Practical Approach for Quantitative Green Esterifications - ACS

Oct 3, 2016 - Practical Approach for Quantitative Green Esterifications. Lei Liu, Suliu ... Department of Chemistry, School of Science, Tianjin Univer...
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Practical Approach for Quantitative Green Esterifications Lei Liu, Suliu Feng, and Chunbao Li* Department of Chemistry, School of Science, Tianjin University, 135 Yaguan Road, Jinnan District, Tianjin 300354, People’s Republic of China S Supporting Information *

ABSTRACT: Subquantitative synthetic esterification reactions have been transformed into quantitative aqueous reactions. The esterification reactions involve carboxylic acids, alkyl halides or mesylate with granular polytetrafluoroethylene (PTFE), lithium carbonate, tetrabutyl ammonium bromide and were mediated solely by water. Various alkyl donors were employed including αhalo ketones, α-halo esters, α-halo amide, allyl bromide, benzyl chloride, alkyl iodides and alkyl mesylate. The scope of the carboxylic acids ranged from aromatic to aliphatic and from watersoluble to water-insoluble. Among the 58 reaction examples, 54 esterifications were quantitative and the other four had yields above 94%. Six of the reactions were scaled up to more than 10 g. In 30 examples and all the enlarged scale examples, no organic solvents were used at all and the products were collected simply by filtration. The yields for esterification reactions with secondary halides were quantitative compared to previous reported yields of only 65−89%. The promotion effect of the granular PTFE in combination with the modified mechanical stirrer is demonstrated based on a set of comparison experiments. Finally, the mechanism for these quantitative esterifications mediated by water is discussed in comparison with those mediated by organic solvents. KEYWORDS: Esterification, Green synthesis, Quantitative reaction, Aqueous reaction, Granular PTFE

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INTRODUCTION The first of the 12 principles of green chemistry states that it is better to prevent waste rather than to treat or clean up waste after it is formed.1 However, the desired products from organic synthetic reactions are often coproduced with various side products. This results in the need for subsequent purifications steps such as silica gel chromatography that both is laborious and consumes large amounts of organic solvents, and this subsequently adds to production costs and pollutes the environment. The necessity of dealing with the undesired side products further exacerbates the situation. For example, in China, the cost of disposing nonhazardous heavy-metal-free solid organic waste is $700−950/ton. In the pharmaceutical industry, the annual cost for organic solvents has been estimated to be four billion pounds.2 Two approaches to this problem are to optimize reactions to produce quantitative yields and to replace organic solvents with water. Although synthetic organic chemistry has made great progress by adopting new synthetic methods that employ new reagents or new reaction media including aqueous reactions,3 ionic-liquid-mediated reactions4 and mechano-reactions,5−8 the situations are that a small number of the reaction yields have been raised and many other reaction yields remain to be improved. A literature survey revealed that all esterification reactions between carboxylic acids and halides are performed in volatile organic solvents such as acetone, DMF and CH3CN. Even though new methods such as ionic-liquid-mediated reactions9 and metal-catalyzed reactions have been employed,10−12 © XXXX American Chemical Society

quantitative yields are rare and chromatography usually has to be employed to purify the products. For esterifications involving secondary halides, the reported yields are only 65− 89%.13−15 The classic esterification reactions such as the Mitsunobu reactions16 and Steglich reactions17−19 produce large amounts of wastes such as triphenylphosphine oxide and urea. We postulated that the reactions between carboxylic acids and halides could be accomplished in a greener way by using bases. Additionally, our group has been successful in using granular polytetrafluoroethylene (PTFE) to promote the reactions of water-insoluble high-melting-point organic compounds on water,20−23 so the granular PTFE might be helpful in realizing quantitative esterifications. Herein, quantitative green esterifications are reported. Among the 58 examples of esterifications using carboxylic acids and alkyl donors including α-halo carbonyl compounds, allyl bromide, benzyl chloride, alkyl iodides and alkyl mesylate, in the presence of granular PTFE, lithium carbonate and tetrabutyl ammonium bromide (TBAB) mediated by water, 54 esterifications were quantitative and the other four had yields above 94%.

