ACCESS FLOW

Application note
Fast scale up of microreactor technology
from lab scale to production
No. 1
The Paal-Knorr synthesis

This application note has been published by Access2Flow Partners:

ACCESS FLOW

Application note

Fast scale up of microreactor technology
from lab scale to production
No. 1
The Paal-Knorr synthesis
Summary
Access2Flow, with its members FutureChemistry, Flowid and Micronit Microﬂuidics, has
shown the fast scalability and applicability of microreactors in a case study for ﬂow chemistry. For the case study, the Paal-Knorr reaction was used as a model reaction. This reaction
is moderately exothermic, posing a problem for conventional industrial scale manufacturing,
while ﬂow chemistry is known to be advantageous for such processes due to high heattransfer capabilities.
The Paal-Knorr reaction was translated from conventional batch processing into continuous
ﬂow chemistry without any major issues. The kinetic parameters reaction time and reagent
ratio were controlled by ﬂow rates. These reaction parameters, together with temperature,
were then screened fully automated to ﬁnd optimal conditions.
After optimization and data interpretation, small preparative runs in a larger microreactor
were performed. While maintaining a sufﬁciently large surface to volume ratio, the lateraldimensions of the reactors were enlarged to 1-2 mm, while maintaining mixing over the fulllength of the reactor by integrating mixers. The small preparative runs resulted in correct
validations and conﬁrmed conversions of 100% at optimal settings.
Finally, the optimized and validated reaction parameters were applied to larger microreactors connected in parallel. A production rate of 55 g per hour could be reached with thisdevice, giving an overall scaling factor from optimization device to preperative lab scale of1250. Further parallelization of the reactors will increase the production rate up to kgs perhour.
Major beneﬁts of the ﬂow chemistry route vs. conventional batch chemistry in this particularcase are the safe and easy operation of an exothermic reaction, fast development time of
approximately 200 man hours and low reagent consumption during optimization.

Summary-- Page 2 of 12 --ACCESS FLOW

Application note

Introduction
Access2Flow, with its members FutureChemistry, Flowid and Micronit Microﬂuidics, has shown thefast scalability and applicability of microreactors in a case study for ﬂow chemistry.
Processes based on more conventional techniques such as batch processes are scaled up by
increasing the physical size of the equipment used. By doing so, several process determining
parameters like heat- and mass transport are changed, resulting in new, time consuming and costly
process optimization for each scale up step.
Microreactor technology comprises continuously mixing and performing chemistry in equipmentwith small internal dimensions. These small dimensions are the base for more efﬁcient, economic
and safer chemistry. Furthermore, the technology is ideal for reaction screening: it is possible totest several reaction parameters in a fast and efﬁcient way. By slightly scaling up the internal
dimensions and then numbering out the reactors, the reaction is planned to be scaled up in thisstudy. It is expected that the newer route through ﬂow chemistry enables a fast trajectory of productdevelopment and scale up.
This document informs about the project, results and equipment used.

Introduction-- Page 3 of 12 --ACCESS FLOW

Application note

Project description
-2H2O
O

+

O

OH

H2N

N

OH
Figure 1 - Reaction scheme Paal Knorr synthesis

For this project the Paal-Knorr reaction (Figure 1) is chosen as model reaction. It is an elegant ringclosing elimination reaction, forming the relatively complex pyrrole from simple primary amines andγ-diketones. Although the procedure requires only one easy addition step, on industrial scale theprocedures requires great care due to the exothermic properties. Therefore, continuous ﬂow is an
excellent alternative for this fast reaction.
R2
O

+

H2N

3

R

O

O
1

1

R

R

Path A

R2
OH
HN
R3

R2

OH
R3

N
HO R1

-H2O

-H2O
Path B

R3

O

R3

O

N
R1

R2

R2

R2

HN
R1

N

R2
R3

HO R1

N

R3

R

Figure 2 - General reaction mechanism Paal Knorr synthesis

While the reaction was already discussed in 1914, the exact mechanism is not certain. Figure 2
shows the two most probable pathways (path A and B), differing only in the order of the ﬁrst elimination step and ring closure. Because all steps in Path A are exothermic, while the enamine ringclosure step in path B is endothermic, path A is the most probable mechanism. Studies have shownthat the reaction rate is decreased by larger R1 and R2 groups. In this case, the methyl groups,
being the smallest possible side groups for a γ-diketone, do not sterically hinder the reaction andthe rate can be expected to be high.
The project is divided into three successive phases:
1.

