Scale-up Study of Benzoic Acid Alkylation in Flow: From Microflow Capillary Reactor to a Milliflow Reactor

Article abstract of DOI:10.1021/acs.oprd.7b00246

The esterification reaction is one of the most important reaction in organic chemistry, and the development of scalable continuous flow conditions is of high interest. Here we describe a scaling-up study of benzoic acid alkylation by MeI in the presence of superbases from a capillary reactor (282 mg·h^-1 at 75 °C) to a low flow reactor (LFR, 6.82 g·h^-1 at 80 °C). First, the optimization of the base demonstrated that 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) was a good compromise in terms of basicity and price. A comparison between batch and LFR reaction showed similar kinetic rates. We also observed a maximum reactivity for a flow rate of 3 mL·min^-1 which corresponds to an optimum mixing of the entering fluids. A colorimetric study permits to show a visual change in the flow regime (dispersed to stratified) by varying the flow rate with a maximum conversion obtained at 3 mL·min^-1 corresponding to a 105 s residence time, demonstrating that the studied reaction is sensitive to mixing conditions and that LFR presents some mixing limitations for low flow rates. After thermal optimization (80 °C), the reaction has been improved to a productivity of 6.82 g/h at the lab scale using DBU as the base and Eyring/Arrhenius plots permitted to extract activation energies.

Full text of DOI:10.1021/acs.oprd.7b00246

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Communication
Scale-up study of benzoic acid alkylation in flow:
from microflow capillary reactor to a milliflow reactor
Christophe Penverne, Benjamin Hazard, Christian Rolando, and Mael Penhoat
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00246 • Publication Date (Web): 01 Nov 2017
Downloaded from http://pubs.acs.org on November 2, 2017
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Scaleꢀup study of benzoic acid alkylation in flow:
from microflow capillary reactor to a milliflow
reactor.
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†
†
†
†*
Christophe Penverne, Benjamin Hazard, Christian Rolando, Maël Penhoat
†
USR 3290, MSAP, Miniaturisation pour la Synthèse l'Analyse et la Protéomique, and FR 2638,
Institut EugèneꢀMichel Chevreul, Université de Lille, Fꢀ59000 Lille, France
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Table of Contents graphic. Esterification of benzoic acid (benchmark reagent) by alkylation in
the presence of superbase/CH I in continuous flow is described. The reaction is scaledꢀup from
3
ꢀ1
ꢀ1
2
82 mg.h at 75 °C in a microflow capillary reactor (13.2 µL) to 6.82 g.h at 80 °C in a
®
CORNING Low Flow Reactor (5.25 mL).
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ABSTRACT
Esterification reaction is one of the most important reaction in organic chemistry and the
development of scalable continuous flow conditions is of high interest. Here we describe a
scalingꢀup study of benzoic acid alkylation by MeI in the presence of superbases from a capillary
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ꢀ1
ꢀ1
reactor (282 mg.h at 75 °C) to Low Flow Reactor® (LFR, 6.82 g.h at 80 °C). First, the
optimization of the base demonstrated that DBU was a good compromise in term of basicity and
price. Comparison between batch and LFR reaction showed similar kinetic rates. We also
ꢀ1
observed a maximum reactivity for a flow rate of 3 mL.min which corresponds to an optimum
mixing of the entering fluids. A colorimetric study permits to show a visual change in the flow
regime (dispersed to stratified) by varying the flow rate with a maximum conversion obtained at
ꢀ1
3
mL.min corresponding to 105 s residence time, demonstrating that the studied reaction is
sensitive to mixing conditions and that LFR presents some mixing limitations for low flow rates.
After thermal optimization (80 °C) the reaction has been improved to a productivity of 6.82
g/hour at the lab scale using DBU as the base and Eyring/Arrhenius plots permitted to extract
activation energies.
KEYWORDS: Scaleꢀup, microflow reactor, milliflow reactor, esterification, alkylation, organic
superbases.
