A fully continuous-flow process for the synthesis of p-cresol: impurity

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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 Downloaded from http://pubs.acs.org on September 11, 2017

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Organic Process Research & Development

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 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 ‡

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. E-mail: [email protected].

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TOC Graphic:


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Abstract: A fully continuous-flow diazotization-hydrolysis protocol has been developed for the preparation of p-cresol. This process started from 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.

Key Words: Diazotization, Fully continuous-flow, Impurity analysis, Hydrolysis.

Introduction p-Cresol 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 p-cresol have been reported3. Among them, two synthetic routes (Scheme 1) have been performed in industrial. Route I: toluene was sulfonated to obtain p-methylbenzenesulfonic acid, which was then treated with sodium sulfite at high temperature to generate sodium p-methylbenzenesulfonate. Nevertheless, the selectivity of this reaction was not satisfied in the view of generation of ortho- and meta- byproducts. Route II: diazotization of p-toluidine ACS Paragon Plus Environment


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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, near-complete conversion5. All in all, diazotization-hydrolysis is one of classical reactions for the preparation of phenolic compounds (e. g. 2,5-dichlorophenol, a key intermediate of herbicide dicamba, is prepared by diazotization-hydrolysis from 2,5-dichloroaniline6). Therefore, the development of a controllable and practical process is highly desired for the synthesis of p-cresol.

Scheme 1. Synthetic Routes of p-Cresol

In last 20 years, continuous-flow 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, ACS Paragon Plus Environment

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azo coupling, etc.,) by using microreactor technology9. We have also done lots of work on continuous-flow preparation of diazonium intermediates and their further reactions10 (such as Balz-Schiemann reaction, reduction, methylthiolation, chlorosulfonation). To the best of our knowledge, preparation of phenolic compound from aromatic amine via diazotization and hydrolysis in a fully continuous-flow reactor has not been reported. We herein describe a practical process for the facile synthesis of p-cresol in a fully continuous-flow reactor, and the reaction sequence was optimized based on the impurity analysis.

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 o

C and hydrolytic product had to be removed from the reaction system (by distillation or in-situ

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 continuous-flow methodology theoretically. Diazotization has been reported to be performed well in continuous-flow reactors9. In theory, as for hydrolysis in a continuous-flow 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 continuous-flow 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.

Scheme 2. Coupling Side Reactions in Diazotization and Hydrolysis

Optimization of Continuous-Flow Diazotization. Our work began from continuous-flow process optimization for the diazotization of p-toluidine. A cascade method was designed with a combination of continuous-flow diazotization and batch hydrolysis process. As shown in Scheme 3, two streams, p-toluidine 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 T-joint (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 and toluene which had been heated to reflux (approximately 90 oC under atmospheric pressure) ACS Paragon Plus Environment

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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 p-cresol. The samples were analyzed by GC. Scheme 3. Setup of Continuous-Flow Diazotization

The related parameters of diazotization (residence time τ1, reaction temperature T1, molar flow ratio of NaNO2 and p-toluidine F2 : F1) were investigated systematically in continuous-flow 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 1-9). 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, 10-17), because of the decomposition rate of diazonium salt outstripping the formation rate when reaction temperature maintained at relatively high temperature (excess than 20 oC); Finally the effect of F2 : F1 on yield of hydrolysis was figured out (entries 13, 18-21), the yield was increased to a constant value with increased F2 : F1. Consequently, a maximum yield of p-cresol (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 p-cresol attained at different reaction conditionsa

a

Entry

τ1 (s)

T1 (oC)

F2 : F1

Yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

5 10 15 20 25 30 40 50 60 20 20 20 20 20 20 20 20 20 20 20 20

10 10 10 10 10 10 10 10 10 -5 5 15 20 25 30 35 45 20 20 20 20

1.02 1.02 1.02 1.02 1.02 1.02 1.02 1.02 1.02 1.02 1.02 1.02 1.02 1.02 1.02 1.02 1.02 1.00 1.01 1.03 1.04

45 75 81 83 84 84 83 83 84 55 70 83 85 84 82 76 64 81 83 85 85

All 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 p-toluidine and corrected on purity.

Overall, we described a continuous-flow 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 continuous-flow diazotization-hydrolysis process.

Initial Design of Fully Continuous-Flow Process. Initial design of fully continuous-flow process was shown in Scheme 4, the device was designed to use two plunger metering pumps in order to introduce the feed streams of p-toluidine in the aqueous


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sulfuric acid solution and aqueous sodium nitrite solution. A T-joint (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 built-in automatic pressure shut-down 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 product at low temperature. Scheme 4. Initial Design of Fully Continuous-Flow Process



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Then, toluene was introduced to prevent hydrolysis tube from sticking or clogging, and create a liquid-liquid biphase flow11 which separated diazonium salt and p-cresol, therefore the consecutive side reaction between them was reduced. As shown in Scheme 5, p-toluidine 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 T-joint. 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 p-toluidine: 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 T-joint 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% yield and 72% purity in the condition of τ2 = 45 s and T2 = 90 oC. 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 GC-MS. 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 Continuous-Flow Process


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Scheme 6. Byproducts in Hydrolysis

Impurity Analysis. 1. Nitration Side Reactions. According to impurity analysis, not only p-cresol 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 ACS Paragon Plus Environment


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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 electron-donating 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). Scheme 7. Two possible formation pathways of Nitric acid

Table 2. Effect of urea on the amount of S1 Entry 1 2 a

Whether or not the introduction of ureaa without the introduction of urea with the introduction of urea

Amount of S1 (%) 6 ＜0.5

Molar flow ratio of p-toluidine 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 electron-donating hydroxyl on benzene and high temperature in hydrolysis promoted sulfonation of p-cresol. In theory, whether sulfonation could be carried out depended on reaction temperature and concentration of sulfuric ACS Paragon Plus Environment

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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%.