Convert batch chemistry to ﬂow chemistry on μL-scale;2.

Scaling up the internal dimensions of the reactor to mL-scale;3.

Numbering out mL-scale reactors towards the capacity desired.

Project description-- Page 4 of 12 --ACCESS FLOW

Application note

Phase 1 – Converting batch to flow chemistry on μL-scale
In this phase, a procedure for continuous ﬂow equipment was prepared. Not only was the actual
procedure translated from conventional batchwise to ﬂow chemistry, but also a full parametric optimization was performed, achieving optimal conditions for the continuous ﬂow equipment. Whena reaction is to be optimized, one can choose from several different optimization criteria, such asreactant conversion, product yield, space-time yield, production rate to total cost ratio, etc. For thesake of clarity and simplicity, in this study conversion was chosen, thus formulating the following
aim:
Reduce reaction time as much as possible, while maintaining 100% conversion.
The optimization was performed on the following parameters: reaction time, diketone / amine ratio
and temperature. A multidimensional optimization method was used, after which a mathematicalmodel was created. However, before the actual optimization, ﬁrst the parameters were screened
independently to establish the ranges having the greatest impact on the reaction.
Diketone
P1
M
R1
Amine
P2

M

Quenchingagent
P3
Microreactor
Collection andoff-line analysis
Temperature control

Product

Figure 3 - Continuous ﬂow setup for Paal-Knorr optimization: Schematic representation (top),
FutureChemistry FlowStart for ﬁrst ﬂow experimentation (bottom left) and FutureChemistry FlowScreen forautomated optimization (bottom right)

Because reaction time in a continuous ﬂow system is determined by ﬂow rate in the system andthe volume of the reactor, the latter must be exactly known. Furthermore, because off-line analysis
was used, stopping the reaction using quenching agents was necessary. It was found that acetone
was an adequate quenching agent, inhibiting the primary amine from further reacting by imine
formation.
The conceptual total ﬂow setup and equipment as used in all experiments is shown in Figure 3. The
quenching agent, marked in grey, was used only in the optimization. Equipment details are given
in Table 1.

Phase 1 – Converting batch to ﬂow chemistry on μL-scale-- Page 5 of 12 --ACCESS FLOW

Application note

Table 1: Details equipment for optimization

Reactor volumes

0.13 and 7.03 μL (dependent on reaction time)

Channel width

120 μmChannel height:

60 μm

Channel length:

26 or 1325 μm (dependent on reaction time)

Reactor material

Borosilicate glass

Pumps

Syringe pumps with stainless steel syringes

In conventional batch procedures, the diketone and the amine are simply mixed without any solvent.
This is an adequate method for small (laboratory) scale, but not possible for industrial manufacturing due to the exothermicity. The reaction could easily be carried out in a continuous ﬂow system
by using continuous feeds of both reagents, but it was found that some fouling occurred by productcrystallization. Therefore, 1:1 mixtures of the reagents dissolved in methanol were used. While
this is an adequate solution to prevent blocking, minimal solvent consumption should be achieved.
However, optimization towards this parameter was not performed in this study.




Amine : diketone: 2.0
Temperature: 20 °C












   






Amine : diketone: 2.0
Reaction time: 12 s












 !!





Reaction time: 12s
Temperature: 20 °C












Figure 4 - Singlevariate reaction screening

The three parameters were ﬁrst screened independently using conventional singlevariate experiments. In Figure 4 the results are shown. Reaction time and amine:diketone ratio both have a major
inﬂuence on the reaction as can be expected. Thus, these two parameters were included into themultidimensional screening study using roughly the same ranges. Although temperature seems tohave barely signiﬁcant inﬂuence on the reaction, which is in itself remarkable, it still was included
into the multidimensional screening because of possible dependent effects between two different
parameters.
Phase 1 – Converting batch to ﬂow chemistry on μL-scale-- Page 6 of 12 --ACCESS FLOW

Application note

Temperature = 20 °C

Temperature = 52.5 °C

Conversion
100%

9

0.

