Reaction Calorimetry in Microreactor Environments - Measuring Heat of Reaction by Isothermal Heat Flux Calorimetry

Article abstract of DOI:10.1021/acs.oprd.7b00092

A novel setup to analyze the heat of reaction of different single- and multiphase reactions carried out in continuous flow is presented. The measurement principle of the calorimetric system is based on true heat flow measurements and therefore ensures precise calorimetric data within 10 mW resolution. In addition to the investigation of simple mixing phenomena (ethylene glycol and water), a number of exothermic, industrially relevant chemical transformations including the nitration of phenol, the reduction of nitrobenzene, as well as several oxidation and reduction processes, were investigated as model systems. For these experiments a commercially available batch calorimeter (ChemiSens CPA202) was equipped with a glass static mixer (250 μL) optionally connected to a tubular microreactor (PFA coil) allowing overall reaction volumes of up to ca. 5.5 mL. Experiments were performed by feeding individual streams with syringe pumps (alternatively substituting one liquid feed with a gaseous feed controlled by a mass flow controller) and mixing the feeds inside the glass static mixer contained in the thermostatted reactor zone of the calorimeter. By adjusting the residence time, volume, and flow rates, chemical transformations were driven to full conversion in order to obtain meaningful calorimetric data. A comparison with literature data indicates that the calorimetric flow system described herein provides comparable data to those obtained by standard batch calorimetry.

Full text of DOI:10.1021/acs.oprd.7b00092

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Full Paper
Reaction Calorimetry in Microreactor Environments –
Measuring Heat of Reaction by Isothermal Heat Flux Calorimetry
Gabriel Glotz, Donald J Knoechel, Philip Podmore, Heidrun Gruber-Woelfler, and C. Oliver Kappe
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00092 • Publication Date (Web): 20 Apr 2017
Downloaded from http://pubs.acs.org on April 26, 2017
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Reaction Calorimetry in Microreactor Environments – Measuring
Heat of Reaction by Isothermal Heat Flux Calorimetry
Gabriel Glotz,†,‡ Donald J. Knoechel,§ Philip Podmore,¥ Heidrun GruberꢀWoelfler,*,¶,‡
and C. Oliver Kappe*,†,‡
† Institute of Chemistry, University of Graz, Heinrichstrasse 28, Aꢀ8010 Graz, Austria
‡ Research Center Pharmaceutical Engineering (RCPE), Inffeldgasse 13, 8010 Graz, Austria
§ Fauske and Associates LLC, 16W070 83rd Street, Burr Ridge, IL 60527, USA
¥ Syrris Ltd., 27 Jarman Way, Royston, Hertfordshire, United Kingdom
¶ Institute of Process and Particle Engineering, Graz University of Technology, Inffeldgasse 13/III,
8010 Graz, Austria
____________________
Corresponding Authors.
*Eꢀmail: woelfler@tugraz.at.
*Eꢀmail: oliver.kappe@uniꢀgraz.at.
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TOC Graphic
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Feed 1
Feed 2
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Output
Peltier
element
Heat flow
sensor
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Abstract
A novel setꢀup to analyze the heat of reaction of different singleꢀ and multiphase reactions
carried out in continuous flow is presented. The measurement principle of the calorimetric
system is based on true heat flow measurements and therefore ensures precise calorimetric
data within 10 mW resolution. In addition to the investigation of simple mixing phenomena
(ethylene glycol and water) a number of exothermic, industrially relevant chemical
transformations including the nitration of phenol, the reduction of nitrobenzene, as well as
several oxidation and reduction processes, were investigated as model systems. For these
experiments a commercially available batch calorimeter (ChemiSens CPA202) was equipped
with a glass static mixer (250 µL) optionally connected to a tubular microreactor (PFA coil)
allowing overall reaction volumes of up to ca. 5.5 mL. Experiments were performed by
feeding individual streams with syringe pumps (alternatively substituting one liquid feed with
a gaseous feed controlled by a mass flow controller) and mixing the feeds inside the glass
static mixer contained in the thermostated reactor zone of the calorimeter. By adjusting the
residence time, volume and flow rates, chemical transformations were driven to full
conversion in order to obtain meaningful calorimetric data. A comparison with literature data
indicates that the calorimetric flow system described herein provides comparable data to those
obtained by standard batch calorimetry.
