Continuous Flow Synthesis under High-Temperature/High-Pressure Conditions Using a Resistively Heated Flow Reactor

Article abstract of DOI:10.1021/acs.oprd.7b00063

A cheap, easy-to-build, and effective resistively heated reactor for continuous flow synthesis at high temperature and pressure is herein presented. The reactor is rapidly heated directly using an electric current and is capable of rapidly delivering temperatures and pressures up to 400 °C and 200 bar, respectively. High-temperature and high-pressure applications of this reactor were safely performed and demonstrated by selected transformations such as esterifications, transesterifications, and direct carboxylic acid to nitrile reactions using supercritical ethanol, methanol, and acetonitrile. Reaction temperatures were between 300 and 400 °C with excellent conversions and good to excellent isolated product yields. Examples of Diels-Alder reactions were also carried out at temperatures up to 300 °C in high yield. No additives or catalysts were used in the reactions.

Full text of DOI:10.1021/acs.oprd.7b00063

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Full Paper
Continuous Flow Synthesis under High Temperature/High
Pressure Conditions using a Resistively Heated Flow Reactor
Ahmed Adeyemi, Joakim Bergman, Jonas Brånalt, Jonas Savmarker, and Mats Larhed
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00063 • Publication Date (Web): 15 Jun 2017
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Continuous Flow Synthesis under High
Temperature/High Pressure Conditions using a
Resistively Heated Flow Reactor
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Ahmed Adeyemi†, Joakim Bergman,‡ Jonas Brånalt,‡ Jonas Sävmarker§ and Mats Larhed┬,*
† Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala Biomedical
Center, Uppsala University, PO Box 574, SE-751 23 Uppsala, Sweden.
‡ Department of Medicinal Chemistry, Cardiovascular and Metabolic Diseases, Innovative
Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 431
83, Sweden.
§ The Beijer Laboratory for Drug Discovery, Department of Medicinal Chemistry, Uppsala
Biomedical Center, Uppsala University, PO Box 574, SE-751 23 Uppsala, Sweden.
┬ Department of Medicinal Chemistry, Science for Life Laboratory, Uppsala Biomedical Center,
Uppsala University, P. O. Box 574, SE-751 23 Uppsala, Sweden
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GRAPHICAL ABSTRACT
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RꢀCOOEt
in MeOH
Rꢀ
Up to 400 °C
and 200 bar
Thermographic
Image of Reactor
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ABSTRACT. A cheap, easy-to-build and effective resistively heated reactor for continuous flow
synthesis at high temperature and pressure is herein presented. The reactor is rapidly heated
directly using an electric current and is capable of rapidly delivering temperatures and pressures
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o
up to 400 C and 200 bar respectively. High temperature and high pressure application of this
reactor were safely performed and demonstrated by selected transformations such as
esterifications, transesterifications, and direct carboxylic acid to nitrile reactions using
supercritical ethanol, methanol, and acetonitrile. Reaction temperatures were between 300 oC and
o
400 C with excellent conversions and good to excellent isolated product yields. Examples of
o
Diels-Alder reactions were also carried out at temperatures up to 300 C in high yield. No
additives or catalysts were used in the reactions.
KEYWORDS. Resistive heating, continuous flow, supercritical solvents, high temperature, high
pressure.
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INTRODUCTION
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Continuous flow (CF) synthesis has evolved into a very important tool in modern organic and
pharmaceutical chemistry.1-3 The unique advantages offered by flow chemistry compared to
batch process reactions have the potential to simplify modern organic synthesis. These
advantages include faster reactions, controlled and quicker optimization, cleaner products, in-line
monitoring and ease of scale up.1-5 Moreover, flow chemistry enables safe handling of reactions
that involve explosive and toxic intermediates.5-8 Active pharmaceutical ingredients (APIs) have
also been synthesized using continuous flow, further underlining the importance of flow
chemistry.3-5 The applicability of flow chemistry can be put down to its ability to meet different
and challenging reaction conditions. Thus, the type of, and applicability of a CF system is
dependent on specific reaction conditions.
