzyl chloride in the product
stream. According to green chemistry and engineering principles, the developed process is of an exemplary type due to its truly
continuous nature, no use of solvent and formation of water as a sole byproduct.
the lower molecular weight of chloride, when compared to
other halogens, substitution of chloride generates less waste.5
Unfortunately, synthesis of chlorides from alcohols requires
highly toxic and waste-intensive chlorinating agents such as
thionyl chloride,6 phosphorus chlorides,7 pivaloyl chloride,8
Vilsmeier reagent,9 tosyl chloride,10 2,4,6-trichloro-[1,3,5]-
triazine with DMF,11 oxalyl chloride,12 and phosgene.13 Mostly,
chlorinating agents are used in stoichiometric or excessive
amounts that lead to a high generation of waste.14
Therefore, the ideal process would involve conversion of neat
alcohols to chlorides by hydrogen chloride (HCl). This will
minimize waste generation since the sole byproduct is water.
Kappe et al. showed utilization of 30 wt % aqueous
hydrochloric acid in chlorination of 1-butanol, 1-hexanol, and
1-decanol within a microreactor.15 In 15 min residence time,
with 3 equiv of 30 wt % aqueous HCl and at elevated
temperatures quantitative yields were obtained. We recently
realized a process utilizing 37 wt % aqueous HCl to afford a
wider scope of aliphatic and benzylic substrates in the same
time range.16 Furthermore, prepared chlorides were coupled
with piperazine derivatives to synthesize cinnarizine, cyclizine,
and buclizine derivatives in multistep continuous synthesis. The
main drawback of both processes was the need for 3 equiv of
hydrochloric acid to prevent synthesis of byproducts, such as
ethers. In addition, continuity of the process was limited by the
need to stop to refill the hydrochloric acid loop, which was used
to circumvent corrosion of the pumps.
INTRODUCTION
■
Sustainable manufacturing of active pharmaceutical ingredients
(APIs) encompasses several aspects such as continuous
processing, process intensification, minimization of solvent
use and advances in bioprocesses.1 Currently, continuous
processing is one aspect within process intensification, which
targets the reduction of equipment size, costs, energy
consumption, solvent utilization, and waste generation.2
Microreactor technology is an actively studied platform aiming
at implementing continuous processing, achieving process
intensification and finally assisting in delivering sustainable
processes for the production of APIs.3
In case of biologically active compound synthesis, the final
target is constructed from intermediates. The quality of the final
product and its cost are inevitably dependent on the manner
intermediates are produced. Chlorides serve as good inter-
mediates in the synthesis of APIs, usually in nucleophilic
substitutions exemplified on Scheme 1, where a chloride atom
is substituted by a nucleophile in the subsequent step.4 Due to
Scheme 1. Possible Scaffolds That Can Be Synthesized from
Chloroalkanes
The limited solubility of hydrogen chloride in water leads to
a limitation in its concentration. The maximum available
concentration in hydrochloric acid is 37 wt %, meaning that in
Special Issue: Continuous Processing, Microreactors and Flow
Chemistry
Received: January 13, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.6b00014
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Figure 1. Hydrogen chloride gas delivery unit (top, dry zone) and chlorodehydroxylation rig (bottom, wet zones), where the reaction takes place.
the nucleophilic substitution case chloride competes with water
as nucleophile. In order to maximize the concentration of
hydrogen chloride within a medium, pure hydrogen chloride
gas can be used. Using hydrogen chloride gas can also solve the
problem of the aforementioned limited continuity and allows
truly continuous processing. Large pressurized reaction vessels
need to be under constant observation when such toxic and
corrosive gases are used, requiring special precautions such as
dedicated high-pressure facilities to avoid any leakages and
allow moderate solubility of gaseous reagents in the reaction
media. Gas−liquid reactions in large batch reactors are usually
performed at lower temperatures to increase gas solubility and
minimize associated risks. Finally, due to the low interfacial
areas in batch reactors and low temperatures, reactions take
place in extended times, which most of the times does not
justify the effort.
surface-to-volume ratio leading to high heat and mass transfer
rates.18 Moreover, due to the low operating volumes of micro
reactors only small volumes are pressurized at a time, while
continuously performing the reaction. The higher safety
associated with microreactors allows investigation of a wide
range of process conditions, usually leading to process
intensification. A number of examples utilizing gases as reagents
within micro flow reactors, such as CF3I,19 C2H2,20 C2H4,21
CH2O,22 CH2N2,23 Cl2,24 CO,25 CO2,26 F2,27 H2,28 NH3,29
31
O2,30 and O3 have been published.
