Subtle Microwave-Induced Overheating Effects in an Industrial Demethylation Reaction and Their Direct Use in the Development of an Innovative Microwave Reactor

Article abstract of DOI:10.1021/jacs.7b00689

A systematic study of the conventional and microwave (MW) kinetics of an industrially relevant demethylation reaction is presented. In using industrially relevant reaction conditions the dominant influence of the solvent on the MW energy dissipation is av

Full text of DOI:10.1021/jacs.7b00689

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Article
Subtle microwave-induced overheating effects in an
industrial de-methylation reaction and their direct use
in the development of an innovative microwave reactor
Mario De bruyn, Vitaliy L. Budarin, Guido S.J. Sturm, Georgios D. Stefanidis,
Marilena Radoiu, Andrzej Stankiewicz, and Duncan J. Macquarrie
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b00689 • Publication Date (Web): 27 Mar 2017
Downloaded from http://pubs.acs.org on March 27, 2017
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Subtle microwave-induced overheating effects in an industrial de-
methylation reaction and their direct use in the development of an
innovative microwave reactor
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Mario De bruyna, Vitaliy L. Budarina, Guido S. J. Sturmd, Georgios D. Stefanidisb, Marilena Radoiuc,
Andrzej Stankiewiczd and Duncan J. Macquarriea*
a Green Chemistry Centre of Excellence, University of York, YO10 5DD, Heslington, York, United Kingdom
b Catholic University of Leuven (KU Leuven), Process Engineering for Sustainable Systems Section, Willem de Croylaan 46
– box 2423, 3001 Leuven, Belgium
c SAIREM, 12 Porte du Grand Lyon, 01702 NEYRON Cedex, France
d Process & Energy Department, Delft University of Technology, Leeghwaterstraat 39, 2628CB Delft, the Netherlands
KEYWORDS (Word Style “BG_Keywords”). demethylation, microwave, electromagnetism, simulation, kinetics, pharmaceu-
tical intermediates, reactor development, process intensification
ABSTRACT:
A systematic study of the conventional and microwave (MW) kinetics of an industrially relevant demethylation reaction is presentꢀ
ed. In using industrially relevant reaction conditions the dominant influence of the solvent on the MW energy dissipation is avoidꢀ
ed. Below the boiling point, the effect of MWs on the activation energy Ea and k0 is found nonꢀexistent. Interestingly under reflux
conditions the microwave heated (MWH) reaction displays very pronounced zero order kinetics, displaying a much higher reaction
rate than observed for the conventionally thermal heated (CTH) reaction. This is related to a different gas product (methyl bromide
– MeBr) removal mechanism, changing from classic nucleation into gaseous bubbles to a facilitated removal through escaping
gases/vapors. Additionally, the use of MWs compensates better the strong heat losses in this reaction, associated with the boiling of
HBr/water and the loss of MeBr, than under CTH. Through modelling MWH was shown to occur inhomogeneously around
gas/liquid interfaces, resulting in localized overheating in the very near vicinity of the bubbles – overall increasing the average
heating rate in the bubble vicinity visꢀàꢀvis the bulk of the liquid. Based on these observations and findings, a novel continuous
reactor concept is proposed in which the escaping MeBr, and the generated HBr/water vapors, are the main driving forces for circuꢀ
lation. This reactor concept is generic in that it offers a viable and low cost option for the use of very strong acids and the managed
removal/quenching of gaseous byꢀproducts.
INTRODUCTION
perature measurement. Also, the energy contained in MWs is
far too low to break even hydrogen bonds.4 In the presence
though of nonꢀMW absorbing solvents the groups of Dudley
and Stiegman argue that both substrate and product can temꢀ
porarily store energy, leading to localized temperature increasꢀ
es at the reactive site, accounting for the observed MW rate
enhancements.5 More recently they also showed that poorly
MWꢀabsorbing molecules can be selectively heated by MWs
provided association to a nonꢀreactive polar molecule as a
good MW absorber – albeit the effect is then less pronounced.6
In a further advancement the Kappe group used SiꢀC vessels
which were proclaimed to impede the penetration of MWs into
the reaction vessel, heating up the SiꢀC material instead, and
thus administrating in essence conventional heating. That way
no difference in reactivity could be observed between convenꢀ
tional and MW heated reactions.7 However, very recently the
Strouse group showed convincingly that 3 mm SiꢀC tube walls
only retain ~48% of the MWs pointing at significant MW
transmission into, and dissipation inside, the reaction vessel.