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INTRODUCTION
To pass from laboratory scale to industrial scale is a recurrent crucial step for every synthetic
chemists. Along last decades continuous chemistry or flow chemistry appeared as a solution to
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overcome scalingꢀup difficulties. Continuous technologies allow realizing studies or production
by using miniaturized continuous reactors (microreactor or microstructured technologies)
presenting higher surface area to volume ratio, higher mass and heat transfer compared to batch
2,3
technology. These reactors differ by their channel sizes which can vary from the micrometer to
the millimeter scale. Optimization reaction is usually performed in a single continuous pilot
ꢀ1
ꢀ1 4
reactor (200 g.h ) and scale up is realized by numberingꢀup (up to ton.d ). Recently, new
ꢀ1
commercially reactors have been introduced to pass from lab scale (10 g.h ) [Corning Low Flow
ꢀ1
Reactor® (LFR)] to pilot scale (200 g.h ) [Advanced Flow Reactor® (AFR)] by increasing the
5
flow reactor dimensions with a very limited optimization effort. In term of green process
engineering a particularly interesting approach concerns the optimization of the continuous
ꢀ1
reaction conditions at a very low scale (few mg.min ) followed by scaling from microfluidic to
ꢀ1
6
mesoscale systems (few g.min ) such as the one described recently by Jensen. Using this
approach, the production rate was increased up to 700 times in the scaling process from a spiral
ꢀ1
ꢀ1
microreactor (6.4 mg.min ) to a LFR mesosystem (0.37 g.min ) and then to an AFR production
ꢀ1
system (4.08 g.min ) that can be later numbered up to access industrial scale.
Our team has recently described innovative esterification reaction conditions by alkylation of
carboxylic acids in the presence of an organic superbase and an alkylating agent (ex: CH I) in a
3
7
capillary microflow setup presenting a very low reaction volume (13.2 µL). This device is
particularly interesting to study very specific and expensive conditions at the lab scale since the
system is highly reproducible and only few mmol of reagents are necessary to perform precise
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physical organic chemistry studies. In this example N,N′ꢀ1,8ꢀ naphthalenediylbis[N,N,N′,N′ꢀ
tetramethyl]ꢀguanidine (TMGN) superbase was found to fit various criteria of high basicity
(pKBH+ in DMF = 16.4–17.5), low Mayr nucleophilicity parameter (N in DMF = 7.8) and high steric
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hindrance in order to optimize the present alkylation reaction and to avoid any selfꢀalkylation
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side reactivity. Indeed, in such reaction mechanism (Scheme 1), the acidꢀbase equilibrium being
fast compared to both alkylation rates (k ,k > kalk1, kalk2), the overall mechanism should be
1
ꢀ1
9
kinetically treated as an extension of CurtinꢀHammett type mechanism similar to Kurz study on
1
0
acidꢀbase catalysis.
Alkylating agent
Alk-X
kalk1
+
-
BH , X
BH+
,
Ester
(Major)
k1
k-1
Alkylating agent
Alk-X
kalk2
+
-
B
B -Alk, X
Alkylated base
(Traces)
Carboxylic
acid
Base
k1
with k , k >> kalk1 > kalk2 and Keq
=
1
-1
k-1
Scheme 1. Alkylation of carboxylic acids in the presence of a superbase and an alkylating
agent ꢀ CurtinꢀHammett type mechanism.