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EXPERIMENTAL SECTION

General Information. All of the chemicals were obtained from commercial sources or prepared according to standard methods. NMR Received: July 22, 2016 Revised: September 7, 2016

A

DOI: 10.1021/acssuschemeng.6b01718 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX

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ACS Sustainable Chemistry & Engineering

Table 1. Optimization of the Esterification of αChloroacetophenone with Benzonic Acida

spectra were recorded with a 400 or 600 MHz spectrometer for 1H NMR and a 100 or 151 MHz instrument for 13C NMR using TMS as an internal standard. Chemical shifts (δ) are reported relative to TMS (1H) or CDCl3 (13C). Multiplicities are reported as follows: singlet (s), doublet (d), triplet (t), quartet (q) and multiplet (m). Melting points were recorded with a micro melting point apparatus. Infrared analyses (KBr pellet) were performed by FT-IR. High resolution mass spectra (HRMS) were recorded on a QTOF mass analyzer with electrospray ionization (ESI). All the aqueous reactions were conducted in 100 mL flasks and agitated by a modified stirring rod (SI, S2, Pictures 1−4). The size of the granular PTFE was 70 pieces/g (SI, S3, Picture 5). General Procedure for the Esterifications of Halides or Mesylate Catalyzed by TBAB. Procedure A: A mixture of halide (500 mg), carboxylic acid (1.05 equiv), Li2CO3 (0.60 equiv), TBAB (0.05 equiv), H2O (5 mL) and granular PTFE (5 g) was mechanically stirred (400 rpm) at 60 or 70 °C. After thin-layer chromatography (TLC) indicated completion of the reaction, the suspended solids were filtered and washed with water (2 × 10 mL) to give a quantitative yield of the product without further purification. Procedure B: A mixture of halide (500 mg), carboxylic acid (1.05 equiv), Li2CO3 (0.60 equiv), TBAB (0.05 equiv), H2O (5 mL) and granular PTFE (5 g) was mechanically stirred (400 rpm) at 60 or 70 °C. After TLC indicated completion of the reaction, ethyl acetate (2 × 15 mL) was added to extract the crude product, which was washed with water (1 × 10 mL) and dried over Na2SO4. Concentration under reduced pressure gave a quantitative yield of the product. Procedure C: A mixture of halide or mesylate (500 mg, 1.05 equiv or 1.50 equiv), carboxylic acid (1.0 equiv), Li2CO3 (0.60 equiv), TBAB (0.05 equiv), H2O (5 mL) and granular PTFE (5 g) was mechanically stirred (400 rpm) at 60 or 70 °C. After TLC indicated completion of the reaction, ethyl acetate (2 × 15 mL) was added to extract the crude product, which was then washed with water (1 × 10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and any remaining starting material (halide) was removed by bulb-to-bulb distillation under reduced pressure at about 60 °C. Products 1a, 1c, 2a−2d, 2f−2h, 3a−3c, 4a−4b, 5a−5c, 6a−6h, 14a−14b and 15a were synthesized according to procedure A. Products 1b and 2e were synthesized according procedure B. Products 7a−7b, 10a−10f, 11a−11f and 12a−12d were synthesized according to procedure C. Typical 500 mg-Scale Esterificaiton Procedure Catalyzed by Aliquat 336 Using the Esterification of N-Benzyl-2-chloroacetamide and Benzoic Acid as an Example. A mixture of N-benzyl2-chloroacetamide (500 mg), benzoic acid (1.05 equiv), Li2CO3 (0.60 equiv), Aliquat 336 (0.05 equiv), H2O (5 mL) and granular PTFE (5 g) was mechanically stirred (400 rpm) at 60 °C. After TLC indicated completion of the reaction, the suspended solids were filtered and washed with water (2 × 10 mL). Then the solid was recrystallized to give the pure product 8a (699 mg, 95% yield). Typical 10 g-Scale Esterification Procedure Using the Esterification of α-Bromoacetophenone and Benzoic Acid as an Example. A mixture of α-bromoacetophenone (10 g), benzoic acid (1.05 equiv, 6.4 g), Li2CO3 (0.60 equiv, 2.23 g), TBAB (0.05 equiv, 810 mg), H2O (50 mL) and granular PTFE (5 g) was mechanically stirred (400 rpm) at 60 °C. After TLC indicated completion of the reaction, the suspended solids were filtered and washed with water (2 × 15 mL) to give a quantitative yield of the product phenacyl benzoate (12.1 g, >99%) without further purification.

