Toward the Efficient Synthesis of Pseudoionone from Citral in a

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Kinetics, Catalysis, and Reaction Engineering

Toward the efficient synthesis of pseudoionone from citral in a continuous-flow microreactor Feng Zhou, Hongchen Liu, Zhenghui Wen, Boyu Zhang, and Guangwen Chen Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.8b02367 • Publication Date (Web): 27 Jul 2018 Downloaded from http://pubs.acs.org on July 31, 2018

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Industrial & Engineering Chemistry Research

Toward the efficient synthesis of pseudoionone from citral in a continuous-flow microreactor Feng Zhou1,2, Hongchen Liu1,2, Zhenghui Wen1, Boyu Zhang1, Guangwen Chen1,* 1. Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. 2. University of Chinese Academy of Sciences, Beijing 100049, China.

Abstract Pseudoionone (PI) is a well-known and widely used precursor for ionones, which have been substantially applied in flavor, fragrance and pharmaceutical industry. The phase behavior in respect to the synthesis of PI was investigated through the combination of simulation and experiment to better understand the reaction process. A continuous-flow microreactor for efficient synthesis of PI was introduced. Various conditions (temperature, molar ratio of acetone to citral, citral concentration, NaOH concentration, residence time, and volume ratio of ethanol to water) were investigated to improve the synthesis process of PI. The condensation reaction preformed in the tubular and packed-bed microreactor under continuous-flow conditions was compared. Using a continuous-flow microreactor, PI could be efficiently synthesized from citral and a high PI yield of 93.8% could be achieved under the optimized conditions. Furthermore, a simplified kinetic model was developed to provide guidance for the synthesis of PI. Keywords: microchannnel, kinetic, citral, pseudoionone, aldol condensation

1. Introduction Ionones, including α- and β-ionone, are considered as important chemicals, owing to their widespread use in flavor, fragrance and pharmaceutical industry, especially as important precursor for synthesis of vitamin A.1,2 Commercially, ionones can be prepared in a two-step process, containing condensation of citral with acetone to yield pseudoionone (PI) and then cyclization of *

Corresponding author. Tel.: +86-411-8437-9031, Fax.: +86-411-8469-1570

E-mail address: [email protected] (G.W. Chen). 1

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Industrial & Engineering Chemistry Research 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

PI to produce ionones (Scheme 1).3,4 The condensation process is a classic aldol condensation, which is a typical carbon-carbon bond formation reaction between carbonylic compounds with acidic or basic catalyst.5 Traditionally, the condensation of citral with acetone is carried out in the liquid phase catalyzed by liquid bases, such as aqueous NaOH, LiOH and Ba(OH)2.1,6,7 However, this process is usually operated in a time-consuming batch reactor and PI yield is only about 60%-80%.7,8 The demand for ionones provides impetus for further exploration of the condensation of citral with acetone, thus improving the conventional process.

Scheme 1. Two-step reaction for the preparation of ionones Under the background of the ever-growing concern for the environmental impact of chemical industry, substantial types of solid-base catalysts have been employed for the synthesis of PI, thus developing more environmentally friendly processes. 6-13 Although many solid-base catalysts show high yield to PI, the technical disadvantages of current solid-base catalysts limit the implementation of that in the industrial production. Take activated hydrotalcites for example, the rapid decay of catalytic activity, unfeasible reusability and time-consuming regeneration steps make them less attractive in the practical industry.13 Phase transfer catalysis (PTC), a practical synthetic organic method and manufacturing process technology, has been applied for improving the synthesis process of PI.14,15 However, PTC for industrial processes suffers from the problems in terms of separation, recovery, and recycle of the catalyst from the product. Moreover, the disadvantages of PTC, like cost and toxicity, have to be considered. The synthesis process of PI has traditionally been performed with batch technology, and this approach indeed has achieved some successes. However, carrying out the synthesis process under continuous-flow conditions can offer obvious advantages over batch in terms of time, safety, and space. Dobler W et al developed a continuous process for producing PI in a tubular reactor.16 Compared with the batch technology, the reaction time was drastically reduced, and an 84% yield of PI was achieved. The combination of flow chemistry and microreactors technology is emerging 2


