A Fully Continuous-Flow Process for the Synthesis of p-Cresol: Impurity Analysis and Process Optimization

Article abstract of DOI:10.1021/acs.oprd.7b00250

A fully continuous-flow diazotization-hydrolysis protocol has been developed for the preparation of p-cresol. This process started from the diazotization of p-toluidine to form diazonium intermediate. The reaction was then quenched by urea and subsequently followed by a hydrolysis to give the final product p-cresol. Three types of byproducts were initially found in this reaction sequence. After an optimization of reaction conditions (based on impurity analysis), side reactions were eminently inhibited, and a total yield up to 91% were ultimately obtained with a productivity of 388 g/h. The continuous-flow methodology was used to avoid accumulation of the highly energetic and potentially explosive diazonium salt to realize the safe preparation for p-cresol.

Full text of DOI:10.1021/acs.oprd.7b00250

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Full Paper
A Fully Continuous-Flow Process for the Synthesis of
p-Cresol: Impurity Analysis and Process Optimization
Zhiqun Yu, Xin Ye, Qilin Xu, Xiaoxuan Xie, Hei Dong, and Wei-Ke Su
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00250 • Publication Date (Web): 11 Sep 2017
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A Fully ContinuousꢀFlow Process for the Synthesis of
pꢀCresol: Impurity Analysis and Process Optimization
Zhiqun Yu,† Xin Ye,† Qilin Xu,‡ Xiaoxuan Xie,† Hei Dong,† and Weike Su*,†,‡
†National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative
Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology,
Hangzhou 310014, P.R. China
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‡Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of
Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P.R. China
* Correspondent. Tel: (+86)57188320899. Eꢀmail: pharmlab@zjut.edu.cn.
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Abstract:
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A fully continuousꢀflow diazotizationꢀhydrolysis protocol has been developed for the preparation
of pꢀcresol. This process started from diazotization of pꢀtoluidine to form diazonium intermediate. The
reaction was then quenched by urea and subsequently followed by a hydrolysis to give the final product
pꢀcresol. Three types of byproducts were initially found in this reaction sequence. After an optimization
of reaction conditions (based on impurity analysis), side reactions were eminently inhibited and a total
yield up to 91% were ultimately obtained with a productivity of 388 g/h. The continuousꢀflow
methodology was used to avoid accumulation of the highly energetic and potentially explosive
diazonium salt to realize the safe preparation for pꢀcresol.
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Key Words: Diazotization, Fully continuousꢀflow, Impurity analysis, Hydrolysis.
Introduction
pꢀCresol is a key intermediate in the synthesis of many pharmaceutically active agents, such as
antibiotic (Amoxillin), antihypertensive (Aldomet), antibacterial synerist (Trimethoprim), antispasmodic
(Papaverine)1. Besides, it is also used as an important raw material in the synthesis of dyes, perfumes,
and pesticides2.
Thus far, various methods of synthesizing pꢀcresol have been reported3. Among them, two synthetic
routes (Scheme 1) have been performed in industrial. Route I: toluene was sulfonated to obtain
pꢀmethylbenzenesulfonic acid, which was then treated with sodium sulfite at high temperature to
generate sodium pꢀmethylbenzenesulfonate. Nevertheless, the selectivity of this reaction was not
satisfied in the view of generation of orthoꢀ and metaꢀ byproducts. Route II: diazotization of pꢀtoluidine
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followed by hydrolysis did engender important safety concerns due to the highly explosive diazonium
salt which may decomposed intensively under a relatively high temperature while releasing heat and
outgassing4. However, the diazonium salt is used as a highly reactive intermediate and plays an
important role in organic synthesis because of its feature of short reaction time, low reaction
temperature, nearꢀcomplete conversion5. All in all, diazotizationꢀhydrolysis is one of classical reactions
for the preparation of phenolic compounds (e. g. 2,5ꢀdichlorophenol, a key intermediate of herbicide
dicamba, is prepared by diazotizationꢀhydrolysis from 2,5ꢀdichloroaniline6). Therefore, the development
of a controllable and practical process is highly desired for the synthesis of pꢀcresol.