As a consequence, if the acidꢀbase equilibrium is fully displaced toward the carboxylate form
(
k >> k high pKBH+), and if kalk1 and kalk2 are in the same order of magnitude, then the major
1 ꢀ1,
product should be the ester with a high degree of selectivity according to Curtinꢀ
Hammett/WinsteinꢀHolness kinetics:
‡
ꢕ∆∆ꢖ
[ꢀꢁꢂꢃꢄ]
ꢇꢍꢎꢏꢐ
ꢇꢍꢎꢏꢐ×ꢇꢐ
= ꢓ( ꢗꢘ )
= ꢇ
ꢒꢓꢔ = ꢇ
(1)
[
ꢅꢆꢇꢈꢆꢉꢂꢃꢊꢋꢌꢉꢁꢃ]
ꢍꢎꢏꢑ×ꢇꢕꢐ
ꢍꢎꢏꢑ
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‡
Were ∆∆ꢙ relates to the difference in activation free energy for these two alkylation
reactions. When alkylation of the base can be neglected (kalk1×K >> kalk2) the overall rate of the
eq
reaction can be approximated to kobs ≈ kalk1×K and consequently any change of base pKBH+
eq
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value will affect the rate of the reaction. In such mechanism, the protonated base which is the
counter ion of the carboxylate should affect the kalk1 value depending on its steric hindrance,
hydrophobicity and electronic properties. In order to avoid any preliminary side alkylation of the
base, fast acidꢀbase reaction has to be performed before alkylation step. Since acidꢀbase reaction
is realized instantly, a convenient method when performing the reaction in a continuous reactor
is to prepare a solution of carboxylate (carboxylic acid + base) prior to inject it for mixing with
the alkylating agent introduced in a second entry.
The productivity of the previously studied capillary microflow system (i.d. = 75 µm, l = 300
ꢀ1
cm), in the presence of TMGN base, was low after optimization (282 mg.h at 70°C) due to the
low volume of the capillary reactor but was found particularly interesting in order to perform
expensive reaction conditions and physical organic studies at the mg scale. The kinetic study
ꢀ1 ꢀ1
established a clean second order reaction rate law (kobs(75°C) = 8.9 L.mol .s ) and by varying the
⧧
temperature the enthalpy and the entropy of activation have been estimated to be ꢁH ꢋ= 40.3
−1
−1
−1
⧧
⧧
kJ.mol and ꢁS = −112.2 J.K ·mol leading to a standard free energy of activation ꢁG = 73.3
−1
kJ.mol at 293 K. In the present study we were interested in scaling up this esterification
reaction into a CORNING LowꢀFlow Reactor® composed of 8 reaction plates and one
quenching plate, designed for labꢀscale studies (Figure 1).
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Figure 1. Description of the fluidic setꢀup.
EXPERIMENTAL SECTION
Materials. All chemicals were in the highest purity available and were used as received without
further purification. DMF was HPLC grade.
Methods. The setꢀup is composed of three pumps connected (Dual Pump KPꢀ22Dꢀ13DC,
Flom, Tokyo, Japan) to the Low Flow Reactor® (Corning, Avon, France) in order to introduce a
solution of CH I (0.473 M) and a solution of benzoic acid (0.364 M) mixed with the base (1.3
3
equiv.) in the two separate entries of the first plate, followed by 7 residence time units for the
reaction to take place (total residence time volume = 5.25 mL). Another selected acidic
quenching solution (formic acid in excess, 2.66 M) is introduced in the last plate to stop the
reaction by protonation of every basic species (free base/carboxylate), and to avoid any ester
1
hydrolysis. At the outlet, the reaction mixture is collected, worked up and then analyzed by H
NMR analysis in deuteriated chloroform (BRUKER AC 300, Billerica, USA). In this system the
temperature can be controlled by circulating a calorimetric fluid throw a layer covering the
reaction channel at every plates. The temperature being applied (5ꢀ85 °C) by a chiller (Huber®
Petite Fleur, Offenburg, Germany). Two thermometers (Selectronic, SEL 96ꢀ10, Fretin, France)
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are connected to the entry and the outlet of this calorimetric layer to control the evolution of
temperature along time.
For kinetic monitoring, the flow rate was modified at each pumps and 10 mL sample of
reaction medium are collected at the outlet after quenching by formic acid solution. The solution
is then extracted by 3 × 37.5 mL of dichloromethane, organic phases are combined and washed
with a solution of hydrochloric acid (3 × 37.5 mL, 1 M). Organic phases are then dried over
magnesium sulfate, evaporated under vacuum and finally analyzed by NMR spectroscopy.
