Overcoming solid handling issues in continuous flow substitution reactions through ionic liquid formation

Article abstract of DOI:10.1039/c8gc00618k

Substitutions such as acylations, arylations, and alkylations are some of the most commonly run reactions for building complex molecules. However, the requirement of a stoichiometric base to scavange acid by-products creates significant challenges when operating in continuous flow due to solid handling issues associated with precipitating base·HX salts. We present a general and simple strategy to overcome these solid handling issues through the use of acid scavenging organic bases that generate low- to moderate-melting ionic liquids upon protonation. The application of these bases towards the most commonly run substitutions are demonstrated, enabling reactions to be run in flow without requiring additional equipment, specific solvents, or dilute reaction conditions to prevent clogging.

Full text of DOI:10.1039/c8gc00618k

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Overcoming solid handling issues in continuous
flow substitution reactions through ionic liquid
formation†
Cite this: DOI: 10.1039/c8gc00618k
Received 24th February 2018,
Accepted 22nd March 2018
DOI: 10.1039/c8gc00618k
Saeed K. Kashani, Ryan J. Sullivan,
Mads Andersen and Stephen G. Newman
*
rsc.li/greenchem
Substitutions such as acylations, arylations, and alkylations are perhaps the most significant of these. Most flow reactions
some of the most commonly run reactions for building complex involve pumping homogeneous reactant streams together into
molecules. However, the requirement of a stoichiometric base to tubular reactors. These tubes and other pieces of equipment
scavange acid by-products creates significant challenges when are prone to clogging or other failures in the presence of even
operating in continuous flow due to solid handling issues associ- small quantities of insoluble reaction components. Many strat-
ated with precipitating base·HX salts. We present a general and egies have been developed to allow certain solid-forming reac-
4
simple strategy to overcome these solid handling issues through tions to work in flow; however, it is still generally rec-
5
the use of acid scavenging organic bases that generate low- to ommended to use batch processing in these cases, limiting
moderate-melting ionic liquids upon protonation. The application the widespread adoption of this technology.
of these bases towards the most commonly run substitutions are
The severity of this problem is clearly evident when consid-
demonstrated, enabling reactions to be run in flow without requir- ering the most important and frequently performed reactions
ing additional equipment, specific solvents, or dilute reaction con- in the pharmaceutical industry: acylations, arylations, and
ditions to prevent clogging.
alkylations using acyl, aryl, and alkyl halides, respectively
6
(
Scheme 1A). To avoid the build up of acid that can stall the
Over the past decade, continuous flow chemistry has gone
from an academic curiosity to one of the primary strategies
used by the pharmaceutical industry to improve the efficiency
reaction, a stoichiometric base is needed. However, inorganic
bases are insoluble in most organic solvents, as are the conju-
gate acids of many organic bases (e.g., NEt ·HCl). While this is
3
not problematic in batch, it creates a major hurdle to over-
come when ‘adapting’ such a transformation to flow.
1
of chemical synthesis. Benefits from conducting chemical
reactions in flow include improved safety at a range of temp-
eratures and pressures, smaller reactor volumes, more efficient
scale-up, and waste reduction through telescoping multi-step
As a result, researchers may turn to extensive reoptimiza-
tion to ensure homogeneity, ultimately running reactions at
lower concentrations, at higher temperatures, and/or with
limited choices of solvent than an optimal batch procedure.
These sacrifices can negate the many green chemistry benefits
of converting a batch process to flow, specifically, the ability to
perform reactions at much higher concentrations due to
2
processes. It is thus no surprise that leaders in the pharma-
ceutical and fine chemical industries have identified continu-
ous processing as the most important area of research for
3
improving sustainability.
Despite the power of continuous flow in green chemistry,
there is a general belief that one must ‘adapt’ batch processes
to enable them to work in flow, which creates an economical
and psychological barrier to implementation. This is no doubt
due to the fact that the vast majority of chemical reactions
were invented and optimized in traditional flasks, and were
designed to tolerate the weaknesses of batch processing but
not the weaknesses of flow. The need to avoid solids is
2d
efficient control of exotherms, a benefit that is often unrea-
lized in practice except in limited cases where solid handling
7
issues are absent.