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Scheme 1. Synthetic Routes of pꢀCresol
In last 20 years, continuousꢀflow technology has been widely reported and researched in both
industry and academia7. Compared to traditional batch vessels, flow reactors have many advantages
such as better thermal and mass transfer; more accurate control of reaction parameters such as
temperature, stoichiometry, molar ratio, pressure, residence time; safer; and easier to implement
continuously8. There have been many reports for generating aromatic diazonium salts as reactive
intermediates (followed by iododeamination, chlorodeamination, bromodeamination, Heck coupling,
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azo coupling, etc.,) by using microreactor technology9. We have also done lots of work on
continuousꢀflow preparation of diazonium intermediates and their further reactions10 (such as
BalzꢀSchiemann reaction, reduction, methylthiolation, chlorosulfonation). To the best of our knowledge,
preparation of phenolic compound from aromatic amine via diazotization and hydrolysis in a fully
continuousꢀflow reactor has not been reported. We herein describe a practical process for the facile
synthesis of pꢀcresol in a fully continuousꢀflow reactor, and the reaction sequence was optimized based
on the impurity analysis.
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Results and discussion
Adapting the Batch Chemistry to Continuous Flow.
In the batch process, diazotization was generally carried out at a low temperature, then followed by
hydrolysis at a high temperature. The diazotization reaction temperature was strictly controlled bellow 5
oC and hydrolytic product had to be removed from the reaction system (by distillation or inꢀsitu
extraction with inert solvents3b) to avoid coupling reaction between diazonium salt and hydrolytic
product. The total yield of the batch process was ranging from 75 to 80%. There were two classes of
consecutive azo coupling side reactions compared to main reactions (Scheme 2), which can be inhibited
effectively by continuousꢀflow methodology theoretically. Diazotization has been reported to be
performed well in continuousꢀflow reactors9. In theory, as for hydrolysis in a continuousꢀflow reactor,
phenols generated from hydrolysis hardly contacted diazonium salts because of negligible back mixing,
hence side coupling reaction was inhibited. Therefore, our objectives aimed to develop a
continuousꢀflow process of both diazotization and hydrolysis in tandem, avoids mass accumulation of
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diazonium intermediate to improve procedure safety; inhibiting consecutive side reactions to increase
total yield.
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Scheme 2. Coupling Side Reactions in Diazotization and Hydrolysis
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Optimization of Continuous-Flow Diazotization.
Our work began from continuousꢀflow process optimization for the diazotization of pꢀtoluidine. A
cascade method was designed with a combination of continuousꢀflow diazotization and batch hydrolysis
process. As shown in Scheme 3, two streams, pꢀtoluidine in 24 wt % aqueous sulfuric acid solution and
20 wt % aqueous sodium nitrite solution, were pumped into a reacting tube (Hastelloy C276, 1.77 mm
i.d., 3.18 mm o.d.) via a Tꢀjoint (Hastelloy C276, 1.77 mm i.d.) by two plunger metering pumps (PTFE,
WOOK®) respectively. The reacting tube was immersed in a thermostat. Inside the reacting tube laid
several temperature sensors to monitor reaction temperature. After a residence time τ1, diazotization
mixture flowed into a stirring collection vessel containing aqueous urea to quench reaction. The
diazonium salt was then added dropwise into another vessel containing 20 wt % aqueous sulfuric acid
o
and toluene which had been heated to reflux (approximately 90 C under atmospheric pressure)
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beforehand. The mixture was stirred for 30 min at reflux temperature after the adding completed, then
cooled to room temperature and the blackish brown toluene layer was separated by gravity, followed by
adjusting pH to 7 with aqueous sodium bicarbonate, and removed solvent by distillation to gain crude
pꢀcresol. The samples were analyzed by GC.