The 20th century has been mainly dominated by the use of
conventional thermal energy to drive chemical reactions. The
use of alternative energy sources, such as microwave (MW)
technology, appeared in the late 1970s and its use could overꢀ
come existing bottlenecks in chemical manufacturing and
improve the carbon footprint of many reactions.1 While it is
clear that poor instrumentation has led to erroneous reports
and set off unrealistic expectations2, a systematic and conꢀ
trolled investigation of the influence of MWs on chemical
reactions and their kinetics has been lacking. Such background
information is however indispensable for possible future imꢀ
plementation of MW technology on an industrial scale. To
date many types of thermal and nonꢀthermal MW effects have
been reported; as a guide to past research in these the interestꢀ
ed reader is referred to the critical review by De La Hoz and
coworkers.3 Presently many of the "nonꢀthermal MW effects"
have been disproven as being the result of an incorrect temꢀ
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Scheme 1. Overview of the reaction
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This MW leakage through SiꢀC tube walls is particularly acute
when a strongly absorbing solvent is used.8 Fan et al. have
pioneered the use of MW technology to the hydrothermal
depolymerisation of cellulose to glucose, demonstrating a
distinct influence of the applied MW density and a MW heat
input via molecular radiators9; notably, they used proꢀ
ton/deuterium exchange techniques to also obtain structural
information. Many research groups continue to propose differꢀ
ing activation energies for reactions run in the presence of
CTH visꢀàꢀvis MWH. However, the determination of the kiꢀ
netic parameters (Ea, k0) of a reaction strongly depends on the
applied model and requires thus a solid understanding of the
reaction mechanism. Also, a sufficient number of data points
is needed to assure confidence, thus requiring a thorough
analytical method. In this study we have investigated the MW
activation of an industrially (pharmaceutically) relevant deꢀ
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methylation
methylammonium
reaction,
converting
(3ꢀmethoxyphenyl)ꢀ
into (3ꢀ
bromide
(3MPMA)
hydroxyphenyl)ꢀmethylammonium bromide (3HPMA) (see
Scheme 1) 10, 11 with a detailed kinetics study. For this purpose
we have used both a SAIREM MiniFlow200SS12 with TM
monomode cavity and an Anton Paar Monowave 300, both of
which are equipped with fibre optic temperature measurement.
The MiniFlow200 uses a solid state MW generator, which
enables precise frequency and microwave power control; in
addition, it features forward and reflected power measurement
so that an energy balance can be obtained. The absence of this
latter feature in most commonly used MW heating equipment,
has been demonstrated to result in significant misreadings of
the actual MW power transferred to the sample under investiꢀ
gation.13 The experimental study is complemented with a
simulation study to obtain additional insight into the interactꢀ
ing physical phenomena: electromagnetics, fluid dynamics and
heat transfer. The demethylation reaction at study is typically
run on multi tonnes scale, and employs generally limited
amounts of solvent and reagents, therewith increasing the
efficiency of the process and its productivity. This reaction has
though received little mechanistic attention and then especially
under relevant reaction conditions. From a MW point of view
Figure 1. A) Conversionꢀtime plots for the CTH reaction. The
temperatures displayed in bold are measured by internal fibre
optic probe while those in brackets refer to oil bath temperatures.
B) comparison between the target (oil bath) temperatures and the
temperatures recorded by internal fibre optic probe.
done in a dual way recording both the oil bath temperature
and, by fibre optic temperature probe (FOTP), the internal
reaction temperature. Interestingly, Figure 1A shows that the
rate of the reaction becomes equal for oil bath temperatures ≥
115 °C, equating by FOTP to an effective internal maximal
reaction temperature of 112ꢀ112.5 °C. A linear correlation
between the target (oil bath) temperatures and the recorded
fibre optic temperatures is observed only up to 113 °C (oil
bath) (Figure 1B).