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In handling different reaction temperatures, CF reactors have been reported which employ
water baths, oil baths, heating mantles, microwave heating and even gas chromatography ovens
(GC-ovens), as heat sources.2, 9-12 The choice of a heating methodology is sometimes dictated by
the temperature limit attainable.1 Water bath is unsuitable for reactions above 100 oC. Oil bath is
inappropriate at temperatures above 300 oC due to its low convenience, slow heating rate and
safety concerns.13 Microwave (MW) systems and GC-ovens have been reported as heating
sources in CF for temperatures up to 350 oC.14, 15 However, MW heating is limited to MW
absorbing reaction mixtures or reactors, while temperature control in GC-ovens can be time
consuming with respect to rate of heating and cooling.
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The number of flow systems that handle reactions above 300 oC are limited despite the
advantages offered by high temperature and high pressure conditions.8,16b,16c The few available
systems are expensive and require a degree of expertise to operate. Heat transfer is an important
consideration when using CF synthesis at high temperature. Effective heat transfer between the
heat source and the reactor is necessary to attain the temperature inside the reactor, except in the
case of MW heating with MW transparent reactors.
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One heating option that is suitable for high temperature and pressure is the application of direct
resistive heating. Direct resistive heating involves the use of the electrical resistance in the
reactor itself to generate heat. Kunz and coworker reported a directly heated CF reactor, albeit
operational at a lower temperature than the commercially available reactors.13 The heating rates
were remarkably higher than by using a GC-oven as heat source. An indirect conductively heated
batch reactor was also recently reported by Obermayer and co-workers.17 They were able to
demonstrate the a batch reactor operational at temperature up to 250 oC and 20 bar using indirect
conductive heating. Overall, compared to the traditional batch heater, the resistively heated CF
reactors may offer a promising alternative for organic synthesis.11,13,14,16a,18
We have previously reported on systems that use microwaves as heating method in CF
synthesis.15a We have also reported on the use of MW-heated silicon carbide reactors to
overcome the problem of metal precipitation, hotspot formation and reactor failures in metal-
catalyzed reactions.15c The success of the silicon carbide reactors has prompted us to develop
simpler systems that can provide direct heating to the reactor, with cheaper materials. Herein we
present a CF reactor, directly heated by electric resistance, capable of delivering temperatures up
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to 400 oC and pressures up to 200 bar. Safety concerns and cost issues are addressed, with
solutions proffered with the resistively heated CF reactor. The resistively heated reactor is
relatively cheap and energy efficient. Three high temperature transformations that involve
supercritical ethanol, methanol, and acetonitrile were selected to validate the reactor
effectiveness in esterification, transesterification and direct conversion of carboxylic acids to
nitriles respectively. Furthermore, Diels-Alder reaction involving electron deficient dienophiles
were successfully carried out at high temperature using the resistively heated CF reactor.
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RESULTS AND DISCUSSION
Reactor Design. We set out to design a low-cost, simple, robust and effective CF reactor using
a material suitable for high temperature and high-pressure. In addition, the material had to be
chemically inert and resistant to corrosion over a reasonable period. The reactor should also be
easily replaceable, preferably at lower expense relative to other similar CF reactors designed for
high temperature and pressure conditions.
Steel was an obvious material of choice as it fulfilled the aforementioned requirements,
especially the ability to withstand temperatures up to 400 oC and pressure up to 200 bar. A steel
coil with both ends open was thus constructed (6 mL volume). Potential difference was created at
the two ends of the coil by connecting opposing charges to both ends (see Figures 1 and 2).
Direct current was passed through the coil using a direct current (DC) power source. The power
source used is capable of supplying a current of 20 A and voltage of 42 V, and generating a
maximum power output of 320 W.
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Figure 1. Schematic overview of the resistively heated CF reactor system. A potential difference
is applied between two ends of the steel reactor. The power source regulates the voltage applied.
A thermostat (in orange) sits on the reactor, is connected to the power supply to regulate and
record temperature relative to the current and voltage input. The power supply is capable of up to
320 W (maximum current of 20 A and maximum voltage of 42 V). Backpressure regulator
(BPR) controls the pressure, and is capable of providing up to 200 bar pressure.
One open end of the resistively heated reactor is connected to a standard liquid
chromatography (LC) pump using capillary tubing. The other end is attached to a backpressure
regulator (BPR) which is then linked to a collection outlet. Pressure is controlled by the BPR that
is connected to the exit end of the reactor, and the processed liquid is collected after the BPR.