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Keywords: Continuous Flow Synthesis, Heat Flow, Microreactor Technology, Multiphase
Reactions, Reaction Calorimetry
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Introduction
During the last two decades continuous flow chemistry has become increasingly popular in
the field of organic synthesis.1,2 The advantages of this enabling technology are also
progressively appreciated by the pharmaceutical industry and thus a growing number of
scientists from research and academia to process chemists and chemical engineers in industry
are now employing continuous flow technologies. The small internal volume of microreactors
and their high surface areaꢀtoꢀvolume ratios enhance mass and heat transfer, resulting in rapid
mixing, enabling precise control over the reaction parameters, increasing overall process
efficiency and safety.1,2 Furthermore, microreaction technology enables chemical
transformations to be executed under conditions that are impractical or virtually impossible to
perform using traditional batch conditions.1,2
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Despite all of the mentioned benefits of flow technology, there is still a need to obtain
accurate thermal data for chemical reactions as a basis for appropriate reactor design for both
laboratory and industrial scale applications. Chemical transformations are often accompanied
by a significant heat release and must therefore be thoroughly understood to allow safe
processing on industrial scale. In that aspect reaction calorimetry can be considered as
powerful tool for providing information about the enthalpy of a reaction, heat capacity of the
reaction mixture and activation energy.3 These parameters are of significant importance in
order to obtain a fundamental understanding of the reaction behavior and kinetics.3 Currently,
such calorimetric data are generally obtained in batch or semiꢀbatch mode, using standard
batch calorimeters such as the RC1 from Mettler Toledo and related instrumentation.4 This
approach suffers from the fact that a comparatively large test volume (0.3 to 2 L) is typically
required, which not only poses a severe safety hazard for fast and exothermic reactions
(adequate control of temperature an mixing), but also limits the exploration of critical process
parameters.4
In recent years, there has been growing interest in obtaining calorimetry data under
continuous flow conditions, mainly using microstructured devices. Apart from numerous
applications in biochemical research in the area of high throughput screening of drugꢀenzyme
binding and the analysis of enzymatic reactions,5 seminal contributions to the field of process
chemistry have been made by the Frauenhofer Institute for Chemical Technology (ICT) in
Germany.6 The calorimetric device developed by ICT consists of a glass microreactor
embedded between thermoelectric modules (soꢀcalled Seebeck elements) acting as direct
heatꢀflow sensors allowing fast screening as well as determining the thermokinetic
characteristics of chemical reactions.6
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With the increase in popularity and use of flow technology from academic research
institutions to process chemists, there is a growing need for measurement systems that allow
the direct analysis of thermochemical behavior of chemical transformations inside flow
(micro)reactors in real time. We herein present an experimental setꢀup that is able to generate
real time reaction calorimetry data (Heats of Reaction) under continuous flow conditions
employing microreaction technology. Key to the setꢀup is the use of a precision batch reaction
calorimeter (ChemiSens CPA202) equipped with a glass static mixer (micromixer) and/or a
coiled tubular reactor, to investigate the heat of reaction of chemical transformations carried
out in continuous flow mode. Starting with the evaluation of simple mixing experiments,7 the
focus of this work was to determine the heat of the reaction of several industrially important
exothermic transformations involving both singleꢀ and multiphase systems, including liquidꢀ
liquid and gasꢀliquid chemistry.
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Results and Discussion
ChemiSens CPA202 Reaction Calorimeter.8 The ChemiSens CPA, or Chemical Process
Analyzer, is a preꢀcalibrated highꢀprecision calorimeter for analyzing chemical processes. The
absolute heat production from the process is presented onꢀline in real time without subjective
interpretations of calibration pulses or unknown baselines. The main part of the CPA system
is the reactor (250 mL volume) operating from ꢀ50 °C to 200 °C and up to 20 bar pressure
with power resolution to 10 mW and glass sidewalls so the reaction mixture can be directly
observed. Stirring is controlled (and variable) between 50 and 2000 rpm with a variety of
impeller designs and a baffle insert. During operation the reactor is positioned in a precisely
controlled thermostatic bath, which also acts as a safety shield. The CPA202 works on a
unique principle called “True Heat Flow”. The heat flow from the reaction process is directly
measured using a constantꢀarea thermopile comprised of hundreds of temperature sensors.
