The deacylation of amides, which is widely employed in the pharmaceutical industry, is not a fast reaction under normal conditions. To intensify this reaction, a high-temperature and high-pressure continuous microreaction technology was developed, whose space-time yield was 49.4 times that of traditional batch reactions. Using the deacylation of acetanilide as a model reaction, the effects of the temperature, pressure, reaction time, molar ratio of reactants, and water composition on acetanilide conversion were carefully studied. Based on the rapid heating and cooling capabilities, the kinetics of acetanilide deacylation at high temperatures were investigated to determine the orders of reactants and activation energy. This microreaction technology was further applied to a variety of other amides to understand the influence of substituents and steric hindrance on the deacylation reaction.
. [J]. Frontiers of Chemical Science and Engineering, 2022, 16(12): 1818-1825.
Pengcheng Zou, Kai Wang, Guangsheng Luo. Continuous deacylation of amides in a high-temperature and high-pressure microreactor. Front. Chem. Sci. Eng., 2022, 16(12): 1818-1825.
D G Brown, J Bostrom. Analysis of past and present synthetic methodologies on medicinal chemistry: where have all the new reactions gone? Miniperspective. Journal of Medicinal Chemistry, 2016, 59( 10): 4443– 4458 https://doi.org/10.1021/acs.jmedchem.5b01409
3
P Etayo, A Vidal-Ferran. Rhodium-catalysed asymmetric hydrogenation as a valuable synthetic tool for the preparation of chiral drugs. Chemical Society Reviews, 2013, 42( 2): 728– 754 https://doi.org/10.1039/C2CS35410A
4
C B Yu, J Wang, Y G Zhou. Facile synthesis of chiral indolines through asymmetric hydrogenation of in situ generated indoles. Organic Chemistry Frontiers, 2018, 5( 19): 2805– 2809 https://doi.org/10.1039/C8QO00710A
5
I Kreituss, Y Murakami, M Binanzer, J W Bode. Kinetic resolution of nitrogen heterocycles with a reusable polymer-supported reagent. Angewandte Chemie International Edition, 2012, 51( 42): 10660– 10663 https://doi.org/10.1002/anie.201204991
6
P B Arockiam, C Bruneau, P H Dixneuf. Ruthenium (II)-catalyzed C–H bond activation and functionalization. Chemical Reviews, 2012, 112( 11): 5879– 5918 https://doi.org/10.1021/cr300153j
7
S Rej, N Chatani. Rhodium-catalyzed C(sp2)– or C(sp3)–H bond functionalization assisted by removable directing groups. Angewandte Chemie International Edition, 2019, 58( 25): 8304– 8329 https://doi.org/10.1002/anie.201808159
8
X G Zhang, H X Dai, M Wasa, J Q Yu. Pd (II)-catalyzed ortho trifluoromethylation of arenes and insights into the coordination mode of acidic amide directing groups. Journal of the American Chemical Society, 2012, 134( 29): 11948– 11951 https://doi.org/10.1021/ja305259n
9
R Y Zhu, M E Farmer, Y Q Chen, J Q Yu. A simple and versatile amide directing group for C–H functionalizations. Angewandte Chemie International Edition, 2016, 55( 36): 10578– 10599 https://doi.org/10.1002/anie.201600791
10
F Zhang, D R Spring. Arene C–H functionalization using a removable/modifiable or a traceless directing group strategy. Chemical Society Reviews, 2014, 43( 20): 6906– 6919 https://doi.org/10.1039/C4CS00137K
A Dey, S K Sinha, T K Achar, D Maiti. Accessing remote meta- and para-C(sp2)-H bonds with covalently attached directing groups. Angewandte Chemie International Edition, 2019, 58( 32): 10820– 10843 https://doi.org/10.1002/anie.201812116
13
R L Schowen, H Jayaraman, L Kershner. Catalytic efficiencies in amide hydrolysis. The two-step mechanism. Journal of the American Chemical Society, 1966, 88( 14): 3373– 3375 https://doi.org/10.1021/ja00966a034
14
M L Bender, R D Ginger. Intermediates in the reactions of carboxylic acid derivatives. IV. The hydrolysis of benzamide. Journal of the American Chemical Society, 1955, 77( 2): 348– 351 https://doi.org/10.1021/ja01607a032
15
I Meloche, K J Laidler. Substituent effects in the acid and base hydrolyses of aromatic amides. Journal of the American Chemical Society, 1951, 73( 4): 1712– 1714 https://doi.org/10.1021/ja01148a084
16
R L Schowen, G W Zuorick. Amide hydrolysis. Superimposed general base catalysis in the cleavage of anilides. Journal of the American Chemical Society, 1966, 88( 6): 1223– 1225 https://doi.org/10.1021/ja00958a025
17
P Duan, L Dai, P E Savage. Kinetics and mechanism of N-substituted amide hydrolysis in high-temperature water. Journal of Supercritical Fluids, 2010, 51( 3): 362– 368 https://doi.org/10.1016/j.supflu.2009.09.012
18
Z Yu, K Geisler, T Leontidou, R Young, S Vonlanthen, S Purton, C Abell, A Smith. Droplet-based microfluidic screening and sorting of microalgal populations for strain engineering applications. Algal Research, 2021, 56 : 102293 https://doi.org/10.1016/j.algal.2021.102293
19
Z Yang, Y Yang, X Zhang, W Du, J Zhang, G Qian, X Duan, X Zhou. High-yield production of p-diethynylbenzene through consecutive bromination/dehydrobromination in a microreactor system. AIChE Journal, 2022, 68( 2): e17498 https://doi.org/10.1002/aic.17498
20
Y Feng, M Zhang, H Zhang, J Wang, Y Yang. Continuous synthesis of isobutylaluminoxanes in a compact and integrated approach. Chemical Engineering Journal, 2021, 425 : 131750 https://doi.org/10.1016/j.cej.2021.131750
21
S Marre, A Adamo, S Basak, C Aymonier, K F Jensen. Design and packaging of microreactors for high pressure and high temperature applications. Industrial & Engineering Chemistry Research, 2010, 49( 22): 11310– 11320 https://doi.org/10.1021/ie101346u
22
K Qin, K Wang, R Luo, Y Li, T Wang. Dispersion of supercritical carbon dioxide to [Emim] [BF4] with a T-junction tubing connector. Chemical Engineering and Processing, 2018, 127 : 58– 64 https://doi.org/10.1016/j.cep.2018.03.003
23
A K Goodwin, G L Rorrer. Reaction rates for supercritical water gasification of xylose in a micro-tubular reactor. Chemical Engineering Journal, 2010, 163( 1–2): 10– 21 https://doi.org/10.1016/j.cej.2010.07.013
24
H Kawanami, M Sato, M Chatterjee, N Otabe, T Tuji, Y Ikushima, T Ishizaka, T Yokoyama, T M Suzuki. Highly selective non-catalytic Claisen rearrangement in a high-pressure and high-temperature water microreaction system. Chemical Engineering Journal, 2011, 167( 2–3): 572– 577 https://doi.org/10.1016/j.cej.2010.09.084
25
A Adeyemi, J Bergman, J Branalt, J Sävmarker, M Larhed. Continuous flow synthesis under high-temperature/high-pressure conditions using a resistively heated flow reactor. Organic Process Research & Development, 2017, 21( 7): 947– 955 https://doi.org/10.1021/acs.oprd.7b00063
26
K F Jensen. Flow chemistry—microreaction technology comes of age. AIChE Journal, 2017, 63( 3): 858– 869 https://doi.org/10.1002/aic.15642
27
H P Gemoets, Y Su, M Shang, V Hessel, R Luque, T Noel. Liquid phase oxidation chemistry in continuous-flow microreactors. Chemical Society Reviews, 2016, 45( 1): 83– 117 https://doi.org/10.1039/C5CS00447K
28
D Liu, Y Jing, K Wang, Y Wang, G Luo. Reaction study of α-phase NaYF4:Yb,Er generation via a tubular microreactor: discovery of an efficient synthesis strategy. Nanoscale, 2019, 11( 17): 8363– 8371 https://doi.org/10.1039/C8NR09957J
29
D Liu, J Yan, K Wang, Y Wang, G Luo. Continuous synthesis of ultrasmall core-shell upconversion nanoparticles via a flow chemistry method. Nano Research, 2022, 15( 2): 1199– 1204 https://doi.org/10.1007/s12274-021-3625-3
30
M Shang, T Noël, Y Su, V Hessel. Kinetic study of hydrogen peroxide decomposition at high temperatures and concentrations in two capillary microreactors. AIChE Journal, 2017, 63( 2): 689– 697 https://doi.org/10.1002/aic.15385
31
A Tanimu, S Jaenicke, K Alhooshani. Heterogeneous catalysis in continuous flow microreactors: a review of methods and applications. Chemical Engineering Journal, 2017, 327 : 792– 821 https://doi.org/10.1016/j.cej.2017.06.161
32
Y Li, K Wang, K Qin, T Wang. Beckmann rearrangement reaction of cyclohexanone oxime in sub/supercritical water: byproduct and selectivity. RSC Advances, 2015, 5( 32): 25365– 25371 https://doi.org/10.1039/C5RA01929J
