Telescoped Sequence of Exothermic and Endothermic Reactions in Multistep Flow Synthesis

Article abstract of DOI:10.1021/acs.oprd.8b00008

A multistep sequential flow synthesis of isopropyl phenol is demonstrated, involving 4-step exothermic, endothermic, and temperature sensitive reactions such as nitration, reduction, diazotization, and high temperature hydrolysis. Nitration of cumene with fuming nitric acid produces 2- A nd 4-nitrocumene which are converted into respective cumidines by the hydrogenation using Pd/Ni catalyst in H-cube with gravity separation. Hydrolysis of in situ generated diazonium salts in the boiling acidic conditions is carried out using integration of flow and microwave-assisted synthesis. 58% of 4-isopropyl phenol was obtained. The sequential flow synthesis can be applied to synthesize other organic compounds involving this specific sequence of reactions.

Full text of DOI:10.1021/acs.oprd.8b00008

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Full Paper
Telescoped Sequence of Exothermic and
Endothermic Reactions in Multistep Flow Synthesis
Yachita Sharma, Arun V Nikam, and Amol A. Kulkarni
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00008 • Publication Date (Web): 21 Dec 2018
Downloaded from http://pubs.acs.org on December 22, 2018
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Telescoped Sequence of Exothermic and Endothermic Reactions in Multistep Flow
Synthesis
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Yachita Sharma, Arun V. Nikam and Amol A. Kulkarni*
Chemical Engineering & Process Development Division,
CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, INDIA
*Corresponding author, Phone: +91-20-25902153, E-mail: aa.kulkarni@ncl.res.in
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Abstract:
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A multi-step sequential flow synthesis of isopropyl phenol is demonstrated, involving 4-steps
exothermic, endothermic, and temperature sensitive reactions like nitration, reduction,
diazotization and high temperature hydrolysis. Nitration of cumene with fuming nitric acid
produces 2 and 4-nitrocumene which is converted into respective cumidines by the
hydrogenation using Pd/Ni catalyst in H-cube with gravity separation. Hydrolysis of in-situ
generated diazonium salts in the boiling acidic conditions is carried out using integration of flow
and microwave-assisted synthesis. 58 % of 4-isopropyl phenol was obtained. The sequential flow
synthesis can be applied to synthesize other organic compounds involving this specific sequence
of reactions.
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Keywords: Multistep Flow Synthesis, Nitration, Reduction, Diazotization, Phenol-Verkochung
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1. Introduction:
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Translation of batch process to continuous flow synthesis provides a promising technique for
scale-up of exothermic, multiphase, and temperature sensitive reactions. Smaller dimensions
help to enhance heat & mass transfer rates, reduce the equipment size, energy consumption, and
thereby reduce reaction time with increase in production capacity. All these features help to
achieve an economical process. In flow synthesis, dead time is almost negligible when
automated and integration of multistep in continuous synthesis eliminates laborious off-line
isolation of intermediates. Multi-step flow synthesis and purification of Ibuprofen,1 synthesis of
alkaloid natural product Oxomaritine,2 a library of 5-amino-2-aryl-2H-[1,2,3]-triazole-4-
carbonitriles,3 Suzuki-Miyaura cross coupling reaction,4 process intensification of the synthesis
of poly(vinyl butyral),5 diazotization with subsequent reactions6, Taxadienone synthesis
involving 2 copper mediated addition, a Diels-Alder reaction, palladium catalyzed Negishi
coupling reaction,7 rhodium-catalysed, syngas-mediated C–C bond formation for
hydroformylation of styrenes,8 and so many other multistep flow synthesis have been
successfully demonstrated and reported by academia as well as by industries.9-11 Continuous
flow synthesis of a few important molecules viz. HIV NNRTI Doravirine,12 Vildagliptin an oral
antibiotic drug13, Efavirenz,14 etc. is also reported in the literature with improved yield. Glasnov
et al. have reported multistep flow synthesis of Boscalid involving Suzuki–Miyaura
cross‐coupling and heterogeneous catalytic hydrogenation.15 Cantillo et al. have developed
multistep continuous-flow process for the synthesis of triaminophloroglucinol using sequential
nitration/reduction of phloroglucinol.16 Chen and Buchwald have designed a multistep synthesis
