Translation of microwave methodology to continuous flow for the efficient synthesis of diaryl ethers via a base-mediated SNAr reaction

Article abstract of DOI:10.3762/bjoc.7.160

Whilst microwave heating has been widely demonstrated as a synthetically useful tool for rapid reaction screening, a microwaveabsorbing solvent is often required in order to achieve efficient reactant heating. In comparison, microreactors can be readily h

Full text of DOI:10.3762/bjoc.7.160

Translation of microwave methodology to continuous
flow for the efficient synthesis of diaryl ethers via a
base-mediated SNAr reaction
Charlotte Wiles*1 and Paul Watts2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1360–1371.
1Chemtrix BV, Burgemeester Lemmensstraat 358, 6163 JT, Geleen,
The Netherlands and 2Department of Chemistry, The University of
Hull, Cottingham Road, Hull, HU6 7RX, UK
doi:10.3762/bjoc.7.160
Received: 31 May 2011
Accepted: 13 September 2011
Published: 04 October 2011
Email:
Charlotte Wiles* - c.wiles@chemtrix.com
This article is part of the Thematic Series "Chemistry in flow systems II".
Guest Editor: A. Kirschning
* Corresponding author
Keywords:
automated synthesis; continuous flow; microreactor; microwave;
nucleophilic substitution; organic bases
© 2011 Wiles and Watts; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Whilst microwave heating has been widely demonstrated as a synthetically useful tool for rapid reaction screening, a microwave-
absorbing solvent is often required in order to achieve efficient reactant heating. In comparison, microreactors can be readily heated
and pressurised in order to “super-heat” the reaction mixture, meaning that microwave-transparent solvents can also be employed.
To demonstrate the advantages associated with microreaction technology a series of SNAr reactions were performed
under continuous flow by following previously developed microwave protocols as a starting point for the investigation. By this ap-
proach, an automated microreaction platform (Labtrix® S1) was employed for the continuous flow synthesis of diaryl ethers at
195 °C and 25 bar, affording a reduction in reaction time from tens of minutes to 60 s when compared with a stopped-flow
microwave reactor.
Introduction
Diaryl ethers are a synthetically interesting subunit [1], with Ullmann ether synthesis [6], Pummerer-type rearrangements
examples found in a series of medicinally significant natural [7], Buchwald–Hartwig couplings [8], phenolic additions to
products, such as (−)-K-13 (1) [2], riccardin C (2) [3] and amines [9], fluoride mediated couplings [10,11], and the use of
combretastatins [4], along with synthetic herbicides, such as solid supports [12].
RH6201 (3) [5] (Figure 1). Installation of the diaryl ether can,
however, be synthetically challenging, and this is illustrated by Until recently, the nucleophilic substitution of aromatic halides
the wide number of techniques developed, which include to phenolic substrates has been largely overlooked, with Ueno
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tration depth [19]. Coupled with the fact that microwave heating
is eight times more expensive than conventional heating [20],
techniques for efficient heat transfer are required if costs are to
be reduced, particularly at the production level.
Looking towards another emerging technology, that of
continuous-flow methodology, Kappe and coworkers [21] and
Ryu et al. [22] demonstrated that the “microwave effect” can be
mimicked in high-temperature flow reactors, which can be
scaled to increase production volume without changing the
reaction conditions employed [23-25], resulting in a reduction
in energy usage per mole. With this in mind, we report herein
the translation, and further development, of a microwave
method for the SNAr reaction of chloroarenes to a series of
Figure 1: Illustration of synthetically interesting diaryl ethers.
and coworkers [13] reporting the use of triethylsilane and a para-substituted phenols to afford a general and efficient route
phosphazene “super base”, Holmes [14] describing the use of to the diaryl ether subunit.
scCO2, and Moseley et al. [15] employing microwave irradi-
ation as a means of efficiently heating the reaction mixture in Results and Discussion
order to significantly reduce reaction times (Scheme 1). With the optimised conditions from Marafie and Moseley’s [15]
Although microwaves have found widespread application in the stopped-flow investigation taken as a starting point, the syn-
research laboratory, their implementation at a large scale, whilst thesis of diaryl ethers (Scheme 2) was investigated under
increasing, is not as well established, largely due to the chal- continuous-flow conditions. As the continuous-flow reactor
lenges associated with the uniform irradiation of large reactor enables the reaction chamber to be maintained at the reaction
vessels [16].