This “True Heat Flow transducer” is preꢀcalibrated with all of the heat flow occurring at the
wellꢀdefined bottom of the reactor (the rest of the reactor being insulated and immersed in the
thermostatic bath, thus minimizing heat losses). Unlike other reaction calorimeters, the
measured heat flow is not sensitive to changes in heat transfer coefficient or wetted heat
transfer area. This means that evolved (or consumed) power is directly available onꢀline
without any calibration or post processing. The temperature of the process reactants is
controlled using a Peltier element which acts as a reversible heat pump to transfer heat to (or
from) the thermostating liquid that is maintained at the same temperature as the process
reactants. The True Heat Flow transducer is sandwiched between the Peltier element and the
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bottom of the reactor vessel. The 13 L volume of the thermostatic bath surrounds the reactor,
providing a large heat sink. The reactant volume in batch operation is typically in the range
from 10 to 180 mL, substantially smaller than most traditional reaction calorimeters. In the
circumstance of nonꢀisothermal behavior, however, the True Heat Flow must be corrected by
the accumulated heat that has either entered or left the reaction mass requiring knowledge of
the reaction mass heat capacity and temperature change to do so.
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Continuous Flow Calorimeter Setup. For the calorimetric measurements the ChemiSens
CPA202 system was modified for continuous operation by placing either a glass static mixer
or a Tꢀmixer in combination with a tubular reactor inside the thermostated reactor zone. An
image of the internal arrangements in the reactor zone of the calorimeter is shown in Figure 1.
A schematic view of the setup for the calorimetric analyses is shown in Figure 2. Feeding of
the liquids streams was performed using Syrdos dosing pumps from HiTEC Zang. For the
control of the gas flow, a mass flow controller (MFC) was used (Bronkhorst) with a fixed
value back pressure. Depending on the reaction conditions (gas development during reaction
or reaction temperature higher than the atmospheric boiling point of the solvent) back
pressure regulators (BPR) of up to 7 bar were applied. For the gasꢀliquid reactions we found
that two BPRs connected in series with the algebraic sum of the nominal values of each BPR
reduced the BPRꢀinduced noise in the measured calorimetric signal, compared to using only
one BPR of the double value. With two BPRs the noise in the signal was effectively reduced
by up to 50%, thus allowing the recording of a more accurate signal. For reactions involving
gases and one liquid feed a simple Tꢀmixer was used, while for the experiments with two
liquid feeds a glass static mixer was implemented in the setup. This microchip includes a
micromixer with two inputs and one output with 250 µL of overall residence volume. After
the chip an additional residence time coil made out of perfluoroalkoxy polymer (PFA) with an
outer diameter of 1.8 mm and inner diameter of 0.8 mm was added in order to increase
residence time volume up to ca. 5.5 mL and thus to ensure that the investigated chemical
transformations reached complete conversion.
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Figure 1. Left: Overview of ChemiSens reaction chamber; middle: schematic view of
microreactor and residence time coil setup, right: image of microreactor and residence time
coil.
Figure 2. Setup for calorimetric measurements in the ChemiSens CPA202 calorimeter in
continuous flow mode. The magnified heat flow sensor depicts the principle of operation
where T2 is the temperature inside the reactor and T1 is the temperature of the thermostatic
bath. 200 Seebeck elements are arranged in a cone shape and the temperature difference T2ꢀ
T1 is measured across the Seebeck elements as the true heat flow.
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Data Collection and Evaluation. The CPA202 calorimeter, owing to its large thermostatic
bath, allows for preheating of the reactions feeds before entering into the reactor. For our
experiments we decided to pump the reaction feeds (at room temperature) directly into the
heated microreactor setꢀup thermostated at 50ꢀ130 °C without temperature preꢀequilibration.