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entry T (°C) 1 2 3 4 5 6 7 8 9 10 11 12 13

25 40 50 60 60 60 60 60 60 60 60 60 60

H2O (mL) 7 7 7 7 5 3 0 5 5 5 5 5 5

PTC (equiv)

t (h)

yieldb (%)

Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) Aliquat 336 (0.15) TBAB (0.15) SDS (0.15) TEBAC (0.15) TBAB (0.10) TBAB (0.05)

12 12 9 2 2 1.85 12 1.5 12 2.5 1.85 2.5 12

NRc 42 >86 >99 >99 >99 incompletion >99 NRc >99 >99 >99 NRc

Reaction conditions: α-chloroacetophenone (500 mg), benzoic acid (1.05 equiv), PTC, Li2CO3 (0.60 equiv), H2O, granular PTFE (5 g), mechanical stirring (400 rpm). bAll yields were isolated yields. cNR: No reaction. a

At 60 °C, the reaction was slightly faster using 3 mL of water (Table 1, entry 6) instead of 7 or 5 mL of water (Table 1, entries 4 and 5). It was noted that with 3 mL of water more products tended to stick to the flask than with 5 or 7 mL of water. When no water was used, the reaction was incomplete (Table 1, entry 7); this is because the reaction mixture stuck on the flask walls, preventing smooth stirring. It is postulated that the water serves as both lubricant and the reaction medium, which is probably needed in the forming micelles between the substrates and reagents. Therefore, the conditions at 60 °C using 5 mL of water were chosen. Because Aliquat 336 is a lipophilic compound, which contaminates the product, watersoluble PTCs such as tetrabutyl ammonium bromide (TBAB), sodium dodecyl sulfate (SDS) and benzyl triethylammonium chloride (TEBAC) were also investigated (Table 1, entries 8− 10). The reaction catalyzed by 0.15 equiv of TBAB produced the ester quantitatively in 1.5 h (Table 1, entry 8). Reducing the amount of TBAB increased the reaction time from 1.5 to 2.5 h (Table 1, entries 8, 11 and 12). Anion surfactant SDS did not catalyze the reaction at all (Table 1, entry 9). The esterification did not take place without a PTC (Table 1, entry 13). Therefore, the optimized conditions are α-chloroacetophenone (1.0 equiv), benzoic acid (1.05 equiv), Li2CO3 (0.60 equiv), TBAB (0.05 equiv) and granular PTFE (5 g) at 60 °C with mechanical agitation at 400 rpm. Under the optimized conditions, esters 1a−c (Scheme 1) were produced using α-chloroacetophenone and three carboxylic acids. Esters 1a−c and 2a−h (Scheme 1) were synthesized from α-bromoacetophenone and 11 carboxylic acids. It is clear that the reactions starting from αbromoacetophenone were faster than that starting from αchloroacetophenone. For both α-halo ketones, the more lipophilic the carboxylic acids, the faster the reaction rates (Scheme 1, 1c vs 1b in the case of α-chloroacetophenone, and 1b, 2c, 2f vs 1c, 2a, 2d, 2h in the case of αbromoacetophenone). The reaction scope was broad, ranging from water miscible carboxylic acids (solubility: >106 mg/L for

RESULTS AND DISCUSSION

The esterification reactions were first investigated using benzoic acid and α-chloroacetophenone as the alkyl donor in the presence of phase transfer catalyst (PTC), Li2CO3, granular PTFE and water. The reaction did not occur when methyl trioctyl ammonium chloride (Aliquat 336) (0.15 equiv) was used as the PTC at rt (Table 1, entry 1). At 40 °C, the reaction yield was 42% and when the temperature was further raised to 60 °C the yield became quantitative (Table 1, entries 2 and 4). B

DOI: 10.1021/acssuschemeng.6b01718 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX

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ACS Sustainable Chemistry & Engineering Scheme 1. Esterifications between Primary α-Halo Ketones and Carboxylic Acidsa