temperature (once the steady state is reached) time is not wasted
for heating and cooling of the stopped-flow “batches”. Conse-
In a critical assessment of microwave-assisted organic syn- quently, the system has the potential to be more efficient. The
thesis, Moseley and Kappe [17] recently concluded that on a quantity of material generated can therefore be determined by
small scale (1 to 50 mL) any energy savings made as a result of the length of continuous operation and not by the number of
using microwave irradiation were attributable to the reduction “batches” performed.
in reaction time achieved through the use of sealed vessels, and
not because microwave irradition is a more energy efficient To perform the flow reactions, the microreactor development
method of heating. When considering large-scale reactors [18], apparatus Labtrix® S1 (Chemtrix BV, NL), illustrated in
multimode microwave reactors have been found to be more Figure 2, was employed. The heart of the system is a glass
energy efficient than small single-mode systems, but not more microreactor that is positioned on a thermally regulated stage,
efficient than conventional heating, due to their minimal pene- which enables reactions to be performed between −15 and
Scheme 1: Illustration of the model reaction used to compare the enabling technologies of microwave and microreactor synthesis.
Scheme 2: Illustration of the model reaction used to benchmark Labtrix S1 against batch and stopped-flow microwave reactors.
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195 °C. Reagent solutions are delivered to the reactor through a can be accessed (3221 (1 µL), 3222 (5 µL), 3223 (10 µL) and
series of syringe pumps (0.1 to 25 µL·min−1) and the system is 3227 (19.5 µL)). In order to increase the efficiency of thermal
maintained under a back pressure of 25 bar, which enables reac- and mass transport on the microscale, the devices contain
tants and solvents to be heated above their atmospheric boiling preheating channels, which bring reagents to the reaction
point whilst staying in the liquid phase. The reactant flow rates, temperature ahead of mixing, and static micromixers (stag-
reactor temperature and sample collection point is automated gered oriented ridge (SOR-2)) [26] are incorporated where any
and the system has an in-line pressure sensor that monitors the two reagent streams meet in order to increase the efficiency of
system pressure throughout the course of an investigation. The mixing (Tmix ≤ 0.3 s), compared with T-mixers, and to increase
software enables the effect of reaction time, temperature and the remaining channel volume available for reaction (Figure 3).
reactant stoichiometry to be investigated in an automated
manner whilst the system is operated, unattended, within a fume Employing a two-feed system, Figure 4, where one stock solu-
cupboard.
tion contained 3,4-dichloronitrobenzene (4, DCNB) and
4-methoxyphenol (5, 1.3 M and 1.56 M respectively) in
dimethylacetamide (DMA) and the second 1,8-diazabicy-
cloundec-7-ene (DBU, 6, 1.95 M) in DMA, we investigated the
nucleophilic substitution reaction under flow conditions. By
using a reaction time of 10 min, achieved by setting a total flow
rate of 1 µL·min−1, the effect of reactor temperature on the syn-
thesis of 2-chloro-1-(4-methoxyphenoxy)-4-nitrobenzene (7)
was investigated. Reactions were initially performed in the
absence of a base, in order to monitor the background reaction
by means of offline GC-FID analysis. After a reaction time of
10 min at a reactant temperature of 195 °C, analysis of the reac-
tion products by GC-FID confirmed no background reaction
had occurred, with DCNB (4) and 4-methoxyphenol (5) recov-
ered without reaction or degradation. Introducing DBU (6) into
the reactor produced comparable results in the glass micro-
reactor to those reported by Moseley et al. [15] (Figure 5).
Figure 2: Photograph illustrating Labtrix® S1, the automated micro-
reactor development apparatus from Chemtrix BV (NL), used for the
evaluation described herein.
Effect of reaction time: Satisfied by this result, we looked at
increasing the efficiency of the reaction, and thus we subse-
quently investigated the effect of reaction time at 195 °C with a
The glass microreactors employed herein have a footprint view to increasing the space yield time. This approach was
of 44 mm × 22 mm and contain etched microfluidic channels successful and revealed that the reaction did not require a
(300 µm (wide) × 120 µm (deep)) in which the reactions take 10 min reaction time, with quantitative conversion of DCNB (4)
place. By varying the channel length a series of reactor volumes to the diaryl ether 7 achieved in 60 s. It is important to note that
Figure 3: Schematic illustrating the 10 µL reactor manifold used for the SNAr reactions described herein (3223; Chemtrix BV, NL), with the important
features highlighted.
