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.

Radical reactions, mediated by a reactive intermediate bearing an unpaired electron, are one of the fundamental classes of organic synthesis.[1] A wide range of organic compounds with highly attractive functions have been produced by these reactions.[2] Since the radicals are mainly generated in situ by light or heat, the reaction rate is directly related to the efficiency of the radical-generating step.

Recently, flow microreactors have attracted considerable attention as a new class of reaction vessel.[3] [4] Since flow microreactors have a micrometer-sized reaction space, the surface area is significantly larger than that of conventional batch reactors, which generally have linear dimensions in a centimeter range. Based on this feature, in 2016, Ryu and Fukuyama reported that radical reaction initiated by photoirradiation could be accelerated by using a microflow photoreactor.[5–7] The big surface area of the reactor made the light path-length short, which reduced attenuation of the light, according to the Lambert–Beer law. Thus, the radical generation became highly efficient, leading to accelerated reaction kinetics.

Inspired by that work, we envisaged that flow microreactors could accelerate heat-initiated radical reactions.[8] The big surface area of flow microreactors, which makes a tiny temperature gradient inside, helps efficient heat transfer. In this letter, we report that radical-chain reactions (i.e., reactions comprising an initiation step, in which radical species are generated, and a propagation step, in which products are generated along with new radical species that enable further propagation steps) were significantly accelerated by using flow microreactors. Moreover, especially in the case of radical-chain reactions involving a slow propagation step, it is also problematic that radical initiators generated by the initiation step are deactivated, for example by a homocoupling, if inappropriate amounts of the radicals are present. We also report that a separate and sequential addition of the initiator using flow microreactors enhanced the efficiency of the radical reactions.

We chose to study a radical reduction of alkyl halides using trialkylstannyl hydride because this reaction is familiar to most organic chemists. In this reaction, a radical initiator such as azobis(isobutyronitrile) (AIBN, 1) provides a radical species by a homolytic cleavage triggered by heat (initiation step). The radical withdraws a hydride radical from organotin hydride (generally, tri-n-butyltin hydride, 2) to generate a stannyl radical (nBu₃Sn^•) in P-1 step of propagation step. Thus-generated tin radical 4 pulls out halide radicals on the alkyl halides to produce alkyl radicals (P-2 step), which get a hydride radical from 2, leading to regenerate the tin radical 4 (P-3 step).

First, we conducted the reduction of 1-bromotetradecane (3) as a primary alkyl bromide both in a batch and flow reactor. As a batch reactor, a 50 mL round-bottomed flask dipped in an oil bath heated at 100 °C was used. In the batch reactor, a 5 mL of toluene solution containing 3 and 1.2 equiv of tri-n-butyltin hydride (2) was mixed with a 5 mL of toluene solution containing AIBN (1, 5 mol%), shown in Figure [1a]. Whereas, as a flow reactor, a stainless tube having 1000 μm of inner diameter and 1/16 inch of outer diameter was used. The solutions were introduced into a T-shaped micromixer M1 and were mixed together. The mixed solution passed through the stainless microtube reactor which was dipped in the oil bath heated at 100 °C (Figure [1b]).[9] The results of those reactions with varied reaction times are summarized in Figure [1c], which shows that the batch reactor requires 600 s to obtain a quantitative amount of the desired product (tetradecane) whereas the flow microreactor achieves a similar result within 165 s.

To clarify the effect of the heat transfer of flow microreactors, we conducted the similar flow reactions using various tube reactors such as thicker stainless tubes and polytetrafluoroethylene (PTFE) tubes. The inner and outer diameters of each tubes are summarized in Table [1], where the result for the radical reduction of 3 is also summarized. From the comparison between entry 1 and 2 and that between entry 3 and 4 it is indicated that a larger surface-to-volume allows the reaction to be efficient. The comparison between entry 1 and 3 is also clarified that the reaction in the stainless reactor tube was faster than one in the PTFE tube. That is due to the higher thermal conductivity of stainless (SUS316) tubes than that of PTFE tubes (SUS316: 17 W/m·K, PTFE: 0.23 W/m·K). These tendencies suggest that this radical reduction can be accelerated by an efficient heat transfer from the outer of reaction systems, which is one of the characteristics of the flow microsynthesis.