The BPR used in this study has been previously reported in earlier works within our group.15 It is
water cooled when attached to the resistively heated CF reactor and capable of maintaining a
pressure of up to 200 bars within the reactor.
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Temperature of the reactor was measured by connecting a thermostat to the top end of the
reactor coil. The thermostat was then coupled to the power source so that it can be controlled by
the voltage input. This allowed for precise temperature control by regulating the current and
voltage (see Figure 1), and subsequent rapid heating of the reactor. The reactor was placed in an
insulated enclosure to minimize heat loss. When the reactor is operational, a closed system is in
place, with an insulated lid covering the insulated enclosure shown in Figure 2. Once the target
temperature is reached, very little oscillation was observed around the set temperature
(maximum 5 oC).
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Figure 2. Photographs of the 6 mL resistively heated CF reactor (left) with a potential difference
created by the two wires (black and red) connected to the two ends of the reactor. On the right is
the 6 mL CF reactor placed in an insulated casing to minimize temperature loss during
experiments.
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Initial tests to investigate the heating rate with organic solvents flowing through the directly
heated flow system showed the heating rate was about 100 oC/min. The tests were conducted
with three different solvents; methanol, ethanol and acetonitrile flowing through the reactor at a
constant flow rate of 0.5 mL/min. The reactor was heated from room temperature to 400 oC using
the maximum power input of about 320 W in less than 5 min. The results for acetonitrile shown
in Figure 3 is similar to the results obtained with the other two solvents: methanol and ethanol
flowing through the reactor. Cooling rates were also measured by disconnecting the power
supply and removing the reactor insulators. Cooling from 400 oC to 100 oC was done in 4 min at
room temperature without external cooling devices. Further cooling from 100 oC to room
temperature took an extra 6-10 min across all three solvents. The rapid heating and cooling rates
are important in optimization reactions requiring temperature control ‘on the fly’. This rapid
heating is of great importance in CF reactor design.
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Figure 3. The heating rate with acetonitrile passing through the system. A thermostat located
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near the exit of the reactor recorded temperature according to Figures 1 and 2.
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As these CF reactors are designed for frequent usage, replacement should be possible.
Precipitation within the reactor can also necessitate the need for reactor replacement. Steel
tubings are commercially available at relatively low cost, and can be cut into desired length
(volume). Creating a potential difference on the reactor to generate heat is simple and can be
easily done. The size of the reactor and the required temperature influences the amount of
voltage/current applied. The larger the size of the reactor, the higher the required input of
voltage/current needed to heat the reactor. Similarly, the reactor size also influences the heating
and cooling rates. Reactors with smaller sizes tend to heat up and cool down at a faster rate than
larger sized reactors. This can be particularly useful in optimization studies that require rapid
heating and cooling. This set up allows for great flexibility as the system will accept various
dimensions (volumes) of the reactor coil. A 6 mL coil reactor was fabricated and used in all
reactions reported in this paper.
The residence time of a CF process is a function of the flow rate (in mL/min) and the volume
of the reactor. However, as this system was designed for high temperature and high pressure
usage, it was important to take into account solvent expansion and higher diffusion rate that
occur at high temperature. The effect of solvent expansion and diffusion of reagents within the
reactor were taken into consideration by estimating the average residence time of reactants
within the reactor. This was investigated using three test solvents: methanol, ethanol and
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acetonitrile using benzoic acid as a test substrate. Benzoic acid was dissolved in each test
solvents and passed through the reactor at different temperatures. The residence time was
determined by spotting the output on a thin layer chromatography (TLC) paper and recorded to
the nearest 30 seconds. It was discovered that relative to room temperature, there was a two-fold
decrease in residence time at 300 oC, while the residence time decreased up to four-folds at 400
oC (see SI for data). For a reaction in ethanol with a flow rate of 0.5 mL/min in a 6 mL
resistively heated CF reactor, the residence times were estimated as 6 min and 3 min if the
reactions were carried out at 300 oC and 400 oC, respectively. There was no solvent expansion
observed when toluene was used as the solvent.