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Beilstein J. Org. Chem. 2011, 7, 1360–1371.
Figure 4: Schematic illustration of the reactor manifold used to evaluate the continuous-flow synthesis of 2-chloro-1-(4-methoxyphenoxy)-4-nitroben-
zene (7) in the presence of DBU (6).
series of solvents with low boiling points. The microreactions
were performed under 25 bar of back pressure, which means
that solvents such as acetonitrile (MeCN) can be readily
employed at temperatures exceeding their atmospheric boiling
point (81–82 °C), and upon replication of the investigation
summarised in Figure 5, comparable results were obtained,
illustrating that MeCN is a suitable alternative to DMA.
Screening of organic bases: With one of the salient features of
microreaction technology being the speed of reaction optimisa-
tion, due to the low system hold-up volume, we subsequently
investigated the effect of base type and stoichiometry on the
Figure 5: Comparison of the results obtained in Labtrix® S1 with
reported data generated in a microwave synthesiser.
reaction in MeCN. Whilst this would conventionally be
performed by preparing a series of solutions with different base
concentrations, the control software for Labtrix® S1 enables
no degradation of the diaryl ether 7 was observed when facile programming of reactant stoichiometries from a single
extended reaction times of up to 45 min were employed. The stock solution. Figure 6 illustrates the use of a 1.0 M DCNB
ability to decrease the reaction time required in flow when (4) 4-methoxyphenol (5) solution (reactant A), a 1.0 M base
compared to the microwave methodology can be rationalised if solution (reactant B) and MeCN as the diluent (added through
you think that part of the reaction time for a microwave reac- the quench input (Figure 4)). At this stage, it was also decided
tion involves the heating up and cooling down of the system, that the 4-methoxyphenol (5) equivalents would be reduced
and it is this increase in processing time that is removed by a from 1.2 to 1.0 equiv in order to reduce the post reaction purifi-
flow reactor once it has reached steady state.
cation required in order to isolate the diaryl ether 7 in high
purity.
Effect of reaction solvent: When performing reactions under
microwave irradiation, it is important to select a solvent that is Using this approach, we investigated stoichiometries from 0.01
not transparent to microwave radiation in order to ensure effi- to 2.00 equiv for 10 additional organic bases (Table 1), with
cient heating of the reaction mixture. With this in mind, the 1.0 M stock solutions prepared owing to the variable misci-
method reported in the literature employed DMA, but the high bility of the selected bases with the reaction solvent, MeCN. In
boiling point of the solvent (164–166 °C) makes it difficult to order to gauge the effect of the base, reactions were performed
isolate the diaryl ethers when reactions are performed on a under the suboptimal conditions of 30 s at 195 °C, with each
small scale. Consequently, the reaction was investigated in a screen taking only 14 min to generate the samples for analysis.
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Figure 6: Screen shot from the Labtrix® S1 control software illustrating the system file that enables the user to readily program a stoichiometry
screen; this example varies the base stoichiometry at a fixed reaction time and temperature, however, the user can alter all 3 variables at any point.
As Figure 7 illustrates, a wide range of reactivities was parison, DBU (6), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN) and
obtained, with pyridine, N-methylpiperidine, tetramethylpiperi- 1,1,3,3-tetramethylguanidine (TMG) afforded 55.5, 56.3 and
dine, lutidine, tetramethylethylenediamine (TMEDA) and 55.1% conversions (at 1 equiv), respectively. If we compare the
triethylamine affording negligible conversions of DCNB (4) to results obtained with the dissociation constant of the bases
2-chloro-1-(4-methoxyphenoxy)-4-nitrobenzene (7). In com- employed (Table 1), a clear link can be seen. Importantly, in all
Table 1: Illustration of the organic bases investigated, ranked in order of increasing basicity and the conversion to diaryl ether 7 obtained when 1
equiv of base was used (residence time = 30 s; reactor temperature = 195 °C).