consisting of a C-N bond formation-hydrogenation-diazotization-cyclization sequence starting
from 2-chloronitroben-zenes and amines to synthesize 1-substituted benzotriazoles.17
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Among the several multistep synthesis, one of the important sequence is the aromatic nitration
followed by its reduction and then diazotization followed by hydrolysis. This sequence is
followed for the synthesis of aromatic alcohols used as intermediates in the fine and specialty
chemicals industry and also as API (viz. phenylrephren hydrochloride). Here, we have used this
sequence for flow synthesis of isopropyl phenol, which is useful organic intermediate for
synthesis of agrochemicals and perfumery products.18, 19 It is also used for the production of
phosphorus containing plasticizers instead of cresol, as diphenylisopropylphenyl phosphate is
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less toxic than tricresylphosphate.18 Generally, isopropyl-phenols are synthesized by either
rearrangement of saturated alkylphenylethers or by the selective oxidation of di-
isopropylbenzene. In the rearrangement approach first an alkyl phenyl ether is synthesized by
reaction of phenol with an alkyl halide in the presence of potassium hydroxide under reflux
condition. Rearrangement of this alkylphenylether takes place in sulfuric acid and glacial acetic
acid solution which gives predominantly the ortho isomer as the major product.20 The second
approach involves oxidation of p-di-isopropylbenzene in a two stages: (i) liquid phase oxidation
of p-di-isopropyl benzene to monohydroperoxide by atmospheric oxygen, which follows radical
mechanism, followed by (ii) acid catalyzed decomposition of the monohydroperoxide into
isopropyl phenol in the presence of a cation exchange resin. The yield of monohydroperoxide
depends on the temperature and distillation rate. Literature data shows 98% yield at 90 0C and at
a distillation rate of 0.05-0.07 l/hr.21 Safe handling of organic peroxide needs special attention.
Isopropyl phenol can also be synthesized by Fe2O3 catalyzed rapid oxidation of arylboronic acids
in the presence of atmospheric oxygen under solar visible range light irradiation,22 and via a
three step reaction starting from the reduction of nitrocumene (Raney Ni catalyst, 130 ˚C, 15
kg/cm2 and distillation give 90% yield) followed by diazotization and hydrolysis (steam
distillation, 60% yield) which involves many separation and purification steps.23 In such a
sequence comprising of exothermic reactions (viz. nitration, reduction and diazotization) and
handling of sensitive and reactive intermediates (diazonium salt), flow synthesis seems to be a
better approach.24-29 Fully continuous flow diazotization-hydrolysis has recently been reported
for synthesis p-cresol starting from p-toluidine as starting material. Optimized reaction
temperature and low concentration has enhanced yield of p-cresol as well as reduced
byproducts.30
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In this work, isopropylphenol is synthesized in a 4-step continuous flow process with special
emphasis on the hydrolysis reaction following a classical approach (see Schematics 1).
Commercially available cumene was chosen as starting material, upon nitration of cumene
followed by reduction, diazotization and hydrolysis gives isopropyl phenol with complete
elimination of separation and isolation steps. Among these steps, the first three steps are known
to be feasible in flow synthesis and a good amount of literature is available in the recent time.
For these three reactions, rapid mixing, high interfacial mass transfer rates, excellent temperature
control through efficient heat transfer and with adequate residence time, the reactions usually
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show enhanced yields of the products.31-33 However, the last step of converting an aniline into a
phenol is a classical conversion known as "Phenol-Verkochung".34 It is a SN1 type reaction of
the diazonium salt with water in the presence of concentrated acids at high temperature, which
yields respective phenols.35, 36 Although Phenol-Verkochung is well –known reaction, here we
demonstrate it for the first time in continuous mode under highly acidic conditions. This reaction
needs excess water under boiling conditions. The reaction should have relatively higher
activation energy as even in the acidic environment, phenol formation happens in a short time
only close to boiling conditions. Although Phenol-Verkochung reaction is known, here we
demonstrate a continuous microwave method for the first time under highly acidic conditions.