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Validation of the resistively heated reactor. Supercritical solvent reactions. One class of
chemical processes that can best demonstrate the advantages of high temperature and pressure
are reactions involving common solvents at supercritical states. Ethanol, methanol, and
acetonitrile reach supercritical states at temperatures between 250 oC and 400 oC, at pressures
above 70 bar.19 At supercritical state, these solvents exhibit properties not obtainable at ambient
temperatures. Hence, we decided to investigate reactions involving supercritical ethanol,
methanol and acetonitrile using the resistively heated reactor system. These reactions do
otherwise require the use of additional reagents or catalysts to be carried out at lower
temperatures. The time taken to react under supercritical conditions is also remarkably
decreased.14,16a
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Supercritical ethanol. Esterification. Ethanol attains supercritical state when compressed to
pressures above 65 bars and heated above 250 oC.19, 20 Previous use of supercritical ethanol in
high temperature CF synthesis was reported for the catalyst free transformation of carboxylic
acids to the corresponding ethyl esters in good yields.16a This reaction class has been extensively
utilized for biodiesel production on industrial scale.21 Previously reported esterification of
benzoic acid using supercritical ethanol was done at 300 oC and 100 bar.16a We attempted to
achieve these supercritical conditions as a test of our newly build CF reactor. Using the
resistively heated CF reactor, steady state parameters were reached by pumping absolute ethanol
through the reactor at the desired temperature and pressure for about 10 minutes. The flow rate
and temperature were used for the estimation of residence time as earlier discussed, thus taking
solvent expansion at high temperature in the 6 mL CF reactor into consideration (see SI).
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Benzoic acid, 1a¸ was dissolved in absolute ethanol to make a solution of concentration 40
mg/mL. The solution was pumped into the reactor under different conditions as depicted in Table
1. By collecting a known volume of eluent, the reacting mass can be calculated as the
concentration was kept constant. The isolated yield for benzoic acid esterification (Table 1) is
similar to the yield reported with similar reaction using a commercially available flow system.16a
Conversion was determined by 1H NMR, quantitatively from the percentage of carboxylic acid
reacted to ethyl ester formed. Pressure was maintained at 120 bars, and concentration was
constant throughout the experiment. The highest yield was achieved at 300 oC and in 6 min (flow
rate 0.5 mL/min). Increasing the temperature or lowering the flow rate did not give higher yield,
although conversion was marginally improved. Increasing the temperature above 300 oC was
unfavorable for the esterification, as can be seen in Table 1. At 375 oC, entry 6 in Table 1,
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extensive decomposition of the benzoic acid was detected, an observation previously seen by
Kappe et al.14,16a
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Table 1. Effect of temperature and residence time on the esterification of benzoic acid to ethyl
benzoate using supercritical ethanol in a resistively heated CF reactor.
Entry
Temperature
(oC)
Flow rate Residence
(mL/min)
Conversionb
Yieldc
(%)
Timea (min) (%)
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a. Residence time is reported after adjusting for solvent expansion at supercritical conditions. b.
Conversion is reported as the percentage of carboxylic acid that was transformed, and estimated
by 1H NMR. c. Isolated yield. The purity of isolated product in all instances was more than 95%
as estimated by NMR.
The reaction scope was further investigated with additional carboxylic acids (Table 2) and
similar good yields were generally observed. The flow rate was kept at 0.5 mL/min which
translates to a residence time of 6 min, after considering solvent expansion at 300 oC. Derivatives
of benzoic acid such as carboxylic acids 1b, 1c and 1d were converted to their corresponding
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esters in good yield at 300 oC. Other heterocyclic carboxylic acids such as furan-3-carboxylic
acid 1f and thiophene-3-carboxylic acid 1g gave low conversion at 300 oC, but near full
conversion at 350 oC.
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Table 2. Scope of esterification reactions using different carboxylic acids and supercritical
ethanol in a resistively heated CF reactor.
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Conditions: 6 mL reactor was used. Flow rate was 0.5 mL/min. Residence time is reported after
adjusting for solvent expansion at supercritical conditions. a. Isolated yield is recorded in which
purity was over 95% as determined by 1H NMR.