Since the acceleration effect of the flow microreactor was confirmed, we then investigated the scope of initiators and alkyl halides for which the method is suitable. Table [2] shows the reaction times necessary for the reaction yield reaching to a certain value (typically >85% or >99% yield, see Supporting Information for detail). It was revealed that the reaction was accelerated even if a smaller amount of AIBN (1 mol%) was utilized (entry 2). This proves that this speeding-up ability of the flow microreactor works well with smaller amounts of initiators. Moreover, this effect was not limited to AIBN initiated reactions; when using V-70 [2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile)], another azo-type radical initiator, instead of AIBN, the reaction rate was also increased by the flow microsystem (entries 3 and 4). The flow microreactor was also found to accelerate the reactions with an alkyl iodide and an alkyl chloride When using a primary alkyl iodide (1-iodohexadecane), the reaction was accelerated (entry 5). The reduction of a primary alkyl chloride (1-chlorotetradecane) was also accelerated, although the yield was quite low (entry 6).

Table 2 Radical Reduction of Primary Alkyl Halides in a Batch and a Flow Reactor^a

Entry	X	Initiator (mol%)	Reached yield (%)	Method	Time (s)
1	Br	AIBN	>99	batch flow	600  165
2	Br	AIBN	>85	batch flow	1800  377
3	Br	V-70	>99	batch flow	180   24
4	Br	V-70	>85	batch flow	240   57
5	I	V-70	>95	batch flow	120   38
6	Cl	AIBN	>1	batch flow	1440   70

^a Reaction conditions are the same as those in Figure [2]. 1-Iodohexadecane, 1-bromotetradecane, and 1-chlorotetradecane were used as a primary alkyl iodide, bromide, and chloride, respectively.

Because the acceleration ability of flow microreactors for the radical reduction of primary alkyl halides was confirmed, our interest moved to the reduction of alkyl chlorides. Although the reaction rate of the alkyl chloride reduction was certainly increased, the product yields were low both in batch and flow conditions. In order to achieve better yields, the reaction temperature, the concentration of alkyl chlorides, and the amount of the initiator were optimized. When using 0.2 M of 1-chlorotetradecane as an alkyl chloride with 20 mol% of AIBN at 120 °C, the reaction yield increased to more than 75% both in a batch and a flow reactor. Moreover, the flow microreactor achieved the reaction acceleration (>70% yield was obtained within 377 s in flow, whereas 10 min in batch, shown in Figure [2]).

Under the optimized conditions, we then investigated the reduction of alkyl chlorides in both batch and flow reactors. The results are summarized in Table [3]. It is noteworthy that the reactions in flow increased the product yields, because the reaction efficiency was enhanced by flow reactors. In can be seen in Table [3], the reaction yields are shown as ‘reached yield’ which means the yield was recorded when the reaction stopped (see the Supporting Information for details). In the reaction of secondary chloride (2-chloroadamantane), the batch reaction stopped after 600 s (65% yield), whereas the flow conditions reached to 71% yield in the same reaction time. Finally, the flow conditions achieved 82% yield in 942 s (entry 1). The acceleration tendency was also found in the reactions of tertiary alkyl chlorides (entries 2 and 3), and the final yield in entry 3 was increased from 73% to 85%.

We found that when using alkyl chloride as a reaction substrate, a certain amount of distannane was produced. This is likely due to a big bond-dissociation energy (BDE) of the C–Cl bond relative to those of C–I and C–Br bonds. It is well-known that radical reactions involving a C–Cl bond cleavage are less efficient,[10] which means the P-2 step would become slower when X is Cl. The slow propagation step leads to an accumulation of the stannyl radical, which tends to dimerize when the concentration is high, generated by the initiation and P-1 step. In fact, the reaction profile of 1-chloroadamantane (shown in Figure S-1 in the Supporting Information) indicated that 2 was consumed faster than the starting material even in the flow reactor. This result means that some of the tin radicals generated by a faster initiation step was consumed unproductively because the P-2 step is slower.

In general, to control such a reaction in a batch reactor, chemists have taken advantage of a dropwise addition to control the concentration of the radical initiator. This technique prompted us to speculate that if radical initiators were added separately, their concentration would be kept low. That would allow the suppression of the fast consumption of 2, resulting in an increase of the product yield. According to this idea, we constructed a sequential-addition flow system (Figure [3], upper), where initiators can be added at both micromixer M1 and M2. The interval time between those addition events is equal to the residence time in microtube reactor R1 (t ₁). Using this new system, we tried the radical reduction of 1-chloroadamantane (4) with a sequential addition of AIBN. The total amount of AIBN was not changed from 20 mol% but the ratio (x ₁ mol% vs. x ₂ mol%) was varied. Similarly, the interval time between the first addition of AIBN with the second one was varied by changing the length of R1, although the total reaction time (t ₁ + t ₂, 1885 s) was not changed.[11] The yields of the product (adamantane, 5) at the respective AIBN ratios (x₂ mol%) and interval times (t ₁) are summarized in Figure [3] (lower) as a contour map.