Reaction conditions: α-halo ketones (500 mg), carboxylic acid (1.05 equiv), H20 (5 mL), Li2C03 (0.60 equiv), TBAB (0.05 equiv), granular PTFE (5 g), mechanical stirring (400 rpm) at 60 °C. A: Solubility for carboxylic acid. B: Solubility for the lithium carboxylate.

a

acids have higher nucleophilicity. The faster rates for the more lipophilic carboxylic acids is due to the higher concentration of these acids such as stearic acid and ursolic acid in the organic phase containing the α-haloacetophenones than in aqueous

acrylic acid and acetic acid) to water-insoluble ones (solubility: 1.88 × 10−3 mg/L for ursolic acid) and the lower the acidity of the carboxylic acids, the higher the reaction rates (Scheme 1, 1c, 2d, 2h vs 1a, 1b, 2a−2c). This is because weak carboxylic C

DOI: 10.1021/acssuschemeng.6b01718 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX

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ACS Sustainable Chemistry & Engineering Scheme 2. Esterifications between Secondary α-Halo Ketones and Carboxylic Acidsa

Reaction conditions: secondary α-ohalo ketones (500 mg), carboxylic acid (1.05 equiv), H20 (5 mL), Li2C03 (0.60 equiv), TBAB (0.05 equiv), granular PTFE (5 g), mechanical stirring (400 rpm) at 60 °C.

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phase. For two modified α-chloro- and α-bromoacetophenones (3, 4), the esterification rates were roughly the same. As the esterification reaction proceeded, the reaction mixture phase on water changed from solid via semisolid/syrup to solid (the final products esters). Simple filtrations yielded pure products quantitatively. Except the synthesis of 1b and 2e, where the products were syrup and extractions were needed to collect the products, the synthesis of other products did not consume any organic solvents in the entire process. In the literature, although some quantitative examples are known,24,25 in most cases the yields are subquantitative,15,26,27 and the products should be purified by additional steps such as chromatography. Often, large amounts of organic solvents such as ethyl acetate and petroleum ether had to be used to obtain pure products. Further application of the optimized conditions to reactions between various carboxylic acids and secondary α-halo ketones also resulted in the desired esters (Scheme 2). Similar to primary α-halo ketones in Scheme 1, the reactions were fast and quantitative, although the reaction rates were slightly lower than those with the primary α-halo ketones. The scope of the carboxylic acids was broad such as hydroxyl (Scheme 2, 5b, 6c and 6h), sulfonamide (Scheme 2, 5b and 6c), imido (Scheme 2,

6e), aldehyde carbonyl (Scheme 2, 6d), ketone carbonyl (Scheme 2, 6g), chloro (Scheme 2, 6f) and olefinic (Scheme 2, 5c, 6e and 6h) groups; these acids all tolerated the optimized conditions. This represents an advance in esterification reactions because previously no quantitative esterification reactions starting from secondary α-halo ketones and carboxylic acids have been reported in the literature. These reactions are quite important because many of the products are bioactive compounds or medicinal intermediates.28,29 The reactions between benzoic acid and tertiary α-bromo cyclohexyl phenyl ketone or phenyl iso-propyl ketone did not produce the desired esters. It suggests that the possible mechanism for the esterification is not SN1. The reaction is probably micelle-catalyzed. Although TBAB and TEBAC are rarely used for this purpose due to its hydrophilicity, a lipophilic salt formed via their ion exchanges with carboxylates can form micelles with halides. And in a few cases, the more lipophilic PTC Aliquat 336 has to be used to replace TBAB. For this reason, anion surfactant SDS could not catalyze the esterifications. The advantage of the micellecatalyzed aqueous esterification reactions is that the highly lipophilic halides, lipophilic tetrabutyl ammonium carboxylates/ carboxylic acids and product esters are all in the same phase. D

DOI: 10.1021/acssuschemeng.6b01718 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX

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ACS Sustainable Chemistry & Engineering Scheme 3. Esterifications between α-Halo Esters or Amide and Carboxylic Acids

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Reaction conditions: Ethyl bromoacetate (500 mg, 1.05 equiv), carboxylic acid (1.00 equiv), H2O (5 mL), Li2C03 (0.60 equiv), TBAB (0.05 equiv), granular PTFE (5 g), mechanical stirring (400 rmp) at 60 °C. bα-halo amide or steroidal ester (500 mg, 1.00 equiv), carboxylic acid (1.05 equiv), H20 (5 mL), Li2CO3 (0.60 equiv), Aliquat 336 (0.05 equiv), granular PTFE (5 g), mechanical stirring (400 rmp) at 60 °C.