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Supercritical methanol. Transesterification reactions. Methanol reaches supercritical state
when compressed to about 140 bar, at temperatures above 300 oC.22 At this state, the
nucleophilic properties of methanol are enhanced, and it acts as a nucleophile rather than an inert
solvent that it is at room temperature. These properties are utilized in the transesterification
reactions of supercritical methanol. As with supercritical ethanol, this direct transesterification
reaction can be important in late stage functionalization in organic synthesis.16a Ethyl -3-
phenylpropanoate 3a was chosen as test compound, having being previously reported in similar
transesterification reaction to its methyl ester 4a (Table 3).16a
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With temperatures at 400 oC and pressure up to 180 bar, this experiment afforded a chance to
assess the effectiveness as well as the safety and ease of handling of the resistively heated CF
system at extreme conditions. Using the same resistively heated CF reactor and procedures as in
earlier esterification reactions, the conversion and yield of transesterification reaction was
investigated at different temperatures and residence times. The results are presented in Table 3,
with isolated yield recorded for the highest conversion entries only.
Table 3. Scope of transesterification to form methyl esters directly using a resistively heated
CF reactor.
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Entry Reactant
Product
Temperature Timea Conversionb Yieldc
1
2
3
(min) (%)
(%)
(oC)
4
5
1
350
4
62
-
6
7
8
9
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
375
400
375
4
3
4
81
99
87
-
92
-
2
3
400
375
3
4
99
50
90
-
400
350
3
4
88
69
86
-
4
375
400
350
4
3
4
73
94
25
-
91
-
5
375
400
4
3
43
85
-
82
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a. Time is reported as the residence time after adjusting for solvent expansion at supercritical
conditions. b. Conversion was estimated using H NMR. c. Isolated yield is recorded for the
highest conversion entries only and purity was over 95% as determined by 1H NMR.
1
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9
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59
60
In all compounds examined, improved conversion (and yield) was observed at higher
temperatures. Decomposition of starting material or products inside the reactor was not observed,
from the high yields and 1H NMR data. The yields were generally higher than the supercritical
ethanol esterification reactions. As the flow rate was kept constant, the residence time decreased
with increasing temperature. This decreased residence time did not however affect conversion or
isolated yield. Ethyl esters 3a, 3b and 3d gave isolated yields of 90% and above at 400 oC. Other
substrates such as benzoic anhydride 3c and allyl ester 3e also gave good conversions and
isolated yield at 400 oC (Table 3, entries 3 and 5).
Supercritical acetonitrile. Direct conversion of carboxylic acids to nitriles. Supercritical
acetonitrile is attained at temperatures above 275 oC and 48 bar.23 Chemical reactions utilizing
supercritical acetonitrile have previously been reported.23 The direct conversion of carboxylic
acids to nitriles is yet an additional example of a valuable high temperature and pressure organic
transformation.14 As a further test of reactor capabilities at elevated temperature and pressure, the
reaction was attempted using the resistive heated CF reactor. As previously observed by Kappe,
the residence time could not be directly estimated from the flow rate and reactor volume since
solvent expansion of acetonitrile within capillary reactor at supercritical conditions was
experienced.14 In our case, acetonitrile expansion between 250 oC - 350 oC and 100 bar was
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between 1.7 to 3 folds (see SI). This was taken into consideration in estimating the residence
time reported in Table 4.
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The conversion of 2-methoxybenzoic acid 5a to its corresponding nitrile 6a was attempted
using the 6 mL resistively heated reactor (Table 4). The pressure was kept constant at 100 bar.
As there are no easily distinguishable protons between the starting acid and product,
characterization and conversion estimation by 1H NMR was avoided. GC-MS analysis was
selected for characterization and conversion estimation, using naphthalene as internal standard.
Naphthalene was chosen as internal standard due to its stability at temperatures between 300 oC
and 400 oC.24
Table 4. Direct transformation of 2-methoxybenzoic acid 5a to nitrile 6a using supercritical
acetonitrile in a resistively heated CF reactor.
Entry
Temperature
(oC)
Flow
(mL/min)
rate Residence timea Conversionb (%)
48
49
50
51
52
53
54
55
56
57
58
59
60
(min)
[Isolated Yield]
1
2
3
250
300
325
0.5
0.5
0.5
8
6
6
49
76
74
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7
8
9
4
5
6
7
350
350
350
375
0.5
4
2
8
4
82
1.0
0.25
0.5
66
100 [82]c
100
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59
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a. Residence time is reported after adjusting for solvent expansion at supercritical conditions. b.