Kinetic analysis of the reaction profiles in Figure 1A shows a
complex kinetic behaviour which can generally not be exꢀ
plained as a single 1st or 2nd order process for the entire conꢀ
version range. More specifically, the beginning and the end of
the reaction appear to behave as different consecutive 2nd order
processes, which interchange at the 50ꢀ60% conversion level
(Figure 1S). In the 90 °C case the conversion level is below
50% showing thus only the first process. To explain this comꢀ
plex behaviour, it was hypothesized that throughout the reacꢀ
tion the number of available protons is reduced by (reversible)
protonation of 3HPMA (scheme 1S). This becomes particularꢀ
ly important in the later stages of the reaction, as close to
stoichiometric amounts of reagents are employed in this reacꢀ
tion. As shown in Figure 2 this model (scheme 1S, equation
15a) fits very well the experimental kinetic data for all temꢀ
peratures. In a second approach conversionꢀtime plots were
also established for the MWH reaction. Kinetic analysis of this
data shows that the twoꢀstep model presented in scheme 1S
(equation 15a) can only be applied up to 111.2 °C (FTOP)
(Figure 3A). Furthermore in the 90ꢀ113 °C range the Ea/k0
values of the CTH and MWH reactions vary only slightly
(Figure 3B/2B). As shown in Figure 4A the reaction rate obꢀ
served at ~98 °C is independent of the type of heating while at
the investigation of
a polar reaction with high subꢀ
strate/product dipoles and continuously changing dielectric
properties, as the reaction progresses, presents a great opporꢀ
tunity to gain more knowledge and understanding of how the
use of MWs could potentially benefit such chemical reacꢀ
tions.14
DISCUSSION
To assess the potential influence of different heating methods
on the 3MPMA to 3HPMA demethylation reaction, kinetic
reaction profiles (as conversionꢀtime plots) were first estabꢀ
lished for the case of an open vessel CTH covering the 90ꢀ118
°C temperature range (Figure 1A). The reaction mixture conꢀ
sisted of 5.038 g of 3MPMA (0.0367 mol) and 12.38 g 48%
HBr (0.0734 mol HBr; twice excess visꢀàꢀvis substrate) and no
additional solvent was added. Temperature measurement was
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Figure 3. A) Plots of the 'reaction rate' to 'substrate concentration'
Figure 2. A) Plots of the 'reaction rate' to 'substrate concentration'
data for the MWH reaction and consequent fitting of the twoꢀ
stage model (scheme 1S) B) calculated Ea and k0 values for the
MWH reaction
data for the CTH reaction and consequent fitting of the twoꢀstep
model shown in scheme 1S (equation 15a) B) calculated Ea and k0
values for the CTH reaction displayed in scheme 1S.
stirring. Furthermore, in order to correctly predict the electroꢀ
magnetic field inside the cavity and the reactor, knowledge
was required of the dielectric properties of the reaction mixꢀ
ture at the relevant temperatures. The medium properties were
measured and determined to be ε' = 17 and σ = 3.3 S/m. The
dissipative (σ) term is best described as an electrical conducꢀ
tivity due to the high concentration of ions in solution. A visuꢀ
al set up is provided in Figure 5a and additional details are
available from supplementary information and table 1S. The
fluid agitation in the reactant mixture was simulated by applyꢀ
ing a rotating geometrical domain, to account for stirrer bar
rotation, in combination with the kꢀε Reynoldsꢀaveraged Naꢀ
vier–Stokes model accounting for turbulence and turbulent
heat transfer. Figures 5bꢀe show the main modeling results for
~113 °C MW operation leads to a markedly higher rate of
reaction than observed with CTH (Figure 4B). Moreover Figꢀ
ure 4B shows pronounced zero order behavior under MW
operation at 113.85 °C, while under CTH classic 2nd order is
observed. As the recorded temperature for both heating types
(MWH, CTH) is 113 °C, within experimental error, this does
demonstrate a pronounced change in the reaction mechanism
between the MW and the conventional thermally run reaction.
A multiphysics simulation, primarily using Comsol Mulꢀ
tiphysics 5.2 (see also section on numerical simulation in
supplementary), was conducted to create additional insight
into the electromagnetics, the fluid dynamics and the heat
transfer. To the best of our knowledge only two studies have
previously been published covering the combined simulation
of electromagnetic heating and conductive/convective heat
transfer in bench scale MW chemistry systems. These studies
both concerned heating in a CEM Discover MW device. More
specifically, Robinson et al. studied the MW heating of a
variety of solvents in a stirred vial but their conducted simulaꢀ
tion did not include a complete fluid dynamics model.15 In
contrast Sturm et al. focused on the heating of water in a MW
field, including a laminar fluid dynamics model as to simulate
the free convection under nonꢀstirring conditions.13 In addiꢀ
tion, for the continuous flow case, Patil et al. present an experꢀ
imentally verified numerical study into a MW heated milliꢀ
reactor; in particular, they demonstrate temperature measureꢀ
ment deviations due to large thermal gradients around the
sensor.16 To model the MWH demethylation reaction case
adequately a much more advanced methodology was though
required, covering all the relevant physical phenomena and
Figure 4. Illustrative overlays of the 'reaction rateꢀ substrate conꢀ
centration' plots for the ConvTH and MWH reactions at 100 °C
(A) and 118 °C (B).