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in the modern chemical industry, which can correlate chemical engineering, organic synthesis with green chemistry.17 Performing reactions in a continuous-flow microreactor is now widely reported in the literatures, focusing on the optimization of reaction conditions,18-23 extraction of reaction kinetic information,24,25 investigation of reaction mechanism,26 improvement of process safety,27,28 exploration of the scalability 29-31 et al. The merits of the continuous-flow microreactor, including superior heat and mass transfer characteristics, precise residence time control, readily manipulation of reaction condition and intrinsic safety, have been reviewed extensively.32-38 Hence, the continuous-flow microreactor was utilized to perform the aldol condensation reaction of citral with acetone at elevated temperatures and pressures safely, to develop a more reliable, efficient and safer approach for the synthesis of PI in our work. Besides, the particularly attractive benefit of continuous-flow microreactor lies in the distinctive scalability via scale-out or numbering-up concepts. In this work, the phase behavior in respect to the condensation of citral with acetone was investigated to better understand the reaction process. Besides, a continuous-flow microreactor was exploited to obtain a more efficient approach for preparing PI from citral catalyzed by aqueous NaOH. Various conditions were investigated under continuous-flow conditions for the optimization of reaction conditions. Furthermore, the kinetic modeling investigation was also involved, which could guide the design and optimization for the synthesis of PI.

2. Experimental 2.1. Chemicals Ethanol was purchased from Damao chemical reagent factory. n-octane, n-dodecane, NaOH, HCl, NaCl and acetone were purchased from Tianjin Kemiou Chemical Reagent Co., Ltd. Citral was purchased from Shanghai Aladdin Bio-Chem Technology Co., LTD. Pseudoionone was supplied by Wanhua Chemical Group Co., Ltd. Deionized water was prepared in our laboratory and used throughout. All of the chemicals were used without further purification.

2.2. Procedures

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A schematic overview of the continuous-flow synthetic system of PI is shown in Figure 1. In the experiments, both NaOH solution (NaOH dissolved in water) and citral solution (citral/acetone dissolved in ethanol) were delivered into the system by metering pumps (series II pump, Chrom Tech, Inc., Apple Valley, MN, USA). Check valves were installed in the reaction system to prevent the reverse flow of the reactants. The mixing was performed in a stainless steel T-shaped mixer with a 1.2 mm diameter through-hole. A delay loop with an internal diameter of 0.6 mm constructed by stainless steel was directly connected to the micromixer to play the role of the reactor channel for the synthesis of PI. The whole delay loop was divided into two sections including reaction section and inhibition section. In the reaction section, the delay loop was immersed in the air bath to control the reaction temperature accurately. In the inhibition section, the delay loop was immersed in the ice water bath to inhibit the reaction. The delay loop was helically coiled with a radius of curvature of 2.5 cm to increase the mass and heat transfer coefficients and decrease the axial dispersion. A back-pressure valve (BPR) with a fixed pressure of 17 atm was installed at the end of the delay loop to ensure the reaction was operated in liquid phase. The residence time inside the reaction section could be accurately controlled by altering the flow rates. Besides, the tubular microreactor with a length of 9.3 m was replaced by a packed-bed microreactor (void fraction 0.223) to compare the reaction performed in the tubular microreactor and in the packed-bed microreactor. The packed-bed microreactor was constructed by filling 20~30 mesh SiO2 into a 316L stainless steel tube with an internal diameter of 4 mm and a length of 25 cm. A pressure sensor was installed to measure pressure at point A. After the system reached steady state, the samples were collected at the outlet and quenched by HCl solution. Metering pump

Check vavle

NaOH solution

Metering pump Check vavle

Citral/acetone solution

A Micromixer

BPR Delay loop Icewater Bath

P

Air Bath

Sample

Figure 1. Schematic overview of the continuous-flow synthetic system of PI

2.3. Analysis 4


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The quenched samples were extracted with n-octane for three times and NaCl was added into the emulsion phase for demulsification. After extraction, the organic phase was collected and the n-dodecane served as internal standard was added into the collected organic phase. The components in organic phase were analyzed on the Agilent 7890A gas chromatograph with a flame ionization detector to obtain the conversion of citral (X) and the selectivity of PI (S). The conditions for gas chromatography were as follows: HP-5 column, 30 m × 0.32 mm × 0.25 µm; carrier gas: nitrogen; injection temperature, 250 °C; detector temperature, 305 °C; oven temperature, 80 °C (2 min hold) to 260 oC (40 oC/min, 1 min hold).