Entry
Organic base (1 equiv)
pKa
Conversion (%)
1
2
Pyridine
5.20
5.60
3.00
5.01
1,4-Diazabicyclo[2.2.2]octane (DABCO)
Lutidine
3
6.75
0.00
4
Tetramethylethylenediamine (TMEDA)
N-Methylpiperidine
8.97
0.00
5
10.08
10.50
10.70
11.07
12.00
12.80
13.60
1.62
6
Diisopropylethylamine (DIPEA)
Triethylamine
25.27
0.85
7
8
Tetramethylpiperidine (TMP)
1,8-Diazabicycloundec-7-ene (6, DBU)
1,5-Diazabicyclo(4.3.0)non-5-ene (DBN)
1,1,3,3-Tetramethylguanidine (TMG)
0.00
9
55.54
56.27
55.10
10
11
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Figure 7: Summary of the results obtained for the organic base screen towards the SNAr reaction between DCNB (4) and 4-methoxyphenol (5) (resi-
dence time = 30 s; reactor temperature = 195 °C).
cases the hydrochloride salt of the base, formed as a byproduct
in the reaction, remained in solution.
With this information in hand, we retained DBU (6) as the base
(1.5 equiv) and 2-chloro-1-(4-methoxyphenoxy)-4-nitroben-
zene (7) was synthesised in 99.7% yield with a reaction time of
60 s at 195 °C, affording a throughput of 7 of 108.5 mg·h−1
with a 1:1 ratio of 4-methoxyphenol (5) and DCNB (4).
Effect of phenol substitution. Having optimised the reaction
for the synthesis of 2-chloro-1-(4-methoxyphenoxy)-4-nitroben-
zene (7), the next step in the investigation was to evaluate the
effect of the para-substituent on the phenolic derivative. To do
this a series of commercially available phenols were evaluated;
4-nitrophenol (8), 4-cyanophenol (9), 4-bromophenol (10) and
4-fluorophenol (11). Again after a reaction time of 30 s and a
reactor temperature of 195 °C, the reactivities of the four
phenols were compared before each reaction was optimised for
diaryl ether isolation. As expected, Figure 8 illustrates that
those phenol derivatives bearing an electron-donating
substituent were found to be more reactive.
Figure 8: Illustration of the substituent effect on the synthesis of diaryl
ethers under continuous flow (residence time = 30 s; reactor tempera-
ture = 195 °C).
Use of inorganic bases: Whilst the use of organic bases
enabled a comparison of microwave and microreactor tech-
nologies to be performed, the use of organic bases can be
viewed as disadvantageous due to their relatively high cost
compared with inorganic bases [27]. In addition, standard
“batch” conditions afforded slurries and were identified by
Moseley [15] as being disadvantageous for the stopped-flow
microwave reactor. Herein, we employed an aqueous solution
of K2CO3, which resulted in a biphasic microreaction system.
In batch this approach would prove disadvantageous as it would
result in a biphasic system in which poor mass transport
between the organic and aqueous layers would reduce the reac-
tion rate.
For each para-substituted phenol, the reaction time was opti-
mised and, as Table 2 illustrates, this enabled the synthesis of
five diaryl ethers in high yield and excellent purity as verified
by MS and NMR spectroscopy. Compared to the work of
Moseley [15], the use of a flow reactor meant that it was
possible to optimise the reaction of 4-cyanophenol (9) to obtain
2-chloro-1-(4-cyanophenoxy)-4-nitrobenzene (13) in >99%
yield, compared with 42% in the microwave reactor.
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Table 2: Summary of the reaction conditions employed for the DBU (6) mediated SNAr reaction under continuous flow.
Phenol
Residence time (min)
1
Conversion (%)
quant.
Yield (%)
99.69
5
8
5
10
1
quant.
quant.
quant.
quant.
99.84
99.72
99.86
99.79
9
10
11
2
In a microfluidic channel, reproducible droplets can be formed
within a continuous phase, giving rise to a high interfacial
surface area, with mixing further promoted by internal circula-
tion within the droplets (Figure 9). With this in mind the use of
aqueous K2CO3 as the base was investigated as a means of
simplifying postreaction processing and reducing the costs asso-
ciated with the synthetic methodology developed.