This required the subsequent measurement of reference experiments where typically only
“nonꢀreacting” mixtures/solvents (i.e. without catalyst or reaction partner) were pumped
through the system, thereby taking the “cooling” effect on the calorimeter into account. All of
the experiments were performed in isothermal mode taking advantage of the longꢀterm
temperature stability of the thermostatic bath and the calorimetric system.
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Calculations of Heat of Reaction were performed according to Eq 1 where
reaction enthalpy, P is the power in Watt obtained from the instrument (as the data output
from the ChemiCall software), is the flow rate in mL/s and is the molar concentration of
H is the
f
c
the limiting reactant in mol/mL. The power data from the instrument were obtained by
averaging data from a linear region (or steady state of operation) with a minimum of 150 data
points. In order to obtain meaningful calorimetric data power values were obtained for both
the chemical reaction and for the “cooling” effect of the reaction mixture, which were
subsequently subtracted in order to obtain the power value for the reaction only. These values
were then used for the calculations.
ꢅ
ꢆ
ꢅ
ꢆ
ꢇꢉꢊ
ꢁ
ꢋ
ꢀ =
= ꢄꢇꢈ
=
=
ꢌꢍꢎꢏ
Eq. 1
ꢇꢉꢊ
ꢇꢈ
ꢂ ×ꢃ
×
ꢆ
ꢆ
What is actually being measured in the flow experiment is a "total heat flow." This total heat
flow is a combination of the steady state enthalpy of reaction (per time) for the specific
chemical transformation taking place (bond breaking/bond making) plus a variety of physical
effects (heats of mixing of solvents, sensible heat effects due to streams of different
temperatures, etc., per time) that occur simultaneously upon combining the streams. A series
of reference experiments attempt to correct for some of these physical effects. A "heat of
reaction" is then derived from the corrected steady state total heat flow, the flow rate and
concentration of the streams and serves as the basis of comparison to previous work.
It has to be kept in mind that for a flow system, the "total heat flow" is what ultimately
must be handled by the cooling system. Of the three contributions to total heat flow
mentioned above (enthalpy of reaction, heat of mixing, sensible heat), in a real flow reactor
system only the temperature of the streams (sensible heat) may be manipulated to help with
heat transfer challenges (intentionally precooling a stream for example).
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Mixing Experiments: Ethylene Glycol-Water. Mixing experiments in continuous flow
mode are often performed in order to evaluate the performance of micromixing devices.9 The
heat of formation of 1:1 ethylene glycol (EG) in water is ꢀ456.1 kJ/mol and that for pure EG is
ꢀ454.8 kJ/mol. This suggests that the heat of mixing to make 1:1 EG:water would be ꢀ1.3
kJ/mol.10 In our initial experiments we wanted to compare the measured mixing enthalpy data
for ethylene glycol and water obtained in the 250 µL glass static mixer with the values
previously reported by Greiner and coworkers utilizing different micromixers but a similar
general experimental setꢀup involving the ChemiSens CPA202 calorimeter.7 For the mixing
experiment a setup using only the glass static mixer with an internal volume of 250 µL was
used. Ethylene glycol and water with flow rates of 0.900 mL/min and 0.300 mL/min,
respectively, were chosen in order to obtain the desired 1:1 molar ratio of liquids. The mixing
was conducted at 60 °C in order to be well above room temperature for the thermostatic bath
of the calorimeter and the cooling system to retain the temperature as stable as possible. In
order to subtract the cooling effect of the mixing, a mixture of ethylene glycol and water was
prepared and left overnight at room temperature; the mixture was then pumped through the
system with a flow rate of 1.20 mL/min. An enthalpy of mixing of ꢀ1.19 kJ/mol was obtained
which is in good agreement with the theoretically calculated value of ꢀ1.3 kJ/mol (diluting
pure EG to 1:1 mole ratio in water) (Figure 3).10
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Figure 3. Data obtained for the mixing of ethylene glycol (EG) and water. Before event point
1 there was no flow, providing the baseline of the experiment. Event point 1 represents both
EG and water fed separately and mixed; event point 2 presents feeding of a preꢀprepared
mixture of EG and water, and event point 3 represents the stop of the flow. The appropriate
power value was obtained by extracting data between point 1 and 2 and then subtracting the
value of the cooling effect.
