Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Organic Process Research & Development
Article
CSTRs in series. To each of these CSTRs crotonaldehyde was
fed using separate pumps and the residence time in each CSTR
was maintained at 45 min. The reaction mass was collected in a
third CSTR where it was maintained for 60 min at the reaction
temperature. This yields a total residence time of 150 min,
which is lesser than 200 min as in batch reactor. The outlet of
this CSTR was used for collecting the product mass for workup
as explained in Section 2. The total residence provided in this
configuration is same as the batch time. The comparison of
batch and continuous experiments for different substrates is
given in Figure 3.
Figure 4. Selectivity of the desired product with different substrates.
second stages of workup. The residence time for either reactors
is lesser than 10% of the reaction time, and hence workup
needs relatively small volume CSTRs. In general continuous
workup has resulted in higher yields when compared to batch
operation. For the case of 6-nitroquinaldine yield from
continuous isolation is 88.9% when compared to 86% obtained
from batch approach. The continuous isolation of other aniline
derivatives can be performed in the same manner by adjusting
the molar requirement of alkaline solution. While all the
products are solids, some may require further purification
through recrystallization or column chromatography after the
workup. Also, if the workup temperature is higher than the
melting point of the product, workup yields an oily layer which
can be separated continuously by layer separation or a
membrane filter. Thus, among the recent reports on multistep
synthesis (which largely ensure to keep the reaction mass in
fluid phase) followed by its workup using variety of separation
techniques,22,23 simple techniques like pH adjustment, use of
antisolvent, or catch-and-release approach24 will actually help to
make the translation from lab scale to kilo scale much faster.
Hence the optimized percentage of sulfuric acid, lower
crotonaldehyde concentration, and flow reactor configuration
along with continuous isolation together make this process
green, economical, and commercially viable. The approach is
extendable for other systems where different aldehydes can be
used in the reaction.
Figure 3. Comparison of yield from batch and continuous flow
synthesis of various quinaldines for different anilines (1: aniline, 2: 3-
nitroaniline, 3: p-toluidine, 4: p-anisidine, 5: p-chloroaniline, 6: 4-
nitroaniline).
With p-chloroaniline as a starting material, continuous
reactions have issues like the solubility of reactant and transfer
of material in flow configuration. In this case the reactor set up
has to be modified with proper insulation to the tubing, which
can avoid precipitation of solids along the walls of the tubes.
With 3-nitroaniline as a starting material, two isomers, namely,
5-nitroquinaldine as a major product and 7-nitroquinaldine, are
formed which are confirmed by NMR. The comparison of
conversion between batch and CSTRs in series showed that,
while a batch reactor when operated for sufficiently longer time
would always achieve complete conversion, CSTRs in series
helped to achieve as much as 92−96% conversion depending
upon the substrate. A relatively diluted condition of the
reaction mixture in both the CTSRs results in slightly less
conversion. However, this characteristic also helped to improve
the selectivity of the desired product which can be seen in
Figure 4. Comparison of selectivity between a batch reactor and
CSTR shows higher selectivity for the case of aniline, 4-
nitroaniline, and 3-nitroaniline. The amount of polymer formed
in batch reactor was higher than in CSTR due to dilution of
inlet crotonaldehyde concentration. Hence the configuration of
CSTRs in series is favorable for slow reactions. It is possible to
enhance the reaction rates by increasing temperature; however
in that case the rate of polymerization increases significantly
and gives very low conversions of aniline.
4. CONCLUSIONS
The Doebner−Miller synthesis of quinaldine and its derivatives
is demonstrated in continuous flow conditions. In the absence
of using any solvents the reaction was not suitable to be
conducted in tubular reactors as sticky polymer clogs the
channels and tubes almost instantaneously. Hence a reactor
configuration that consists of CSTRs in series is used.
The effect of mole ratio of crotonaldehyde to aniline,
concentration of sulfuric acid, reaction temperature, and
residence time were studied, and a set of parameters that
gives maximum yields for different anilines is identified. The
flow synthesis approach is found to give better yields than batch
process.
At a residence time identical to the batch reaction time,
distributed dosing of crotonaldehyde to a configuration of
CSTRs in series helped to achieve better yields than a batch.
Continuous workup by a change of pH helped to recover the
product in an elegant manner. Reactions of six different anilines
As mentioned before, the isolation of the product happens in
two stages and is time-consuming with handling losses which
can be avoided in continuous isolation with better yield of the
product. In all the cases mentioned above the isolation was
carried out in continuous mode. The molarity of sodium
hydroxide solutions need be 4 and 8.75 M for the first and
D
DOI: 10.1021/acs.oprd.6b00179
Org. Process Res. Dev. XXXX, XXX, XXX−XXX