Figure 10: Comparison of base effect on the synthesis of 2-chloro-1-
(4-methoxyphenoxy)-4-nitrobenzene (7) (residence time = 30 s; reactor
temperature = 195 °C).
Figure 9: Schematic illustrating the mixing of immiscible reagent
streams in a microfluidic channel, whereby the continuous phase com-
position depends on the ratio of organic and aqueous reactants
employed.
Under the optimal conditions, the target compound 7 would be
obtained in a throughput of 109 mg·h−1 however this can be
increased by using a more concentrated base solution and there-
fore reducing the proportion of the second solution within the
reaction channel. Increasing the K2CO3 concentration to 4.5 M
enabled the throughput to be increased to 152 mg·h−1 whilst
maintaining a 1:1:1.5 reactants-to-base ratio.
Using this approach, we investigated the effect of K2CO3 stoi-
chiometry at 195 °C with a reaction time of 30 s, and, as
Figure 10 illustrates, comparable results to those obtained for
DBU (6) were recorded.
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Conclusion
Experimental
Employing a microreactor with a small hold-up volume enabled Materials. In all cases, materials were used as received from
us to screen a large number of reaction conditions using only Acros Organics, with reaction solvents purchased as “Extra
mg quantities of substrate. Using this approach, we were able to Dry” and stored over molecular sieves and analytical grade
build on the methodology developed by Moseley and coworkers solvents purchased for use in aqueous extractions.
[15]; by replacing the high-boiling-point reaction solvent DMA
with MeCN and simultaneously reducing the proportion of Instrumentation. Unless otherwise stated, nuclear magnetic
phenol derivative employed, product isolation was more facile. resonance (NMR) spectra were obtained at room temperature
Furthermore, in the case of 4-methoxyphenol (5) it was possible from solutions in deuterated chloroform (CDCl3 0.01% TMS)
to reduce the reaction time from tens of minutes to 60 s at a by means of a Jeol GX400 spectrometer; in the case of known
reactor temperature of 195 °C; a time saving which can be compounds, all spectra obtained were consistent with the litera-
attributed to the efficient heat transfer obtained within the ture. The following abbreviations are used to report NMR spec-
microreactor, and the fact that in a microwave reactor the time troscopic data; s = singlet, d = doublet, t = triplet, br s = broad
to heat up and cool down the system can significantly increase singlet, q = quartet, dd = double doublet, dt = doublet of triplets,
the reaction time.
m = multiplet and C0 = quaternary carbon. Analysis of samples
by gas chromatography-flame ionisation detection (GC-FID)
In addition, compared to previously reported microwave were performed on a Varian GC (430) with a CP-Sil 8 (30 m)
methodologies, employing a microreactor enabled us to investi- column (Phenomenex, UK) and ultrahigh purity helium
gate the use of a biphasic reaction system, reducing the costs (99.9999%, Energas, UK) as the carrier gas. Reaction products
associated with the transformation through the use of an inor- were analysed by the following method; injector temperature
ganic base, to afford the target diaryl ethers in high yield and 200 °C, carrier-gas flow rate 1.60 mL·min−1, oven temperature
purity, after a simple offline aqueous extraction.
50 °C for 0.1 min then ramped to 300 °C at 60 °C·min−1 and
held at 300 °C for 1.0 min (Table 3). Mass spectrometry data
Whilst it can be seen from the data described herein that was obtained by means of a Shimadzu QP5050A instrument
microreaction technology can be utilised for the rapid genera- with an EI ionisation source.
tion of reaction information and small quantities of isolated ma-
terials, the production volume of such units is inherently small. Microreactor setup: Microreactions were performed in the
With efficient heat and mass transfer key to the success of Labtrix® S1 (Chemtrix BV, NL), illustrated in Figure 2, fitted
microreactors, it is important that these features are retained with a glass microreactor (3223, reactor volume = 10 µL)
when flow-reactor volume is increased. If this is not the case containing an SOR-2 static micromixer. Reactant solutions were
then the same issues arise as observed in batch when a process introduced into the reactor through three 1 mL gas-tight
fails to scale either from a changing product-quality or safety syringes (SGE, UK) capable of delivering three solutions at
perspective.
flow rates between 0.1 and 100 μL·min−1. The system was
Table 3: Summary of the retention times obtained for the key starting materials and products employed herein.