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Reaction Calorimetry in Continuous Flow. In order to test our setup for the determination
of the heat of reactions for chemical transformations carried out in flow mode, we first started
with a simple model reaction, the hydrolysis of acetic anhydride with aqueous HCl, in order to
compare the accuracy of the obtained data with literature values. We then moved to
industrially more relevant reactions including singleꢀ and multiphase processes. All chemical
transformations were previously developed (mainly in our laboratories) for continuous
processing and (if necessary) the conditions were slightly modified in order to allow
processing in the ChemiSens reactor.
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Hydrolysis of Acetic Anhydride. The acidꢀcatalyzed hydrolysis of acetic anhydride is often
used as calibration reaction for calorimetric systems11 and was therefore also selected for
evaluating the performance and accuracy of the ChemiSens CPA202 flow system described
above. The reaction was performed in the 250 µL glass static mixer (Dolomite microreactor).
Before investigating the actual reaction, a mixture of acetic anhydride (neat) and 5 M aqueous
HCl was prepared and left overnight to react and reach the same temperature as the reactants.
The preꢀprepared mixture was subsequently pumped with a flow rate of 1.50 mL/min through
the setꢀup in order to determine the cooling effect of the reaction mixture. The data obtained
by this experiment were used for the calculation of the real ∆Hr without the need for
calculating cp of the reaction mixture. After the cooling effect experiment, reactants were
pumped separately with a total flow rate of 1.50 mL/min (0.500 mL/min Ac2O and 1.00
mL/min of 5M HCl) at 60 °C. With the obtained data a ∆Hr with a value of ꢀ179 kJ/mol) was
calculated, which compares well with a literature value of ꢀ174.32 kJ/mol.12 The result
obtained in these experiments is somewhat higher because of the use of concentrated
hydrochloric (5M) acid in order to obtain complete hydrolysis in such short residence time.
Nitration of Phenol. The procedure for the nitration of phenol with concentrated HNO3 was
adopted from the method reported by Durcy and Roberge13 with some modifications owing to
the formation of solids and/or polymers (Scheme 1). These authors have studied the nitration
of phenol by both batch and flow calorimetry using the RC1 calorimeter from Mettler
Toledo.13 Despite the similar setup the results are not comparable since in our experiments a
much larger molar excess of HNO3 was leading to a higher proportion of dinitrated products.
Scheme 1. Nitration of Phenol Leading to Mono and Dinitrated Products.
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The reaction setup included two pumps to transport the two feeds. One feed was the substrate
solution that consisted of 23 wt% phenol dissolved in 71 wt% water and 6 wt% acetic acid
(acetic acid was used to increase the solubility of the phenol in water). The second feed was
65 wt% (concentrated) nitric acid. Feeds were pumped with flow rates of 0.2 mL/min and 0.6
mL/min, respectively, producing a molar ratio of HNO3 to phenol of 20:1. A PFA residence
coil with 5.2 mL internal volume was used as reactor, the two feed streams were mixed in a
standard T mixer, and a BPR with a nominal value of 7 bar. Because of gas evolution during
the reaction the experimentally determined overall residence time of 6.5 min was slightly
shorter than the one calculated from the nominal flow rates. According to HPLC analysis the
major product formed was 2,4ꢀdinitrophenol (92.5%), along with 2ꢀnitrophenol (1.4%) and 4ꢀ
nitrophenol (0.5%). In addition, trace amounts of higher substituted nitrophenols, unreacted
phenol and polymers were obtained (total of 5.7%).