Conversion is reported as the percentage of carboxylic acid that reacted. It was determined from
the ratio of nitrile product to carboxylic acid peak areas in the GC-MS. c. Isolated yield is
recorded in which purity was over 95% as determined by 1H NMR.
Temperature and residence times were investigated and the results are presented in Table 4.
The most productive conditions were found to be 0.25 mL/min at 350 oC (entry 6). The results
obtained were similar to results previously reported using a GC-oven powered CF systems.14
Conversion recorded using the resistively heated CF reactor was slightly better (100% vs 98%)
than that achieved when a GC-oven powered CF reactor was used. The isolated yield was
however lower with the resistively heated CF reactor (82% vs 98%), although 82% yield was
achieved in shorter residence time with the resistively heated system (8 min vs 25 min).
Although increasing the temperature resulted in increased transformation, there was no
corresponding increase in isolated yield. Increasing the residence time also increased the
conversion, but 350 oC was preferred to minimize compound decomposition.
N-heterocyclic nitriles are valuable intermediates in medicinal chemistry projects, often used in
cyclisation reactions to form heterocycles.25 Due to low solubility of some N-heterocyclic
carboxylic acids in acetonitrile, N-methyl-2-pyrrolidone (NMP) was used as a co-solvent (up to
20% v/v). Acetylpiperidyl carboxylic acid 5c was selected to investigate the effect of co-solvents
on the direct conversion of carboxylic acids to nitriles using supercritical acetonitrile. The best
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conditions for the conversion to nitrile when using NMP as co-solvent was investigated, and the
results presented in Table 5. We decided to quantify the outcome as a ratio of the product peak to
that of the internal standard.
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Table 5. Direct conversion of 1-acetylpiperidine-4-carboxylic acid 5c to nitrile 6c using
supercritical acetonitrile and NMP as a co-solvent in a resistively heated CF reactor.
Entry
Temperature
(C)
Flow
(mL/min)
rate Residence
timea (min)
Conversionb
(%)
Product/Internal
Standardc
1
2
3
4
5
6
7
8
9
10
250
250
300
300
325
325
350
350
375
375
0.5
8
86
0.24
0.25
0.5
16
6
91
2.23
92
2.16
0.25
0.5
12
6
98
2.81
98
3.02
0.25
0.5
12
4
99
3.24
100
100
100
100
3.38 [63%]
3.36
0.25
0.5
8
4
3.36
0.25
8
3.32
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a. Residence time is reported after adjusting for solvent expansion at supercritical conditions.
b. Conversion is determined by GC-MS, with naphthalene as internal standard. c. The relative
yield was quantified as a ratio of the product to internal standard.
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59
60
The reaction was still clean, with only the peaks of the co-solvent, product and/or starting
material observed in most cases. In these test situations, the conversion of the carboxylic acids to
nitriles was quite high, above 85% in all instances. The isolated yields were, however, below
65%, in contrast to the over 75% observed with non N-heterocyclic nitrile 6a.
Table 6. Conversion of carboxylic acids to corresponding nitriles using supercritical
acetonitrile.
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Residence
Time (min)
Temperature (oC)
Product
Yielda,b (%)
Entry
1
Reactant
OMe
OMe
CN
COOH
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350
8
8
82
5a
5b
6a
COOH
CN
350
85
63
2
3
6b
O
O
N
N
350
4
4
CN
COOH
5c
6c
COOH
CN
N
N
350
60
4
5
O
O
O
O
5d
6d
COOH
CN
N
N
350
4
55
O
O
6e
5e
CN
COOH
350
350
4
4
77
81
6
7
5f
6f
COOH
CN
5g
6g
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a. Residence time was estimated by adjusting the flow rate with solvent expansion at high
temperature (see SI for detailed information).b. Yield is reported as isolated yield with purity
over 95% according to NMR.
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Having identified appropriate CF conditions for the conversion of 5c to 6c with NMP as co-
solvent, the transformation was further screened with different carboxylic acids. In all
compounds listed in Table 6, there was a conversion of over 90% observed. The isolated yields
of 6 with aromatic and aliphatic carboxylic acid starting materials were between 77% to 85% in
entries 1, 2, 6 and 7. However, the outcome was lesser for N-heterocyclic nitriles 6c, 6d and 6e
(entries 3-5). Some N-heterocyclic carboxylic acids such as pyrrole-based acids preferentially
gave the decarboxylative elimination products (not included).