Herein, we report for the first time the use of hydrogen
chloride gas as a reagent for a continuous synthesis of
chloroalkanes in microflow. Highly corrosive in the presence
of moisture, hydrogen chloride requires special precautions
during the design of the process. We present related
challenging aspects and corresponding solutions. Finally, the
merit of the use of hydrogen chloride along with its limitations
are presented.
Meanwhile, microreactors offer a great platform for gas−
liquid reactions due to the formation of distinct, regular flow
patterns with high periodicity or symmetry.17 These offer a high
B
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into the heating media upon operation was observed, due to the
thinner wall thickness. A hot product stream was allowed to
flow through 30 cm long tubing prior to entering the Equilibar
back pressure regulator (BPR) to allow cooling. For present
application, an Equilibar BPR demonstrated a unique ability to
apply pressure and keep gas−liquid flows stable up to 16 bar
pressure. Its use circumvented the need for gas−liquid
separation prior to the pressurization unit. (NOTE: Inline
cartridge based BPRs could not provide constant flow, and
resulted rather in stop-flow behavior, which affected the
operation of the mass flow controller, thus causing inaccuracy
in the gas flow rate.) Table 1 demonstrates the window of
operating conditions of the operating platform.
EXPERIMENTAL PLATFORM
■
In order to control the flow rate of hydrogen chloride, a gas
mass flow controller is needed. In general, mass flow controllers
are made of stainless steel and hastelloy, which are susceptible
to corrosion. Hydrogen chloride in its pure state is harmless to
stainless steel and hastelloy. However, the moment the
moisture content rises above 10 ppm, severe corrosion starts
to take place. Therefore, absolute dry conditions are needed to
prevent the corrosion of the device. By splitting the
experimental setup into two zones, dry and wet, first as a
hydrogen chloride gas delivery unit and second as a reaction rig,
the corrosion was circumvented.
Hydrogen Chloride Delivery Unit. Figure 1 (top) shows
the assembly of the hydrogen chloride supply unit. In order to
keep moisture out of the unit all connections were of VCR type
from Swagelok. Moreover, due to the fact that polymer based
tubing is permeable to moisture, stainless steel tubing of 1/4″
size was used. One out of three nitrogen bottles was set to 40
bar for startups and shutdowns of the system. The other two
were set to 15 bar pressure to be used in constant purging of
the system in between experiments to prevent diffusion of
moisture into the mass flow controller. Despite purging, a
diffusion front is still present, which takes place in the direction
opposite to the flowing nitrogen. Therefore, a stainless steel 2
m long “pig tail” with 250 μm internal diameter was added
following the last valve of the delivery unit. In our experience,
inline nonmetallic check valves sometimes fail at high pressures
and allow liquid to enter the gas stream. In case of such an
unexpected failure, the liquid shall destroy the mass flow
controller upon reaching it due to corrosion.
Table 1. Operating Parameters of Chlorodehydroxylation
Flow Setup
parameter
range
reactor volume
reactor internal diameter
gas mass flow rate
reactant flow rate
temperature
4 mL
762 μm
0.001−0.600 g/min (0.1−80 mL/min)
0.09−0.15 mL/min
25−120 °C
pressure
16 bar
RESULTS AND DISCUSSION
■
Benzyl chloride is used as an intermediate in the preparation of
pharmaceuticals, flavorants, plasticizers, and perfumes. Accord-
ing to Gerrard et al., hydrogen chloride dissolves in benzyl
alcohol under atmospheric pressure to a significant extent as
shown in Figure 2.32 A significant absorption of gas, as shown
In order to visually verify if any liquid ever was moving
toward the mass flow controller, transparent ethylene
tetrafluoroethylene (ETFE) tubing of 250 μm was added
after stainless steel tubing. A polyether ether ketone (PEEK)
valve was attached, which can be shut in case liquid flow was
detected. Another 2 m of ETFE tubing of 750 μm was added
after, followed by an inline check valve.