A simpler, more universal solution to efficiently enable
these classical reactions in flow would be to use bases for
which neither the free base nor conjugate acid is prone to pre-
cipitate formation. For instance, in the BASF BASIL process,
N-methylimidazole (MIm) is used as a base in the conden-
8
sation of alcohols with chlorophosphines. N-Methylimid-
Centre for Catalysis Research and Innovation, Department of Chemistry and
Biomolecular Sciences, University of Ottawa, 10 Marie Curie, Ottawa, Ontario,
Canada, K1N 6N5. E-mail: stephen.newman@uottawa.ca
azolium chloride, the conjugate acid, is a protic ionic liquid
9
(
pK
a
= 7.1; mp = 70 °C) that forms a discrete second liquid
phase as the reaction progresses, avoiding solid-handling
issues and enabling easy separation and recovery of all reaction
†
Electronic supplementary information (ESI) available: Experimental details,
characterization data of compounds. See DOI: 10.1039/c8gc00618k
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operating in continuous flow due to precipitation. This chal-
lenge is further enhanced when operating under relatively con-
centrated conditions with non-polar solvents. We thus decided
to use toluene as the solvent at a range of concentrations to
evaluate the effectiveness of using a base that generates an
ionic liquid by-product. This not only illustrates the conven-
ience of this strategy for direct batch-to-flow transitioning,
since no artificial limitations on solvent or concentration
choice are imposed, negating the need for extensive re-optim-
ization, but also provides the ability to reduce waste by mini-
mizing the need for large quantities of solvent.
Using benzoyl chloride (1) and phenol (2) to produce ester
3
as a test case was informative (Table 1). Performing this reac-
tion at 90 °C in 0.5 M toluene with triethylamine (entry 1),
N-methylmorpholine (entry 2) or N-methylpiperidine (entry 3)
as base led to rapid clogging of the 1 mm i.d. tubing with pre-
cipitated conjugate acid. In contrast, running the reaction with
N-methylimidazole (entry 4), tributylamine (entry 5) or DBU
(
entry 6) allowed the reaction to proceed smoothly and pro-
vided high yields. In each case, formation of a new ionic liquid
phase was evident in the transparent PFA reactor prior to
addition of water, which serves to prevent precipitation of the
salt upon exiting the heated reaction zone. Furthermore, per-
Scheme 1 Challenges associated with performing continuous flow forming a reaction at 2 M concentration, where the volume of
substitution reactions can be overcome by selecting organic bases that
form ionic liquid conjugate acids.
the phase-separated ionic liquid generated was comparable to
the organic phase, clearly demonstrated that this strategy does
not limit users to low concentrations since solubility of the
protonated acid scavenger in the organic phase is not a
requirement (entry 7).
The strategy of using N-methylimidazole as a base to enable
continuous acylation reactions at high concentrations proved
components. Other salts with moderate melting points
1
0
include tributylammonium chloride (pK = 10.9; mp = 60 °C)
a
1
1
a
and DBU hydrochloride (pK = 13.5; mp = 66 °C).
While these protic ionic liquids are well known to some as
potential solvents or catalysts, the synthetic consequences of
forming these species as side products is seldom recognized.
a
We proposed that, with this range of organic bases, the BASF Table 1 Influence of bases on clogging in the acylation of phenol
BASIL strategy could be generalized for a variety of important
reactions that require acid scavenging in flow, without impos-
ing limitations on the concentrations or solvents that could be
used (Scheme 1B). The synthesis of ionic liquids in flow
1
2
systems has been demonstrated in many different contexts;
however, to our knowledge, a set of guiding principals that
exploit the low melting point of select conjugate acids to facili-
tate the implementation of continuous substitution reactions
1
3
has not been reported. Herein, we present our results that
illustrate this strategy for acylation, arylation (S Ar), alkylation
2), and silylation reactions. This simple solution should Entry
N
b
(S
N
Base
Et
N-Me morpholine
N-Me piperidine
Conc. (M)
Temp. (°C)
Yield (%)
facilitate rapid conversion of batch processes into efficient
1
2
3
4
5
6
7
3
N
0.5
0.5
0.5
0.5
0.5
0.5
2
90
90
90
90
90
90
90
Clog
Clog
Clog
95
95
91
flow processes free of solid-handling issues.
N-Me imidazole
n
Bu
3
N
DBU
N-Me imidazole
Results and discussion
99
a
At the outset of our studies, we investigated the use of acid
chlorides in continuous flow acylation chemistry with oxygen,
nitrogen, and sulfur-centered nucleophiles. These seemingly
Reactions performed in a 0.5 mL PFA coil with 1.25 eq. of phenol and
b
base with tres = 2.5 min. See ESI for full experimental details. Yield
determined by H NMR of the crude mixture of a sample collected at
steady state. 1,3,5-Trimethoxybenzene was used as an internal stan-
1
trivial transformations can give significant problems when dard in the benzoyl chloride stream.