all in quantitative yields. The carboxylic acids contain various functional groups such as hydroxyl (Scheme 4, 10b and 11c), sulfonamide (Scheme 4, 10b and 11c), imido (Scheme 4, 10c and 11e), aldehyde carbonyl (Scheme 4, 10e and 11d), ketone carbonyl (Scheme 4, 10d and 11b) and olefinic (Scheme 4, 10a, 10c, 11a and 11e) groups. The fact that the reaction times were substantially longer than those esterifications starting from α-halo carbonyl compounds (Scheme 4 vs Schemes 1 and 2) can be explained by the efficient association of Li+ with both halogen atom and oxygen atom in the latter, which activates the halides and facilitates the substations by carboxylates. In the fourth stage of the research, alkyl iodides and alkyl mesylate were investigated as alkyl donors (Scheme 5). Again, the reactions were quantitative with fast reaction rates, and in fact the rates were slightly faster than those starting from allyl bromide and benzyl chloride. A selective esterification of pseudo-diosgenin-derived diiodide 15 was obtained with a yield >99% (Scheme 5, 15a). All these facts indicate that these aqueous esterifications proceed via an SN2 pathway. In the fifth stage of the research, six quantitative esterifications were achieved at more than 10 g scales (Scheme 6). This demonstrates that these reactions are easily scalable for potential industrial applications. In the sixth stage of the research, product 1a was transformed into two heterocyclic compounds in high yields (Scheme 7). Heterocyclic products imidazole and oxazole are privileged structures in medicinal chemistry.34 Finally, the promotion effect of the granular PTFE on the esterification reactions was demonstrated in a set of comparison experiments shown in Table 2. 300, 1000 and 5000 mg of 1

Consequently, because of the high concentration of the substrates the reaction rates are fast. Strong polar nucleophiles such as OH− are mainly distributed in water. Even small amounts of OH− might enter into the lipophilic phase, they are neutralized by the carboxylic acids. Therefore, ester hydrolysis was successfully avoided in this procedure. In contrast, in organic solvent-mediated reactions the concentrations of both the carboxylates and halides are normally lower, therefore, large amounts of organic solvents are required to dissolve both of them. In these cases, high temperatures and excess bases are required to achieve reasonable reaction rates. These harsh conditions could cause side reactions such as HX elimination and the Claisen condensation. The consequence is lower esterification yields and longer reaction times. The recorded reaction times are 3−20 h, with organic solvent media to substrate ratios 5−10 mL/g (not including the solvents used in the workups and chromatography).30−33 In the second stage of the research, the substrates were extended from α-halo ketones to α-halo esters and amide and the results are shown in Scheme 3. For ethyl bromoacetate (7), the esterification proceeded quantitatively with the watersoluble TBAB. For amide 8 and steroidal ester 9, Aliquat 336 had to be used in place of TBAB. Although the conversions were 100% and the yields were close to quantitative, the esters had to be crystallized to get rid of the lipophilic Aliquat 336. And it was this purification process which resulted in a slight loss of product giving the lower yields. In the third stage of the research, allyl bromide and benzyl chloride were investigated in place of α-halo carbonyl compounds (Scheme 4). Altogether 11 esters were synthesized, E

DOI: 10.1021/acssuschemeng.6b01718 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX

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ACS Sustainable Chemistry & Engineering Scheme 4. Esterifications between Allyl Bromide or Benzyl Chloride and Carboxylic Acidsa

a

Reaction conditions: allyl bromide, benzyl chloride (500 mg, 1.5 equiv), carboxylic acid (1.0 equiv), H2O (5 mL), Li2CO3 (0.60 equiv), TBAB (0.05 equiv), granular PTFE (5 g), mechanical stirring (400 rpm) at 70 °C.

