Article pubs.acs.org/joc
Cite This: J. Org. Chem. 2019, 84, 851−859
Microdroplets as Microreactors for Fast Synthesis of Ketoximes and Amides Wenwen Zhang,† Shiwei Yang,† Qiuyu Lin,† Heyong Cheng,*,†,§ and Jinhua Liu*,‡,§ †
College of Material Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 311121, China Qianjiang College, Hangzhou Normal University, Hangzhou 310036, China § Key Laboratory of Organosilicon Chemistry and Material Technology, Hangzhou Normal University, Hangzhou 311121, China ‡
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ABSTRACT: The formation of amide bonds is one of the most valuable transformations in organic synthesis. Beckmann rearrangement is a well-known method for producing secondary amides from ketoximes. This study demonstrates the rapid synthesis of ketoximes and amides in microdroplets. Many factors are found to affect the yield, such as microdroplet generation devices, temperature, catalysts, and concentrations of reactants. In particular, the temperature has a great influence on the synthesis of amide, which is demonstrated by a sharp ascendance to the yield when the temperature was increased to 45 °C. The best amide yield (93.3%) can be obtained by using coaxial flowing devices, a sulfonyl chloride compound as a catalyst, and heating to 55 °C in microdroplets. The yields can reach 78.7− 91.3% for benzoylaniline and 87.2−93.4% for benzophenone oximes in several seconds in microdroplets compared to 10.1−66.1% and 82.5−93.3% in several hours in the bulk phase. Apart from the dramatically decreased reaction time and enhanced reaction yields, the microdroplet synthesis is also free of severe reaction environments (anhydrous and anaerobic conditions). In addition, the synthesis in microdroplets also saves reactants and solvents and reduces the waste amounts. All of these merits indicate that the microdroplet synthesis is a high-efficiency green methodology.
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INTRODUCTION Due to the widespread presence of amides in drugs, natural products, and biologically active compounds, amide synthesis is one of the most valuable transformations in organic chemistry.1 The most common methods for producing amides need the activation of carboxylic derivatives, such as acyl chlorides, anhydrides, and esters. Alternatively, carboxylic acid is reacted directly with amine, assisted by a coupling agent of stoichiometric amount, such as a carbodiimide or a 1Hbenzotriazole derivative.2,3 However, these classical methods have low atomic efficiency, leading to environmental pollution. Therefore, the Pharmaceutical Roundtable identified “amide formation adopting high atom economy reactants” as one of the most challenging tasks in organic chemistry.4 New effective and sustainable methods to synthesize important compounds are desirable.5 In the search for more efficient, atomic, and economical methods, the appearance of metal catalytic conversions in recent years provides a new synthetic route and expands the previous synthetic substrates.6 With the aid of transition metals, many functional groups, such as nitriles, aldehydes, ketones, oximes, primary alcohols, and amines, can be conveniently used as starting materials for the construction of amide bonds. The use of oximes as starting materials to obtain amides by rearrangement has a long history, the so© 2018 American Chemical Society
called Beckmann rearrangement reaction. The reaction was first discovered by the German chemist Beckmann in 1886.7,8 For example, ε-caprolactam which is a precursor to produce nylon-6, is synthesized by the Beckmann rearrangement of cyclohexanone oxime.9 The Beckmann rearrangement of oximes involves the translocation of a group which is located in the trans position of hydroxy groups from the carbon to nitrogen atom. This process usually requires a Brønsted or Lewis acid as a catalyst and is completed under severe temperature conditions.10,11 In the last five decades, chemists have been working on the screening of this catalytic reaction system. Diverse catalytic systems have been developed, including liquid phase systems,12 vapor phase systems,13 supercritical water systems,14 ionic liquid systems,15 etc. The advantages of mild conditions, ease of postprocessing, and industrial applicability have stimulated many researchers to learn about liquid phase catalysis of the Beckmann rearrangement. They have developed a lot of catalysts, such as inorganic and organic catalysts, and metal Lewis acids ([RhCl(cod)] 2, 16 Y(OTf)3, 17 Ga(OTf)3 ,18 FeCl3,19 AlCl3,20 and HgCl221). However, these methods suffered from several drawbacks, such as the use of toxic/costly Received: October 19, 2018 Published: December 24, 2018 851
DOI: 10.1021/acs.joc.8b02669 J. Org. Chem. 2019, 84, 851−859
Article
The Journal of Organic Chemistry
Figure 1. (A) Synthetic ketoximes in microdroplets with the online mixing device. (B) Synthetic amides in microdroplets with the coaxial flowing device.
