Development and Scale-up of the Rapid Synthesis of Triphenyl Phosphites in Continuous Flow.

A novel method for the synthesis of triphenyl phosphite and its derivatives has been developed in continuous flow. With a total residence time of 20 s, the target product was prepared in a microreactor, and the reaction time was significantly shortened compared with standard single batch reaction conditions. In addition, the reaction of various substrates gave the corresponding products in good to excellent yields under optimized conditions. The reactants could be employed in a stoichiometric ratio, making the reaction more efficient, economical, and environmentally friendly. In addition, scale-up apparatus was designed and assembled, and the kilogram-scale production (up to 18.4 kg/h) of tris(2,4-di-tert-butylphenyl) phosphite was achieved in 88% yield.

Introduction

Triphenyl phosphites are excellent organic phosphite antioxidants which possess high efficiency, low toxicity, low volatility, and other advantageous characteristics. Generally, triphenyl phosphites are used as stabilizers for polymers, such as polyethylene, polypropylene, polystyrene, polyvinyl chloride, and synthetic rubber.[1] There are a number of available synthetic methods for the preparation of triphenyl phosphites (Table ). These methods comprised the utilization of various bases to obtain satisfactory yields. In these methods, Na, Et3N, pyridine amines, and benzothiazole were employed as bases. Excellent yields were given when using pyridine and benzothiazole as bases in the reaction (Table , entries 4 and 6). According to the reaction mechanism in Scheme , there are three steps to synthesize triphenyl phosphites from phenols and PCl3. HCl was released in every step. Therefore, using a base as the acid binding agent improved the reaction efficiently. Also, the main byproducts were the intermediates of mono-substituted and di-substituted PCl3 in step 1 and 2, when the base was insufficient to neutralize HCl from the reaction process. Besides, different solvents such as MeOH, tetrahydrofuran (THF), CH3CN, CH2Cl2, xylene, dimethylformamide (DMF), and hexane were utilized in these methods. Mostly, polar aprotic solvents were beneficial for the reaction except for MeOH when using Na as the base (Table , entry 1). In addition, only middle yield was given when the reaction was performed under reflux without a base (Table , entry 3). Nevertheless, all of these synthetic methodologies are carried out in a batch reactor and require complex operations. Because in batch reaction conditions, PCl3 was introduced into the reactor by dripping, which cost much time and easily caused uneven distribution of PCl3 concentration in the reactor.

Table 1

Various Methods for the Preparation of Phosphites in the Traditional Reactor

entry	author	base	solvent	product	yield (%)	refs
1	Seiceira	Na	MeOH	triphenyl phosphite	87	(2)
2	Goycoolea	Et3N	THF	triphenyl phosphite	80	(3)
3	Górniak		CH3CN	tris(4-methylphenyl) phosphite	58	(4)
4	Akbarali	pyridine	CH2Cl2	tris(2,4-di-tert-butylphenyl) phosphite	94	(5)
5	Herzog	amines	xylene + DMF	tris(2,4-di-tert-butylphenyl) phosphite	85	(6)
6	Hunter	benzothiazole	hexane	tris(2,4-di-tert-butylphenyl) phosphite	94	(7)

Scheme 1

Reaction Mechanism of Synthesis of Triphenyl Phosphites

In recent years, microreactor technology has emerged as an efficient technique[8−18] because of improved synthetic efficiency and its application to new strategies for various compounds.[19] The most significant advantage behind the utilization of microreactors is that the synthetic approach can enable rapid reaction optimization without compromising safety,[20−23] which is a result of the large surface-to-volume ratio and the enhanced heat and mass transfer.[24,25] In addition, microreactor technology can improve the safety of the process, and allows for easy scale-up, in-line workup, and automated operations.[26−31] Therefore, it is clear that many challenges for traditional methods can be overcome with microreactor technology. Herein, we report a novel procedure for preparing triphenyl phosphites and derivatives under continuous flow conditions.