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Two additional experiments were performed, the first one in order to determine the
heat of dilution of nitric acid in water. For that purpose the first feed was concentrated nitric
acid and second feed was distilled water. The flow rates were the same as in the nitration
experiment. The second experiment was to determine the cooling effect, or rather the cp, of
the reaction mixture. Here the first feed was distilled water and the second was a solution of
phenol in water and acetic acid. Again, flow rates were the same as in the nitration
experiment. From all three sets of experiments the collected data were used to calculate a ∆Hr
value. Calculation was performed using the equation 1 with the difference that in this case
three values for power were obtained: power for the nitration (P1), power for dilution of nitric
acid (P2) and power for the cooling experiment, cp of the reaction mixture (P3). The overall
value for power (PF) vas obtained in following manner: ꢐꢑ = ꢐ − ꢐꢓ − ꢐꢔ. With the final
ꢒ
value of PF and equation 1. ∆Hr was calculated to be ꢀ121kJ/mol for this particular nitration
reaction. Somewhat similar results were previously obtained for the nitration of other
aromatic compounds (i.e.,110 kJ/mol for the nitration of toluene, and 120 kJ/mol for the
nitration of 3,4 disubstituted ethyl benzoate).6,14
Reduction of Aromatic Nitrogroups by Hydrazine. The reduction of a nitro group is a very
popular conversion in order to obtain amine functionalities, which are important in
pharmaceutical applications. We have recently described a continuous flow procedure that
allows the selective reduction of aromatic nitro groups employing hydrazine hydrate as
reductant and inꢀsitu formed Fe3O4 nanoparticles as catalyst (Scheme 2).15 This highly
exothermic protocol can be performed safely using continuous flow technology within a few
minutes at temperatures of 150 °C.15 For the current study nitrobenzene was selected as
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substrate. The reaction mixture as one single feed was composed of nitrobenzene (30 mmol, 1
mol/L), hydrazine hydrate (1.2 equiv, 36 mmol) and 0.5 mol% Fe(acac)3 as precursor for the
iron oxide nanoparticles catalyst. The reaction was conducted at 125°C with a 1.00 mL/min
flow rate of the single liquid feed employing a PFA coil of 5.2 mL affording a total residence
time of 5.2 min. For this transformation it was necessary to use a BPR with a nominal
pressure of 7 bar in order to keep the reaction mixture in the liquid state and to account for the
development of gaseous nitrogen. Under these reaction conditions a conversion of 99% could
be achieved according to GCꢀMS analysis. Additionally, cooling experiments were carried out
to determine the cooling effect of the reaction mixture. These experiments were conducted in
the same way as the main reaction but without any substrate (Figure 4). From the obtained
experimental data ∆Hr was calculated to be ꢀ218kJ/mol.
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Scheme 2. Selective Reduction of Nitrobenzene.
0.5 mol% Fe(acac)3
1.5 N2H4
NO2
NH2
MeOH
+ 1.5 N2 + 2H2O
125 °C, 5.2 min, 7 bar
Figure 4. Data obtained for the reduction of nitrobenzene with hydrazine hydrate and Fe3O4
nanocatalyst. The region before event point 3 represents flowing a solution of the substrate
and hydrazine in methanol without the Fe(acac)3 preꢀcatalyst through the calorimeter
providing the “cooling” effect value. Event point 3 represents the start of flow of the reaction
mixture with 0.5% Fe(acac)3. Subtracting the cooling effect value from reaction value
provides the heat of reaction.
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Oxidation of Alcohols. The oxidation of alcohols using hydrogen peroxide as oxidant and
tungstenꢀbased catalysts enjoys great popularity in the synthetic community as it can be
considered as a wasteꢀfree and green method, avoiding the use of stoichiometric (metalꢀbased
oxidants).16 For the current evaluation racemic 1ꢀphenylꢀ1ꢀpropanol was used as a substrate,
25% H2O2 solution as oxidant and sodium tungstate (1.0 mol%) as catalyst (Scheme 3). Since
1ꢀphenylꢀ1ꢀpropanol is not soluble in water, methyl trioctyl ammonium hydrogen sulfate was
used as phase transfer catalyst (PTC).