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Schematic 1: Classical approach for synthesis of isopropylphenol from cumene via multistep
approach involving 1) nitration (FNA: Fuming nitric acid), 2) catalytic hydrogenation, 3)
diazotization and 4) hydrolysis
2. Experimental Section:
Experimental set-up used for continuous nitration of cumene is shown in schematics 2. Typical
setup consisted of two continuous syringe pumps (Holmarc Opto-Mechatronics, Pvt. Ltd. India).
Stainless steel syringes were mounted on syringe pump to pump nitric acid (50 mL volume)
while PTFE syringes were used for the pump for dosing cumene. These syringes were connected
to SS316 tubes (1/8” o.d.) which were further connected to AMaR1 micromixer (Amar
Equipments Pvt. Ltd., India) followed by a 1/8” helical coil of 10 m length to maintain residence
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time. The reactor assembly was immersed in a constant temperature bath (ME-12, Julabo GmbH,
Germany) to maintain the system at isothermal condition. The entire assembly had four outlets
(one immediately after the micromixer i.e. after 2 mL volume and remaining along the length at
about every 3.33 m) connected to needle valves for sampling. The flow rates of the both
reactants were varied to achieve the desired mole ratio as well as the residence time. To extract
nitrocumene in organic phase, the pinched tube reactor of 36 mL volume was used and organic
and aqueous layer was separated using inline gravity separator as shown in schematics 2. For
analysis of samples, known quantity of samples were collected at the different outlets
(corresponding to different residence times), in a fixed quantity of ice-cold-water. A known
quantity of toluene (Merck Life Science Pvt. Ltd.) was used to extract the organic phase from
these samples. The extracted organic phase was washed thrice with water followed by brine and
separated by gravity. Trace quantity of water was removed by passing the organic phase through
a bed of anhydrous sodium sulphate. Products were confirmed by GCMS and NMR. Conversion,
yield and selectivity was estimated using gas chromatography (Thermo Fischer trace GC Ultra,
Column HP-5, i.d. = 0.25 mm, L = 30 m and FID detector). Nitrobenzene was used as an internal
standard.
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Schematic 2: Experimental setup for nitration of cumene followed by in-line quenching and
separation.
To the outlet of nitration reactor, toluene was dosed for continuous extraction of organic phase
(the mixture of Nitrocumenes) in toluene using a pinched tube reactor and the outlet was
subjected to a continuous settler where the phase separation happened by gravity and the organic
layer was continuously fed to the next step of reduction. H-cube® (ThalesNano Nanotechnology
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Inc., Hungary) with different catalyst Raney-Ni and Pd/Ni was used with temperature range of
40 to 100 °C and pressure range of 10 to 50 bar (see Schematics 3). Internal volume of the
catalyst cartridge was 0.3 mL. The nitro-derivatives of cumene were passed through the H-
cube® at flow rates over a range of 0.2-2 mL/min and samples were collected for each
experiment (see Table 1). These samples were analyzed without any separation or isolation using
GC with HP-5 column and a FID detector. Nitrobenzene was used as an internal standard. The
analysis showed that the outlet stream contained 16.7% 2-cumidine and 59.4% 4-cumidine (yield
are on the basis of Cumene).
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Schematic 3: Experimental set-up for nitrocumene reduction using H-cube followed by
cumidine salt generation using a CSTR.
After hydrogenation of nitro-cumene was dissolved in toluene, cumidines were subjected to
diazotization. Before diazotization, it was converted into (substituted) ammonium salt by
treatment with HCl and water, for which a continuous stirred reactor (also known as CSTR or
mixed flow reactor) was used (see setup in Schematic 3). This (substituted) ammonium salt is
completely soluble in water, and aqueous phase was separated by gravity. Peristaltic pump was
used to flow this aqueous phase containing (substituted) ammonium salt to react with 1.2
equivalent NaNO2 (10%) solution. The NaNO2 was injected using syringe pumps with PTFE
syringe and mixed with (substituted) ammonium salts in T mixer (see the schematic 4). This
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reaction was carried out at 5 C in 4.5 mL coiled reactor and reaction solution maintained 113
seconds residence time. In order to estimate yield of diazonium salt by HPLC, the reaction
mixture at the outlet of the reactor was collected in several vials containing 2 to 10 ml of aqueous
solution of β-naphthol (0.45 M) and NaOH (1.5 M)/.37, 38 The samples was collected over a
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period of 15–30 s to maitain required stoichiometry to give Sudan-I dye and the completion of
reaction was monitored using HPLC.
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Schematic 4: Experimental setup for the diazotization of cumidine salt.
The diazonium salt from the outlet of the previous step was directly fed into the CSTR placed in
a continuous microwave oven operated at 210 W, 2.45 GHz (Ragatech Pvt. Ltd. India), at the
flow rate of 2.4 mL/min at 80 °C (residence time ~ 4 – 13.4 min depending upon volume of
CSTR, see the reaction setup in Schematic 5). HCl (36% aq. solution) was used to provide acidic
media for hydrolysis at high temperature.34 The collected sample was extracted in organic phase
using toluene. Organic layer was separated by gravity. After thrice water wash followed by brine
wash, sample was directly submitted to GC analysis with HP-5 column and FID detector. On
using 16 mole sulfuric acid, 5% 2-isopropylphenol with 4% isopropylphenol was obtained in
PFR, while on using 2 mole of HCl in microwave 58% 4-isopropyl was achieved with 2% 2-
isopropylphenol (yields are on the basis of cumene). NMR and GCMS were used for product
conformation.
3. Result and discussions
In the first step commercially available cumene was chosen as starting material and nitration was
performed using fuming nitric acid being a greener reagent avoiding the use of sulfuric acid.39
Isoproyl group in cumene is ortho/para (o:p) directing and gives more para-isomer and negligible
amount of meta-isomer. The o:p isomer ratio depends on nitrating agent and solvent. Initially,
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nitration reactions were performed with 1 mole of nitric acid in residence time range of 2.64-10
min, maximum 38% conversion was achieved in residence time of 10 min. In order to get
complete conversion of cumene, 2 moles of fuming nitric acid was used at 30 °C and 40 °C, at
both temperatures and achieved in the range 65 and 66% conversion respectively at 10 min
residence time (see Figure 1), which clearly shows that nitrating reagent is limiting reagent for
this reaction. Using larger quantities of the fuming nitric acid (4 moles) at the same temperatures
resulted in very rapid reaction and exceedingly rapid heat generation. Even the outlet stream was
dark in color with a few impurities getting formed (mostly dinitro derivatives, confirmed from
GC Mass). Hence, further experiments were carried out at lower temperatures (0 0C and 10 0C).
On using 4 moles of fuming nitric acid 99.6% conversion was achieved with 19.5%, 1% and
79% yield for 2-nitrocumene, 3-nitrocumene and 4-nitrocumene, respectively in 6.4 min
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residence time at 10 C. Rest of the 0.5% mass was impurities that could not be isolated. In
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another set of experiments at 0 C, complete conversion was achieved in 8.2 min with almost
identical outlet composition. Thus it was possible to get complete conversion of the substrate by
achieving a suitable combination of temperature and residence time. Reaction was quenched
inline using ice-cold water and toluene was added continuously to this stream for extraction of
organic compound from aqueous phase using a pinched tube.40
Figure 1: Graphical representation of influence of reaction temperature and residence time on
the conversion of cumene.
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To achieve maximum separation efficiency, pinched tube reactor (1/8” o.d., 10 mL volume) was
used for liquid-liquid extraction which enhances mass transfer rates.40 Toluene layer containing
nitro derivatives was then continuously separated by liquid-liquid separator. The organic stream
was subjected to continuous reduction.
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Extracted nitrocumene solution exhibits concentration of 0.642 M. First reduction experiment
using H-cube® was carried out using Raney-Ni catalyst at 100 0C and at 40 bar with solution of
same molarity at 0.3 mL/min. However, no conversion was achieved at this condition due to
much smaller catalyst quantity loaded in the catalyst cartridge compared to the substrate
concentration. In view of this, nitrocumene solution was diluted to 0.1068 M and 0.0222 M using
toluene and hydrogenation was carried out at the conditions mentioned before (see table 1). This
resulted in only 10% and 13.83% yield at 40 bar pressure indicating that the catalyst was
inappropriate for reduction of nitrocumene and hence for all further experiments Pd-Ni (100mg)
was used as the catalyst.41 Nitrocumene solution (0.018 M) in toluene was subjected for its
reduction with Pd-Ni catalyst over a temperature range of 40 to 100 0C and pressure range of 10
to 50 bar with flow rate of 0.2 mL/min. At 100 °C and 40 bar pressure, 76.8% yield was
achieved with 16.7% 2-cumidine and 59.4% 4-cumidine.
Without any further separation or isolation steps this cumidine mixture was treated with HCl and
water to generate (substituted) ammonium ion in a CSTR. HCl was continuously added with the
help of a syringe pump that generated water soluble (substituted) ammonium ion and the water
was also continuously added to dissolve this (substituted) ammonium salt. At room temperature,
30 min residence time was found be sufficient for dissolution. Subsequently, the (substituted)
ammonium ion containing aqueous phase and organic phase separated using a gravity separation
unit. This (substituted) ammonium ion was treated with 1.2 equivalents NaNO2 (10%). The
aromatic diazonium salts can be a very unstable intermediate and can decompose above 5 0C or it
can undergo coupling reaction resulting in ethers or anhydride molecules, which is beyond the
scope of the present work. Thus retaining suitable temperature that avoids decomposition
reaction is necessary along with optimal reaction time. Various reports are available on flow
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synthesis of unstable diazonium intermediate at different temperatures.42,
Therefore,
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diazotization reaction was carried out in a residence time range of 30 to 120 s at 0 C. 100%
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diazotization was achieved with a residence time of 113 s, which was also confirmed via
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coupling with β-naphthol.
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On hydrolysis at higher temperature, diazonium salts are expected to give corresponding
phenols. It is known that this hydrolysis reaction follows first order kinetics with water being in
far excess and thus only the concentration of diazonium salt governs the rate of reaction.44
Following this aspect, the mixture of diazonium salts of 2-cumidine and 4-cumidine from the
previous steps were directly injected to a tubular reactor (of 9.5 mL volume) having multiple
outlets corresponds to different residence times. The coiled reactor was immersed in constant
temperature bath to provide isothermal conditions. Since, the reaction is facilitated only at higher
temperatures, experiments were carried out at 70 °C, 80 °C and 90 °C. However, the maximum
yield was 10% implying that either it needs stronger acidic media or higher temperature or both
together. It was thought desirable to transfer phenol in organic phase to enhance the reaction in
aqueous phase by avoiding possibility of lowering the reactant concentration in aqueous phase.
An organic solvent having lower dielectric constant would help as it does not get significantly
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Table 1: Details of reaction parameters for reduction of nitrocumene mixture dissolved in
toluene, with flow rate of 0.2 mL/min except in case of 0.642 molar solution, it’s 0.3 mL/min.
Yields are calculated using the GC data and are on the basis of nitrocumene. (H-cube catalyst
cartridge: *Raney-Ni, ** Pd-Ni)
Cumidine isomer
% yield
Nitrocumene
(mol/L)
Temp.