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Table 2 Continuous flow acylation reactions without clogging through tions in flow due to the low solubility of the base·HX salts, and
use of N-methylimidazole or DBU as ionic liquid-forming acid
scavengers
highly tailored conditions are often used including dilute con-
a
ditions, aqueous co-solvent, or exceptionally high tempera-
1
4
tures (Table S1†). To test if the use of the ionic-liquid
forming acid scavengers N-methylimidazole and DBU would
N
be similarly effective at preventing clogging in S Ar reactions,
a series of experiments was carried out with a range of nucleo-
philic and electrophilic partners (Table 3). The reaction of ali-
phatic amines with (hetero)nitroarenes proceeded smoothly
when using NMP as a solvent at 1 M concentration to form
13–15 in excellent yield in 5 minutes at 115 °C. As was the case
for acylation reactions, use of DBU was necessary to prevent
competing protonation and precipitation of the amine nucleo-
phile. The high basicity of DBU also enabled the synthesis of
ether 16 in 89% yield under similar conditions via deprotona-
tion of the corresponding phenol nucleophile. In contrast,
thioether 17 could be prepared using less expensive
a
N-methylimidazole as the base due to the lower pK of the thio-
phenol nucleophile.
A series of S 2 reactions was next studied using tributyl-
N
amine as a general, inexpensive base (comparable in cost to
triethylamine) that provides an ionic liquid conjugate acid
upon protonation (Table 4). Without case-by-case optimiz-
ation, N-methylaniline was alkylated using three different elec-
trophiles with variation of the R substituent and the halide
leaving group to form 18–20 in good yields, using only the
a
Reactions performed in a 0.5 mL coil submerged in a 90 °C oil bath
with 1.25 eq. of nucleophile and N-methylimidazole as base. tres
.5 min. Toluene was used as solvent for 3–6. THF was used as solvent
=
2
for 7–12. Pure products were isolated by column chromatography or minimal amount of solvent needed to make the electrophile
b
extraction (see ESI) after collection of 1.25 mL at steady state. DBU
used as base.
starting material solutions (4 M in NMP) and dosing the
N
Table 3 Continuous flow S Ar reactions without clogging through use
of DBU or N-methylimidazole as ionic liquid-forming acid scavengers
to be general (Table 2). By running reactions at 0.5 M in
toluene with 1.25 equivalents of phenol and base, phenyl ben-
zoate 3 could be isolated in 83% yield. The same conditions
could be applied using an electron-deficient or electron-rich
phenol derivative to isolate 4 and 5, respectively. Use of an ali-
phatic alcohol did not require reoptimization, enabling ester 6
to be prepared in 78% yield. Due to their moderate solubility
in toluene at 0.5 M, anilides 7–10 were prepared in good yields
using THF instead as the reaction solvent with the inclusion of
a 40 psi back pressure regulator at the product outlet to
prevent boiling. Lastly, the preparation of amides via substi-
tution of acid chlorides with aliphatic amine nucleophiles
required modification of the choice of base. The low basicity
of N-methylimidazole makes it ineffective for these reactions,
where the amine nucleophile itself is prone to protonation and
precipitation/clogging. For these reactions, DBU was
a
a
sufficiently basic (pK of conjugate acid = 13.5) to prevent com-
petitive protonation of the nucleophile, allowing amides 11
and 12 to be synthesized in 95% and 91% yield, respectively.
We next turned out our attention to other classes of substi-
tution reactions: arylations and alkylations via S
N
Ar and
a
Reactions performed in a 0.5 mL coil submerged in a 115 °C oil bath
SN2 mechanisms, respectively. These more challenging trans- with 1.5 eq. of nucleophile and DBU as base. tres = 5 min. NMP was
used as solvent. Pure products were isolated by column chromato-
formations are commonly run in polar, highly solubilizing sol-
vents such as DMF and EtOH. However, solid-handling issues
b
graphy after collection of 1.25 mL at steady state. Reaction performed
c
in a 1 mL coil at 130 °C. tres = 30 min. Reaction at 90 °C. tres = 20 min
are still commonly encountered when trying to run these reac- at 0.5 M concentration with N-methylimidazole as base.
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Table 4 Continuous flow S
N
2 reactions without clogging through use giving 0.63 g (3.2 mmol) of product per hour through the 1 mL
n
a
of Bu
3
N or DBU as ionic liquid forming acid scavengers
reactor coil. Use of thiophenol as a nucleophile was similarly
straightforward, providing 21 in 83% yield. Lastly, the use of
DBU again allowed the use of aliphatic amine nucleophiles,
providing access to alkylated products 22 and 23. Notably, pre-
cipitate-free solutions were produced regardless of the halide
−
−
−
−
leaving group (F , Cl , Br and I ) demonstrating the general-
ity of this acid scavenging strategy. Furthermore, control
3
reactions were performed using Et N as base in batch with
otherwise identical conditions to the flow experiments.