Analyte
Retention time (min)
Purity (%)
3,4-Dichloronitrobenzene (4)
3.20
3.36
3.47
3.22
2.92
2.23
5.10
5.50
6.81
5.07
4.37
99.0
4-Methoxyphenol (5)
98.0
4-Nitrophenol (8)
99.0
4-Cyanophenol (9)
99.0
4-Bromophenol (10)
97.0
4-Fluorophenol (11)
99.0
2-Chloro-1-(4-methoxyphenoxy)-4-nitrobenzene (7)
2-Chloro-1-(4-nitrophenoxy)-4-nitrobenzene (12)
2-Chloro-1-(4-cyanophenoxy)-4-nitrobenzene (13)
2-Chloro-1-(4-bromophenoxy)-4-nitrobenzene (14)
2-Chloro-1-(4-fluorophenoxy)-4-nitrobenzene (15)
99.99a
99.98a
99.99a
99.99a
99.98a
aAs determined by GC-FID analysis.
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Beilstein J. Org. Chem. 2011, 7, 1360–1371.
maintained at 25 bar of back pressure by means of a preset allowed to equilibrate before a sample was taken for analysis in
ultralow dead-volume back-pressure regulator (Upchurch order to quantify the proportion of diaryl ether synthesised; this
Scientific, USA), in order to prevent boiling of the reactants and procedure was repeated up to the Tmax (195 °C) of the system.
solvent system when temperatures above the atmospheric
boiling point were employed. The system was controlled General procedure for diaryl ether synthesis with DBU (6).
through the Labtrix® S1 software, which enables control of By using the Labtrix® S1, fitted with a glass microreactor
reactant flow rate (total flow rate ≤80 µL·min−1, reactant resi- (3223, reactor volume = 10 µL) and a back-pressure
dence time (7.5 s to 50 min (for a 10 µL reactor)), reactor regulator set to 25 bar, a solution of 3,4-dichloronitrobenzene
temperature (−15 to 195 °C), equilibration time and sample (4) and phenol derivative (1.3 M respectively) was pumped
collection into one of twenty-nine 2 mL sample vials. The soft- into the reactor from inlet 1 and a solution of 1,8-
ware also archives system parameters such as the set and actual diazabicyclo[5.4.0]undec-7-ene (6, 1.95 M) was introduced
temperature, system pressure, reactor type, and flow rates from inlet 2. After a reactant residence time of 1 to 10 min
programmed, along with the sample collection time and vessel, (Table 2), a 500 µL aliquot of the reaction product was
for review both during and after the experiment (Figure 11).
collected in a round-bottomed flask and concentrated in vacuo
to remove the reaction solvent prior to aqueous extraction. The
General procedure for temperature and base screening. By organic residue was dissolved in DCM (25 mL) and then
using the Labtrix® S1, fitted with a glass microreactor (3223, washed with an aqueous solution of saturated ammonium chlo-
reactor volume = 10 µL) and a back-pressure regulator set to ride (3 × 25 mL) to remove the organic base. The organic layer
25 bar, thermostatted to 25 °C, a solution of 3,4-dichloroni- was then dried with MgSO4, filtered under suction and the
trobenzene (4) and phenol derivative (1.3 M respectively) was filtrate concentrated in vacuo to afford the target diaryl ether.
pumped into the reactor from inlet 1, a solution of base (1.00 M The reaction product was then analysed by mass spectrometry
or 1.95 M) was introduced from inlet 2 and the solvent system and 1H/13C NMR spectroscopy in order to characterise the ether
under investigation was introduced as a diluent from inlet 3. and determine the product purity.
After the system volume had passed through the reactor three
times the reaction was at steady state and a sample then 2-Chloro-1-(4-methoxyphenoxy)-4-nitrobenzene (7). A solu-
collected and analysed offline by GC-FID (Table 3). The tion of DCNB (4) and 4-methoxyphenol (5, 0.2496 g and
reactor temperature was then increased by 25 °C and the system 0.1614 g·mL−1, 1.3 M) in MeCN was introduced into the micro-
Figure 11: Graphical representation of an automated flow reaction for equilibration and screening of reactor temperature effects.