(°C)
P
(bar)
40
2
4
0.642*
-
-
-
40
4.50
1.72
3.48
4.85
3.27
5.79
3.42
5.88
2.72
4.87
6.27
4.61
8.03
5.71
10.39
4.44
8.35
11.12
7.88
13.83
9.13
0.107*
60
20
0.0445*
100
40
20
0.0222*
40
50
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40
60
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50
1.0
6.6
7.3
8.43
32.7
43.5
53.1
53.0
58.3
58.6
59.4
58.6
39.70
53.52
67.45
67.32
75.35
75.62
76.79
76.02
9.6
80
13.7
13.7
16.4
16.3
16.7
16.7
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0.01836**
100
heated. This makes the system two phase and using a pinched tube facilitated the mass transfer
of phenol from aqueous to organic phase. Hence, the next set of experiments was carried out
0
using sulfuric acid. On using 16 moles of H2SO4 at 80 C in a residence time of 4.2 min, the
highest yield was 39% (see Table 2 section Tubular reactor). Longer residence time resulted in
significant loss in the yield due to decomposition of diazonium salt as coupling of phenol with
undecomposed diazonium salt and their is formation of tar.45, 46 Also, slow heating of the
reaction mixture through an immersed tubular reactor also led to decomposition of diazonium
salt.
The approach using sulfuric acid led to generation of water vapors containing nitrophenols,
which could be avoided to some extent by using lower number of moles of H2SO4 and higher
temperature in further experiments. Moreover to avoid the volume of expansion due to
evaporation, further experiments were carried out in a continuous stirred tank reactor (CSTR)
rather than in a tubular reactor. CSTR attached to a condenser was used as it helped releasing the
water vapors from the reaction mass and its condensation to a steady state without affecting the
residence time. This also ensured that no pressure is built-up in the reactor, which is an unsafe
situation. In order to achieve rapid heating under stirring, the conventional method of circulation
of heating fluid through jacket was insufficient to achieve rapid heating compared to reaction
rates, a CSTR without any jacket was used and placed inside a microwave oven with inbuilt
magnetic stirring, having inlet and outlet ports and a condenser to condense the condensable
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vapors and release non-condensable gases (see schematics 5). CSTR was a favoured choice of
reactor as it helps rapid mixing, release of vapours avoiding pressure built-up in the reactor, with
a microwave while the heating rate remains constant using CSTR helped change residence time
independently.
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Schematic 5: Experimental step for microwave-assisted continuous flow hydrolysis of
diazonium salt.
This also helped to achieve a localized heating in a much shorter time. Initial continuous
microwave experiments at 140 W power at 80 °C with 7 minutes residence time resulted in a
total 41.7% yield of the phenols in which 10.5 % 2-isopropylphenol and 31.1 % 4-
isopropylphenol was obtained (see Table 2, section microwave). At 210 W the yield increased to
55.4%, however at 240 W the yield decreased to 44.9%. The temperature inside the reactor
0
measured using an IR gun (Testo) was found to be about 98 C. Despite circulating ice cold
water in the condenser brown fumes of isopropyl phenol were visible at the outlet of the
condenser. Sulfuric acid being a very strong hydrolyzing agent, controlling the reaction rates
under rapid heating was relatively difficult. In order to control the rate of hydrolysis further
experiments were carried out using 2 mole of HCl at 210 W, which resulted in 61.7% yield with
3.3% 2-isopropylphenol and 58.4% 4-isopropylphenol in 13 minute residence time. This yield of
4-isopropylphenol is close to the observations in the literature.34 In order to avoid any spark
inside the reactor, it was necessary to ensure that no charring happens and no carbon deposition
takes place on the surface of reactor or connecting joints.21 Further increase in residence time or
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microwave power resulted in rapid generation of brown fumes and lower yield of the desired
product in solution. Hence, 210 W power for microwave, 13 min residence time with 2 mol HCl)
was considered as optimum for this reaction step.
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Table 2: Details of reaction parameters for the hydrolysis of diazonium salt (yields are on the
#
basis of diazonium salt). Pinched tube tubular reactor, *H2SO4 catalyst, **HCl catalyst, -
without catalyst, the HCl used in the preparation of diazonium salt carried forward for hydrolysis
reaction).