For kinetic monitoring in batch a similar work up and initial concentrations than for the flow
version are used on a total volume of DMF of 140 mL. For the monitoring 20 mL of reaction
medium are taken at various reaction times. For mixing conditions, a 250 mL round bottom flask
equipped with magnetic stirrer (IKA®, RCT standard model) and an olive shaped stirring bar
was used at 900 RPM.
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Typical preparative procedure for optimum conditions in LFR:
Temperature is fixed at 80 °C on the chiller and the reaction is initiated after complete
stabilization of the temperature at 80°C. At the first entry, DBU (0.473 M) and benzoic acid
ꢀ1
(0.364 M) in DMF are introduced at 1.5 mL.min . At the second entry, CH I (0.473 M) in DMF
3
ꢀ1
is delivered at 1.5 mL.min . At the third entry, formic acid (2.66 M) in water is delivered at 1
ꢀ1
mL.min ). After 5 minutes of reaction, the collection of the crude mixture is realized at the
outlet of the LFR for 10 minutes corresponding to a total volume of 40 mL. The solution is then
extracted by 3 × 100 mL of dichloromethane, organic phases are combined and washed with a
solution of hydrochloric acid (3 × 100 mL, 1 M) to remove DBU excess and DMF. Organic
phases are then extracted by 40 mL of Na CO solution (0.6 M) to remove unreacted benzoic
2
3
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acid and then washed with NaCl solution. After drying over MgSO and filtration, the organic
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phases are evaporated under vacuum to deliver a pale yellow oil (628 mg, 84%).
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RESULTS AND DISCUSSION
Due to the larger quantities used in this study we reꢀorientated our process toward the use of
cheaper bases (1,8ꢀdiazabicyclo[5.4.0]ꢀundecꢀ7ꢀene (DBU), 1,1,3,3ꢀtetramethylguanidine
(TMG), 2ꢀtertbutylꢀ1,1,3,3ꢀtetramethylguanidine = Barton’s base) for which basicities
1
1,12
(pKBH+(DMF) 14.7–16.8)
are in the same range than the one of TMGN and sufficiently basic to
1
3
fully deprotonate benzoic acid (pKa(DMF) = 12.27). We first studied conditions previously
described by Mal in the presence of DBU in acetonitrile (Table 1, entry 1) and DMF (entry 2)
1
4,15
demonstrated to be a much better solvent.
This can be explained by higher polarity of DMF
1
6
compared to CH CN that avoids the formation of aggregates or strong ion pairs. The study of
3
various organic superbases (entries 2ꢀ4) showed similar conversions after 105 s and we finally
decided to continue our study with DBU as the base which was a good comprise in term of pKa
and price. Since it is extracted during the aqueous workꢀup, no trace of the methylated base side
product has been detected.
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ꢀ1
Table 1. Base and solvent study at 20 °C and 3 mL.min in a Corning Low Flow Reactor.
Base
20 °C
3 mL.min-
1
0.4 M
(
105 s)
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0.364 M
CH3I
HCOOH
.66 M
0.473 M
2
Bases
DBU
TMG
Barton's base
e
pKBH+
pKBH+
T
Time Conv.
a
Entry
Base
Solvent
d
(
CH CN) (DMF)
(°C)
(s)
(%)
8
3
b
1
2
3
4
DBU
DBU
TMG
CH
3
CN 24.33
15.7ꢀ16.8 20
15.7ꢀ16.8 20
14.7ꢀ15.8 20
14.9ꢀ16.0 20
105
105
105
105
b
DMF
DMF
24.33
47
43
52
b
23.3
c
Barton’s base DMF
23.56
a
Conditions: benzoic acid 0.364 M and molar ratios of base and iodomethane to benzoic acid
b
c
of 1.3, in HPLC grade solvents used as received. pK
1
values: from ref. 10; from ref.