Table 3 Radical Reduction of Alkyl Chlorides in a Batch and a Flow Reactor^a

Entry	R-Cl	Reached yield (%)	Method	Time (s)
1		>65b	batch flow	600  282
		82c	flow	942
2d		100b,c	batch flow	1800  282
3		>73b	batch flow	600  188
		85c	flow	1414

^a The reactions were carried out using alkyl chlorides (0.2 M), 2 (1.2 equiv), and 1 (20 mol%) dissolved in xylene at 120 °C.

^b Maximum yield in batch reaction.

^c Maximum yield in flow reaction.

^d Toluene was used instead of xylene because of difficulty in separating the product from xylene in GC.

The map shows that the yields are varied by both x ₂ and t ₁, and that there is a sweet spot to obtain the highest yield. The yields are increased at the right and lower side of the map, and the conditions, where 6 mol% of AIBN was primarily added and after 1200 s, 14 mol% AIBN was added, is the best one (94% yield). The tendency suggests that at the beginning the reaction can proceed with a small amount of the radical species. Thus, lower x ₁ is beneficial because less generation of the tin radical makes the radical deactivation less. On the other hand, at the latter part of the reaction, the concentrations of all reagents become less. Thus, large x ₂ is necessary to make the reaction proceed. Similar tendency was found when using V-70 instead of AIBN (Figure [4], see the Supporting Information for the contour map). This proves that this sequential addition flow system is applicable for increasing the product yield of other radical reduction reactions.

In conclusion, we have demonstrated the acceleration effect of flow microreactors in the context of the radical reduction reactions. The reaction rate for the reduction of the alkyl iodide and bromide, which have smaller bond-dissociation energy, was obviously increased by using a flow microreactor. Meanwhile, as for the reduction of the alkyl chlorides having greater BDE, the flow microreactor enabled not only the acceleration of the reaction but an increase of the reaction yield. The yield was further increased by means of the sequential addition of the initiator, which was accurately controlled by the flow system. Further investigation of radical reactions using this present sequential-addition flow system is underway.

• References and Notes

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

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

Recent examples:
• 4a Fuse S, Mifune Y, Nakamura H, Tanaka H. Nat. Commun. 2016; 7: 13491
  Search in Google Scholar
• 4b Nagaki A, Takahashi Y, Yoshida J. Angew. Chem. Int. Ed. 2016; 55: 5327
  Search in Google Scholar
• 4c Kim H, Min K.-I, Inoue K, Im DJ, Kim D.-P, Yoshida J. Science 2016; 352: 691
  Search in Google Scholar
• 4d Seo H, Katcher MH, Jamison TF. Nat. Chem. 2017; 9: 453
  Search in Google Scholar
• 4e Inuki S, Sato K, Fukuyama T, Ryu I, Fujimoto Y. J. Org. Chem. 2017; 82: 1248
  Search in Google Scholar
• 4f Ashikari Y, Saito K, Nokami T, Yoshida J, Nagaki A. Chem. Eur. J. 2019; 25: 15239
  Search in Google Scholar
• 4g Miyamura H, Tobita F, Suzuki A, Kobayashi S. Angew. Chem. Int. Ed. 2019; 58: 9220
  Search in Google Scholar
• 4h Masui S, Manabe Y, Hirao K, Shimoyama A, Fukuyama T, Ryu I, Fukase K. Synlett 2019; 30: 397
  Search in Google Scholar
• 4i Elsherbini M, Winterson B, Alharbi H, Folgueiras-Amador AA, Génot C, Wirth T. Angew. Chem. Int. Ed. 2019; 58: 9811
  Search in Google Scholar
• 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
  Search in Google Scholar
• 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
  Search in Google Scholar
• 4l Ichinari D, Ashikari Y, Mandai K, Aizawa Y, Yoshida J, Nagaki A. Angew. Chem. Int. Ed. 2020; 59: 1567
  Search in Google Scholar
• 4m Colella M, Tota A, Takahashi Y, Higuma R, Ishikawa S, Degennaro L, Luisi R, Nagaki A. Angew. Chem. Int. Ed. 2020; 59: 11924
  Search in Google Scholar
• 5 Fukuyama T, Fujita Y, Rashid MA, Ryu I. Org. Lett. 2016; 18: 5444
  Search in Google Scholar
• 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
  Search in Google Scholar
• 7b Mizuno K, Nishiyama Y, Ogaki T, Terao K, Ikeda H, Kakiuchi K. J. Photochem. Photobiol., C 2016; 29: 107
  Search in Google Scholar
• 7c Cambié D, Bottecchia C, Straathof NJ. W, Hessel V, Noël T. Chem. Rev. 2016; 116: 10276
  Search in Google Scholar
• 7d Otake Y, Nakamura H, Fuse S. Tetrahedron Lett. 2018; 59: 1691
  Search in Google Scholar
• 7e Politano F, Oksdath-Mansilla G. Org. Process Res. Dev. 2018; 22: 1045
  Search in Google Scholar
• 8 Fukuyama T, Kobayashi M, Rahman MT, Kamata N, Ryu I. Org. Lett. 2008; 10: 533
  Search in Google Scholar
• 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
  Search in Google Scholar
• 10b Ingold KU, Lusztyk J, Scaiano JC. J. Am. Chem. Soc. 1984; 106: 343
  Search in Google Scholar
• 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.