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Scheme 3. Oxidation of 1-Phenyl-1-Propanol with Hydrogen Peroxide. a) Oxidation of 1ꢀ
Phenylꢀ1ꢀPropanol with Hydrogen Peroxide. b) Decomposition of hydrogen peroxide with
sodium tungstate
The chosen reaction temperature was 130°C and a reaction setup with two liquid feeds was
used. Feed 1 consisted of 1ꢀphenylꢀ1ꢀpropanol with 1 mol% of PTC and was pumped with a
flow rate of 0.100 mL/min, the second feed was 25 wt% solution of hydrogen peroxide with 1
mol% of sodium tungstate dihydrate. The flow rate was set to 0.476 mL/min, providing a
molar ratio of 4.4:1 (H2O2/substrate). The oxidation was performed in the glass static mixer
with an internal volume of 250 µL in addition to a 2.36 mL PFA residence time coil attached
to it, providing a total volume of 2.61 mL and a thus a residence time of 4.53 min. After the
reaction coil, outside of the calorimeter, a BPR with 7 bar nominal pressure was used. At the
end of the reaction, the formation of the ketone product was confirmed by GCꢀMS and HPLC
analysis (92.3%, area% at 215 nm). In order to determine the ∆Hr of the reaction, we
conducted again the cooling effect experiment where the flow rates were the same as in
original experiment. The only difference was the absence of any catalyst and PTC. For this
experiment, the conversion was confirmed to be 0% by HPLC and GCꢀMS. A ∆Hr value of ꢀ
245kJ/mol was calculated for the oxidation reaction.
Olefin Reductions Using Diimide. We recently have reported the highly selective reduction of
olefins to alkanes using inꢀsitu generated diimide (HN=NH) under continuous flow
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conditions.17 In this process the diimide is generated at elevated temperature and pressure
directly from hydrazine hydrate and pure oxygen in a catalystꢀfree procedure. At temperatures
of 100ꢀ120 °C selective olefin reductions can be obtained within minutes. This protocol has
proven to be very useful in the context of API manufacturing, i.e., for the selective reduction
of artemisinic acid18 and thebaine.19 For the current evaluation of this intensified gasꢀliquid
reaction system allylbenzene was used as substrate. The reaction was performed in the glass
static mixer (internal volume of 250 µL) in addition to a 5.2 mL PFA residence time coil
attached to it, providing a total volume of 5.45 mL and a thus a residence time of ca. 2.5 min.
The reaction procedure was slightly modified by increasing the concentration of hydrazine
hydrate from 4 to 6 equiv. The flow rate of oxygen was increased from 2.00 mL/min to 4.00
mL/min (6.0 equiv). Allylbenzene was dissolved in 1ꢀpropanol (10.4 mol/L) and the
temperature inside the reactor was 100°C. Compared to our original protocol17 the amount of
hydrazine hydrate and oxygen was increased in order to drive the reaction to complete
conversion in desired residence volume. The liquid feed was pumped with a flow rate of
0.400 mL/min and the oxygen feed at 4.00 mL/min. Since a noisy signal was obtained with
only one BPR due to the opening and closing of the BPR, two 7 bar BPRs were used yielding
total of 14 bar backpressure (see above). For this reaction, cooling experiments were
performed with 1ꢀpropanol and hydrazine hydrate without the substrate allylbenzene. The
flow rates of the liquid feed and oxygen were the same as in the main experiment. The
cooling experiment has been performed in order to cancel out any effect of undissolved
oxygen and the formation of diimide during the reaction. The effect of the large amount of
undissolved nitrogen is only on the flow pattern of the reaction mixture which by employing
two BPRs can be minimized to not affect the calculations. Under the conditions described
above conversion to product was confirmed to be 99% by GCꢀMS. A ∆Hr value of ꢀ
501kJ/mol was calculated for this gasꢀliquid process.
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Scheme 4. Reduction of Allylbenzene with In-Situ Generated Diimide. A) reduction of
allylbenzene with diimide. b) Generation of diimide from hydrazine and molecular oxygen.
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Conclusion
The commercially available calorimeter system ChemiSens CPA202, equipped with a glass
static micromixer and a tubular reactor, was successfully tested for the investigation of
exothermic reactions in continuous flow. With this novel setꢀup the heat of reaction can be
derived from the measured total heat flow under continuous flow conditions in a safe manner.
The tested model reactions included industrial relevant applications including singleꢀ and
multiphase reactions. However, it should be emphasized that the results presented herein were
obtained under conditions optimized for continuous flow processing. This typically means
realization of reaction times (residence times) that are in the order of a few minutes, generally
achieved by processing at elevated temperatures and/or using a larger excess of reagent(s).