BH+(CH3CN)
d
e
1. from ref. 8. Time calculated as following t = V /Q = 60 × 5.25/3 = 105 s with t =
R R R
ꢀ
1
residence time in s; V = residence volume in mL; Q = flow rate in mL.min .
R
We next monitored the kinetics of the reaction with DBU in DMF at 20 °C in order to optimize
ꢀ1
the reaction time (Figure 2). At short residence time (t < 105 s, flow rates > 3 mL.min ), the
R
ꢀ1 ꢀ1
kinetic curve follow a second order rate law (k20LF = 0.021 L.mol .s ) nevertheless for longer
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ꢀ1
residence times (t > 105s, flow rates < 3 mL.min ) the kinetic curve decrease linearly with a
R
ꢀ4
ꢀ1 ꢀ1
slope of ꢀ2.23 × 10 mol.L .s . This result strongly suggest that the reaction, when performed in
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the low flow reactor, is sensitive to mixing conditions.
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Figure 2. Kinetics of benzoic acid alkylation by CH I in the presence of DBU in the Low Flow
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reactor. Observation of the change in regime (upper panel). Second order kinetic treatment
(bottom panel).
In order to verify this hypothesis, we performed the same reaction in a batch reactor at 20 °C at
longer times (> 105 s) under strictly identical conditions (temperature, concentrations, workꢀup).
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The kinetics measurements show that at longer times in batch the reaction follow a second order
ꢀ1 ꢀ1
rate law (k20B = 0.020 L.mol .s ) that finely superimpose with the kinetics measurements
performed in the Low Flow reactor, demonstrating that the change in reactivity is due to a
change in the flow regime (Figure 3).
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Second order kinetic treatment (upper panel). Batch (long times) and Low Flow (short times)
superimposition (bottom panel).
Such phenomena is usually attributed to a change from engulfment (dispersed) flow at high flow
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rates (high Reynolds number Re) to a stratified flow at low flow rates (Low Re), and it has been
recently discussed by Jensen and Kuhn in the particular case of Corning Low Flow (LF) and
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Advanced Flow (AF) reactors.
In order to demonstrate visually this effect we introduced a
blue dye (Coomassie Blue) diluted in DMF at an entry of the Low flow reactor and pure DMF at
the second entry. By varying the flow rates we were able to observe visually the change in the
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ꢀ1
flow regime from stratified flow (Flow rate < 3 mL.min ) to dispersed flow (Flow rate > 3
ꢀ1
mL.min ) (Figure 4).
Figure 4. Observation of the change between dispersed flow regime (upper panel) to stratified
flow regime (bottom panel) by decreasing the flow rate (for a better view of the phenomena the
first heart mixing area has been zoomed).
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Consequently, due to mixing limitations, the time can’t be extended to optimize the conversion
and we started a temperature study from 5 °C to 80 °C. The results are summarized in table 2.
ꢀ1
Higher is the temperature higher is the rate of the reaction, and the conversion at 3 mL.min
105 s). Under optimized conditions, the conversion rise to 85% corresponding to a productivity
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(
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of 6.82 g.h . The rate constants were used to construct an Arrhenius plot (Figure 5) which is
2
−1
linear (R = 0.95) in the studied temperature range (5−80 °C) and gives a value of 30.8 kJ.mol
for the activation energy. From these data the enthalpy and the entropy of activation are
−
1
−1
−1
estimated to be ꢁH⧧
ꢋ
= 28.2 kJ.mol and ꢁS = −182.76 J.K ·mol leading to a standard free
⧧
−1
⧧
energy of activation ꢁG = 81.8 kJ.mol at 293 K. This value is higher than the previous value
ꢀ1
obtained for TMGN (ꢁG⧧TMGN = 73.3 kJ.mol ). This difference can be partially explained by the
calculated pKBH+ value of DBU in DMF (15.7ꢀ16.8) which is 0.7 units lower than the one of
ꢀ1
TMGN and which representing a difference of 4 kJ.mol . We also suppose that the higher steric
hindrance of TMGN compared to DBU greatly contribute to its higher reactivity by dissociating
the carboxylate anion from the protonated base (weaker ion pair). A similar hypothesis can be
proposed to explain the higher reactivity of Barton’s base, which is also highly hindered,
compared to DBU (Table 1 entries 2,4).