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Beilstein J. Org. Chem. 2011, 7, 1360–1371.
reactor at a flow rate of 5 µL·min−1 and a solution of DBU (6, of reaction product was collected in a round-bottomed flask
0.2968 mL·mL−1, 1.95 M) in MeCN was introduced at a flow (10 mL) and concentrated in vacuo to remove the reaction
rate of 5 µL·min−1. The microreactor was heated to 195 °C (in solvent prior to aqueous extraction. The organic residue was
25 °C stages) and, after an equilibration time of 3 min, 500 µL dissolved in DCM (25 mL) and then washed with an aqueous
of reaction product was collected into a round-bottomed flask solution of saturated ammonium chloride (3 × 25 mL) to
(10 mL) and concentrated in vacuo to remove the reaction remove the organic base. The organic layer was then dried with
solvent prior to aqueous extraction. The organic residue was MgSO4, filtered under suction and the filtrate concentrated in
dissolved in DCM (25 mL) and then washed with an aqueous vacuo to afford the target diaryl ether, affording 2-chloro-1-(4-
solution of saturated ammonium chloride (3 × 25 mL) to nitrophenoxy)-4-nitrobenzene (12) as a yellow solid (95.4 mg,
remove the organic base. The organic layer was then dried with 99.8%); 1H NMR (400 MHz, CDCl3) δ 7.12 (2H, d, J = 9.1, 2 ×
MgSO4, filtered under suction and the filtrate concentrated in ArH), 7.21 (1H, d, J = 9.0, 1 × ArH), 8.21 (1H, dd, J = 2.8 and
vacuo to afford the target diaryl ether, affording 2-chloro-1-(4- 9.0, 1 × ArH), 8.30 (2H, d, J = 9.1, 2 × ArH) and 8.42 (1H, d,
methoxyphenoxy)-4-nitrobenzene (7) as a pale yellow solid J = 2.8, 1 × ArH); 13C NMR (100 MHz, CDCl3) δ 118.2 (2 ×
(90.4 mg, 99.7%); 1H NMR (400 MHz, CDCl3) δ 3.87 (3H, s, CH), 120.7 (CH), 123.9 (CH), 126.2 (2 × CH), 126.8 (CH),
OCH3), 6.80 (1H, dd, J = 3.0 and 9.2, 1 × ArH), 6.96 (2H, d, 127.0 (C0Cl), 144.1 (C0NO2), 144.5 (C0NO2), 160.4 (C0O) and
J = 9.0, 2 × 1 ArH), 7.04 (2H, d, J = 9.0, 2 × ArH), 8.01 (1H, 160.6 (C0O); m/z (EI) 297 (M+ + 1, 25%) 296 (65), 295 (55),
dd, J = 3.0 and 9.2, 1 × ArH) and 8.35 (1H, d, J = 3.0, 1 × 294 (50), 282 (45), 267 (25), 265 (45), 264 (100), 251 (7), 249
ArH); 13C NMR (100 MHz, CDCl3) δ 55.6 (OCH3), 115.3 (2 × (20), 167 (10), 91 (15) and 76 (10). The spectroscopic data
CH), 115.5 (CH), 121.6 (2 × CH), 123.5 (CH), 123.8 (C0), obtained were consistent with those reported in the literature
126.4 (CH), 142.1 (C0NO2), 147.4 (C0), 157.3 (C0) and 159.8 [15].
(C0); m/z (EI) 280 (M+ + 1, 25%), 279 (100), 264 (20), 233
(10), 198 (7), 183 (5), 123 (5), 108 (2) and 76 (5). The spectro- 2-Chloro-1-(4-cyanophenoxy)-4-nitrobenzene (13): A solu-
scopic data obtained were consistent with those reported in the tion of DCNB (4) and 4-cyanophenol (9) (0.2496 g and
literature [15].