These data are therefore not necessarily comparable with those obtained by standard batch
calorimetry using the RC1 or related calorimeters. In addition, flow processing involving
gases as reagents or products in microstructured environments induces specific flow regimes,
i.e. segmented flow patterns. In order to minimize the influence of these effects on the flow
rate backꢀpressure regulators (BPRs) need to be employed. In this way the influence on the
calculation of calorimetric data can be reduced and valid data can be generated.
In summary, the novel setꢀup described herein proves to be a very attractive alternative
to existing calorimetric systems, especially for microreaction applications in flow. Future
efforts will take advantage of temperature preꢀequilibration so as to simplify the experimental
protocol to not have to run reference experiments to account for the “cooling” effect. In this
manner, the evaluation of the thermochemistry will be less complex.
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Experimental Section
1
General. HꢀNMR spectra were recorded on a Bruker 300 MHz instrument. Chemical shifts
(δ) are expressed in ppm downfield from TMS as internal standard. The letters s, d, t, q, and
m are used to indicate singlet, doublet, triplet, quadruplet, and multiplet. GCꢀMS spectra were
recorded using a Thermo Focus GC coupled with a Thermo DSQ II (EI, 70 eV). A HP5ꢀMS
column (30 m × 0.250 mm × 0.025 ꢁm) was used with Helium as carrier gas (1 mL minꢀ1
constant flow). The injector temperature was set to 280 °C. After 1 min at 50 °C the
temperature was increased in 25 °C minꢀ1 steps up to 300 °C and kept at 300 °C for 4 minutes.
Analytical HPLC (Shimadzu LC20, diode array detector) analysis was carried out using a C18
reversedꢀphase (RP) analytical column (150 × 4.6 mm, particle size 5 ꢁm) at 25 °C using a
mobile phase A (water/acetonitrile 90:10 (v/v) + 0.1 % TFA) and B (MeCN + 0.1 % TFA) at
a flow rate of 1.0 mL minꢀ1. The following gradient was applied: linear increase from solution
30% B to 100 % B in 8 min, hold at 100% solution B for 2 min. Melting points were
determined on a Stuart™ SMP3 melting point apparatus. Reagents and solvents were
purchased from commercial sources and were used without further purification. Conversion
of starting materials and the amount of product were determined by GCꢀMS and/or HPLC at
wavelength of 215 nm (unless otherwise mentioned).
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Continuous Flow Calorimetry. The experimental setup consisted of the ChemiSens CPA202
calorimeter8 and a Huber 240 mini cryostat connected to the calorimeter as the source of
cooling liquid. The cooling liquid inside the cryostat was Galden HT200 thermoliquid cooled
to 20⁰C and circulated through the calorimeters thermostatic bath. The liquid for the
thermostatic bath of the calorimeter was diethylene glycol (>99%) kept at 50ꢀ130 °C
depending on the specific experiment. Inside the thermostatic bath the reactor was reactor
filled with Galden HT200 thermoliquid. The flow reactor setꢀup either consisted of a 250µL
glass static mixer with three inputs (one blocked) and one output (Dolomite, 250µL inner
volume), or a standard PTFE Tꢀmixer, optionally connected to a residence volume coil (2.36
– 5.20 mL) made from fluoropolymer tubing (PFA, 1/16’’ o.d., 0.8 mm i.d.) (Figures 1 and 2,
the detailed setꢀup for each of the experiments is given in the Supporting Information).
SyrDos dosing pumps (1 mL syringe volume, HiTEC Zang) were used for liquid feeds, and
oxygen gas from a gas cylinder (5.0) was fed into the system via a calibrated mass flow
controller (Bronkhorst). The stirrer speed in the reactor was 500 rpm for all experiments and
the data were collected with the ChemiCall v2 program via a connected laptop. All the
experiments including the cooling experiments were run for a minimum of 30 min in order to
achieve steady state operation and to extract a sufficient amount of data for the analysis. This
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required ca. 30 mmol of reagent owing to the high sensitivity of the instrument. The specifics
of each experiment are described in the Supporting Information.
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Supporting Information
Diagrams of the obtained data for calorimetric experiments, additional experimental
information and supplementary figures.
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References
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,
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(7)
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Jahrestagung Reaktionstechnik, Würzburg, Germany, 2014.
(8)
(9)
The ChemiSens Calorimeter is commercially available from Syrris Ltd. For further
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