Results and Discussion

First, the operation conditions were optimized in the batch reactor by exploring the effects of temperature, solvent, and types or amounts of the base. Tris(2,4-di-tert-butylphenyl) phosphite was chosen as the model product for optimization of the reaction parameters because of its wide use as an antioxidant in polymers. We started our investigation by reacting phosphorus trichloride, 2, with 2,4-di-tert-butylphenol, 1a, in the ratio of 1:1 in a batch reactor. Because the reaction is vigorous when adding phosphorus trichloride to the reaction mixture, the reaction was performed at 40 °C initially to reduce the heat releasing from the reaction mixture. Then, the reaction was performed at a higher temperature to increase the reaction rate for higher yield of the desired product. Different bases such as triethylamine (TEA), pyridine, 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIEA), imidazole, and N-methylimidazole were screened under the same conditions (Table , entries 1–6). TEA was found to be the most effective base for the reaction (Table , entry 1). Besides, increasing the amount of TEA to 3.3 equiv resulted in a higher yield (Table , entries 7 and 8). Then, 3.3 equiv TEA was chosen as the optimal condition in the following studies. In addition, the solvent effect was researched by screening toluene, CH2Cl2, xylenes, MeCN, THF, CHCl3, and ClCH2CH2Cl (Table , entries 8–14). The highest yield was given when using toluene as the solvent (Table , entry 8). To the best of our knowledge, high reaction temperature is beneficial for the reaction yield in the preparation of triphenyl phosphites. Therefore, the desired product was produced in 82% yield on increasing the second-stage reaction temperature to 70 °C (Table , entry 16). When the reaction was performed at 80 °C, the yield was decreased to 75% because of the volatilization of PCl3 (Table , entry 17).

Table 2

Optimization of Reaction Conditions in Batch Processa

entry	base	equivb	reaction temp/(°C)	solvent	yieldc/(%)
1	TEA	3	40 + 50	toluene	55
2	pyridine	3	40 + 50	toluene	52
3	DMAP	3	40 + 50	toluene	49
4	DIEA	3	40 + 50	toluene	41
5	imidazole	3	40 + 50	toluene	33
6	N-methylimidazole	3	40 + 50	toluene	50
7	TEA	3.15	40 + 50	toluene	60
8	TEA	3.3	40 + 50	toluene	74
9	TEA	3.3	40 + 50	CH2Cl2	69
10	TEA	3.3	40 + 50	xylenes	72
11	TEA	3.3	40 + 50	MeCN	70
12	TEA	3.3	40 + 50	THF	63
13	TEA	3.3	40 + 50	CHCl3	72
14	TEA	3.3	40 + 50	ClCH2CH2Cl	68
15	TEA	3.3	40 + 60	toluene	80
16	TEA	3.3	40 + 70	toluene	82
17	TEA	3.3	40 + 80	toluene	75

Reaction conditions: 1a (0.06 mol), 2 (0.02 mol), 250 mL 3-necked round bottom flask equipped with a stirrer, reflux condenser and dropping funnel, the initial temperature was 40 °C and then reacted at a higher temperature for 3 h.

The equivalent of base refers to the molar ratio with phosphorus trichloride.

Isolated yield.

After the completion of the optimization studies in the batch process, we set out to explore the synthesis of tris(2,4-di-tert-butylphenyl) phosphite in continuous flow. In this system, solvents were found to have a notable effect for the clog during the reaction process. According to the reaction phenomena of preliminary results in the batch process, various commonly used solvents (toluene, CH2Cl2, xylenes, MeCN, THF, and ClCH2CH2Cl) were limited in the continuous flow system because of an undissolved solid. The solid was triethylamine hydrochloride which formed during the reaction, and its poor solubility in these solvents resulted in blockage of the microreactor. Fortunately, chloroform exhibited excellent solubility for triethylamine hydrochloride, also including the substrate and the corresponding product. Thus, chloroform was chosen as the reaction solvent instead of toluene. In addition, the reactions were performed by using 2,4-di-tert-butylphenol and phosphorus trichloride with a stoichiometric ratio (3:1) to minimize the chemical waste production. We commenced our investigations by employing TEA, pyridine, DMAP, imidazole, and N-methylimidazole as the bases, respectively (Table , entries 1–6). Highest yield was given when N-methylimidazole was the base (Table , entry 6). Also, very similar yield was obtained when the reaction was carried out by utilizing TEA as the base (Table , entry 1). Because N-methylimidazole is more expensive, TEA was selected as the optimal base to cut the economic cost.