recyclable. It was prepared by cutting PTFE plates into small granules. We have previously used it as a stirring agent in many aqueous reactions of water-insoluble high melting-point compounds.20−23 The modified stirring rod was made by fastening six PTFE blades on to an ordinary stirring rod with PTFE wire. The blades are 3.8−4.2 cm in length with 2 holes on one side (r = 0.15 and 1.0 cm) (see SI, S2, Pictures 1−4). The stirring rod fits into the bigger holes and PTFE wires were fed through the smaller holes and secured to the stirring rod. This modified stirring rod overcomes the problem of some of the reaction mixture adhering on the upper part of the flask wall where the ordinary stirring rod could not reach. Our method has several advantages over the current solventfree methods such as the ball-milling technique.37,38 The first one is that our method is more energy-efficient. In the ballmilling methods, four types of equipment are now available, SPEX mixer mill, planetary ball mill, attritor and rolling ball mill. The attritor is inefficient because only a small amount of the substrate powder lies in the place where efficient mixing occurs, and the rest three types of ball mills need energy to power the high-speed rotation of the substrates, the milling balls and the chamber.39 The combined mass of substrate, milling balls and chamber is much larger than the one of substrate and granular PTFE in our method. In our method, the substrate/PTFE weight ratio is 2/1 (Scheme 6), whereas the substrate/milling ball weight ratio is in a range of 1/3−130 in the ball-milling method,40−52 leading to 6−260 times of mass differences. In addition, the chamber needs to be strong to hold the milling balls, which is often heavy. In the literature, larger

with 1.05 equiv of benzoic acid in the presence of 5 g of the granular PTFE resulted in quantitative yields in 2.5, 1.5 and 0.67 h, respectively (Table 2, entries 1−3). Similar results were found with other amount variations of 1, 2, 5 and 6 (Table 2, entries 4−13). In contrast, using only 1 g of the granular PTFE resulted in incomplete esterifications (62% for 300 mg of 1, 82% for 1000 mg of 1 and 92% for 5000 mg of 1) (Table 2, entries 1−3). For a given amount of 1, larger amounts of the granular PTFE resulted in faster reactions rates. However, for a fixed amount of the granular PTFE (1 or 5 g), larger amounts of 1 resulted in faster reaction rates. The reason for this may be the configuration of the 100 mL round-bottom flask and the modified mechanical stirring rod (SI, S2, Picture 4). The momentum of granular PTFE is higher in the middle of the flask with 5 or 10 g of 1 than at the bottom of the flask with 1 or 3 g of 1. This indicates the high industrial potentials for this method as the granular PTFE amount can be reduced for largescale preparations by raising the agitation efficiency. Throughout the entire process, the reaction mixtures were heterogeneous. Therefore, mechanically agitated granular PTFE can efficiently disperse the solid or semisolid reaction mixtures because it acts as hundreds of moving stirrers. Without granular PTFE, the reactions were either sluggish or incomplete (Table 2, entries 1−3), this is because both the starting materials and products are water insoluble and the starting materials become included in the solid or semisolid reaction mixtures. PTFE has many unique properties including no selfcoagulation, no electrostatic effect, a low friction coefficient, and tolerances to acids, bases, reducing and oxidizing reagents.35,36 It is also inexpensive, wearable and highly F

DOI: 10.1021/acssuschemeng.6b01718 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX

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ACS Sustainable Chemistry & Engineering Scheme 5. Esterifications between Alkyl Iodides or Mesylate and Carboxylic Acids

a

Reaction conditions: alkyl mesylate or alkyl iodides (500 mg, 1.05 equiv), carboxylic acid (1.0 equiv), Li2C03 (0.60 equiv), TBAB (0.05 equiv), H20 (5 mL), granular PTFE (5 g), mechanical stirring (400 rpm) at 70 °C. bpseudo-diosgenin-derived diiodide (500 mg, 1.0 equiv), carboxylic acids (1.05 equiv), Li2C03 (0.60 equiv), H20 (5 mL), qranular PTFE (5 q), mechanical stirrinq (400 rmp) at 70 °C.