tion when hydroxylamine hydrochloride and sodium hydroxide were mixed, which led to tip clogging of capillaries of small internal diameters. Thereafter hydroxylamine was selected as a reactant (Scheme 1). From Figure 2a, it can be seen that a
solvents, cocatalysts, expensive reagents, production of a considerable amount of byproducts, low yields, and long reaction time. In the Beckmann rearrangement reaction, organic sulfonyl chlorides are widely used reagents for stoichiometric dehydrogenation. p-Toluenesulfonyl chloride (TsCl) can efficiently catalyze the conversion of various oximes to corresponding amides under mild conditions with excellent yields.22 The mechanism of this catalyst has been proposed by a new autonomous cycle, where TsCl initiates the Beckmann rearrangement by producing an azayne cation intermediate.23 Scientists also explored the use of ZnCl2 as a cocatalyst, where the amide yield was improved.24 Generally, the rearrangement reaction catalyzed by TsCl needs to be carried out under severe conditions, including anhydrous, anaerobic, and at a certain high temperature for several hours. Many researches have demonstrated that microdroplet reactions can be accelerated by orders of magnitude in comparison with bulk reactions.25,26 Although the study of ultrafast reactions in microdroplets is in the early stage, it is worth noting, that important applications have emerged.27−29 The synthesis of large quantities of isoquinoline using the Pomeranz−Fritsch reaction is taken as a typical example. It takes a long time (a few days) and requires a very high concentration of acid in bulk solution.30 The same reaction occurring in microdroplets from an electrospray ionization source, however, can be completed in milliseconds with no need of any external acid.31 Green chemistry has increasingly attracted the interest of chemical workers in recent years.32,33 Scientists are looking for a gentle, efficient, and green method for the synthesis of ketoximes and amides. In this article, we explored synthesized ketoximes and amides with different substituents in microdroplets (which were produced by homemade sheath-gas-assisted spray emitters without applying any high voltage in Figure 1). The products in microdroplets were collected and then analyzed by high-performance liquid chromatography (HPLC) for yields. Microdroplet synthesis accelerates the reaction and meets the expectations of green chemistry.
Scheme 1. Synthesis of Ketoximes from Ketones in Microdroplets
good yield of benzophenone oxime is obtained with 5−10 mol L−1 NH2OH, indicating a selection of 5 mol L−1 NH2OH for the following experiment. The reaction mechanism of ketones to form oximes is the nucleophilic addition. Briefly, the lone electron pair on the nitrogen of hydroxylamine attacks the carbonyl to make the formation of a hydroxyl group between the hydrogen hydroxylamine and the carbonyl oxygen. The −CHNOH group is then generated by the carbon dehydroxylation and nitrogen dehydrogenation under the alkaline conditions. From Figures 2b, S1, and S2, we can see at low temperatures (25−45 °C), that the yield of benzophenone oxime increases gradually when the sodium hydroxide concentration increases from 1.0 to 2.0 mol L−1, but the yield is stable by using 2.0−3.0 mol L−1 NaOH. However, when the reaction temperature is higher than 45 °C, the yield decreases dramatically with the increase of the sodium hydroxide concentration. Sodium hydroxide of high concentrations is apt to crystallize at high temperatures in capillaries of small internal diameters to clog the capillary tip, leading to a failure in microdroplet generation. It is also observable from Figure 2b, that the yield of benzophenone oxime using low NaOH concentrations gradually increases upon increasing the temperature from 25 to 45 °C, but it is apparently reduced upon further increasing the temperature to 65 °C. When NaOH is of a high concentration (2.0−3.0 M NaOH), the yield is reversely drastically decreased with the temperature increase. Moderately increased temperature facilitates the solvent evaporation of microdroplets, leading to highly concentrated reactants to enhance the reaction rate
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RESULTS AND DISCUSSION Screening of Optimal Conditions for Ketoxime Synthesis. Hydroxylamine hydrochloride is commonly used in the preparation of oximes because hydroxylamine is stable under acidic conditions. In the preliminary experiment, we tried to use hydroxylamine hydrochloride as a reactant for synthesizing benzophenone oxime. We observed salt deposi852
DOI: 10.1021/acs.joc.8b02669 J. Org. Chem. 2019, 84, 851−859
Article
The Journal of Organic Chemistry
Figure 2. Production of benzophenone oxime in microdroplets using different NH2OH concentrations (a) and sodium hydroxide concentrations (b) at different temperatures.
Table 1. Synthesis of Various Ketoximes in Microdroplets and Bulk Solution
a
Synthesis of ketoxime in microdroplets. bSynthesis of ketoxime in bulk solution.
ketoxime is initiated with a hydroxylamine attack toward carbonyl, which can be reasonably promoted by more hydroxylamines (high concentrations in microdroplets). Similarly, the reaction ends with carbon dehydroxylation and nitrogen dehydrogenation, which can also be boosted under strong alkaline conditions (high NaOH concentrations in microdroplets).
(not rate constant) in microdroplets. However, the wet microdroplets may be converted into dry particles upon the evaporation of the solvents at high temperatures. A 2.5 mol L−1 NaOH was finally selected for the oxime synthesis at a temperature of 35 °C. In addition, a deep checking to Figure 2 demonstrates that the reactant concentrations had a more obvious influence on the conversion than the reaction temperature. As is well-known, the conversion of ketone to 853
DOI: 10.1021/acs.joc.8b02669 J. Org. Chem. 2019, 84, 851−859
Article
The Journal of Organic Chemistry
by catalysts for the setup a). The conversion ratios by using the two coaxial flow devices (85.1−88.7%) were significantly superior over those by the offline and/or online mixing device (Figure S3). The yield was slightly enhanced when the catalyst (TsCl) flowed in the inner capillary (the coaxial flowing device b) instead of the outer capillary (the coaxial flowing device a). Therefore, the coaxial flow device a was selected for microdroplet-based synthesis of amides. It is observable that the Beckmann rearrangement of ketoxime is highly relative to the reaction temperature (Figure 3a). Ketoximes are hardly converted into amides when the reaction temperature is below 25 °C. A sharp ascendance to the yield is observed when the temperature is ramped to 45 °C (Figure 3b). However, the yield is drastically reduced upon further increasing the temperature from 55 to 75 °C. It is wellknown, that TsCl is an initiator in this reaction.34 A comparison experiment was performed to ensure if the reaction was irradiatively initiated, where the reaction took place in microdroplets at room temperature with and without UV lighting. The experimental results demonstrated no apparent difference to the yields on both occasions. All of these results proved the thermally initiated conversion of oximes to amides. The reaction temperature was chosen at 55 °C considering the best yield. However, we observe that more ketoximes are converted into corresponding amides at a higher temperature for the bulk-phase reaction (Figure 3c). Such a different temperature effect on the Beckmann rearrangement from the microdroplet synthesis can be ascribed by rapid solvent evaporation of microdroplets. Solvent evaporation of microdroplets at moderately high temperatures increases reagent concentrations to promote the reaction (not rate constant). However, microdroplets may be transformed into dry particles to inhibit the liquid reaction owing to excessive evaporation at extremely high temperatures. In comparison with microdroplets, solvent evaporation of the bulk solution was very mild to maintain the liquid reaction in bulk phase. It was reported that the Beckmann rearrangement reaction can be catalyzed by acids (citric acid, trifluoroacetic acid, etc.), salts (anhydrous aluminum, FeCl3, etc.) and sulfonyl chlorides.19,20,22,35 Therefore, we explored the catalyzed actions of the above compounds for the synthesis of amides in microdroplets. It was observable that benzophenone oxime cannot be converted into the corresponding amide under the catalysis of citric acid, CF3COOH, and AlCl3, except sulfonyl chlorides, which was ascribed by harsh reaction conditions required by these catalysts (high temperature without solvents for citric acid, anhydrous environment for AlCl3, etc.). We then investigated several sulfonyl chlorides (2,4,6-trimethylbenze-
Under the optimal conditions, several aromatic oximes were synthesized in microdroplets by the online mixing device (Figure 1A) from their corresponding ketones. It is observable from Table 1 that the yields in microdroplets are comparable to those in bulk solution. However, the reaction in microdroplets can be completed within several seconds whereas the synthesis in bulk solution typically takes 1 h. Table 1 also demonstrates high yields around 90% for all tested benzophenones in microdroplets or bulk phase, no matter if activating or deactivating substituents are attached to the benzene ring because the carbonyl is the target group in the synthesis of benzophenone ketoximes. The crude oxime products after 6 h collection were purified by column chromatography for structure certification by NMR spectra (Figures S12−S19).
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SCREENING OF OPTIMAL CONDITIONS FOR AMIDE SYNTHESIS Following the synthesis of oximes in microdroplets, we further investigated the feasibility of the transformation of oximes to amides in microdroplets (Scheme 2). Benzophenone oxime Scheme 2. Catalytic Synthesis of Amides by Oximes
was taken as an example to explore the effects of different synthetic conditions on the Beckmann rearrangement. We preliminarily tested the reaction in microdroplets produced by the same device used in the synthesis of oximes (Figure 1A). Conversion ratios no more than 67.6% were obtained, no matter how the reaction temperature was optimized (Figure S3). We then tried to offline mix benzophenone ketoxime with TsCl ahead of the pneumatic spraying, which demonstrates a slightly improved yield (