90%

8
80%
7

70%

6

60%

5

50%

1

Amine stoichiometry

Temperature = 80 °C

40%

4

30%

3

20%
2
10%
1
0.1

1

0

10

100

0

Reaction time (s)

0%
0.1

1

10

Reaction time (s)

100

0.1

1

10

100

Reaction time (s)Figure 5 - Contour plots of multivariate optimization

The results from the multivariate optimization run are shown in Figure 5, visualized by three contour
plots representing slices in the three-dimensional space (as shown above the contour plots).
Again, it is clear that temperature only has a minor inﬂuence on the reaction results. An optimum
was found at the following settings:
Reaction time

100 s

Amine : Diketone ratio

5

Temperature

20 °C

Although the optimum is on the edge of the experimental domain, it complies with the original aimof the study: 100% conversion at the lowest possible reaction time.
Experimental
For the microreactor set up, FutureChemistry’s FlowScreen was used, equipped with microreactors
from Micronit Microﬂuidics (details in Table 1).
The ﬁrst syringe was loaded with solution A containing 2,5-hexadione (45% v/v) and 2-bromotoluene(5% v/v, internal standard) dissolved in methanol. The second syringe was loaded with solution B
containing ethanolamine (40% v/v) and dimethoxyethane (10% v/v, internal standard) dissolved inmethanol. The third syringe was loaded with acetone as a quenching agent. The syringes were thenconnected to the microreactor system and the optimization program was run. The ﬂow rates were varied
using a preset program to control reaction time and reagent ratio, while the temperature was controlledwith the built-in temperature controller. Of each reaction mixture, 25 μL was collected into 1 mL portionsof collection liquid containing 2-bromonaphthalene (0.6% v/v) as an external standard in methanol.
Due to the varying ﬂow rates, sampling times differ for every experiment. All reaction conditions wererandomized. The samples were analyzed with GC-FID. Flow rates were calculated from calibrated
responses of the internal standards against the external standard. Conversion was calculated fromcalibrated responses of the diketone substrate against the internal standard 2-bromotoluene.

Phase 1 – Converting batch to ﬂow chemistry on μL-scale-- Page 7 of 12 --ACCESS FLOW

Application note

Phase 2 – Scaling up to mL-scale

Figure 6 - Micronit mL scale microreactor

Now that optimal conditions for ﬂow chemistry were established, the reaction was scaled up to
mL-scale using large scale Micronit Micoreactors (Figure 6, details of the setup are shown in
Table 2). While maintaining a sufﬁciently large surface to volume ratio, the lateral dimensions ofsuch reactors are enlarged to 1-2 mm. Mixing due to diffusion is not sufﬁcient anymore at thesescales, and therefore continuous mixing is established by the integration of split-and-recombine
mixers over the total length of the channel.
Table 2: Details equipment for mL-scale

Reactor volumes

2.4 mL

Reactor material

Borosilicate glass

Pumps

Uniqsis FlowSyn integrated pumps

In order to obtain conﬁdence for scalability, two validation points were performed with the mL-scale
system. The ﬁrst point obviously represents the optimal conditions found in the previous step. The
second is an arbitrary point resulting in 50% conversion within the optimization study. Parameters
and results of these points are summarized in Table 3.
Table 3: Validation points

Optimized point

Validation point

Reaction time

100 s

10 s

Amine : Diketone ratio

5.0

2.5

Temperature

20 °C

20 °C

Conversion predicted

100%

54%

Conversion observed

100%

57%

The results clearly indicate that scaling up to mL scale is very well possible. After validation wasachieved, a production run was performed, using the same optimal conditions as in the optimization
experiments. Details of settings and results of the production run are shown in Table 4.
Table 4: Production run single meso-scale microreactor

Total feed [mL/min]

1.43

Amine : Diketone ratio

5.0

Run time [min]72 minIsolated yield

98%

Phase 2 – Scaling up to mL-scale-- Page 8 of 12 --ACCESS FLOW

Application note

Experimental
For the milliliter scale microreactor set up, FutureChemistry’s FlowSyn was used, equipped with amilliliter microreactor from Micronit Microﬂuidics (details in Table 2).
The ﬁrst bottle was loaded with solution A containing 2,5-hexadione (45% v/v) and 2-bromotoluene(5% v/v, internal standard) dissolved in methanol. The second bottle was loaded with solution B
containing ethanolamine (50% v/v) dissolved in methanol. The bottles were then connected to theinlet ports of the FlowSyn, while the microreactor was connected to the outlet tubing of the FlowSyn.
The ﬂow rates were manually set and the experiments were run, while the outﬂow was collected into abottle containing acetone as a quenching agent. The samples were analyzed with GC-FID. Conversion
was calculated from calibrated responses of the diketone substrate against the internal standard
2-bromotoluene. Isolation was performed as follows: the reaction mixture was partially concentrated
on a rotary evaporator. The remaining mixture was extracted with diethyl ether (three portions of 100mL) and washed ﬁrstly with 150 mL 1M hydrochloric acid and secondly with 50 mL brine. After drying on
magnesium sulfate and ﬁltration, the organic layer was concentrated on a rotary evaporator. A yellow
oil was obtained, which crystallized shortly after the solvent was evaporated.