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MW field around a bubble. The MW field is deformed by the
1
presence of the bubble. Red zones, representing localized
overheating, and blue zones, indicative of relatively cooler
zones, can be observed. These however do not cancel out:
there is a ~40% average increase in heat generation in a layer
of ~0.1 times the bubble radius. Generally the evaporation of
hydrobromic acid into a bubble extracts heat from the reactant
liquid adjacent to this bubble due to the expansion of the bubꢀ
ble, which can result in a reduction of vapor pressure and
consequently a potential bubble collapse. Though the flow
regime in the reactor is turbulent due to stirring, the Kolmogoꢀ
rov length scale is calculated to be 30 to 240 µm.17 Below this
scale bubbles do not benefit from turbulent convective heat
transfer, and their growth potential is limited unless a directly
adjacent heat source is present. For the CTH case, only the
bubbles contacting the heated reactor wall can grow, so that
fewer and larger bubbles are formed. In comparison, for the
MWH case, the presence of a locally enhanced volumetric
heat source enables many more bubbles to form. This mechaꢀ
nism agrees well with the differences in boiling regime obꢀ
served during experimentation; illustrative videos of the
MWH (video 2S) and CTH (video 3S & 4S) demethylation
reaction at 112 °C are included in supplementary.
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ꢄ
ꢅ
ꢀ ꢁ ꢂꢃ ↔ ꢆ ꢁ ꢇꢈ
ꢄ
ꢊ
ꢇꢈ ꢁ ꢉ ↔ ꢇꢈꢉ
ꢋ
ꢌ
ꢇꢈꢉ → ꢇꢍ ꢁ ꢉ
ꢄ
ꢎ
ꢆ ꢁ ꢂꢃ ↔ ꢆꢂꢃ
Scheme 2. Proposed alternative model for the demethylation
reaction under MW exposure at high reaction temperatures. A is
3MPMA, P is 3HPMA, ML is methyl bromide in the liquid phase,
MG is methyl bromide in the gas phase, S is the surface of the
bubbles.
Figure 5. Simulation results of electromagnetic dissipation and
heat transfer. 5a: visual setꢀup for measurement of the dielectric
properties; 5b: MW field in and around the cavity applicator and
reactor; 5c: heating rate distribution; 5d: temperature distribution
in the reactor; 5e: overall electromagnetic dissipation both the
simulated and the experimental case versus temperature; 5f: heatꢀ
ing rate around a bubble.
As the removal of MeBr gas through water/HBr vapour will be
governed by the available surface between the reaction mixꢀ
ture and the water vapour bubbles, the occurrence of zero
order kinetics may relate to the available interface becoming
insufficient to remove all produced MeBr formed at one given
point in time. Scheme 2 represents the proposed mechanism
for higher temperature MW operation. The asꢀderived rate
equation fits very well the high temperature MW kinetic data
(See Scheme 2S, equation 28b, and Figure 2S). An additional
observation in the MW transmission transient during experiꢀ
ments can be made; Figure 3S shows that fluctuations in the
power regulation occur less rapidly with increasing reaction
temperature, which indicates a change in medium properties as
the reactant mixture progresses from mechanism 1 to 2. Furꢀ
ther to the use of open vessel reactors, we also evaluated the
the multiphysics simulation. Additionally, an animated video
is available from supplementary [video 1S]. More specifically
Figure 5b shows the MW field – by means of the electric field
intensity on logarithmic scale – in and around the cavity appliꢀ
cator and reactor. The simulation shows that the electromagꢀ
netic emission and dissipation in the reactor and cavity conꢀ
struction materials are negligible. In addition, it also reconꢀ
firms the general nonꢀuniformity of MW fields.13 The latter
feature does also express itself in the heat generation simulaꢀ
tion presented in Figure 5c, where it can be seen that the main
zone of heat generation occurs close to the MW antenna of the
cavity. However, in Figure 5d it is shown that for the applied
stirring speed the temperature variations in the reactor are too
small to have any significant effect on the reaction rate, i.e.
less than 1.5% rate variation for the highest temperatures, and
less than 0.4% below 111°C. Figure 5e displays the overall
electromagnetic dissipation and heat loss to the surroundings
versus temperature for both the simulated and the experiꢀ
mental case. It can be seen that the simulation correctly apꢀ
proximates the characteristics of the experimental energy
balance. The curves lie close to each other and both have an
accelerating heat loss as the temperature approaches the boilꢀ
ing point. Figure 5f shows a quasiꢀelectrostatic analysis of the
Table 1. Conversion levels for the demethylation reaction perꢀ
formed at 118°C in an Anton Paar MW and, for the conventional
heated counterpart, an NMR pressure tube.