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Scheme 3. Setup of ContinuousꢀFlow Diazotization
The related parameters of diazotization (residence time τ1, reaction temperature T1, molar flow ratio
of NaNO2 and pꢀtoluidine F2 : F1) were investigated systematically in continuousꢀflow process. And an
appropriate reaction condition was established. As shown in Table 1, the yield increased to a constant
value with prolonged residence time (entries 1ꢀ9). And when τ1 = 20 s, yield reached the maximum
number of 83%; The maximum yield occurred at 20 oC, and decayed rapidly with increased temperature
(entries 4, 10ꢀ17), because of the decomposition rate of diazonium salt outstripping the formation rate
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when reaction temperature maintained at relatively high temperature (excess than 20 C); Finally the
effect of F2 : F1 on yield of hydrolysis was figured out (entries 13, 18ꢀ21), the yield was increased to a
constant value with increased F2 : F1. Consequently, a maximum yield of pꢀcresol (85%) was achieved
in the condition of τ1 = 20 s, T1 = 20 oC, F2 : F1 = 1.02.
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Table 1. Data showing yield of pꢀcresol attained at different reaction conditionsa
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Entry
τ1 (s)
T1 (oC)
F2 : F1
Yield (%)b
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aAll hydrolysis sections were carried out at 90 oC for 30 min, and the reaction condition of hydrolysis was described in
detail in Experimental section. bYield was calculated from pꢀtoluidine and corrected on purity.
Overall, we described a continuousꢀflow process for synthesis of diazonium salt. The results showed
that the process of diazotization in flow was carried out successfully, and then we attempted to conduct
fully continuousꢀflow diazotizationꢀhydrolysis process.
Initial Design of Fully Continuous-Flow Process.
Initial design of fully continuousꢀflow process was shown in Scheme 4, the device was designed to
use two plunger metering pumps in order to introduce the feed streams of pꢀtoluidine in the aqueous
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sulfuric acid solution and aqueous sodium nitrite solution. A Tꢀjoint (Hastelloy C276, 1.77 mm i.d.) was
used as a mixer, which was connected with three tandem reacting tubes (Hastelloy C276, 1.77 mm i.d.,
3.18 mm o.d.). Tube I was submerged in a thermostat for diazotization, then the mixture was ensured to
enter tube II for hydrolysis at 90 oC. In consideration of nitrogen release in hydrolysis step may result in
uncontrollable residence time in a flow reactor, a back pressure regulator (BPR) was selected to install
in the tail of flow reactor. In addition, hydrolysis reaction temperature could reach higher than the
boiling point in atmospheric conditions. The back pressure was set to 145 psi, and all the plunger
metering pumps (PTFE, WOOK®) were set a builtꢀin automatic pressure shutꢀdown device to prevent
reactor from overpressure. After a residence time (τ2), the hydrolysis mixture was cooled then gathered
in a collected vessel. Unfortunately, pressure excessed than the trigger point and the pumps shut down
after the reaction device had run for a period of time. Quite a few viscous oil was found sticking in the
tube III to cause the raise of pressure in tube, which resulted due to the poor fluidity of the crude
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product at low temperature.
Scheme 4. Initial Design of Fully ContinuousꢀFlow Process
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Then, toluene was introduced to prevent hydrolysis tube from sticking or clogging, and create a
liquidꢀliquid biphase flow11 which separated diazonium salt and pꢀcresol, therefore the consecutive side
reaction between them was reduced.