3. Results and discussion 3.1. Phase behavior Conventionally, the synthesis of PI is operated in a batch reactor, which is suffering from the problems of low process efficiency, unsatisfactory yield and so on. The poor mass transfer in the batch reactor can be improved by introduction of PTC, which also has some obvious disadvantages as mentioned before. As alternative approaches, the addition of ethanol or the increase of acetone both can increase the mutual solubility of the reaction system. For example, Dobler W et al developed a continuous process for producing PI with heavy usage of acetone, allowing the process to be operated in a homogeneous system.16 The condensation process of citral with acetone involves a quaternary system of water-acetone-citral-PI, switching from heterogeneous system to homogeneous system as system composition undergoes a change. Deep understanding of the phase behavior of the quaternary system is beneficial for guiding the reaction process. In this work, the UNIFAC model was attempted to predict the phase behavior of the quaternary system using the software Aspen Plus.39 Figure 2 demonstrates the quaternary phase diagram for water-acetone-citral-PI at 25 oC and 1 atm predicted by UNIFAC model. It can be observed from Figure 2 that the presence of acetone increases the mutual solubility of the quaternary system. Besides, there is no noticeable transformation in the phase behavior when citral gradually turns into PI, which illustrates the reaction process maintains a stable phase state. The phase behavior of the ternary system of water-acetone-citral was experimentally studied to test model predictions (Figure 3). The experiments were carried out in a home-made jacked glass 5



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vessel with two sampling outlets, and similar experimental procedure can be found in the literature.39 The absolute average deviation (AAD) is defined as m

2

3

exp cal AAD = ∑ ∑∑ | wlpc | / 6m − wlpc

(1)

l = 1 p =1 c =1

where w refers to mass fraction, m refers to the number of tie-lines and the subscripts l, p and c designate the tie-line, phase and component respectively. As shown in the figure, the predictions for the system are in well agreement with the experimental values and the AAD is 1.48%, which demonstrates the predictions from UNIFAC model can indeed make a well estimation of the phase behavior in the reaction system. An Othmer-Tobias plot for the ternary system was constructed to test the reliability of experimental data (Figure 4), indicating the consistency of the experimental data.39 Point A in Figure 3, representing the initial component profile of water-acetone-citral adopted in the work of Dobler W et al,16 confirms the process been operated in the homogeneous regime.

Figure 2. Quaternary phase diagram for water-acetone-citral-PI at 25 oC and 1 atm predicted by UNIFAC model

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Experimental point in literature Experimental data Predicted data Phase Envelope

0.00 1.00

A 0.25

C it r al

0.75

Ac

0.50

0.50

eto ne

0.75

1.00 0.00

0.25

0.25

0.50

0.00 1.00

0.75

Water

Figure 3. Ternary phase diagram for water-acetone-citral at 25 oC and 1 atm. Comparison of experimental data with the data predicted by UNIFAC model. 1.5

0.5

ln ((1-a )/a )

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


-0.5 y = 1.1032x + 0.4424 2 R = 0.9992

-1.5

-2.5 -2.5

-1.5

-0.5

0.5

ln ((1-b )/b )

Figure 4. Othmer-Tobias plot for the experimental data from the water-acetone-citral system at 25 o

C. a is the mass fraction of citral in organic phase and b is the mass fraction of water in aqueous phase.

3.2. Efficient synthesis of pseudoionone in a continuous-flow microreactor Although increase of acetone can relieve the influence of mass transfer on the synthesis of PI, acetone is not an inert solvent in the reaction system which suffers from a loss by the