Selectivity (%)
2-IPP 4-IPP
Catalyst
mole
Residence
time (min)
Overall
yield %
Temp. ᵒC
70
-
-
4
4
8.43
11.32
22.84
5.51
0.98
2.6
2.5
80
4.4
90
60
-
4
7.2
10.3
7.4
8*
16*
16*
16*
16*
-
6
1.91
0.85
2.09
6.27
3.51
34.9
31.16
39.56
29.9
47.1
58.4
60
6
11.64
16.15
32.76
21.86
11.36
10.53
15.82
14.98
10.9
12.5
18.3
39.0
25.4
30.2
41.7
55.4
44.9
58.0
61.7
70
6
80
4
80
9
70#
15
7
140w, 20%
210w, 30%
240w, 35%
210w, 30%
210w, 30%
-
-
13
13
13
13
-
0.8**
2**
3.3
Upon integrating the hydrolysis step with the previous steps of continuous nitration,
hydrogenation and diazotization (see schematic 5), the analysis of reaction mass showed 3.3%
yield of 2-isopropylphenol and 58.4% yield of 4-isopropylphenol. For the isolation of the
phenolic isomers, we used column chromatography using 10% ethyl acetate/petroleum ether and
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also crystallization using methanol/hexane (1:1) mixture. In crystallization protocol, almost
quantitative yield of 4-isopropylphenol (melting point 59–60 ºC) was obtained with 2-
isopropylphenol remaining in the liquid (melting point ~ 12–16 ºC). Upon further
recrystallization, 4-isopropylphenol was isolated in pure form with 52.3% yield.
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Schematic 6: Integrated multistep multi step flow synthesis of isopropylphenol.
The purpose of this work was to not only demonstrate the telescoped 4-step integration of flow
synthesis of isopropyl phenols but to also show that the classical approach of transforming an
aniline to a phenol works very well and can be improved through synergy of flow synthesis and
microwave heating. In this specific example, the overall reaction time of 21 hours in batch
synthesis for all 4 steps was seen to be reduced by at least 25 times with no intermittent isolation
stages. More such examples can be demonstrated using this approach.
4. Conclusions
4-step integrated continuous flow synthesis of isopropylphenol has been established with
reduction of overall process time from 21 hours to 50 min with complete elimination of any
intermittent isolation, separation, and purification steps. The sequence of reactions includes
exothermic reactions like nitration and hydrogenation47, 48, temperature sensitive and unstable
diazonium intermediate and endothermic continuous hydrolysis. The last stage of hydrolysis
follows the classical approach of reacting diazonium salt with water under strong acidic and at
boiling conditions. The entire sequence of stages covers a very wide range of experimental
conditions with the final stage under microwave to achieve rapid heating. The reaction sequence
followed cumene nitration with fuming nitric acid that gives 2 and 4-nitrocumene, which gives
respective cumidines upon reduction using H-cube with Pd/Ni catalyst. Upon diazotization of
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mixture of cumidines in acidic environment followed by high temperature continuous hydrolysis
in a microwave gives 2-isopropyl phenol and 4-isopropyl phenol with complete elimination of
intermittent separation, isolation and purification steps. The yield of 4-isopropylphenol after
purification was 52.3%. The hydrolysis step was seen to be extremely sensitive to acidic
environment as well as microwave power and hence should be optimized for individual anilines
separately. The approach can be used for the synthesis of other useful intermediates for
agrochemicals and pharmaceutical industry.
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Acknowledgements:
YS and AN thank CSIR New Delhi for proving fellowship. All authors acknowledge the
financial support from Indus Magic Program of CSIR’s 12th FYP. Authors thank Dr. C. V.
Ramana for proving facility (H-cube).
Description of Supporting Information: Supporting information includes the NMR spectra for
various intermediates and products and GC and GC-MS methods and chromatograms for various
intermediates and products that are formed at various stages in this multistep synthesis.
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Table of Contents graphic
Four step flow synthesis involving nitration, reduction, diazotization and hydrolysis
163x121mm (144 x 144 DPI)
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