High temperature DielsꢀAlder reactions.
As a further validation of the reactor, Diels-Alder cyclisations were carried out at elevated
temperature. The reaction of diene 7a with electron-deficient dienophile 8a has been reported to
take 5 days to completion at 100 °C and 20 min at 250 °C with microwave heating.26 The
reaction (residence) time was further reduced to 2 min using CF processing at 280 °C and 130
bar.
We investigated this reaction using the resistively heated CF reactor at different temperatures
and flow rates (Table 7). The pressure was kept constant at 90 bar, and no catalysts or additives
were used in the reaction. Unlike ethanol, methanol and acetonitrile, solvent expansion was not
noticed in toluene. The flow rate was directly translated to the residence time within the reactor
by using the reactor volume (6 mL). The results shown in Table 7 show that the conversion of
the diene 7a to cyclohexyl 9a increased with increasing temperature and reducing flow rate
(increasing residence time). Full conversion to the cyclized product 9a was achieved at 200 °C
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with a residence time of 6 min (entry 4, Table 7). By using the high temperature performance of
the system, it was possible to reduce the residence time to 2 min at 300 oC (entry 5, Table 7),
with full conversion.
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Table 7. Effect of temperature and residence time on the Diels-Alder reaction between diene 7a
and dienophile 8a in the resistively heated CF reactor. Pressure was kept constant at 90 bar.
Entry
Temperature
(°C)
Flow rate
Residence
Conversiona
(%)
(mL/min)
Time (min)
1
2
3
4
5
100
1
3
2
1
3
6
2
3
6
2
0.3
200
10
200
85
200
100 [87]b
100 [84]b
300
a. Conversion is reported as the percentage of diene that reacted. It was determined
from the ratio of proton alpha to nitrile group in 9a to allylic protons in the diene.
b. Isolated yield is recorded in which purity was over 95% as determined by 1H
NMR.
The transformation was also repeated with dienophile 8b and similar results were obtained
(Scheme 1). However, the transformation was slower than the reaction in Table 7 and full
conversion was obtained after 6 min at 300 °C, with a slightly higher yield.
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Scheme 1. Diels-Alder reaction with butyl acrylate was carried out in 6 min using the resistively
heated CF reactor.
CONCLUSION
We have demonstrated a highly effective, yet simple flow system suitable for organic synthesis
requiring conditions up to 400 oC and 200 bar. Assembling the resistively heated CF reactor is
considerably cheaper and easier than alternative reactors with similar efficiency. The material
used for the reactor is readily available and replacement and cleaning easily done. High
temperature and high pressure application of this reactor were safely performed and
demonstrated by selected transformations such as esterifications, transesterifications, and direct
carboxylic acid to nitrile reactions using supercritical ethanol, methanol, and acetonitrile. Diels-
Alder reactions were also safely done at 200 oC-300 oC, providing high yields.
Although, applying direct current to a reactor raises safety concerns, the insulated enclosure
minimizes contact and prevents heat loses. This CF reactor stand out particularly for its rapid
heating rate, even up to 400 oC. The cooling rate is also rapid, and its ability to heat and cool
safely is impressive. Residual solvent volume of up to 6 mL can be contained in the reactor at a
particular time. The connection of the heater with a thermostat enables high process control, even
at high temperatures. In addition, bypassing a secondary heat transfer minimizes the power
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required. The current and voltage applied is enough to heat up the reactor, while also unlikely to
trigger electrochemical reactions.
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In summary, the resistively heated reactor is a viable option for CF synthesis over a range of
temperature and pressure conditions. The simplicity to assemble and the user friendliness of the
resistively heated reactor makes it a promising alternative for continuous flow synthesis in both
academia and industry. More so, the resistively heated CF reactor system can potentially be used
in demonstrating CF synthesis in educational and research establishments. Overall, a robust, easy
to use, cheap, fast and effective continuous flow reactor has been presented and validated for
high temperature and high pressure reactions.
