Angewandte
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Chemie
Hydrogen gas was supplied by a commercial H generator
Telescoped Process: Steady State Operation
2
with an integrated mass flow controller (Thales Nano, H-
Genie) and the pressure was controlled by a back pressure
regulator (Equilibar, Zero Flow) linked to a pressurized
nitrogen supply, with automated electronic regulation
As discussed for each of the PAT instruments individually,
their placement in the multistep process has been thoroughly
planned. NMR can distinguish the different regioisomers
arising from the nitration reaction, as well as analyzing the
separations, based on chemical shifts due to varying pH. UV/
Vis takes advantage of colored product formation in the
hydrolysis step, whilst inline IR distinguishes well between
amino and nitro groups. Each of these techniques has a fast
sampling time (NMR = 10 s, UV/Vis = 2 s, IR = 15 s), so
provide good resolution of the process data. UHPLC is
positioned at the end of the process, to deliver a precise
quantification of all process species every 7.5 min.
After optimization of the individual reaction steps, these
were brought together to run as a telescoped process (Fig-
ure 6). Integration of all component parts within the same
operational system was key to the smooth operation and
management of this multistep process and its acquired data.
This was achieved using open platform communication
unified architecture (OPC UA), a modern industry standard
for inter-platform equipment communication. By this proto-
col, all pumps, probes, thermostats and other equipment were
actively monitored and controlled through a single super-
visory control and data acquisition (SCADA) software (Evon,
XAMControl). Achieving this with equipment from numer-
ous different suppliers represents a significant challenge, due
to the lack of unified communication protocols and docu-
mentation. However, this also allowed real-time readouts of
concentrations from the PAT tools, using the developed
chemometric models. It should be noted that UHPLC and
UV/Vis results were delivered by a direct connection to the
computer rather than OPC UA, with report file monitoring
for new results (UHPLC) or a direct connection to the
SCADA software (UV/Vis).
To demonstrate the multistep process, a long run experi-
ment under the optimized conditions was carried out for 3.5 h
of steady state operation (Figure 7). The startup period in this
case was of particular interest, since it demonstrates the
distribution of the species as they progress through the system
and reach each of the respective PAT instruments (Figure 7a).
Steady state concentration was reached at the NMR after
22 min, UV/Vis after 38 min and IR after 54 min. The use of
analytical instruments with fast scan rates allow this charac-
terization to be carried out in a straightforward manner,
whilst preserving the reaction media viscosity and separation
properties, since a different tracer reagent is not necessary.
Another important aspect is the relative gradient of
concentration increase at each point during the startup, which
can be taken as a measure of flow dispersion. It would be
expected that this gradient would become increasingly
shallow as the time within the system increases, due to
a broadening residence time distribution. The buffer vessel
before the hydrolysis was of key concern here, but owing to
the intentionally small holdup volume ( ꢀ 4 mL), this appears
to have had a minimal effect. This is evidenced by the
comparable concentration gradients for the NMR, UV/Vis
and IR analyses. This relatively narrow distribution (i.e. good
overall plug flow character) implies that the effect of
(
Bronkhorst, EL-PRESS). This setup facilitated reaction
optimization, including automated adjustment of gas and
liquid flow rates, system pressure and temperature. A study
was also carried out for this reaction step, to provide a clear
view of the influence of each reaction parameter and develop
a robust operating space.
This study simply examined the conversion of 5-NSA to 5-
ASA, under the assumption that the observed factor influen-
ces could be applied to other nitro compounds present in
a telescoped process mixture. Aside from residence time,
temperature (40–808C examined) was found to have the most
significant influence, followed by the flow rate of H (25–
2
À1
7
5 mLNmin examined). Pressure (6–12 bar examined) was
also found to significantly increase reaction rate, and numer-
ous parameter interactions were also identified. It was
extrapolated from this data that, when working at 808C and
1
2 bar pressure, all nitro species present in the reaction
stream would be quantitatively reduced to their correspond-
ing anilines (in particular, the desired reaction pathway: 5-
NSA to 5-ASA).
In order to provide real-time quantification of this step,
a simple gas-liquid separator was constructed (see Supporting
Information), and connected to an IR probe (Mettler Toledo,
ReactIR 15). Here, a spectrum was acquired every 15 s and
the data was processed using a partial least squares (PLS)
[20]
regression model (Figure 5b).
This model was selected
instead of an IHM in this case, due to better performance, but
was also set up and processed in real time using PEAXACT
software.
The models were validated using 10 separate averaged
spectra from process data. Here, the errors were found to be
low, considering the difficulty of quantification. The main
product 5-ASA was evaluated to have a validation error of
7
.7 mM, which is < 5% of the expected 180 mM concentra-
tion in the process stream. The models for other analytes
provided validation errors of between 1.4 and 15.4 mM,
implying overall excellent quantification accuracy. Further-
more, the variation between measurements was found to be
very low, so no additional filter/averaging of the data was
required. This set of PLS models provided useful concen-
tration predictions for all nine of the examined species.
To achieve a detailed overview of the final reaction
composition after the multistep procedure, online ultra-high
performance liquid chromatography (UHPLC, Shimadzu,
Nexera X2) was incorporated, using a 10 nL sample injector
(
Vici, Cheminert Nanovolume). A fast gradient-based meth-
od was developed, which allowed an injection every 7.5 min
Figure 5c). Despite this short analysis time, all nine of the
(
identified process components could be separated, allowing
precise quantification. Again, all nine components were
calibrated simultaneously, using seven injection mixtures of
different concentration levels.
8
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ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 8139 – 8148