Phase 2 – Scaling up to mL-scale-- Page 9 of 12 --ACCESS FLOW

Application note

Phase 3 – Numbering out towards desired capacity

Figure 7 - Micronit parallel multi-layered reactor module

For these experiments 4 meso-scale reactors were integrated into one Micronit parallel multilayered reactor module (15 x 15 x 5 cm, Figure 7), with a total internal volume of 9 mL (see Table
5 for details). This multi-layered reactor is custom engineered, and consists of two sections, eachsection containing two reactors that are placed in parallel. The sections can operate independently,
in series or in parallel. For this experiment the sections were placed in series.
Table 5: Details equipment for mL-scale

Reactor volumes

9 mL

Reactor material

Borosilicate glass

Pumps

Bronkhorst Liquid Dosing System

All reaction parameters as determined in phase 1 are taken over for the phase 3 experiments,
approximately quadrupling the liquid feed rates, as shown in Table 6.
Table 6: Production run parallel multi-layered reactor module

Total feed [mL/min]

5.4

Amine : Diketone molecular ratio

5.0

Run time [min]60 minConversion

100%

Isolated yield

55.8 g / 96% (Figure 8)

Results show that scaling out this reaction using parallel microreactors give the same results,
indicating again excellent scalability of the Paal-Knorr reaction in ﬂow chemistry.

Figure 8 - Solid product after isolation - total yield 55.8 g; 96%

Phase 3 – Numbering out towards desired capacity-- Page 10 of 12 --ACCESS FLOW

Application note

Experimental
For the parallel multi-layered reactor module set up, two Bronkhorst Liquid Dosing Systems were used,equipped with a reactor module from Micronit Microﬂuidics (details in Table 5).
The ﬁrst bottle was loaded with solution A containing 2,5-hexadione (50% v/v) dissolved in methanol.
The second bottle was loaded with solution B containing ethanolamine (50% v/v) dissolved in methanol.
The bottles were then connected to the inlet ports of the pumps, while the microreactor was connected tothe outlet tubing of the pumps. The ﬂow rates were manually set and the production run was performed,
while the outﬂow was collected into a bottle containing acetone as a quenching agent. Isolation was
performed as in Phase 2.

Phase 3 – Numbering out towards desired capacity-- Page 11 of 12 --ACCESS FLOW

Application note

Conclusions
This application note shows that Access2Flow has the capability of translating batch chemistry
to ﬂow chemistry and holds the technological and engineering expertise to quickly scale up thecapacity of a process. For example, for the project as described in this application note, roughly
200 man hours were required.
Furthermore, the 3-phase methodology of Access2Flow has proven to be successful. Processparameters determined on small microreactor chips in phase 1 still hold when the internal dimensionof the reactor are increased in phase 2, while maintaining the reaction results. Phase 3 demonstrated the scalability of microreactors by numbering out towards production capacities.

Organizational benefits
Access2Flow is able to implement microreactor technology within your organization. By increasing
the controllability of a reaction; exothermic, fast, hazardous or sub-optimal reactions can be
performed, increasing the chemical scope for route scouting and product development. In thiscase, it was actually proven that an exothermic reaction could be readily scaled out.
The small volumes in the ﬁrst Phase ensure low reactant consumption, a key issue when only small
amounts of testing substances are available.
Furthermore, the complete process of feasibility through optimization up to outscaling to productionlevel proceded without any complications, showing the time efﬁciency of scaling out ﬂow chemistry
in comparison to scaling up conventional batch chemistry.
If you are interested in this technology, Access2Flow is able to provide you with the expertise andtechnology needed within each phase: from early stage exploration to advanced process implementation.

Contact
For more information concerning the Access2Flow consortium, please visit www.access2ﬂow.com
or contact Mr. P.J. Nieuwland: +31 (0) 24 711 4029, Pieter.Nieuwland@Access2Flow.com.

Organizational beneﬁts-- Page 12 of 12 --