33
B Li, R Li, P Dorff, J C McWilliams, R M Guinn, S M Guinness, L Han, K Wang, S Yu. Deprotection of N-Boc groups under continuous-flow high-temperature conditions. Journal of Organic Chemistry, 2019, 84( 8): 4846– 4855 https://doi.org/10.1021/acs.joc.8b02909
34
A Polyzoidis, T Altenburg, M Schwarzer, S Loebbecke, S Kaskel. Continuous microreactor synthesis of ZIF-8 with high space-time-yield and tunable particle size. Chemical Engineering Journal, 2016, 283 : 971– 977 https://doi.org/10.1016/j.cej.2015.08.071
35
J Sui, J Yan, K Wang, G Luo. Efficient synthesis of lithium rare-earth tetrafluoride nanocrystals via a continuous flow method. Nano Research, 2020, 13( 10): 2837– 2846 https://doi.org/10.1007/s12274-020-2938-y
36
H Zhang, Q Jin, R Xu, L Yan, Z Lin. Kinetic studies of xylan hydrolysis of corn stover in a dilute acid cycle spray flow-through reactor. Frontiers of Chemical Science and Engineering, 2011, 5( 2): 252– 257 https://doi.org/10.1007/s11705-010-1010-y
37
S H Jin, J H Jung, S G Jeong, J Kim, T J Park, C S Lee. Microfluidic dual loops reactor for conducting a multistep reaction. Frontiers of Chemical Science and Engineering, 2018, 12( 2): 239– 246 https://doi.org/10.1007/s11705-017-1680-9
38
H Shang, P Ye, Y Yue, T Wang, W Zhang, S Omar, J Wang. Experimental and theoretical study of microwave enhanced catalytic hydrodesulfurization of thiophene in a continuous-flow reactor. Frontiers of Chemical Science and Engineering, 2019, 13( 4): 744– 758 https://doi.org/10.1007/s11705-019-1839-7
39
S Lu, K Wang. Kinetic study of TBD catalyzed delta-valerolactone polymerization using a gas-driven droplet flow reactor. Reaction Chemistry & Engineering, 2019, 4( 7): 1189– 1194 https://doi.org/10.1039/C9RE00046A
40
X Lin, K Wang, B Zhou, G Luo. A microreactor-based research for the kinetics of polyvinyl butyral (PVB) synthesis reaction. Chemical Engineering Journal, 2020, 383 : 123181 https://doi.org/10.1016/j.cej.2019.123181
41
M Mansour, Z Liu, G Janiga, K D Nigam, K Sundmacher, D Thévenin, K Zähringer. Numerical study of liquid–liquid mixing in helical pipes. Chemical Engineering Science, 2017, 172 : 250– 261 https://doi.org/10.1016/j.ces.2017.06.015
42
D Zahn. On the role of water in amide hydrolysis. European Journal of Organic Chemistry, 2004, 2004( 19): 4020– 4023 https://doi.org/10.1002/ejoc.200400316
43
R L Schowen, H Jayaraman, L Kershner. Kinetic evidence for a two-step mechanism of amide hydrolysis. Tetrahedron Letters, 1966, 7( 5): 497– 500 https://doi.org/10.1016/S0040-4039(00)72910-8
44
J W Barnett, C O’Connor. Evidence for a first order mechanism in amide hydrolysis. Journal of the Chemical Society. Chemical Communications, 1972, ( 9): 525– 525 https://doi.org/10.1039/c39720000525
45
C O’Connor. Acidic and basic amide hydrolysis. Quarterly Review of the Chemical Society, 1970, 24( 4): 553– 564 https://doi.org/10.1039/qr9702400553
46
H Slebocka-Tilk, A J Bennet, J W Keillor, R S Brown, J P Guthrie, A Jodhan. Oxygen-18 exchange accompanying the basic hydrolysis of primary, secondary, and tertiary toluamides. The importance of amine leaving abilities from the anionic tetrahedral intermediate. Journal of the American Chemical Society, 1990, 112( 23): 8507– 8514 https://doi.org/10.1021/ja00179a040
47
S S Biechler, R W Jr Taft. The effect of structure on kinetics and mechanism of the alkaline hydrolysis of anilides. Journal of the American Chemical Society, 1957, 79( 18): 4927– 4935 https://doi.org/10.1021/ja01575a028
48
R H DeWolfe, R C Newcomb. Hydrolysis of formanilides in alkaline solutions. Journal of Organic Chemistry, 1971, 36( 25): 3870– 3878 https://doi.org/10.1021/jo00824a005
49
M L Bender, R J Thomas. The concurrent alkaline hydrolysis and isotopic oxygen exchange of a series of p-substituted acetanilides. Journal of the American Chemical Society, 1961, 83( 20): 4183– 4189 https://doi.org/10.1021/ja01481a021