0.1548 g·mL−1, 1.3 M) in MeCN was introduced to the micro-
reactor at a flow rate of 0.5 µL·min−1 and a solution of DBU (6,
2-Chloro-1-(4-methoxyphenoxy)-4-nitrobenzene (7). A solu- 0.2968 mL·mL−1, 1.95 M) in MeCN was introduced at a flow
tion of DCNB (4) and 4-methoxyphenol (5, 0.2496 g and rate of 0.5 µL·min−1. The microreactor was heated to 195 °C (in
0.1614 g·mL−1, 1.3 M) in MeCN was introduced to the micro- 25 °C stages) and, after an equilibration time of 30 min, 500 µL
reactor at a flow rate of 7 µL·min−1 and a solution of K2CO3 of reaction product was collected in a round-bottomed flask
(4.5 M) in MeCN was introduced at a flow rate of 3 µL·min−1. (10 mL) and concentrated in vacuo to remove the reaction
The microreactor was heated to 195 °C (in 25 °C stages) and, solvent prior to aqueous extraction. The organic residue was
after an equilibration time of 3 min, 500 µL of reaction product dissolved in DCM (25 mL) and then washed with an aqueous
was collected in a round-bottomed flask (10 mL) and concen- solution of saturated ammonium chloride (3 × 25 mL) to
trated in vacuo to remove the reaction solvent prior to aqueous remove the organic base. The organic layer was then dried with
extraction. The organic residue was dissolved in DCM (25 mL) MgSO4, filtered under suction and the filtrate concentrated in
and then washed with an aqueous solution of saturated ammoni- vacuo to afford the target diaryl ether, affording 2-chloro-1-(4-
um chloride (3 × 25 mL) to remove the organic base. The cyanophenoxy)-4-nitrobenzene (13) as a pale yellow solid
organic layer was then dried with MgSO4, filtered under suction (88.8 mg, 99.72%); 1H NMR (400 MHz, CDCl3) δ 7.10 (2H, d,
and the filtrate concentrated in vacuo to afford the target diaryl J = 8.8, 2 × ArH), 7.14 (1H, d, J = 9.1, 1 × ArH), 7.27 (2H, d,
ether, affording 2-chloro-1-(4-methoxyphenoxy)-4-nitroben- J = 8.8, 2 × ArH), 8.16 (1H, dd, J = 2.8 and 9.1, 1 × ArH) and
zene (7) as a pale yellow solid (152.0 mg, 99.8%); spectro- 8.42 (1H, d, J = 2.8, 1 × ArH); 13C NMR (100 MHz, CDCl3)
scopic data obtained were consistent with those reported above δ 108.4 (C0CN), 118.1 (CN), 119.0 (2 × CH), 120.3 (CH),
and in the literature [15].
123.8 (CH), 126.8 (C0Cl), 126.9 (CH), 134.6 (2 × CH), 144.4
(C0NO2), 156.3 (C0O) and 158.8 (C0O); m/z (EI) 277 (M+ + 1,
2-Chloro-1-(4-nitrophenoxy)-4-nitrobenzene (12): A solu- 15%), 276 (30), 275 (17), 274 (100), 267 (10), 245 (15), 243
tion of DCNB (4) and 4-nitrophenol (8, 0.2496 g and (12), 198 (35), 181 (20), 167 (5), 92 (10) and 76 (15). The spec-
0.1899 g·mL−1, 1.3 M) in MeCN was introduced to the micro- troscopic data obtained were consistent with those reported in
reactor at a flow rate of 1 µL·min−1 and a solution of DBU (6, the literature [15].
0.2968 mL·mL−1, 1.95 M) in MeCN was introduced at a flow
rate of 1 µL·min−1. The microreactor was heated to 195 °C (in 2-Chloro-1-(4-bromophenoxy)-4-nitrobenzene (14): A solu-
25 °C stages) and, after an equilibration time of 15 min, 500 µL tion of DCNB (4) and 4-bromophenol (10, 0.2496 g and
1369

Beilstein J. Org. Chem. 2011, 7, 1360–1371.
0.2249 g·mL−1, 1.3 M) in MeCN was introduced to the micro- 161.3 (C0O); m/z (EI) 269 (M+ + 1, 35%), 268 (19), 267 (100),
reactor at a flow rate of 5 µL·min−1, a solution of DBU (6, 249 (10), 222 (15), 186 (40), 157 (30), 139 (10), 112 (5), 107
0.2968 mL·mL−1, 1.95 M) in MeCN was introduced at a flow (5) and 76 (7). The spectroscopic data obtained were consistent
rate of 5 µL·min−1 and acetone was introduced at a flow rate of with those reported in the literature [15].
10 µL·min−1 (to prevent crystallisation of the product in the
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