Table 3

Optimization of Reaction Conditions in Continuous Flowa

entry	base	equivb	residence time/(s)	temp/(°C)	yieldc/(%)
1	TEA	3.15	150	60	75
2	pyridine	3.15	150	60	64
3	DMAP	3.15	150	60	69
4	DIEA	3.15	150	60	52
5	imidazole	3.15	150	60	48
6	N-methylimidazole	3.15	150	60	76
7	TEA	3	150	60	70
8	TEA	3.3	150	60	84
9	TEA	3.5	150	60	81
10	TEA	3.3	300	60	82
11	TEA	3.3	50	60	84
12	TEA	3.3	30	60	85
13d	TEA	3.3	20	60	87
14d	TEA	3.3	20	65	88
15d	TEA	3.3	20	70	91
16d	TEA	3.3	20	75	87
17d	TEA	3.3	20	80	86
18e	N-methylimidazole	3.3	20	80	clogging
19e	N-methylimidazole	3.3	20	90	83

Reaction conditions: 1a (0.06 mol) and 2 (0.02 mol) in chloroform, 5.0 mL microreactor.

The equivalent of base refers to the molar ratio with phosphorus trichloride.

Isolated yield.

Attached to an 8 bar BPR at the end of the microreactor.

The solvent was toluene.

Next, the effect of the amount of TEA was investigated. Notably, the highest yield was obtained when the ratio of phosphorus trichloride and TEA was 1:3.3 (Table , entry 8). We also tried to increase the equivalents of TEA to 3.5 equiv, but the yield decreased to 81 from 84% (Table , entry 9). The reason is that the crude product was a little sticky under this condition, and then led to the desired product being lost in the process of recrystallization. Subsequently, we investigated the influence of residence time on the reaction yield (Table , entries 10–13). To our delight, satisfactory results were obtained with a short residence time when accelerating the flow rate under the same microreactor volume. Because the efficiency of mass transfer was improved significantly at the micromixer under the high flow rate.[32−35] The best yield of 87% was obtained when the residence time was reduced to 20 s at 60 °C (Table , entry 13). Moreover, different reaction temperatures were also screened (Table , entries 14–17). The results showed that 70 °C was the most suitable reaction temperature (Table , entry 15). It should be noted that a back pressure regulator (BPR) was used to suppress gasification when the reaction temperature was above the boiling point of the solvent. Encouraged by the positive preliminary results in the batch process, we investigated reaction temperatures of 75 and 80 °C, respectively. In contrast to the previous results, the yields were lower than 91% (Table , entries 16 and 17 compared to entry 15). Considering that toluene is the commonly use solvent in the industry, we chose N-methylimidazole as the base to avoid clogging in the microreactor based on the BASF’s method.[36,37] Owing to the melting point of the ionic liquid N-methylimidazolium chloride being 75 °C, the reaction was carried out at 80 °C (Table , entry 18). However, the microreactor was clogged because the ionic liquid formed during the process was an adhesive colloid at 80 °C. To avoid the microreactor clogging, the reaction temperature was increased to 90 °C. Surprisingly, the reaction proceeded smoothly under this condition in continuous flow. Nevertheless, the corresponding product was obtained in 83% yield (Table , entry 19), which is lower than the best results given by using TEA. Because of the excellent solubility of ionic liquids, small amount of the product was lost during the separation of ionic liquid from the reaction mixture. Besides, N-methylimidazole is more expensive and harder to recycle than TEA. Thus, it was decided to use TEA as the base, chloroform as the solvent, and the ratio of 2,4-di-tert-butylphenol 1a, phosphorus trichloride 2, and TEA was 3:1:3.3 as the optimal conditions in further studies.