EXPERIMENTAL SECTION
General Procedure 1. Esterification of carboxylic acids using supercritical ethanol under
continuous flow conditions. Carboxylic acid (1.20 g) was dissolved in 30 mL absolute ethanol to
get a 40 mg/mL reaction mixture. The reaction mixture was ultra-sonicated for 15 min to get a
completely homogenous solution. Reaction conditions such as temperature and pressure were
preset on the resistively heated CF system. Absolute ethanol was first pumped through the
system at a flow rate of 0.5 mL/min until steady state (ca. 15 min). The reaction mixture was
then pumped into the resistively heated reactor at the preset flow rate. Collection of the
processed solution was started after processing of 10 mL following constant pumping in of the
carboxylic acid. Some of the product mixture (0.5 mL) was collected, dried with N2 and analyzed
for conversion. Conversion of the carboxylic acid to ethyl ester was estimated from the ethyl
ester protons ratio using 1H NMR.
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Processing was continued, and 10 mL of the processed mixture was collected and dried in
vacuo. The processed mixture was then dissolved in 15 mL ethyl acetate and washed twice with
saturated Na2CO3 (10 mL). The organic phase was dried with Mg2SO4 and concentrated in vacuo
to get the crude product, needing no further purification. The ethyl ester formed was then
characterized by NMR.
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General Procedure 2. Transesterification reactions using supercritical methanol under
continuous flow conditions. The starting ester (1.20 g) was dissolved in 30 mL laboratory grade
methanol to get a 40 mg/mL solution (unless otherwise stated). The solution was ultra-sonicated
for 15 min. Reaction conditions such as temperature and pressure were preset on the flow
system. Methanol was pumped through the system at the desired flow rate until steady state was
reached (ca. 15 minutes). The starting ester solution was then pumped into the resistively heated
reactor at the desired flow rate. Collection of the processed solution was started after pro of 10
mL following constant pumping in of the starting ester. Some of the processed solution (0.5 mL)
was collected, dried with N2 and analyzed for conversion. Conversion of the starting material was
estimated from the methyl ester formation using 1H NMR. Processing was continued, and 10 mL
of the processed solution was collected and dried in vacuo to afford the methyl ester. The methyl
ester formed was characterized by NMR, with purity over 95%, thus needing no further
purifications. In instances where purity was below 95%, purification by column chromatography
was carried out.
General Procedure 3. Direct conversion of carboxylic acids to nitriles using supercritical
acetonitrile under continuous flow conditions. Carboxylic acid (0.30 g) was dissolved in 30 mL
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acetonitrile to get a 10 mg/mL solution. The solution was ultra-sonicated for 15 min. Reaction
conditions such as temperature and pressure were preset on the flow system. Acetonitrile was
first pumped through the system at the desired flow rate until steady state was reached (ca. 15
min). The acid solution was then pumped into the resistively heated reactor at the desired flow
rate. Collection of the processed solution was started after processing of 10 mL following
constant pumping in of the carboxylic acid. Processing was continued, and 10 mL of the
processed solution was collected and dried in vacuo. The product was then dissolved in 15 mL
ethyl acetate, washed twice with saturated Na2CO3 (10 mL). The organic phase was dried with
Mg2SO4 and concentrated in vacuo to get the crude product, needing no further purification.
Where N-methyl pyrillidone (NMP) was used as co-solvent, the work up procedure was
slightly changed. In this case, 10 mL of processed product was collected and dried in vacuo. The
product was then dissolved in 20 mL ethyl acetate and washed twice with saturated sodium
carbonate. The organic phase was further washed with brine until NMP was removed (5-7
times). The organic phase was dried with Mg2SO4 and concentrated in vacuo to get the crude
product. The nitrile formed was analyzed by NMR. For nitriles 6a and 6c, some of the processed
product (0.1 mL) was collected and dissolved in dichloromethane (DCM). GC-MS analysis was
carried out to establish the conversion. Conversion was estimated from the peak area, with
naphthalene used as internal standard.
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General Procedure 4. Diels-Alder reaction under continuous flow conditions. 2,3-Dimethyl-
1,3-butadiene (3.3 g, 40 mmol) and dienophile (80 mmol, 2 equiv) were added together and the
volume made to 30 mL by adding toluene. The mixture was ultra sonicated for 5 min. Toluene
was pumped into the reactor at the set temperature and flow rate until steady state was reached
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