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 p-cresol 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 hydrolysis-azo coupling can be written in a simplified form as: ACS Paragon Plus Environment


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where A, B, P, kP, kS, EaP and EaS represent diazonium salt intermediate, water, p-cresol, 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. = [] [ ]

(1)

= [] [ ]

(2)

= A

(3)

Arrhenius equation (3) was substituted into equations (1) and (2).

= [] [ ]

(4)

= [] [ ]

(5)

We hypothesize that ̅ represents contrast selectivity between hydrolysis reaction rate and azo coupling reaction rate. Thus, ̅ is shown by equation (6). ̅ =

=

[] [ ] [ ]

(6)

(I) Changeable temperature while the concentration of reagent keeps constant ̅ = (K1=

(7)

[] [ ] [ ] )

A set of test experiments involved temperature were conducted. p-Toluidine was performed by continuous-flow diazotization-hydrolysis process at given temperatures. It was found that amount of S3 decreased from 12% to 7% when temperature increased from 90 oC to 150 oC (Figure 2), which meant the selectivity was increased with increasing temperature. Thus, it led to the conclusion that activation ACS Paragon Plus Environment

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energy of hydrolysis is higher than that of azo coupling reaction. Nevertheless, it is noteworthy that S2 increased significantly when temperature exceed 130 oC while the yield of target product increased slightly. Consequently, 130 oC was selected.

Figure 2. Effect of temperature varied on the amount of S3 (II) Changeable reagent concentration while the temperature keeps constant

̅ = [] [ ] [ ] (K2=

(8)

)

Another set of experiments were carried out to find out the relation between concentration of p-toluene diazonium hydrogen sulfate and hydrolysis selectively. The p-toluene 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, a- a’ < 0. The concentration of ACS Paragon Plus Environment


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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.

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. p-Toluidine 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 p-toluidine: H2SO4: NaNO2 was 1.0: 3.0: 1.02. A T-joint (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 T-joint (Hastelloy C276, 1.77 mm i.d.) and mixed with diazonium salt followed by ACS Paragon Plus Environment

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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 p-toluidine: 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 thermostat-controlled 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 Continuous-Flow Process



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Figure 4. Instrument set of fully continuous-flow 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 product with yield of 91% and purity ≥ 99.6% was obtain when T3 = 130 oC and τ3 = 30 s. A kilogram-scale 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. ACS Paragon Plus Environment

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Figure 5. Effect of τ3 on the yield of p-cresol To emphasize the advantage of continuous-flow 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 continuous-flow system. Ultimately, diazotization-hydrolysis was performed in a fully continuous-flow reactor in a total residence time of 70 s, and target product was directly obtained in an excellent yield with high purity. Table 3. Comparison of different operate manners operate manner

batch

cascade

fully continuous-flow

yield of refined product (%) purity of crude product (%) reaction time temperature of diazotization (oC) temperature of hydrolysis (oC)

75-80 ≤ 96 hrs. ≤5 90

83 96-98 20 s + hrs. 20 90

91 98.5 70 s 20 130

Conclusion A fully continuous-flow process has been described to allow the safe handling of the highly energetic and potentially explosive diazonium intermediate, which allows the continuous diazotization-hydrolysis ACS Paragon Plus Environment


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for the synthesis of p-cresol from p-toluidine in a three sequential continuous-flow 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 p-cresol is 388 g/h. 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 GC-2010 Plus gas chromatograph. GC conditions: Rtx-1 column 30 m × 0.25 mm × 0.25 µm, 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) → 295 oC (20 oC/min, 3 min hold). 1H NMR spectra were recorded in (CD3)2SO with tetramethylsilane (TMS, δ = 0) as an internal standard at ambient temperature on a Varian 400 MHz spectrometer.

13

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 p-toluidine (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 in a thermostat (20 oC), via a T-joint 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 ACS Paragon Plus Environment

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placed with 5 wt % urea (60 g, 0.05 mol) solution beforehand. 20 wt % Aqueous sulfuric acid (490 g, 1 mol) and 300 mL of toluene were placed in a vessel, which were heated to reflux (approximately 90 oC 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 distillation to gain 90.0 g of colorless liquid product in 83% yield with purity of 99.7%. 1H NMR (400 MHz, (CD3)2SO) δ/ppm: 9.06 (br s, 1H, -OH), 6.94 (d, J = 8.0 Hz, 2H, Ar-H), 6.62 (d, J = 8.0 Hz, 2H, Ar-H), 2.17 (s, 3H, -CH3).

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C 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 p-toluidine (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 T-joint 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 T-joint 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 ACS Paragon Plus Environment


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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 (in a 20 oC thermostat), then flowed through the outlet and accumulated in a collection vessel. The 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 built-in automatic pressure shut-down device to prevent reactor from overpressure. 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 continuous-flow reactor performed for 3 h to gain 1150 g p-cresol in 90% isolated yield with purity of 99.8%. The result was shown that the fully continuous-flow 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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A fully continuous-flow process for the synthesis of p-cresol: impurity

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