With the optimized reaction conditions in hand, we probed the applicability of this method with regard to a series of diversely substituted phenols. As shown in Table , phenols bearing a variety of substituent groups, including electron-donating groups (Me, MeO, t-butyl, t-pentyl) and electron-withdrawing groups (F, Cl, Br, I, Ph), provided the desired triphenyl phosphates in good to excellent yields in continuous flow. Generally, the electron-donating group-substituted phenols (Table , 3a, 3c–3j) furnished the corresponding products in higher yields than those electron-withdrawing-substituted phenols (Table , 3k–3s, 3w) with the exception of p-methoxyphenol (Table , 3t). Moreover, the alkyl-substituted phenols exhibited higher reactivity than those phenols containing halogen substituents with the exception of 2,4-dichlorophenol (Table , 3n). In addition, most of the para-substituted phenols gave higher yields of the desired products by comparing with the ortho-substituted phenols (Table , compare 3c to 3e, 3g to 3h, 3o to 3p, 3q to 3r). The reason for this phenomenon is probably the steric hindrance of the ortho-substituted groups limiting the nucleophilic ability of the phenolic hydroxyl group. Furthermore, 2-phenylpropan and benzyl-substituted derivatives also produced the corresponding products in satisfactory yields (Table , 3x and 3y).

Table 4

Substrate Scope of Triphenyl Phosphitea

Reaction conditions: 1 (0.06 mol), 2 (0.02 mol), and TEA (0.066 mol) in chloroform, 5.0 mL microreactor, at 70 °C for 20 s.

As a further demonstration of the synthetic expediency of this flow method, a pilot-scale equipment was designed and assembled (Figure ). The preparation of tris(2,4-di-tert-butylphenyl) phosphite was conducted using the optimized reaction conditions. The reactants were conveyed using diaphragm pumps combined with flow meters. BPR (2.0 bar) was used to decrease the pulse of the pump to maintain smooth fluid delivery. The inner diameter of the reaction coil was increased from 0.8 to 4.4 mm. As a result, the reactor volume was increased from 5.0 to 300.0 mL. A cooling coil (ID = 4.4 mm, inner volume 50.0 mL) was attached to the end of the reactor to avoid the gasification of chloroform when the reaction mixture flows out of the system. Additionally, another BPR (6.0 bar) was attached at the end of the flow system to avoid any gasification during the reaction process. Remarkably, the purified tris(2,4-di-tert-butylphenyl) phosphite was obtained in 88% yield in this pilot apparatus with a 20 s residence time. The purified product could be prepared at a rate of up to 18.4 kg/h.

Figure 1

Scale-up synthesis of tris(2,4-di-tert-butylphenyl) phosphite.

Conclusions

In summary, we have developed an efficient method for the preparation of triphenyl phosphite and its derivatives in continuous flow. Because of the enhanced mass and heat transfer in the microreactor, this method provides many advantages such as simplified operation, the use of a theoretical dosage of PCl3, and short reaction time. A wide range of products were obtained in good to excellent yields by employing reactants in a stoichiometric ratio, using TEA as the base and by conducting the reaction in chloroform at 70 °C over 20 s. This method allows for the preparation of triphenyl phosphite with a lower operating cost and enhances process safety for easy scale-up in the industry.

Experimental Section

All reagents and solvents were commercially available and used without any further purification. Unless otherwise noted, all reactions were run under air and the indicated reaction temperature was that of the water or oil bath. Purification of reaction products was carried out by recrystallization with isopropyl alcohol or flash chromatography using 100–200 mesh silica gel. 1H and 13C NMR spectra were recorded on a Bruker Ascend instrument at 400 and 101 MHz respectively. Chemical shifts were reported in δ ppm referenced to an internal TMS standard for 1H NMR, CDCl3 (δ 77.00) for 13C NMR. The following abbreviations were used to explain multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, hept = heptaplet, m = multiplet, and br = broad. High-resolution mass spectra were obtained on an Agilent mass spectrometer using ESI-TOF (electrospray ionization-time of flight). Melting points were determined with a WRS-2 apparatus and were uncorrected.