In order to enhance desorption of water molecules from the
surface of the tubing used in construction of the setup, a
vacuum line was installed. A cyclic vacuum-purge procedure
was applied before the start of the operation and before
disassembling the setup. It is important to mention that in case
of no vacuum, and sole purging, components of the setup
corrode upon disassembly and exposure to air. A bypass around
the mass flow controller was installed to assist vacuuming of the
mass flow controller from both ends. Before introducing
hydrogen chloride into the unit for the first time, a dew point
transmitter was used to the measure moisture content. A
moisture content of 0.8 ppm was typical for our system due to
the dry nitrogen that was used for purging after purge-vacuum
procedure. Pictures with a more detailed information regarding
the setup are enclosed in the Supporting Information.
Chlorodehydroxylation Rig. Alcohols that are liquid
under atmospheric conditions were pumped with a Knauer
HPLC pump. A gas−liquid slug flow initiated in a Y-mixer and
continued into the ETFE reactor as shown in Figure 1
(bottom). (NOTE: a T-mixer was not suitable due to the liquid
slugs appearing on the gas feed line prior to the mixer. As a
result, these penetrations brought about fluctuations in the gas
flow rate observed on the mass flow controller.) The reactor
was made of ETFE tubing of 762 μm internal diameter. When
1 mm inner diameter tubing was used instead, escape of gas
Figure 2. Solubility of hydrogen chloride gas in 1-butanol and benzyl
alcohol (redrawn with permission from ref 32. Copyright 2007, John
Wiley and Sons).
in Figure 3, was observed when benzyl alcohol and hydrogen
chloride were mixed in the tubing prior to entering the reactor
coil (at room temperature under 5 bar pressure). In theory, the
solubility of gas in liquid increases with pressure and decreases
with temperature. In addition, throughout the reactor the gas is
consumed as the reaction progresses. With an increase in
temperature, the extent of gas expansion, and thus residence
time as well, are hard to quantify due to its substantial
expansion and faster consumption. Therefore, the sole measure
of success of a reaction was based on the yield of synthesized
chloride, while residence time was estimated based on flow
C
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Figure 3. Gas slug size with respect to the distance from the mixing
Figure 4. Pressure effect on weight distribution among benzyl chloride
point of gas and liquid, Y-mixer.
(red), benzyl alcohol (blue), and dibenzyl ether (green).
behavior. In-line absorption measurements to determine the
residence time were avoided due to the corrosive nature of the
product stream.
bar to 93 wt % at 16 bar, while the formation of byproduct stays
the same and equal to 3−4 wt %. Thus, higher concentration of
hydrogen chloride increased the conversion, while showing no
effect on selectivity. No change in conversion was observed
with increasing pressure at 90 and 100 °C. Dibenzyl either
formed in 4 wt % at 90 °C with 92 wt % of benzyl chloride, and
in 5 wt % at 100 °C with 95 wt % of benzyl chloride. We
proceeded further with increasing equivalents at higher pressure
(10, 12, 16 bar) at 100 °C. The minimum concentration of
dibenzyl ether was 4% at 10 bar at 1.2 and more equivalents.
Therefore, those conditions, i.e., 100 °C, 1.2 equiv, 20 min
residence time, and 10 bar, were set as optimal, yielding full
conversion and 96 wt % of benzyl chloride.
One of the goals in using gas was to minimize excess of HCl
used, thus generated waste. In our previous investigations with
3 equiv hydrochloric acid, in 15 min residence time at 120 °C >
99% yield of benzyl chloride was obtained. Decreasing
equivalents of HCl gas to 1 and allowing the same residence
time resulted in 80 wt % at 60 °C and 89 wt % at 100 °C.
Higher temperatures were not investigated due to a significant
expansion of gas slugs, leading to significantly reduced
residence time. Dibenzyl ether was formed as a sole side-
product in 3 wt % at 60 °C and 5 wt % at 100 °C. Important to
stress is that no gas slugs were observed at the inlet of BPR, and
a minor amount of gas slugs was observed at the outlet.
To see whether benzyl ether formation could be minimized,
while maximizing the yield of benzyl chloride, the effect of
hydrogen chloride excess was studied. Gradually, increasing
equivalents from 1.0 to 2.0 led to no change in side-product
formation at 100 °C. We therefore decided to screen different
reaction temperatures at 1.1 and 1.5 equiv. The results
tabulated in Table 2 show that the selectivity does not improve
Expansion of Scope. Optimized conditions for benzyl
alcohol were applied to a range of aliphatic and benzylic
alcohols. Scheme 2 shows corresponding yields at 100 °C, 1.2
Scheme 2. Prepared Chloroalkanes at Optimal for Benzyl
a
Chloride Conditions
Table 2. Effect on Benzyl Chloride and Dibenzyl Ether
Formation at Various Temperatures and Equivalents of
Hydrogen Chloride
entry
eq HCl
T (°C)
BenzCl (wt %)
DBE (wt %)
1
2
3
4
5
6
7
1.1
1.1
1.1
1.5
1.5
1.5
2.0
80
90
89
92
95
87
96
95
95
3
5
5
3
4
5
5
100
80
90
100
100
a
120 °C, 10 bar with 1.2 equiv of hydrogen chloride. Asterisks (*)
indicate reactions carried out in a 10 mL reactor.