Corresponding Author

Publication History

Received: 04 August 2020

Accepted after revision: 02 September 2020

Article published online:
09 October 2020

© 2020. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References and Notes

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

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

Recent examples:
• 4a Fuse S, Mifune Y, Nakamura H, Tanaka H. Nat. Commun. 2016; 7: 13491
  Search in Google Scholar
• 4b Nagaki A, Takahashi Y, Yoshida J. Angew. Chem. Int. Ed. 2016; 55: 5327
  Search in Google Scholar
• 4c Kim H, Min K.-I, Inoue K, Im DJ, Kim D.-P, Yoshida J. Science 2016; 352: 691
  Search in Google Scholar
• 4d Seo H, Katcher MH, Jamison TF. Nat. Chem. 2017; 9: 453
  Search in Google Scholar
• 4e Inuki S, Sato K, Fukuyama T, Ryu I, Fujimoto Y. J. Org. Chem. 2017; 82: 1248
  Search in Google Scholar
• 4f Ashikari Y, Saito K, Nokami T, Yoshida J, Nagaki A. Chem. Eur. J. 2019; 25: 15239
  Search in Google Scholar
• 4g Miyamura H, Tobita F, Suzuki A, Kobayashi S. Angew. Chem. Int. Ed. 2019; 58: 9220
  Search in Google Scholar
• 4h Masui S, Manabe Y, Hirao K, Shimoyama A, Fukuyama T, Ryu I, Fukase K. Synlett 2019; 30: 397
  Search in Google Scholar
• 4i Elsherbini M, Winterson B, Alharbi H, Folgueiras-Amador AA, Génot C, Wirth T. Angew. Chem. Int. Ed. 2019; 58: 9811
  Search in Google Scholar
• 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
  Search in Google Scholar
• 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
  Search in Google Scholar
• 4l Ichinari D, Ashikari Y, Mandai K, Aizawa Y, Yoshida J, Nagaki A. Angew. Chem. Int. Ed. 2020; 59: 1567
  Search in Google Scholar
• 4m Colella M, Tota A, Takahashi Y, Higuma R, Ishikawa S, Degennaro L, Luisi R, Nagaki A. Angew. Chem. Int. Ed. 2020; 59: 11924
  Search in Google Scholar
• 5 Fukuyama T, Fujita Y, Rashid MA, Ryu I. Org. Lett. 2016; 18: 5444
  Search in Google Scholar
• 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
  Search in Google Scholar
• 7b Mizuno K, Nishiyama Y, Ogaki T, Terao K, Ikeda H, Kakiuchi K. J. Photochem. Photobiol., C 2016; 29: 107
  Search in Google Scholar
• 7c Cambié D, Bottecchia C, Straathof NJ. W, Hessel V, Noël T. Chem. Rev. 2016; 116: 10276
  Search in Google Scholar
• 7d Otake Y, Nakamura H, Fuse S. Tetrahedron Lett. 2018; 59: 1691
  Search in Google Scholar
• 7e Politano F, Oksdath-Mansilla G. Org. Process Res. Dev. 2018; 22: 1045
  Search in Google Scholar
• 8 Fukuyama T, Kobayashi M, Rahman MT, Kamata N, Ryu I. Org. Lett. 2008; 10: 533
  Search in Google Scholar
• 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
  Search in Google Scholar
• 10b Ingold KU, Lusztyk J, Scaiano JC. J. Am. Chem. Soc. 1984; 106: 343
  Search in Google Scholar
• 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.

• Supplementary Material