Optimization Studies for Tris(2,4-di-tert-butylphenyl) Phosphite in the Batch Process

To a 250 mL 3-necked flask equipped with a condenser and a magnetic stir bar, 2,4-di-tert-butylphenol (0.06 mol, 3 equiv), the base, and the solvent (100.0 mL) were sequentially added. Phosphorus trichloride (0.02 mol, 1 equiv) and the solvent (5.0 mL) were charged in the dropping funnel. The 3-necked flask was submerged into a preheated water bath at 40 °C. The mixture in a dropping funnel was added to the 3-necked flask dropwise over 40 min, and then maintained at a temperature of 40 °C for 1 h. Next, the reaction system was heated to the desired temperature and maintained at this temperature over 3 h. The mixture was cooled down to room temperature after the reaction was complete. The reaction mixture was sequentially washed with water (10.0 mL) and 1 mol/L NaOH aq. (10.0 mL) twice, and the solvent was removed by distillation. The crude product was recrystallized with isopropyl alcohol, then the desired product tris(2,4-di-tert-butylphenyl) phosphite was obtained as a white crystalline solid. The melting points of the obtained products were in the range of 182.0–185.0 °C.

General Procedure for the Synthesis of Triphenyl Phosphites in Continuous Flow

The reactants were introduced into a PTFE capillary (ID = 0.8 mm) with an inner volume of 5.0 mL via a syringe pump. 2,4-Di-tert-butylphenol (0.06 mol, 3.0 equiv) and the base (0.066 mol, 3.3 equiv) were dissolved in the solvent and diluted to 50.0 mL and then loaded in one syringe; phosphorus trichloride (0.02 mol, 1.0 equiv) was dissolved in diluted to 50.0 mL and then loaded in another syringe. Those two fluids were mixed in a PTFE T-mixer (ID = 0.8 mm) before entering into the microreactor. The microreactor was coiled and put into a water bath, and an 8.0 bar BPR was used to avoid gasification when the reaction temperature was above the boiling point of the solvent. The injection rate of each syringe pump was 7.5 mL/min, so the flow rate in the microreactor was 15.0 mL/min. The reaction mixture (80.0 mL) was collected in a round bottom flask. The reaction mixture was sequentially washed with water (10.0 mL) and 1 mol/L NaOH aq. (10.0 mL) twice, and the solvent was removed by distillation. When the desired product was solid, the crude product was recrystallized with isopropyl alcohol to obtain the purified product. When the desired product was liquid, purification of reaction products was carried out by column chromatography using 100–200 mesh silica gel. The purities of the obtained products were higher than 98.5% according to the analysis of the HPLC results.

Scale-up Synthesis of Tris(2,4-di-tert-butylphenyl) Phosphite in Continuous Flow

The reactants were introduced into a PTFE tube (ID = 4.4 mm) with an inner volume of 300.0 mL via diaphragm pumps. 2,4-Di-tert-butylphenol (3.6 mol, 3.0 equiv) and Et3N (3.96 mol, 3.3 equiv) were combined, then they were dissolved in chloroform and diluted to 3000 mL. Then, the solution was loaded in one tank. Phosphorus trichloride (1.2 mol, 1.0 equiv) was dissolved in chloroform and diluted to 3000 mL. The solution was loaded in another tank. The two fluids were mixed in a PTFE T-mixer (ID = 4.4 mm) before entering into the flow tube reactor. The flow tube reactor was coiled and put into a water bath at 70 °C, and another PTFE tube (ID = 4.4 mm, 50 mL inner volume) was coiled and put into a water bath at 25 °C to cool the reaction mixture. The flow rate of each pump was 450 mL/min; hence, the flow rate in the microreactor was 900 mL/min. BPR (2.0 bar) after the pump was used to decrease the pulse of the pump to maintain smooth fluid delivery. Another BPR (6.0 bar) was attached at the end of the flow system to avoid any gasification during the reaction process. The reaction mixture (5000 mL) was collected in a round bottom flask. The reaction mixture was sequentially washed with water (600 mL) and 1 mol/L NaOH aq. (600 mL) twice, and the solvent was removed by distillation. The crude product was recrystallized with isopropyl alcohol to obtain the purified product in 88% yield. The melting point of the product was 183.2–184.5 °C.