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As shown in Scheme 5, pꢀtoluidine in sulfuric acid as first feed stream, aqueous sodium nitrite
solution was introduced as second stream. The two streams were pumped into tube I (Hastelloy C276,
1.77 mm i.d., 3.18 mm o.d.) which was submerged in a thermostat via a Tꢀjoint. The flow rates were
78.0 mL/min and 20.3 mL/min respectively to achieve a 20 s residence time for the diazotization
reaction, and the molar flow ratio of pꢀtoluidine: H2SO4: NaNO2 was 1.0: 3.0: 1.02. The third stream
(toluene) was pumped into tube II (Hastelloy C276, 1.77 mm i.d., 3.18 mm o.d.) which was submerged
in a thermostat via another Tꢀjoint and mixed with diazonium salt. Tube III was submerged in a
thermostat to cool down the reaction mixture before it flow into collecting vessel. Toluene layer was
separated from effluent and solvent was removed after adjusting pH to 7 to obtain product with 84%
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yield and 72% purity in the condition of τ2 = 45 s and T2 = 90 C. The results didn’t improve even
residence time (τ2) was varied. The experimental results failed to achieve our expectations. Crude
product was analyzed and identified by GCꢀMS. Nitration byproducts (S1), sulfonation byproducts (S2)
and coupling byproducts (S3) were found in crude product (Scheme 6). It is obviously that inhibiting
these side reactions had priority in present work.
Scheme 5. Improved Design of Fully ContinuousꢀFlow Process
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Scheme 6. Byproducts in Hydrolysis
Impurity Analysis.
1. Nitration Side Reactions.
According to impurity analysis, not only pꢀcresol but also the solvent toluene was nitrated.
Undoubtedly, of all the chemicals in this process, the source of nitro group was sodium nitrite. Generally,
slightly excess sodium nitrite usage assured complete transformation of material aniline. However,
excess nitrous acid could easily transform into nitric acid (by oxidation or disproportionation), which
led to nitration (Scheme 7). At high temperature, like in hydrolysis tube, disproportionation is main
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reason of forming nitric acid, because the reaction mixture is hardly contacted with air in tube and there
is no oxidant in this system other than a slight oxygen dissolved in the mixture. In addition, hydroxyl
and methyl are electronꢀdonating groups which promote electron density on the aromatic ring to reduce
activation energy of nitration and sulfonation. Either way, eliminating nitrous acid could avoid nitration
side reactions. Hence, urea was introduced before hydrolysis to react with excess nitrous acid to avoid
the generation of nitric acid. A set of controlled experiments (whether or not the introduction of urea
solution) were tested and the results showed that this method had a significant effect on the inhibition of
nitration side reactions. The amount of S1 fall below 0.5% after introducing slight excess of aqueous
urea (Table 2).
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Scheme 7. Two possible formation pathways of Nitric acid
Table 2. Effect of urea on the amount of S1
Entry
Whether or not the
introduction of ureaa
without the
Amount of S1 (%)
1
2
6
introduction of urea
with the introduction of
urea
＜0.5
aMolar flow ratio of pꢀtoluidine and urea was 1.0: 0.05.
2. Sulfonation Side Reactions.
Besides excess of sulfuric acid used in this reaction system, the effect of strong electronꢀdonating
hydroxyl on benzene and high temperature in hydrolysis promoted sulfonation of pꢀcresol. In theory,
whether sulfonation could be carried out depended on reaction temperature and concentration of sulfuric
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acid12. The concentration of sulfuric acid required for sulfonation will decrease along with the increase
of reaction temperature. Hence, reducing the concentration of sulfuric acid might be a right way to
inhibit sulfonation side reactions due to the increasing temperature was inescapable for the hydrolysis of
diazonium salt. The experimentations involved various concentrations of diazonium salt (introduced
water before hydrolysis) were tested and the results were shown in Figure 1 (The initial concentration of
diazonium salt was 6.8%, estimated from diazonium salt cation). S2 was decreased along with the
diluting of diazonium salt and became almost disappeared when the concentration of diazonium salt was
diluted to below 2%.
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Figure 1. Effect of concentration on amount of S2
3. Azo Coupling Side Reactions.
Although hydrolysis was performed in a flow reactor, the disturbance of gas induced considerable
back mixing. The formation of S3 resulted from coupling reaction of pꢀcresol with diazonium salt. In
order to figure out the selectivity of hydrolysis law at various temperatures and concentration of
diazonium salt, kinetic analyses of main and consecutive side reactions were discussed. This allows the
simplification of hydrolysisꢀazo coupling can be written in a simplified form as:
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where A, B, P, kP, kS, EaP and EaS represent diazonium salt intermediate, water, pꢀcresol, rate constant of
hydrolysis, rate constant of azo coupling, activation energy of hydrolysis and activation energy of azo
coupling, respectively. The reaction kinetics equations of hydrolysis and azo coupling are given by
equations (1) and (2) respectively.
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ꢀꢁ = ꢂꢁ[ꢃ]ꢄ[ꢅ]ꢆ
(1)
(2)
ꢀ = ꢂꢇ[ꢃ]ꢄꢈ[ꢉ]ꢊ
ꢇ
ꢍꢎ
ꢏꢐ
ꢂ = Aꢋꢌ
(3)
Arrhenius equation (3) was substituted into equations (1) and (2).
ꢍ
ꢏꢐ
ꢎꢑ
ꢀꢁ = ꢃꢁꢋꢌ [ꢃ] [ꢅ]
(4)
(5)
ꢄ
ꢆ
ꢍ
ꢏꢐ
ꢎꢒ
ꢀ = ꢃꢇꢋꢌ [ꢃ] [ꢉ]
ꢄꢈ
ꢊ
ꢇ
̅
We hypothesize that ꢓ represents contrast selectivity between hydrolysis reaction rate and
̅
azo coupling reaction rate. Thus, ꢓ is shown by equation (6).
ꢍ
ꢖꢍ
ꢎꢑ
ꢎꢒ
ꢏꢐ
ꢗ
ꢔ
ꢕ
ꢑ
ꢓ =
=
ꢑ ꢋ
ꢕ
ꢒ
[ꢃ]ꢄꢌꢄ [ꢅ]ꢆ[ꢉ]ꢌꢊ
(6)
(7)
̅
ꢔ
ꢒ
(I) Changeable temperature while the concentration of reagent keeps constant
ꢍ
ꢖꢍ
ꢎꢑ
ꢎꢒ
ꢏꢐ
̅
ꢓ = ꢘꢙꢋ
ꢗ
(K1= ꢕ [ꢃ]ꢄꢌꢄ [ꢅ]ꢆ[ꢉ]ꢌꢊ)
ꢑ
ꢕ
ꢒ
A set of test experiments involved temperature were conducted. pꢀToluidine was performed by
continuousꢀflow diazotizationꢀhydrolysis process at given temperatures. It was found that amount of S3
o
o
decreased from 12% to 7% when temperature increased from 90 C to 150 C (Figure 2), which meant
the selectivity was increased with increasing temperature. Thus, it led to the conclusion that activation
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energy of hydrolysis is higher than that of azo coupling reaction. Nevertheless, it is noteworthy that S2
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o
increased significantly when temperature exceed 130 C while the yield of target product increased
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slightly. Consequently, 130 oC was selected.
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Figure 2. Effect of temperature varied on the amount of S3
(II) Changeable reagent concentration while the temperature keeps constant
ꢗ
ꢄꢌꢄ
[ꢅ]ꢆ[ꢉ]ꢌꢊ
(8)
̅
ꢓ = ꢘꢚ[ꢃ]
ꢍ
ꢖꢍ
ꢎꢑ
ꢎꢒ
ꢏꢐ
(K2= ꢕꢑ ꢋ
)
ꢕ
ꢒ
Another set of experiments were carried out to find out the relation between concentration of
pꢀtoluene diazonium hydrogen sulfate and hydrolysis selectively. The pꢀtoluene diazonium hydrogen
sulfate was prepared in flow reactor in advance (the initial concentration of diazonium salt intermediate
was 6.8%, estimated from diazonium salt cation), then followed by dilution at various desired
concentrations. All diluents were hydrolyzed in a separated flow reactor under the same condition (τ2 =
45 s, T2 = 130 oC). The results were summarized in Figure 3. It was found that amount of S3 decreased
significantly with the diluted diazonium salt, in other words, the selectivity of hydrolysis increased with
decreasing concentration of diazonium salt. Thus we made a conclusion, aꢀ a’ < 0. The concentration of
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diazonium salt reduced from 2% to 1% resulted in only 0.3% yield decrease of S3 while the amount of
water was increased by 1.4 times. Consequently, 2% concentration of diazonium salt was selected.
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Figure 3. Effect of concentration on amount of S3
In summary, high temperature and low concentration diazonium salt are more favorable to hydrolysis
than azo coupling. Increasing water usage gets a double advantage to inhibit azo coupling and
sulfonation due to dilution of diazonium salt and sulfuric acid.
Advanced Design of Continuous-Flow Process.
Based on the analysis of side reactions, an advanced process was developed (Scheme 8). There are
five plunger metering pumps in this setup to introduce the feed streams. pꢀToluidine in sulfuric acid was
selected as first feed stream. Sodium nitrite solution was introduced as a second stream. The flow rates
were 78.0 mL/min and 20.3 mL/min, respectively, and the molar flow ratio of pꢀtoluidine: H2SO4:
NaNO2 was 1.0: 3.0: 1.02. A Tꢀjoint (Hastelloy C276, 1.77 mm i.d.) was used as a mixer, which was
joined by tube I (Hastelloy C276, 1.77 mm i.d., 3.18 mm o.d.) to provide the required residence time (τ1)
for the diazotization reaction. Tube I was submerged in a thermostat. Urea solution as third stream
pumped into another Tꢀjoint (Hastelloy C276, 1.77 mm i.d.) and mixed with diazonium salt followed by
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tube II (Hastelloy C276, 1.77 mm i.d., 3.18 mm o.d.) to achieve a 15 s residence time for quenching.
The flow rate was 3.6 mL/min and the molar flow ratio of pꢀtoluidine: urea was 1.0: 0.05. Tube II was
submerged in a thermostat. The diazotization process had been optimized herein before, hence water
was designed to introduce into tube III (hydrolysis section). A cross joint (Hastelloy C276, 1.77 mm i.d.)
was used as a mixer to connect quenching stream, water and cyclohexane (considering the problem that
solvent was nitrated, cyclohexane replaced toluene) to tube III. Water and cyclohexane were pumped by
two plunger metering pumps (PTFE, WOOK®), respectively. Tube III was submerged in a
thermostatꢀcontrolled oil bath to provide appropriate high temperature for hydrolysis of diazonium salt.
After a residence time (τ3) for hydrolysis, the effluent out of the reaction tube III was cooled and
followed to be collected in a vessel. The back pressure regulator installed in tail of flow reactor provided
145 psi to keep a stable residence time, meanwhile, increase the boiling point of mixture of hydrolysis
in the flow reactor. The aqueous phase was removed from the collection and crude product was then
collected by vacuum rotary evaporation. Refined product was obtained by vacuum distillation.
Scheme 8. Advanced Design of Fully ContinuousꢀFlow Process
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Figure 4. Instrument set of fully continuousꢀflow reactor.
With the introduction of urea solution to the system, side nitration reactions were almost impeded.
Sulfonation byproducts and azo coupling byproducts were significant inhibited with the dilution of
mixture. A set of experiments involved hydrolysis residence time (τ3) were tested to optimize an
appropriate time for the reaction. The results were shown in Figure 5, hydrolysis was completed in
around 30 s with the yield of 92%.
In above condition, a maximum yield of 94% of crude product with purity of 98.5% and refined
o
product with yield of 91% and purity ≥ 99.6% was obtain when T3 = 130 C and τ3 = 30 s. A
kilogramꢀscale process was performed, the reaction system was running for 3 h and 1.2 kg target
product gained with 90% isolated yield and purity of 99.8%, which validated this reaction process
having a remarkable ability to perform stably for a long period of time.
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Figure 5. Effect of τ3 on the yield of pꢀcresol
To emphasize the advantage of continuousꢀflow synthesis, the comparison in three different operate
manners was summarized. As shown in Table 3, reaction time was greatly reduced by increasing
temperature and thereby taking advantage of superior mass and heat transfer arose from a
continuousꢀflow system. Ultimately, diazotizationꢀhydrolysis was performed in a fully continuousꢀflow
reactor in a total residence time of 70 s, and target product was directly obtained in an excellent yield
with high purity.
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Table 3. Comparison of different operate manners
operate manner
batch
cascade
fully
continuousꢀflow
yield of refined product (%)
purity of crude product (%)
reaction time
75ꢀ80
≤ 96
hrs.
≤ 5
83
96ꢀ98
20 s + hrs.
20
91
98.5
70 s
20
temperature of diazotization (oC)
temperature of hydrolysis (oC)
90
90
130
Conclusion
A fully continuousꢀflow process has been described to allow the safe handling of the highly energetic
and potentially explosive diazonium intermediate, which allows the continuous diazotizationꢀhydrolysis
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for the synthesis of pꢀcresol from pꢀtoluidine in a three sequential continuousꢀflow reactor. The side
reactions were significant inhibited in flow process. Final product was directly obtained with a yield of
91% in a total residence time of 70 s and little accumulation of diazonium intermediate in this process.
The process is readily adapted for the preparation of analogous compounds. The productivity of pꢀcresol
is 388 g/h.
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Experimental section:
All chemicals were purchased from Shangyu Linjiang Chemical Co., Ltd. and were used without
further purification. All plunger metering pumps were purchased from Hangzhou Xuyu Technology Co.,
Ltd. Hastelloy C276 tube was purchased from Shanghai Zhaowei Stainless Steel Co., Ltd. Gas
chromatography (GC) analysis was carried out on a Shimadzu GCꢀ2010 Plus gas chromatograph. GC
conditions: Rtxꢀ1 column 30 m × 0.25 mm × 0.25 ꢁm, carrier gas: nitrogen (1.0 mL/min), injection
temp.: 300 oC, detector temp.: 300 oC, oven: 40 oC (3min hold) → 160 oC (10 oC/min, 2 min hold) →
o
o
1
295 C (20 C/min, 3 min hold). H NMR spectra were recorded in (CD3)2SO with tetramethylsilane
13
(TMS, δ = 0) as an internal standard at ambient temperature on a Varian 400 MHz spectrometer. C
NMR spectra were recorded in CDCl3 with tetramethylsilane (TMS, δ = 0) as an internal standard at
ambient temperature on a Varian 400 MHz spectrometer.
Cascade Process. As shown in Scheme 3, a mixture of pꢀtoluidine (107 g, 1 mol), sulfuric acid (98%,
300 g, 3 mol) and 925 g of water was prepared. 20 wt % aqueous sodium nitrite was prepared from
sodium nitrite (70.4 g, 1.02 mol) and 282 g of water. The aniline sulfate and aqueous sodium nitrite
were pumped into the tube reactor (Hastelloy C276, 1.77 mm i.d., 3.18 mm o.d.), which was immersed
o
in a thermostat (20 C), via a Tꢀjoint by P1 and P2 at flow rates of 78.0 mL/ min and 20.3 mL/min,
respectively. After a residence time of 20 s, the diazonium salt was collected in a vessel which was
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placed with 5 wt % urea (60 g, 0.05 mol) solution beforehand. 20 wt % Aqueous sulfuric acid (490 g, 1
3
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5
o
mol) and 300 mL of toluene were placed in a vessel, which were heated to reflux (approximately 90 C
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under atmospheric pressure), then diazonium salt (prepared by flow process in advance) added dropwise
with stirring. The mixture was stirred for 30 min at reflux temperature after dropping finished, then
cooled to room temperature and the blackish brown toluene layer was separated by gravity, followed by
adjusting pH to 7 with aqueous sodium bicarbonate. Toluene layer was separated by gravity again and
removing solvent by distillation to gain blackish brown liquid crude product, then followed by vacuum
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1
distillation to gain 90.0 g of colorless liquid product in 83% yield with purity of 99.7%. H NMR (400
MHz, (CD3)2SO) δ/ppm: 9.06 (br s, 1H, ꢀOH), 6.94 (d, J = 8.0 Hz, 2H, ArꢀH), 6.62 (d, J = 8.0 Hz, 2H,
ArꢀH), 2.17 (s, 3H, ꢀCH3). 13C NMR (CDCl3) δ/ppm: 153.0, 129.9, 115.1, 20.5. Literature data3b: 1H
NMR (300 MHz, CDCl3) δ/ppm: 7.03 (d, J = 8.2 Hz, 2H), 6.73 (dd, J = 8.2, 2.0 Hz, 2H), 4.75 (s, 1H,
OH), 2.27 (s, 3H, CH3). 13C NMR (CDCl3) δ/ppm: 153.2, 130.2, 115.2, 20.6.