Scheme 6. Esterifications at more than 10 g Scales

Scheme 7. Synthesis of Substituted Oxazole and Imidazole from α-Carbonyl Ester 1a

where the reaction mixture is thick syrup at rt or at elevated temperatures. Around 35 pieces of granular PTFE are added to per gram of substrate, which convert the syrup reaction mixture to a semisolid (Scheme 6) under mechanical agitation. It is then easier to disperse the semisolid because it contains a large number of granular PTFE pieces. This cannot be achieved using the ball-milling method because the weight of a single milling ball is large so as to gain high momentum to realize substrate “refinement”37,38 and its number is limited. The third advantage of our method is the equipment is simple and inexpensive. In contrast, the ball mill needs a shield to reduce the blare from the chamber. The fourth advantage of our method is that granular PTFE is more resistant to corrosion than the milling balls.

power ball mills were used for reactions (substrate amount/ball mill power: 0.10 g/100 W;40 0.11 g/150 W;41 0.25 g/100 W;42 0.26 g/100 W;43 0.45 g/150 W;44 0.50 g/370 W;45 3.5 g/1250 W;46 4.0 g/940 W;47 5.0 g/245 W;48 5.5 g/370 W;49 6.2 g/ 1250W;50 7.0 g/1250W;51 31 g/1250 W52). In our methods, an agitator (100 W) was enough for a reaction in more than 10 g scale. The second advantage of our method is for the reactions G

DOI: 10.1021/acssuschemeng.6b01718 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX

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Table 2. Effects of the Granular PTFE on the Reaction Ratesa

Research Article

AUTHOR INFORMATION

Corresponding Author

*Chunbao Li. E-mail: [email protected]. Fax: +862227403475. Author Contributions

entry 1 2 3 4 5 6 7 8 9 10 11 12 13

ester (mg) d

1a (779) 1a (1560) 1a (7778) 1a(601)d 1a (12100)f 2f (1013)d 2f (10100)f 2h (1445)d 2h (11600)f 5b (1241)e 5b (12400)f 6c (952)e 6c (11400)f

time yield of ester granular PTFE (5000 mg)b

time yield of ester granular PTFE (1000 mg)c

time yield of ester granular PTFE (0 mg)c

2.5 h, >99% 1.5 h, >99% 0.67 h, >99% 1.2 h, >99% 0.5 h, >99% 1.8 h, >99% 0.85 h, >99% 1.0 h, >99% 0.67 h, >99% 2.5 h, >99% 1.5 h, >99% 1.5 h, >99% 1.2 h, >99%

2.5 h, 62% 1.5 h, 82% 0.67 h, 92%

2.5 h, 39% 1.5 h, 46% 0.67 h, 65%

Lei Liu and Suliu Feng contributed equally to this work. Notes

The authors declare no competing financial interest.

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a

Reaction conditions: halide, carboxylic acid (1.05 equiv), TBAB (0.05 equiv), Li2CO3 (0.60 equiv), H2O, granular PTFE, mechanical stirring (400 rpm). bIsolated yields. cDetermined by 1H NMR. dScheme 1. e Scheme 2. fScheme 6.

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CONCLUSIONS In summary, we have demonstrated that a combination of granular PTFE, PTC, lithium carbonate and alkyl halides or mesylate mediated by water and agitated by a modified stirring rod can produce esters in an unparalleled green way. In 54 cases, quantitative yields were obtained and in four cases the yields were above 94%. In 30 examples and all the enlarged scale examples, no organic solvents were used in performing the reactions or in collecting the products. Notably, the esterifications of secondary α-halo ketones were quantitative, which is a great improvement over previously reported yields (65−89%). Because lithium carbonate is a very weak base, most common organic functional groups could tolerate the reaction conditions. A set of control experiments demonstrated the promoting effect of granular PTFE. The granular PTFE/ substrate ratio has been reduced without lowering the reaction rates in large-scale preparations. Altogether, six esterifications were performed at more than 10 g scales. It is postulated that this methodology could substantially raise the greenness and profitability of some industrial esterification processes.

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REFERENCES

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acssuschemeng.6b01718. Pictures for the modified stirring rod and the granular PTFE; general information; General procedures for the esterification reactions; procedures for the syntheses of 2,4-diphenyl-1H-imidazole (16) and 2,4-diphenyl-oxazole (17); analytic data of the products; 1H NMR and 13 C NMR spectra for all compounds; references for known compounds (PDF) H

DOI: 10.1021/acssuschemeng.6b01718 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX

Research Article

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DOI: 10.1021/acssuschemeng.6b01718 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX