Microdroplets as Microreactors for Fast Synthesis of Ketoximes and Amides

Article abstract of DOI:10.1021/acs.joc.8b02669

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.

Full text of DOI:10.1021/acs.joc.8b02669

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Article
Microdroplets as microreactors for fast synthesis of ketoximes and amides
Wenwen Zhang, Shiwei Yang, Qiuyu Lin, Heyong Cheng, and Jinhua Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02669 • Publication Date (Web): 24 Dec 2018
Downloaded from http://pubs.acs.org on January 1, 2019
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Microdroplets as microreactors for fast synthesis of ketoximes and amides
Author names and affiliations:
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Wenwen Zhang , Shiwei Yang , Qiuyu Lin , Heyong Cheng a, c*, Jinhua Liu b, c*
a
a
a
a
College of Material Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 311121,
China
b
Qianjiang College, Hangzhou Normal University, Hangzhou 310036, China
c
Key Laboratory of Organosilicon Chemistry and Material Technology, Hangzhou Normal University, Hangzhou
311121, China
*
Corresponding author:
Tel: +86-571-28866903.
Fax: +86-571-28866903.
E-mail: hycheng@hznu.edu.cn (H.-Y. Cheng);
jinhua6903@163.com (J.-H. Liu)
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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, concentration 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 a coaxial flowing
devices and 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 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 these merits indicate the microdroplet
synthesis is a high-efficiency green methodology.
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Keywords: Amides; Oximes; Beckmann rearrangement; microdroplet synthesis; green chemistry
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Introduction
Due to the widespread presence of amides in drugs, natural products and biologically active compounds, amide
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synthesisis one of the most valuable transformations in organic chemistry . 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 1H-benzotriazole derivative2, 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 challengeable tasks in organic chemistry4.
New effective and sustainable methods to synthesize important compounds are desirable5.
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In the search for more efficient, atomic and economical methods, the appearance of metal catalytic conversions
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in recent years provides a new synthetic route and expands the previous synthetic substrates . 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-called Beckmann rearrangement
reaction. The reaction was first discovered by the German chemist Beckmann in 18867, 8. For example,
ε-caprolactam which is a precursor to produce nylon-6 is synthesized by Beckmann rearrangement of
cyclohexanone oxime9.
The Beckmann rearrangement of oximes involves the translocation of a group which locates in the trans
position of hydroxy groups from carbon to nitrogen atom. This process usually requires a Brønsted or Lewis acid
as a catalyst and is completed under severe temperature conditions10, 11. In the last five decades, chemists have
been working on the screening of this catalytic reaction system. Diverse catalytic systems have been developed
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including liquid phase systems , vapor phase systems ,supercritical water systems , ionic liquid systems , etc.
The advantages of mild conditions, ease of post-processing and industrial applicability have stimulated many
researchers to learn about liquid phase catalysis of Beckmann rearrangement. They have developed a lot of
catalysts such as inorganic and organic catalysts, and metal Lewis acids ([RhCl(cod)] 16，Y(OTf)317, Ga(OTf)318，
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FeCl319 ， AlCl320 ，and HgCl221). However, these methods suffered from several drawbacks such as use of
toxic/costly solvents, co-catalysts, expensive reagents, production of considerable amount of byproducts, low
yields and long reaction time.
In the Beckmann rearrangement reaction, organic sulfonyl chlorides are widely used reagents for stoichiometric
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dehydrogenation. p-Toluenesulfonyl chloride (TsCl) can efficiently catalyze the conversion of various oximes to
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corresponding amides under mild conditions with excellent yields . The mechanism of this catalyst has been
proposed by a new autonomous cycle, where TsCl initiates Beckmann rearrangement by producing an azayne
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cation intermediate . Scientists also explored the use of ZnCl as a co-catalyst where the amide yield was
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improved . Generally, the rearrangement reaction catalyzed by p-toluenesulfonyl chloride 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 reactions25,26. Although the study of ultra-fast reactions in microdroplets is in the early stage,
it is worth noting that important applications have emerged27-29. 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
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very high concentration of acid in bulk solution . The same reaction occurring in microdroplets from an
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electrospray ionization source, however, can be completed in milliseconds with no need of any external acid .
Green chemistry has increasingly attracted the interest of chemical workers in recent years32,33. Scientists are
looking for a gentle, efficient and green method for the synthesis of ketoximes and amides. In this paper, we
explored synthesize 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 for yields.
Microdroplet synthesis accelerates the reaction and meets the expectations of green chemistry.
Figure 1 (A) Synthetic ketoximes in microdroplets with the online mixing device; (B) Synthetic amides in microdroplets with the
coaxial flowing device
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Results and discussion
Screening of optimal conditions for ketoxime synthesis
Hydroxylamine hydrochloride is commonly used in the preparation of oximes (Scheme 1) 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 deposition when hydroxylamine hydrochloride
and sodium hydroxide were mixed, which led to tip clogging of capillaries of small internal diameters. Thereafter
hydroxylamine selected as a reactant. From Figure 2a, it can be seen that good yield of benzophenone oxime is
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obtained with 5-10 mol L NH OH, indicating a selection of 5 mol L NH OH for the following experiment.
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HO
O
N
NaOH
NH OH
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R2
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OM4: R , R = F OM5: R , R = Br OM6: R , R = OCH
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Scheme 1 Synthesis of ketoximes from ketones in microdroplets
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Figure 2 Production of benzophenone oxime in microdroplets using different NH OH concentrations (a) and sodium hydroxide
concentrations (b) at different temperatures
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 -CH=NOH group is then generated by the carbon
dehydroxylation and nitrogen dehydrogenation under the alkaline conditions. From Figure 2b and Figures S1 and
S2, we can see at low temperatures (25-45 °C), the yield of benzophenone oxime increases gradually when the
-
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sodium hydroxide concentration increases from 1.0 to 2.0 mol L , but the yield was stable by using 2.0-3.0 mol
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L 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 increased on increasing the temperature from 25 to 45 °C, but was apparently
reduced on further increasing the temperature to 65 °C. When NaOH of high concentrations (2.0-3.0 M NaOH),
the yield was 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 (not rate constant) in microdroplets. However, the wet microdroplets may be converted into dry
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particles upon the evaporation of the solvents at high temperatures. A 2.5 mol L 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 more obvious influence on the conversion than the reaction temperature. As is
well-known, the conversion of ketone to ketoxime initiates 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).
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 were 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 one hour around. 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 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 (Figure S12-19).
Table 1 Synthesis of various ketoximes in microdroplets and bulk solution
a
b
Reagent
Product
Yield (%)
Yield (%)
HO
O
N
9
0.4%
92.5%
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HO
N
O
O
87.2%
91.9%
82.5%
93.3%
91.6%
86.5%
79.9%
F
H3CO
H3C
F
F
F
HO
N
93.5%
88.2%
OCH3
H CO
OCH3
3
HO
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O
O
O
N
CH3
H3C
CH3
HO
HO
N
N
9
9
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1.1%
3.4%
1.2%
Cl
Cl
Br
Cl
Cl
Br
Br
N
Br
O
OH
HO
N
+
O
OH
OH
N
N
9
5.3%
94.6%
H3CO
F
F
OCH3
+
F
OCH3
a
b
synthesis of ketoxime in microdroplets; synthesis of ketoxime in bulk solution.
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 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 (< 70.3%). It indicated that online mixing was as efficient as offline mixing and the transformation
was not merely dependent on the mixing degree. We further tested the coaxial flowing device in Figure 1B
(
ketoxime surrounding catalysts for the setup b and ketoxime surrounded 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.
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HO
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O
Catalyst
N
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AD1: R , R = H AD2: R , R = CH AD3: R , R = Cl
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AD4: R , R = F AD5: R , R = Br AD6: R , R = OCH
3
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AD7: R = H, R = CH
AD8: R = F, R = OCH
1 2 3
1
2
3
Scheme 2 Catalytic synthesis of amides by oximes
It was observable that Beckmann rearrangement of ketoxime is highly relative to the reaction temperature
Figure 3a). Ketoximes are hardly converted into amides when the reaction temperature was below 25°C. A sharp
(
ascendance to the yield is observed when the temperature ramped to 45°C (Figure 3b). However, the yield was
drastically reduced on further increasing the temperature from 55°C to 75°C. It was well-known that
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p-toluenesulfonyl chloride is an initiator in this reaction . 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 the both
occasions. All 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 observed that more ketoximes were
converted into corresponding amides at 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 reagents 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.
Figure 3 HPLC chromatograms (a) and yields (b) showing the microdroplet synthesis of amides at different temperatures, and
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dependence of amide yields upon reaction temperature for bulk-phase Beckmann rearrangement (c). Peak identity: 1, Benzoylaniline;
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, Benzophenone oxime; 3, Tosyl chloride.
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It was reported that the Beckmann rearrangement reaction can be catalyzed by acids (citric acid, trifluoroacetic
acid, etc.), salts (anhydrous aluminum, FeCl , etc.) and sulfonyl chlorides19,20,22,35. Therefore we explored the
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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,
CF COOH and AlCl except sulfonyl chlorides, which was ascribed by harsh reaction conditions required by
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these catalysts (high temperature without solvents for citric acid, anhydrous environment for AlCl , etc.). We then
3
investigated several sulfonyl chlorides (2,4,6-trimethylbenzenesulfonyl chloride, 4-methoxybenzenesulfonyl
chloride, 4-trifluoromethylbenzenesulfonyl chloride and D(+)-10-camphorsulfonyl chloride) for the
microdroplet-based synthesis of amides. The results in Table 2 and Figure S4 show superior yields in
microdroplets over those in bulk solution for all tested sulfonyl chlorides, proving ultra-fast reaction rates (not rate
constant) by microdroplets based reactors. It also demonstrates that the best yield was obtained with tosyl chloride.
Therefore tosyl chloride was selected as the catalyst.
Table 2 Yields of benzoylaniline by different catalysts in microdroplets and bulk solution
a
b
Catalyst
Structural formula
Yield (%)
Yield (%)
Tosyl chloride
H C
SO Cl
91.3%
77.0%
45.4%
3
2
SO Cl
2
2,4,6-trimethylbenzenesulfonyl
chloride
8
9.5%
H C
CH3
3
CH3
4
-methoxybenzenesulfonyl
chloride
H CO
SO Cl
87. 0%
88.7%
33.8%
58.5%
3
2
4
-trifluoromethylbenzenesulfony
l chloride
F3C
O
SO Cl
2
D(+)-10-Camphorsulfonyl
chloride
SO Cl
2
5
3.9%
15.2%
H
a
b
synthesis of benzoylaniline in microdroplets; synthesis of benzoylaniline in bulk solution.
We further extended the Beckmann rearrangement in microdroplets to benzophenone oximes with different
substituents (4,4'-dichlorobenzophenone oxime, 4,4'-dimethylbenzophenone oxime, 4,4'-dimethoxy benzophenone
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oxime etc.) with p-trifluoromethylbenzenesulfonyl chloride as a catalyst and zinc chloride as a co-catalyst. The
yields of these substituted amides produced in microdroplets and in bulk solution are listed in Table 3. HPLC
1
chromatograms of the crude amides are shown in Figures S5-S11, and H NMR spectra and mass spectra of the
amides are shown in Figures S20-S35 after 6 h collection. It demonstrated that the microdroplet can significantly
enhance the conversion yields of oximes to amides in comparison with the reaction in bulk solution. It was
observed from Table 3 that the yield difference between the microdroplet synthesis and the bulk reaction was
significant in the presence of substitutes attached to benzene rings, which can be ascribed by steric hindrance of
all substituted groups. In bulk solution, the steric hindrance was apparent to prohibit the formation of the
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dimer-like cation intermediate , and thus the Beckmann rearrangement was retarded. However, such steric
hindrance may be negligible because of surface effect and small size effect in microdroplets of micrometer to
nanometer sizes. The Beckmann rearrangement was also accelerated sharply in several seconds under mild
experimental conditions in microdroplets versus several hours under harsh conditions (anhydrous and anaerobic)
in bulk solution. In addition, the microdroplets as microreactors saved solvents and reactants, and decreased the
waste amounts dramatically. All these figures meet the expectations of green chemistry.
Apart from the above merits, the product microdroplets in microdroplet synthesis can be conveniently
introduced into a commercial mass spectrometry for mechanism confirmation. We used an LTQ 133 Orbitrap XL
hybrid mass spectrometer to probe residual reactants and products and mainly unstable intermediates for this aim.
Two transient intermediates (IM1 and IM2 in Scheme S1) at m/z 180.0807 (theoretical m/z 180.0808, error -0.56
ppm) and 377.1643 (theoretical m/z 377.1648, error -1.3 ppm) can be observed from the mass spectrum in Figure
+
S36a. The intermediate IM1 at m/z 180.0807 may form a fragment ion at m/z 77.0387 (C H , theoretical m/z
6
5
7
7.0386, error 1.3 ppm) upon collision induced dissolution (CID) mass spectrometry (Figure S36b) to confirm its
structure whereas the intermediate IM2 cannot be confirmed by MS upon CID because of low intensity. The main
peak at m/z 198.0917 (theoretical m/z 198.0913, error 2.0 ppm) in Figure S36a corresponded to the residual
benzophenone oxime and the synthetic benzoylaniline, which can be confirmed by the mass spectrum in Figure
S36c upon CID. By comparing with the mass spectra of the benzophenone oxime and benzoylaniline standard
solutions upon CID (Figures S36d and 36e), the fragment ion at m/z 180.0810 (theoretical m/z 180.0813, error
-
1.7 ppm) belonged to the only precursor ion of the protonated benzophenone oxime by the loss of H O while the
2
fragment ions at m/z 92.0500 (theoretical m/z 92.0500) and 105.0340 (theoretical m/z 105.0340) were attributed
from the only precursor ion of the protonated benzoylaniline by the losses of C H O and C H N, respectively. In
7
6
6
7
addition, the minor peaks at m/z 295.9814, 457.0891 and 493.0660 corresponded to the three adducts of
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benzophenone oxime and benzoylaniline with ZnCl ([M+H+ZnCl] (theoretical m/z 295.9821, error -2.4 ppm),
2
+
+
[2M+Zn] (theoretical m/z 457.0894, error -0.66 ppm) and [2M+ZnCl] (theoretical m/z 493.0661, error -0.2
ppm)). All the MS information proved the synthesis of benzoylaniline from benzophenone oxime following the
reported mechanism (Scheme S1). However, MS can only detect the residual benzophenone at m/z 183.0808
(theoretical m/z 183.0804, error 2.2 ppm) and the synthetic benzophenone oxime at m/z 198.0918 (theoretical m/z
198. 0913, error 2.5 ppm) from the mass spectra in Figure S37. We cannot find any intermediate using MS
because the intermediates were so transient to probe in the ultra-fast transformation of benzophenone to
benzophenone oxime. Overall, the microdroplet synthesis was feasible to couple with MS for mechanism
confirmation. Last but not the least, the microdroplet synthesis coupled with MS detection was invaluable to
pharmaceutical discovery because they facilitated reaction screening and optimization by reducing the analysis
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time . In particular, upon the use of high throughput array design, the microdroplet synthesis will guide scalable
3
6
syntheses in bulk continuous-flow reactions . It must be noted that the obtained amounts of all products were too
-1
small (less than 50 μg min ) to limit its application in large scale synthesis (preparative or industrial production).
By combing with multiplex and array sprayers36-38 or high flux devices using the array internal-mix nozzles29 for
microdroplets generation, the scaling up microdroplet synthesis can achieve high rates of several tens of milligram
per minute for isolated products, which may be comparable to the bulk phase reaction.
Table 3 Synthesis of various amides in microdroplets and bulk solution
a
b
Reagent
Product
Yield (%)
Yield (%)
HO
N
O
9
1.3%
77.0%
37.2%
N
H
HO
F
N
N
O
78.7%
81.1%
N
H
F
F
F
HO
HO
OCH3
O
N
H
32.5%
66.1%
H3CO
H CO
OCH3
3
CH3
N
O
8
7.8%
N
H
H C
CH3
H3C
3
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HO
Cl
N
N
O
N
85.6%
83.1%
10.1%
50.7%
H
Cl
Cl
Cl
HO
Br
O
N
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H
Br
Br
Br
HO
OH
N
H
N
H
N
O
N
O
7
7.6%
13.5%
88.2%
+
OH
OH
N
N
H
H
N
O
F
N
O
OCH3
F
H3CO
93.0%
H3CO
F+F
OCH3
a
b
synthesis of various amides in microdroplets; synthesis of various amides in bulk solution
Conclusion
In summary, we synthesized ketoximes and amides in microdroplets for the first time. Compared with the
bulk-phase counterpart, the yields of amides in microdroplets were improved significantly and the reaction time
was greatly shortened within several seconds. The microdroplets as microreactors saved organic solvents, the
experiment operation is simple, conditions are mild, and decreased the waste amounts dramatically. It shows that
the microdroplet synthesis method is suitable for the synthesis of ketoximes and amides, which also meets the
expectations of green chemistry. Furthermore, the microdroplet synthesis was feasible to couple with MS for
mechanism confirmation, and it also promoted reaction screening and optimization to guide scalable syntheses in
pharmaceutical discovery. However, the formation of amides from ketoximes based on Beckmann rearrangement
in this work is just one but not general method because alcohols, aldehydes/ketones and unsaturated hydrocarbons
3
9
typically react with organic/inorganic amines for the corresponding amides . The obtained amounts of ketoximes
and amides should be further enhanced from micrograms to several tens of milligrams per minute by coupling
with array sprayers36-38 or high flux devices for generating microdroplets.
29
EXPERIMENTAL SECTION
General methods
Benzophenone,
sodium
,4'-dimethoxybenzophenone,
-methylbenzophenone and 4-fluoro-4'-methoxybenzophenone were obtained from Energy Chemical (Shanghai,
hydroxide,
4,4'-difluorobenzophenone,
4,4'-dimethylbenzophenone,
4
4
4,4'-dibromobenzophenone,
4,4'-dichlorobenzophenone,
zinc chloride,
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China). Hydroxylamine hydrochloride, citric acid, hydroxylamine, 4-methoxybenzenesulfonyl chloride,
benzophenone oxime, 4-trifluoromethylbenzenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride,
p-toluenesulfonyl chloride and D-(+)-10-Camphorsulfonyl chloride were purchased from Sinopharm Chemical
Reagent (Shanghai, China). Methanol and acetonitrile of chromatographic grade were purchased from J&K
(Shanghai, China). Benzoylanilide was purchased from TCI (Shanghai, China). Fused-silica capillaries of 50 μm
i.d. × 150 μm o.d., 150 μm i.d. × 365 μm o.d. and 200 μm i.d. × 365 μm o.d. were obtained from Yongnian Optic
Fiber Factory (Hebei, China). A Model 35-2226 syringe pump from Harvard Apparatus (Harvard Apparatus Inc.,
MA, USA) equipped with two 1.0 mL syringes was utilized for solution feeding. A Shimadzu LC-20AT HPLC
system (Shimadzu (Suzhou) Co., Ltd., Suzhou, China) was used for all yield measurements by high performance
liquid chromatography (HPLC). It consisted of two double plunger pumps, a mixer with two inlets and one outlet,
a manual six-port injection valve with a 20 μL sample loop, an Agilent Zorbax C column (4.6 mm i.d. × 15 cm ×
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5 μm) and a 190 ~ 700 nm variable wavelength ultraviolet-visible detector using mobile phases in Table S1. A
Bruker Avance ( Bruker, Germany) was operated at a frequency of 500 MHz for the collection of 1H NMR
spectra using tetramethylsilane as an internal standard. A Hewlett-Packard 5989A mass spectrometer (Agilent,
America) was operated on the ESI mode for recording mass spectra.
Microdroplet synthesis of ketoximes from benzophenone with basic catalyst
-1
For the microdroplet synthesis of ketoximes, benzophenone (0.02 mol L ) in the methanol and hydroxylamine
-1
-1
solution (5.0 mol L ) in 2.5 mol L NaOH were individually loaded into two airtight glass syringe. The syringe
-1
pump ran at 10 μL min to deliver the solutions to the 150 μm i.d. capillary, and the capillary was inserted into a
spray emitter using dry nitrogen gas at 100 psi (Figure 1A). The microdroplets were introduced into an electrically
heated single pass chamber by the sheathing gas with temperature monitoring by a thermocouple thermometer.
The merged plumes from two sprayers flowed through a glass surface for product collection. After 10 min
collection (200 μL collected volume), 2 mL of a water-methanol solution (v:v = 1:1) was used to dissolve the
product. After filtration, the sample was diluted by ten-fold and then analyzed by HPLC and the yield was
calculated based on peak area.
Microdroplet synthesis of amides from ketoximes with catalysts
For the synthesis of amides catalyzed by TsCl, an inner capillary of 50 μm i.d. and 150 μm o.d. was surrounded
by a concentric outer capillary of 200 μm i.d. with the inner capillary tip keeping at 0.1 mm outside the outer
capillary). The outer capillary was then inserted into a spray emitter with a stream of dry nitrogen gas at 100 psi.
-1
The syringe pump fed two solutions of ketoxime (0.02 mol L ) in acetonitrile and TsCl + ZnCl (each 0.02 mol
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L ) to the inner and outer capillaries individually at 10 μL min (Figure 1B). The microdroplets were captured by
10 mL methanol in a 25-mL glass beaker. After 10 min collection (200 μL collected volume), the product was
determined by HPLC after ten-fold dilution with methanol.
Bulk reaction synthesis of ketoximes and amides
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Ketoximes: A 100 μL benzophenone solution (0.02 mol L ) in methanol and a 100 μL hydroxylamine solution
-1
-1
o
(
5.0 mol L ) in 2.5 mol L NaOH were mixed and allowed for 10 min reaction at 40 C. Upon completion of the
reaction, 2 mL of a water-methanol solution (v:v = 1:1) was used to dissolve the product. After filtration, the
sample was diluted by ten-fold and then analyzed by HPLC and the yield was calculated based on peak area.
-1
-1
Amides: A mixture solution of ketoxime (0.02 mol L ) and TsCl + ZnCl (each 0.02 mol L ) in the acetonitrile
2
o
(200 μL) was allowed for 10 min reaction at 70 C. The product was measured by HPLC after twenty-fold dilution
with methanol.
Online monitoring of microdroplet synthesis by mass spectrometry
A Thermo Fisher LTQ-Orbitrap mass spectrometer (Thermo Scientific, San Jose, CA, USA) was used for
mechanism confirmation. Two sprayers for microdroplet generation in Figure 1 were directly placed at 5 cm away
from the inlet capillary of the mass spectrometer with high voltages applied upon the reactant solutions (ketone
-1
and ketoxime). Considering high sensitivity of mass spectrometry, 0.2 mmol L reactants (benzophenone and
-1
-1
benzophenone oxime), 0.2 mmol L catalysts (TsCl and ZnCl ) and other reagents (0.5 mol L hydroxylamine
2
and 0.1 mol L-1 NaOH) were used to avoid interface contamination to the mass spectrometer. The mass
spectrometer worked in the positive mode using the following parameters: spray voltage, +3.5 kV; capillary
temperature, 275 °C; capillary voltage, 30 V; tube lens, 100 V; resolution, 30000. Mass spectra of product ions
upon CID were collected with a 1 m/z isolation window and 26-35 eV collision energies applied to selected
precursor ions.
1
Benzophenone oxime: (white solid, 12.83 mg, 90.4% yield); H NMR (500 MHz, CDCl ) δ 9.23 (s, 1H),
3
7
.40-7.34 (m, 6H), 7.28-7.22 (m, 3H). 4,4'-Dimethylbenzophenone oxime: (white solid, 14.3 mg, 88.2%
1
yield); H NMR (500 MHz, CDCl ) δ 8.73 (s, 1H), 7.31-7.15 (m, 6H), 7.05 (d, J = 7.5 Hz, 2H), 2.33 (s, 3H), 2.27
3
1
(
s, 3H). 4,4'-Difluorobenzophenone oxime: (white solid, 14.6 mg, 87.2% yield); H NMR (500 MHz,
CDCl ) δ 8.46 (s, 1H), 7.38-7.32 (m, 4H), 7.11-7.04 (m, 2H), 6.99-6.90 (m, 2H). 4,4'-Dichlorobenzophenone
3
1
oxime: (white solid, 17.5 mg, 91.1% yield); H NMR (500 MHz, CDCl ) δ 8.19 (s, 1H), 7.38-7.37 (m, 2H),
3
7
.32-7.30 (m, 2H), 7.27-7.23 (m, 4H). 4,4'-Dibromobenzophenone oxime: (brown solid, 23.8 mg, 93.4%
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yield); H NMR (500 MHz, CDCl ) δ 7.77 (s, 1H), 7.55-7.52 (m, 2H), 7.42-7.39 (m, 2H), 7.26-7.24 (m, 2H),
3
1
7.20-7.18 (m, 2H). 4,4'-Dimethoxybenzophenoneoxime: (white solid, 17.3 mg, 93.5% yield); H NMR
(
500 MHz, CDCl ) δ 7.33 (d, J = 8.5 Hz, 4H), 6.90 (d, J = 8.5 Hz, 2H), 6.81-6.72 (d, J = 9.0 Hz, 2H), 3.78 (s, 3H),
3
1
3
.74 (s, 3H). 4-Methylbenzophenoneoxime: (white solid, 12.3 mg, 81.2% ); H NMR (500 MHz, CDCl ) δ
3
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
2
.28 (s, 3H), 2.34 (s, 3H), 7.05 (s, 3H), 7.06 (s, 3H), 7.19-7.40 (m, 18H), 8.50 (s, 2H).
1
4
-Fluoro-4'-methoxybenzophenoneoxime: (white solid, 16.8 mg, 95.3% ); H NMR (500 MHz, CDCl ) δ
3
3.73 (s, 3H), 3.78 (s, 3H), 6.77-7.36 (m, 18H), 8.93 (s, 2H)
1
Benzoylanilide: (white solid, 13.0 mg, 91.3% yield); H NMR (500 MHz, CDCl ) δ 7.87 (s, 1H), 7.78 (d, J =
3
7
7
4
.0 Hz, 2H), 7.7 (d, J = 8.0 Hz,, 2H), 7.47 (t, J = 7.5 Hz, 1H), 7.39 (t, J = 7.5 Hz, 2H), 7.29 (t, J = 8.0 Hz, 2H),
+
.08 (t, J = 7.5 Hz, 1H); HRMS (ESI-TOF) m/z: [M+H] Calcd. for C H NO, 198.0913; found, 198.0912.
1
3
12
1
,4'-Dimethylbenzanilide: (white solid, 14.2 mg, 87.8% yield); H NMR (500 MHz, CDCl ) δ 7.69 (d, J =
3
8
.0 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 7.21-7.19 (m, 2H), 7.09 (d, J = 8.5 Hz, 2H), 2.35 (s, 3H), 2.26 (s, 3H);
+
HRMS (ESI-TOF) m/z: [M+H] Calcd. for C H NO, 226.1226; found, 226.1239. 4,4'-Difluorobenzanilide:
1
5
16
1
(white solid, 13.2 mg, 78.7% yield); H NMR (500 MHz, CDCl
3
) δ 7.82-7.79 (m, 2H), 7.68( s, 1H), 7.52-7.49 (m,
+
2H), 7.11 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 9.0 Hz, 2H); HRMS (ESI-TOF) m/z: [M+H] Calcd. for C13
H
10NOF2,
1
2
34.0725; found, 234.0730. 4,4'-Dichlorobenzanilide: (white solid, 16.4 mg, 85.6% yield); H NMR (500
+
MHz, CDCl ) δ 8.63 (s, 1H), 7.38-7.36 (m, 2H), 7.31-7.23 (m, 6H); HRMS (ESI-TOF) m/z: [M+H] Calcd. for
3
C H NOCl , 266.0134; found, 266.0135. 4,4'-Dibromobenzanilide: (brown solid, 21.3 mg, 83.1% yield);
1
3
10
2
1
H NMR (500 MHz, CDCl ) δ 8.18(s, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 7.25-7.19 (m, 4H);
3
+
HRMS (ESI-TOF) m/z: [M+H] Calcd. for C H NOBr , 353.9124; found, 355.9102.
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,4'-Dimethoxybenzanilide: (white solid, 15.0 mg, 81.1% yield); H NMR (500 MHz, CDCl ) δ 7.76 (d, J =
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8.5 Hz, 2H), 7.59 (s, 1H), 7.45 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 9.0 Hz, 2H), 6.84(d, J = 9.0 Hz, 2H), 3.80 (s, 3H),
+
3.74 (s, 3H); HRMS (ESI-TOF) m/z: [M+H] Calcd. for C H NO , 258.1125; found, 258.1123.
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-Fluoro-4'-methoxybenzanilide. (white solid, 16.4 mg, 93.0% yield); H NMR (500 MHz, CDCl ) δ
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.81-7.75 (m, 5H), 7.70 (s, 1H), 7.65 (s, 1H), 7.52-7.43 (m, 4H), 7.09-6.82 (m, 9H), 3.80 (s, 3H), 3.74 (s, 3H);
+
HRMS (ESI-TOF) m/z: [M+H] Calcd. for C H FNO , 246.0925; found, 246.0929. 4-Methylbenzanilide.
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2
1
(
white solid, 11.8 mg, 77.6% yield); H NMR (500 MHz, CDCl ) δ 7.92-7.94 (m, 2H), 7.76 (d, J = 7.5 Hz, 2H),
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.76 (d, J = 7.5 Hz, 2H), 7.67 (d, J = 8 Hz, 2H), 7.56 (d, J = 8 Hz, 2H), 7.44-7.41 (m, 3H), 7.36-7.33 (m,
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2H),7.27-7.24 (m, 2H), 7.17-7.14 (m, 2H), 7.06-7.03 (m, 3H), 2.25 (s, 3H), 2.32 (s, 3H); HRMS (ESI-TOF) m/z:
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[M+H] Calcd. for C H NO, 212.1082; found, 212.1076.
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
XXXXXXXX. HPLC mobile phases, HPLC chromatograms of oximes and amides under different
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conditions, H NMR spectra and high-resolution mass spectra of oximes and amides and mechanism of
Beckmann rearrangement of ketoxime.
Acknowledgements
The authors acknowledge the financial support from the National Natural Science Foundation of China under
project Nos. 21675037 and 21405030, and Natural Science Foundation of Zhejiang Province under project No.
LGN19B050001. We also thank Dr. Jiang in our institute for his kind help in the collection of mass spectra.
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