Fully Continuous-Flow Process. As shown in Scheme 8, a mixture of pꢀtoluidine (107 g, 1 mol),
sulfuric acid (98%, 300 g, 3 mol) and 925 g of water was prepared. Aqueous sodium nitrite was
prepared from sodium nitrite (70.4 g, 1.02 mol) and 282 g of water. The aniline sulfate and aqueous
sodium nitrite were pumped into the tube reactor (Hastelloy C276, 1.77 mm i.d., 3.18 mm o.d.), which
was immersed in a thermostat (20 °C), via a Tꢀjoint by P1 and P2 at flow rates of 78.0 mL/min and 20.3
mL/min, respectively. After a residence time of 20 s, a mixture of urea (5%, 60 g, 0.05 mol) was
pumped into reactor system via Tꢀjoint by P3 at flow rate of 3.6 mL/ min and converged with diazonium
salt. Then, the mixture flowed into the second tube reactor which was immersed in a thermostat (20 °C);
After a residence time of 15 s, 4206 g of water and 420 mL of cyclohexane were pumped into tubular
react system via a cross mixer by P4 and P5 at flow rate of 276.8 mL/ min and 27.6 mL/ min and
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converged with quenching mixture. Then, the mixture flowed into the third tube reactor which was
immersed in a thermostat (130 °C). After a residence time (30 s) for hydrolysis, the mixture was cooled
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7
o
(in a 20 C thermostat), then flowed through the outlet and accumulated in a collection vessel. The
8
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pressure in reactor was controlled under 145 psi by a BPR. The mixture was separated and organic
lawyer was adjusted pH to 7 by aqueous sodium bicarbonate. Toluene layer was separated by gravity
again and removing solvent by distillation to gain crude liquid product. 98.3 g of colorless liquid refined
product in 91% isolated yield with purity of 99.7% was obtained by vacuum distillation.
P1, P2 and P5 with measurement range of 100.00 mL/min; P3 with measurement range of 10.000
mL/min; P4 with measurement range of 300.00 mL/min. All plunger metering pumps were set a builtꢀin
automatic pressure shutꢀdown device to prevent reactor from overpressure.
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Kilogram-Scale Process for the Synthesis of p-Cresol. To investigate the stability of the reactor, a
validation process was performed. Base on the previous work, the fully continuousꢀflow reactor
performed for 3 h to gain 1150 g pꢀcresol in 90% isolated yield with purity of 99.8%. The result was
shown that the fully continuousꢀflow process had an ability to run stably for a long period of time.
Acknowledgment
We are grateful to the National Natural Science Foundation of China (No. 21406203) and the Public
Projects of Zhejiang Province (No. 2016C33071) for financial support.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
xxxxxxxxxxxx.
Copies of 1H/13C NMR, GC spectrums for compounds
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(11) The flow of mixture is close to turbulent flow, which is based on the estimation of Reynolds
number. It offers good mixing, which leads to the uniform slight beadꢀlike dispersion. Therefore, the
interfacial area increases significantly, which results in the remarkable improvement of mass transfer. In
addition, product is extracted quickly in organic phase.
(12) Chen, R. Y. Optimization of organic synthesis process; Chemical Industry Press: Beijing, 2006.
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