Precipitation was observed in each case, which would inevita-
bly lead to clogging issues if performed in continuous flow.
Last, we investigated the protection of alcohols with TBSCl
(
Scheme 2). These reactions are frequently carried out at mild
temperatures in DCM using imidazole as both a base and
1
5
nucleophilic catalyst, resulting in precipitation of the imida-
zolium salt upon product formation. While the use of
N-methylimidazole at elevated temperatures may allow these
reactions to proceed in flow without clogging issues, we
a
Reactions performed in a 1.0 mL coil submerged in a 140 °C oil bath
n
with 1.25 eq. of electrophile and Bu
3
N as base. tres = 30 min. NMP instead chose to investigate N-butylimidazole. The corres-
9
was used as solvent. Pure products were isolated by column chromato-
graphy after collection of 2 mL at steady state. Reaction performed
neat. DBU used as base.
ponding HCl salt of this base melts at 29 °C, enabling the
silylation reactions to be studied at the mild temperatures
common in the literature. Using 1.15 equivalents of TBSCl and
b
c
2
equivalents of N-butylimidazole, silyl ethers 24 and 25
were prepared in excellent yield at 1 M concentration in
DCM with a 5 minute residence time at 35 °C (Scheme 2).
Due to the higher cost of N-butylimidazole compared to
N-methylimidazole, the ionic liquid by-product was isolated
after the synthesis of 24 as the free base (BuIm·HCl spon-
taneously phase separates from the DCM reaction mixture and
remains as a second liquid phase at room temperature, see
Fig. S7† for a representative photograph). A 95% recovery was
achieved after purification, demonstrating the recyclability of
the base if desired.
nucleophile and base neat. The reaction of benzyl chloride
with N-methylaniline could also be performed completely
neat, providing 90% yield after work-up and purification, and
One of the most impactful applications of flow chemistry is
the design of telescoped processes for pharmaceutical manu-
1
,16
facturing.
Since precipitation-prone substitutions are the
6
most frequently run class of reactions in pharma, the need to
drastically redesign batch routes is costly and time consuming.
Towards demonstrating the simplicity with which the use of
ionic liquid-forming acid scavengers can enable straight-
forward implementation of telescoped flow procedures, the
Scheme 2 Continuous flow silylation reactions without clogging through synthesis of the local anaesthetic lidocaine was investigated.
use of N-butylimidazole as an ionic liquid forming acid scavenger.
Previous flow routes towards this molecule required redevelop-
n
Scheme 3 Telescoped continuous flow synthesis of Lidocaine without clogging using Bu
3
N and DBU as ionic liquid forming acid scavengers.
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7
ment of the literature conditions (i.e. toluene as solvent) to program and Dr Boris Gorin for helpful discussions.
1
8
19
use highly solubilizing CHCl /DMF or NMP/MeOH/H O.
R. J. S. thanks NSERC for a graduate scholarship (CGS-D).
3
2
Using tributylamine as a base and toluene as solvent, 2-chloro-
acetylchloride and 2,6-dimethylaniline were mixed in a flow
reactor at 90 °C, followed by addition of diethylamine
and DBU to give a 66% isolated yield of lidocaine (Scheme 3).
At a 0.4 M concentration with a total residence time of
Notes and references
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0.8 minutes this allowed production of 0.37 g of lidocaine per
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4
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Despite the many advantages of running reactions continu-
ously, the barriers associated with adapting batch procedures
to flow hinder the adoption of this technology. We believe that
the challenges associated with solid formation, particularly in
reactions that require an acid scavenging base, are some of the
most common and frustrating problems in flow chemistry.
Through the careful selection of bases that form ionic liquids
upon protonation, we have demonstrated that these solid-
handling issues can be easily alleviated. In particular,
N-methylimidazole, tributylamine, DBU, and N-butylimidazole
are demonstrated to enable precipitate-free reactions of acyl,
aryl, alkyl, and silyl halide electrophiles using N, O, and S
nucleophiles. These reactions give high yields with short reac-
tion times. Furthermore, concentrations ranging from 0.5 M to
neat are utilized, demonstrating that the use of flow chemistry
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proposed but not demonstrated to enable continuous flow
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2
056–2059.
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This journal is © The Royal Society of Chemistry 2018