2h
4h
6h
Reaction time →
Reactor type ↓
Enꢀ
try
Conversion (%)
Anton Paar MW Closed
Vessel Reactora
1
2
49.5
47.6
64.4
64.5
70.9
70.7
Conventional by NMR
pressure tubea
a ratio gas to liquid phase in Anton Paar reaction vessel and NMR
pressure tube are the same.
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use of closed vessel i.e. using a pressure NMR tube for CTH
ACKNOWLEDGMENT
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and an AntonꢀPaar MW for the MWH reaction. As shown in
Table 1 no distinct MW influence is observed when the reacꢀ
tion is performed in a closed vessel reactor. Indeed, in closed
vessel operation no massꢀtransfer limitation problem arises as
the produced MeBr builds up a pressure of ~110 PSI (54.7%
conversion) (Figure 4S) that way then shifting the equilibrium
from 'MeBr gas' to 'MeBr liquid'.
The authors would like to thank the European Research Council
for the FPVII ALTEREGO project with grant number FP7ꢀNMPꢀ
2012ꢀ309874. MDb would like to thank Ms. A. Storey for the
specialty glass ware and Mr. C. Mortimer for consultancy on
practical reactor development. GSJS would like to acknowledge
Dr. J.W.R. Peeters for valuable feedback on the turbulence modelꢀ
ing, as well as the support staff of COMSOL B.V. (Zoetermeer,
NL) for their prompt technical support.
The observation of intense steam/gas bubble production in the
high temperature MWH reaction provided an interesting opꢀ
portunity for the development of a novel continuous MW
reactor concept in which MW energy is actually converted in
kinetic energy i.e. the escaping MeBr, and the generated
HBr/water vapour, can drive the reaction mixture round a
loop. This concept is similar to gas/airꢀlift reactors, which find
common application in industrial biotechnology and multiꢀ
phase processes, but contrary to the concept proposed here
these rely on the introduction of a separate gas/air stream.18
The development of a continuous MW reactor for the here
presented demethylation reaction holds distinct industrial
advantages, notably 1) a controlled release and thus manageaꢀ
ble scrubbing of toxic MeBr, 2) a continuous all glass reactor
concept tailored to the use of strongly corrosive acids avoiding
the need for expensive specialty alloys (e.g. Hastelloy), 3) the
avoidance of an expensive pumping system capable of withꢀ
standing MeBr/HBr, 4) the absence of moving parts, and 5)
enhanced mass transfer properties. Figure 5S and 6S show
respectively the schematics of the circular and the continuous
MW reactor. A video of the circular MW reactor in operation,
employing a PI of 140 W, is included in supplementary (Video
5S) and the conversionꢀtime plots are shown in Figure 7S.
9
ABBREVIATIONS
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MeBr methyl bromide; MW microwave; 3MPMA 3ꢀ
methoxyphenyl)methylammonium bromide;
hydroxyphenyl)methylammonium bromide; PI power input; RP
reflected power; CTH conventional thermal heat(ed)(ing); MWH
microwave heat(ed)(ing); FOTP fibre optic temperature probe;
3HPMA 3ꢀ
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In summary we have shown that the main influence of MWH,
visꢀàꢀvis CTH, on the kinetic parameters of an industrially
relevant demethylation reaction occurs only under reflux conꢀ
ditions. Then the use of MWs opens a different mechanism for
the elimination of gaseous byꢀproducts (e.g. MeBr), by the
creation of vast amounts of bubbles, therewith changing the
observed reaction order of the demethylation reaction from 2
to 0. Through modelling the origin of this change in reaction
order was shown to relate to a deformation of the microwave
field in the presence of bubbles, leading to localized overheatꢀ
ing in the close vicinity of the bubbles. Based on these insights
a novel continuous MW reactor concept could be proposed in
which MW energy is converted into kinetic energy, making
the production and removal of MeBr the driving force for the
reactor. This offers a generic reactor concept for reaction types
in which significant amounts of gaseous byꢀproducts (e.g.
de(m)ethylation, metathesis, dehydration) are created.
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ASSOCIATED CONTENT
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Experimental
details,
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figures,
reaction
2016, 146, 180ꢀ188.
schemes/models and illustrative videos are available in the Supꢀ
porting Information. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* Dr. Duncan MacQuarrie, Duncan.Macquarrie@york.ac.uk
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