with excess of hydrogen chloride. With the increase of
equivalents, gas-hold up in the reactor increased, which led to
a marginal decrease in residence time.
Assuming that dibenzyl ether is formed due to insufficient
hydrogen chloride, prompted us to increase the system pressure
to allow a higher concentration of hydrogen chloride within the
liquid phase. Figure 4 shows the pressure effect on the reactant,
product and side-product weight distribution at 80 °C. Benzyl
chloride production increases with pressure from 79 wt % at 5
equiv, and 10 bar. When, aliphatic alcohols were used a
significant decrease in gas solubility was observed that lead to
large gas slugs both at the Y-mixer and at the BPR outlet. An
increase in gas slugs drastically decreased the residence time to
<5 min in the reactor (4 mL) used for benzyl alcohol. In order
to have a similar residence time as for benzyl alcohol
experiments, a 10 mL reactor was used instead, which led to
residence time ranging from 15 to 20 min depending on the
D
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substrate used. The difference in residence time is due to the
different extent of gas absorption within the liquid phase.
The rate of nucleophilic substitution reactions depends on
the type of nucleophile, electrophile, solvent, and leaving group.
In order to assist nucleophilic substitution, either polar protic
(SN1) or aprotic (SN2), solvents are used as solvents. One of
the frequently used reaction systems in solvent-free nucleo-
philic substitutions is solvolysis, when the solvent is used as a
nucleophile. The current investigation comprises a reverse
system, where electrophile is a solvent. While the nucleophile is
a chloride anion resulting from dissociation of hydrogen
chloride.
Primary alkanes undergo SN2 type of nucleophilic sub-
stitution, which occurs via a back-attack of an electrophile.33
Due to insufficient polarity and relatively low hydrogen
bonding in primary aliphatic alcohols, dissociation to release
a free chloride anion as a nucleophile is not favorable. In
contrast, due to the higher polarity and/or stronger hydrogen
bonding present within pentanediol, both solubility of HCl gas
and conversion of the alcohol were significantly increased.
Conversion of pentanediol increased to 98%, resulting in the
formation of 1,5-dichloro pentane as a sole side product.
Secondary alkanes can react via SN2 or SN1 depending on the
steric hindrance of an electrophilic carbon or stabilization of the
cationic intermediate. Higher yields in isopropyl alcohol and
cyclohexyl alcohol cases can be explained by this additional
path being available. Among benzylic species 3-methoxy benzyl
alcohol resulted in the largest gas consumption and the highest
yield with no traces of a dibenzyl ether derivative forming.
Conversion decreased when 2,6-difluorobenzyl alcohol was
used, while no side product was formed. In case of 2-
phenylethanol absolutely no conversion was observed. These
observations indicate that resonance stabilization of the benzyl
cation is responsible for better yields when compared to
aliphatic substrates and that SN1 is a main path for the reactions
to take place.
initial objective of minimizing the excess of HCl used from 3
equiv to 1.2. However, the developed process is more beneficial
for SN1 type reactions than SN2. As a result, further
investigations are needed for the synthesis of specific target
chloroalkanes. One of the possible steps is minimal addition of
polar aprotic solvents to promote SN2. Based on green
chemistry and engineering principles, a significant improvement
is demonstrated due to the truly continuous nature of the
process, no use of solvent and formation of only water as a
byproduct.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.6b00014.
■
S
Experimental procedure along with a more detailed
description of operating platform (PDF)
AUTHOR INFORMATION
Corresponding Author
*Email: v.hessel@tue.nl.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank Erik van Herk, Bert Metten, and Bart
van Heugten for their help during different stages of our
investigation. Funding by the Advanced European Research
Council Grant “Novel Process Windows − Boosted Micro
Process Technology” (Grant number: 267443) is kindly
acknowledged.
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DOI: 10.1021/acs.oprd.6b00014
Org. Process Res. Dev. XXXX, XXX, XXX−XXX