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Table 2. Temperature study in a Corning Low Flow Reactor®.
T
1/T
kobs
Conv. Productivity
ꢜꢝꢞꢟ × ꢠ
a
Entry
ꢚꢛꢋ(
)
ꢜꢡ × ꢢ
ꢀ
3
ꢀ1 ꢀ1
b
ꢀ1 b
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(K) (×10 ) (L.mol .s )
(%)
20
47
63
78
85
(g.h )
ꢀ
3
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2
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4
5
278
293
328
338
353
3.59
3.41
3.05
2.96
2.83
6.5×10
2.3×10
4.4×10
9.2×10
ꢀ34.42
ꢀ33.21
ꢀ32.67
ꢀ31.96
ꢀ31.54
1.60
3.77
5.05
6.26
6.82
ꢀ2
ꢀ2
ꢀ2
ꢀ1
1.47×10
a
Conditions: benzoic acid 0.365 M and molar ratios of DBU and iodomethane to benzoic acid
b
of 1.3, in HPLC grade solvents used as received at various temperatures. Determined at 3
ꢀ1
mL.min (t = 105 s).
R
Figure 5. Eyring and Arrhenius plots.
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CONCLUSION
To summary, Low Flow Reactor® permits to scale up benzoic acid alkylation from microꢀflow
to milliꢀflow conditions by a factor of 24 in term of productivity. Replacing the base (TMGN)
with a cheaper one (DBU) presenting a similar basicity and by increasing the temperature to 80
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C permitted to keep a high level of reactivity. Along this study, we also demonstrate that Low
ꢀ1
Flow reactor presents some mixing limitations for flow rates lower than 3 mL.min (stratified
flow regime) and that higher temperature or adding more residence time units should be
considered for slow reactions. The result obtained with Barton’s base along optimization is of
particular interest since it presents characteristics close to TMGN in term of basicity and steric
hindrance. Nevertheless such base is particularly expensive and can’t be easily scaledꢀup.
However, considering the small difference in term of conversion observed for TMG at 20 °C, it
could be an economic solution.
ASSOCIATED CONTENT
Supporting Information. Description of the flow setꢀup, NMR spectra and kinetic
measurements data.
The following files are available free of charge.
Supporting information.pdf
AUTHOR INFORMATION
Corresponding Author
*
Maël Penhoat – eꢀmail: mael.penhoat@univꢀlille1.fr – phone: +33 (0) 3.20.33.70.75
Funding Sources
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This work was supported by the Conseil Régional Haut de France, France. The NMR and Mass
Spectrometry facilities used in this study were funded by the European Community (FEDER),
the Région Haut de France (France), the CNRS, and the Université de Lille. MP thanks the
Region Haut de France for a Young Investigator Grant funded by the Contrat de Projet Étatꢀ
Région (CPER) to the Institut Michel E. Chevreul (FR CNRS 2638).
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ACKNOWLEDGMENT
MP thanks the Region Haut de France for a Young Investigator Grant funded by the Contrat de
Projet ÉtatꢀRégion (CPER) to the Institut Michel E. Chevreul (FR CNRS 2638).
ABBREVIATIONS
LFR, Low Flow Reactor®; AFR, Advanced Flow Reactor®; Re, Reynolds number; TMGN,
N,N′ꢀ1,8ꢀ naphthalenediylbis[N,N,N′,N′ꢀtetramethyl]ꢀguanidine; DBU, 1,8ꢀdiazabicyclo[5.4.0]ꢀ
undecꢀ7ꢀene; TMG, 1,1,3,3ꢀtetramethylguanidine.
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