Accelerating Heat-Initiated Radical Reactions of Organic Halides with Tin Hydride Using Flow Microreactor Technologies

Abstract

We herein report that flow microreactors can promote an efficiency of radical chain reactions. The chain reactions with a fast propagation step can be accelerated by virtue of an efficient heat-transfer character of the microreactors, whereas the yield of those reactions with a slow propagation step was increased by flow microreactors. Moreover, the yield was further increased by a sequential addition of the initiators, which was allowed by a flow-sequential-addition system.

Key words

flow microreactor - flow chemistry - radical chain reduction - reaction acceleration - sequential addition

Publication History

Received: 04 August 2020

Accepted after revision: 02 September 2020

Article published online:
09 October 2020

• References and Notes

• 1a Studer A. Chem. Eur. J. 2001; 7: 1159
• 1b Fischer H. Chem. Rev. 2001; 101: 3581
• 1c Studer A, Curran DP. Angew. Chem. Int. Ed. 2016; 55: 58
• 2a Jasperese CP, Curran DP, Fevig TL. Chem. Rev. 1991; 91: 1237
• 2b Romero KJ, Galliher MS, Pratt DA, Stephenson CR. J. Chem. Soc. Rev. 2018; 47: 7851

Reviews on flow microreactor synthesis:
• 3a Pastre JC, Browne DL, Ley SV. Chem. Soc. Rev. 2013; 42: 8849
• 3b Baxendale IR. J. Chem. Technol. Biotechnol. 2013; 88: 519
• 3c Fukuyama T, Totoki T, Ryu I. Green Chem. 2014; 16: 2042
• 3d Kobayashi S. Chem. Asian J. 2016; 11: 425
• 3e Plutschack MB, Pieber B, Gilmore K, Seeberger PH. Chem. Rev. 2017; 117: 11796
• 3f Cantillo D, Kappe CO. React. Chem. Eng. 2017; 2: 7

Recent examples:
• 4a Fuse S, Mifune Y, Nakamura H, Tanaka H. Nat. Commun. 2016; 7: 13491
• 4b Nagaki A, Takahashi Y, Yoshida J. Angew. Chem. Int. Ed. 2016; 55: 5327
• 4c Kim H, Min K.-I, Inoue K, Im DJ, Kim D.-P, Yoshida J. Science 2016; 352: 691
• 4d Seo H, Katcher MH, Jamison TF. Nat. Chem. 2017; 9: 453
• 4e Inuki S, Sato K, Fukuyama T, Ryu I, Fujimoto Y. J. Org. Chem. 2017; 82: 1248
• 4f Ashikari Y, Saito K, Nokami T, Yoshida J, Nagaki A. Chem. Eur. J. 2019; 25: 15239
• 4g Miyamura H, Tobita F, Suzuki A, Kobayashi S. Angew. Chem. Int. Ed. 2019; 58: 9220
• 4h Masui S, Manabe Y, Hirao K, Shimoyama A, Fukuyama T, Ryu I, Fukase K. Synlett 2019; 30: 397
• 4i Elsherbini M, Winterson B, Alharbi H, Folgueiras-Amador AA, Génot C, Wirth T. Angew. Chem. Int. Ed. 2019; 58: 9811
• 4j Cambié D, Dobbelaar J, Riente P, Vanderspikken J, Shen C, Seeberger PH, Gilmore K, Debije MG, Noël T. Angew. Chem. Int. Ed. 2019; 58: 14374
• 4k Ahn G.-N, Yu T, Lee H.-J, Gyak K.-W, Kang J.-H, You D, Kim D.-P. Lab Chip 2019; 19: 3535
• 4l Ichinari D, Ashikari Y, Mandai K, Aizawa Y, Yoshida J, Nagaki A. Angew. Chem. Int. Ed. 2020; 59: 1567
• 4m Colella M, Tota A, Takahashi Y, Higuma R, Ishikawa S, Degennaro L, Luisi R, Nagaki A. Angew. Chem. Int. Ed. 2020; 59: 11924
• 5 Fukuyama T, Fujita Y, Rashid MA, Ryu I. Org. Lett. 2016; 18: 5444
• 6 For a review of flow radical reactions, see: Fukuyama, T.; Ryu, I. Radical Chemistry by Using Flow Microreactor Technology, In Encyclopedia of Radicals in Chemistry, Biology, and Materials, Vol. 2; Studer, A.; Chatgilialoglu, C., Ed.;Wiley: Chichester 2012, 1243–1258.

For reviews of flow phororeactions, see:
• 7a Matsushita Y, Ichimura T, Ohba N, Kumada S, Sakeda K, Suzuki T, Tanibata H, Murata T. Pure Appl. Chem. 2007; 79: 1959
• 7b Mizuno K, Nishiyama Y, Ogaki T, Terao K, Ikeda H, Kakiuchi K. J. Photochem. Photobiol., C 2016; 29: 107
• 7c Cambié D, Bottecchia C, Straathof NJ. W, Hessel V, Noël T. Chem. Rev. 2016; 116: 10276
• 7d Otake Y, Nakamura H, Fuse S. Tetrahedron Lett. 2018; 59: 1691
• 7e Politano F, Oksdath-Mansilla G. Org. Process Res. Dev. 2018; 22: 1045
• 8 Fukuyama T, Kobayashi M, Rahman MT, Kamata N, Ryu I. Org. Lett. 2008; 10: 533
• 9 The flow reactions were carried out using a toluene solution containing 1-bromotetradecane (3, 0.05 M), tri-n-butyltin hydride (0.06 M), and n-hexadecane (internal standard), with a toluene solution containing AIBN (0.0025 M, 5 mol% to 3). Those solutions were introduced into T-shaped micromixer (internal diameter φ = 250 μm) pumped by a syringe pump (flow rate: 1.0 mL/min, each). The mixed solution passed through a stainless tube R1 (length L = 100 cm, φ = 1000 μm) at room temperature, and then passed through a stainless tube R2 (L = L₂ cm, φ = 1000 μm) heated at 100 °C. Then, the reaction solution was introduced into a stainless tube R3 (L = 100 cm, φ = 500 μm) cooled at 0 °C to stop the reaction. After a steady state was reached, an aliquot of the reaction solution was collected, which was analyzed by gas chromatography.
• 10a Carlsson DJ, Ingold KU. J. Am. Chem. Soc. 1968; 90: 7047
• 10b Ingold KU, Lusztyk J, Scaiano JC. J. Am. Chem. Soc. 1984; 106: 343
• 11 For the sequential-addition flow reactions with system, a flow microreactor system consisting of two T-shaped micromixers (M1 (φ = 250 μm) and M2 (φ = 500 μm)) and four microtube reactors (R1, R2, R3, and R4) was used. R2 and R3 were dipped in an oil bath (120 °C), and R4 was cooled in an ice bath (0 °C). A xylene solution containing 1-chloroadamantane (0.20 M, 4), tri-n-butyltin chloride (0.24 M), and internal standard (n-tetradecane) was introduced into M1 (0.5 mL/min). Also, a xylene solution of AIBN (0.04 M) was introduced into M1 (F₁ mL/min). The mixed solution was passed through R1 (length L = 100 cm, φ = 1000 μm) and R2 (L = L₁ cm, φ = 1000 μm, residence time = t ₁ s) where the reaction proceeds. Another AIBN solution (in xylene, 0.04 M) was introduced into M2 (F₂ mL/min) and mixed with the reaction solution. The resultant mixture was passed through R3 (L = L₂ cm, φ = 1000 μm, residence time = t ₂ s), and R4 (L = 100 cm, φ = 500 μm) where the reaction was stopped. The sum of F₁ and F₂ is 0.5 (mL/min), and the total reaction time (t ₁ + t ₂) was set as 1885 s by varying L ₁ and L ₂. After a steady state was reached, an aliquot of the solution was collected and analyzed by gas chromatography.