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self-condensation of acetone.6 Ethanol, an inert solvent in the reaction system, can provide another solution to relieve the influence of mass transfer. Besides, note that in the condensation of citral with acetone, the possibilities of self-condensation of citral, cross condensation of acetone with PI, cross condensation of citral with PI all can result in the formation of byproducts, thus leading to the decrease of PI selectivity. 1, 9 3.2.1. Effect of M-ratio and Temperature This work focuses on the detailed exploration of various reaction conditions to clarify the synthesis of PI in the continuous-flow microreactor. Having noted the fact that the molar ratio of acetone to citral (M-ratio) in the synthesis of PI was always desirable to maintain an obviously excess stoichiometric ratio, the screening of M-ratio in the range 5-15 was carried out to get insight on M-ratio dependence for the synthesis of PI in a continuous-flow microreactor (Figure 5). As shown in the figure, elevation of temperature and M-ratio are both beneficial for the accelaration of citral conversion. The citral conversion increases from 65% to 87% when M-ratio increases from 5 to 15 at 80 oC and it also can increase from 65% to 99% when temperature increases from 80 oC to 120 oC with an M-ratio of 5. This phenomenon is easy to understand according to the principle of reaction kinetic. The selectivity as a key parameter for the synthesis of PI was also investigated. As shown in the figure, higher selectivity is feasible to be obtained at a lower reaction temperature with a larger M-ratio. The PI selectivity increases from 62% to 92% when M-ratio increases from 5 to 15 at 80 oC and it decreases from 62% to 44% when temperature increases from 80 oC to 120 oC with an M-ratio of 5. The complicated side reactions mentioned above lead to the sharp sensitivity of PI selectivity to M-ratio and reaction temperature. The decrease of reaction temperature and increase of M-ratio are both beneficial for the improvement of PI selectivity. Nevertheless, an excessively high M-ratio is bound to result in the increase in the separation energy consumption and the loss of acetone.

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100

80

X, S / %

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


60

40

X

S

M-ratio

20

15

15

10

10

5

5

0 70

80

90

100

110

120

130

o

T / C

Figure 5. Exploring the influence of the M-ratio on the synthesis of PI in a continuous-flow microreactor. Reaction conditions: T=80-120 oC, t=98.6 s, QC=1.0 mL·min-1, cC'=0.5 mol·L-1, QNaOH=0.6 mL·min-1, cNaOH'=0.2 mol·L-1 and M-ratio=5-15.

3.2.2. Effect of citral concentration The citral concentration was modulated at various temperatures to elucidate the influence of citral concentration on the reaction performance (Figure 6). As shown in the figure, higher citral concentration noticeably increases citral conversion since the reaction rate can be accelerated by the rise of citral and acetone concentration according to the principle of reaction kinetic. As for the selectivity of PI, with the rise of citral concentration, the selectivity obtains an obvious improvement at various temperatures. This phenomenon may have been the case because the reaction system is a complex competitive reaction system and the acceleration of reaction rate by increase of citral concentration for the main reaction is more prominent than that of the side reactions.

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100

80

X, S / %

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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60

X

40

S 0.5

0.5

0.35

0.35

0.2

0.2

-1

c C'/mol·L 20

0 70

80

90

100

110

120

130

o

T / C

Figure 6. Influence of citral concentration on the synthesis of PI in a continuous-flow microreactor. Reaction conditions: T=80-120 oC, t=98.6 s, QC=1.0 mL·min-1, cC'=0.2-0.5 mol·L-1, QNaOH=0.6 mL·min-1, cNaOH'=0.2 mol·L-1 and M-ratio=15.

3.2.3. Effect of NaOH concentration The screening of the NaOH concentration in the range 0.1-0.3 mol·L-1 at various reaction temperatures is shown in Figure 7. The citral conversion goes up rapidly when the NaOH concentration increases from 0.1 mol·L-1 to 0.2 mol·L-1 and further increased NaOH concentration only results in a slight rise of citral conversion. For instance, the citral conversion increases from 68% to 87% with the growth of NaOH concentration from 0.1 mol·L-1 to 0.2 mol·L-1, but the citral conversion increases by merely 7.4% with the increase of NaOH concentration from 0.2 mol·L-1 to 0.3 mol·L-1. The PI selectivity is almost equal at low temperature (

Toward the Efficient Synthesis of Pseudoionone from Citral in a

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