Supporting Information

Transcription

1 Supporting Information Visible light-induced trifluoromethylation and perfluoroalkylation of cysteine residues in batch and continuous-flow Cecilia Bottecchia, Xiao-Jing Wei, Koen P. L. Kuijpers, Volker Hessel and Timothy Noёl* Department of Chemical Engineering and Chemistry, Micro Flow Chemistry & Process Technology, Eindhoven University of Technology Den Dolech 2, 5612 AZ Eindhoven, The Netherlands. 1

2 Content Reaction Set-ups... 3 Light sources and their emission spectra... 5 Quantum Yield measurements... 7 Spectra

3 Reaction Set-ups Batch Set-up A 5 ml vial with septum was loaded with the reagents and placed in the proximity of a 24 W white CFL (around 2 cm distance). Cooling of the reaction was insured via an air stream directed towards the vial. Flow Set-up All microfluidic fittings were purchased from IDEX Health and Science. The syringes were connected to the capillary using ¼-28 flat-bottom flangeless fittings. A syringe pump (Fusion 200 Classic) equipped with 5 ml syringes was used to feed liquid reagents through a high purity perfluoroalkoxyalkane (PFA) capillary tubing (ID = 760 µm) to a Tefzel tee mixer (ID = 500 µm). A Bronkhorst mass flow controller was used to introduce CF 3 I into the reaction mixture, prior to the entrance in the microreactor. For a detailed procedure on the manufacturing of photomicroreactors, we refer to 1. Flow Set-up 1: gas-liquid system The gas-liquid flow set-up 1 was used for the trifluoromethylation of cysteine derivatives 2a-b, 4 and 5, with gaseous CF 3 I as source of trifluoromethyl group. Cooling of the reaction mixture was granted by a stream of compressed air inserted at the bottom of the reactor holder. At the inlet of the reactor, after the gaseous and liquid phases were combined with a T-mixer, the formation of a gas-liquid slug flow was observed. However, due to the high solubility of CF 3 I in CH 3 CN, the slugs are not persistent through the reactor, and a liquid flow is obtained at the outlet of the reactor. A schematic representation of the flow set-up is shown in Figure S1, while a picture is shown in Figure S2. Figure S1: Schematic representation of the gas-liquid flow system used for the trifluoromethylation of derivatives 2a-b, 5. 3

4 Figure S2: Picture of the gas-liquid flow system used for the trifluoromethylation of derivatives 2a-b, 5. Flow Set-up 2: liquid-liquid system The liquid-liquid flow set-up 2 was used for the synthesis of the perfluoroalkylated derivatives 3a-h. Cooling of the reaction mixture was granted by a stream of compressed air inserted at the bottom of the reactor holder. A schematic representation of the flow set-up is shown in Figure S3. B) Perfluoroalkylation of cysteine in flow N-Boc-Cys-OMe, Ru(bpy) 3 Cl 2, ACN 88.3 µl min -1 PFA microreactor 760 µm ID, 883 µl O S R F I-R F,TMEDA, ACN 88.3 µl min -1 MeO C HN OtBu O Figure S3: Schematic representation of the liquid-liquid flow system used for the perfluoroalkylation of derivatives 3a-d, 3h. 4

5 Light sources and their emission spectra The emission of the used light sources was recorded using an integrating sphere equipped with a Labsphere LPS light detector array. Calex daylight Calex high quality CFL, daylight E V, 1460 Lumen, 24 Watt Figure S4: Emission spectrum for the 24 W white Calex CFL. 5

6 Blue LED strip Paulmann YourLED, stripe blue 97 cm, 78 Lumen, 3.12 Watt NORMALIZED INTENISTY ( ) WAVELENGTH (NM) Figure S5: Emission spectrum for Paulmann YourLED, stripe blue 97 cm, 78 Lumen, 3.12 Watt 6

7 Quantum Yield measurements The actinometry experiments were conducted with a AvaSpec- 2048L spectrophotometer from Avantes, equipped with an Avalight-DH-S-BAL light source. In order to quantify the mechanism involved in the trifluoromethylation of N-Boc-Cys-OMe (1), quantum yield measurements were performed. As shown by Scaiano et al., 2 these measurements can be done by the use of a Ru(bpy) 3 Cl 2 actinometer, which in the case of our transformation is also the photocatalyst. The quantum yield measurements consist typically of three steps: 1. First of all, the actinometer is measured, 2. Secondly, the photon flux is determined 3. Thirdly, the reaction of interest is performed with the same catalyst concentration of the actinometer experiment. Every other parameter is also kept under exactly the same conditions (e.g. reactor volume, light irradiation, residence time, temperature, pressure). 4. Finally, by comparison between the actinometer and the reaction of interest, the quantum yield for the transformation of interest can be calculated. It is worth nothing that the quantum yields experiments were performed in flow both for the trifluoromethylation reaction and the actinometer. We decided to use the calibrated oxidation of 1,9-diphenylanthracene (DPA) with singlet oxygen and Ru(bpy) 3 Cl 2 as actinometer. The quantum yield of this transformation is known to be of ϕ =0.019, thus allowing to derive the photon flux (φ) in our system, as depicted in Equation S1. The photon flux results obtained for the system can then be used together with the measured yield of our transformation to obtain the quantum yield of our reaction, as shown in Equation S2. Equation S1: Equation S2: It must be noted that for the quantum yield determination of our reaction, we were limited to some constriction. For instance, we were limited to the use of a 0.1 mm catalyst loading (10 times lower than in the standard reaction conditions) due to the specifications of the spectrophotometer. Also, when we first investigated the trifluoromethylation of cysteine the reaction appeared to be very fast. Thus, in order to provide 4 equiv. of CF 3 I while maintaining a short residence time, a gas flow rate higher than what allowed by the CF 3 I mass flow controller (MFC, 5 ml/min max flow rate) was needed. Therefore, in order to perform all measurements in the linear part of the conversion curve (where the quantum yield should be constant), we chose to use a smaller reactor volume and lower residence times. An overview of the differences between the standard reactor and the shorter reactor used for quantum yields measurements can be seen in Table S1. Table S1: Comparison of conditions between actinometry and the general procedure Parameter Actinometry General procedure Reactor volume ml ml Catalyst concentration 1.0 mm 0.1 mm CF 3 I:cysteine 2:1 4:1 In Figure S6 the measured conversion obtained for our reaction are shown. With only 0.1 mol% of catalyst loading the reaction already showed optimal yield within 30 seconds residence time. It can also be noted that not the full 7

8 linear part of the conversion curve could be obtained with the settings and devices available; however, the conversion values can still be used for a good estimation of the quantum yield. Yield 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Residence time (s) Figure S6: Reaction experiment; C cysteine = 0.1 M, C cat = 0.1 mm, CF 3 I: cysteine ratio = 2:1 Figures S6 and S7 show the conversion of the actinometry reaction and the trifluoromethylation reaction, respectively. Figure S7 also shows the accuracy of the linear part of the actinometry, as a R 2 value of is obtained. This linear part should result in a constant photon flux, which is shown in Figure S8. A photon flux (φ) of Einstein/s was obtained, computed from the four values in the linear part of the conversion curve from Figure S7. 100% 90% Conversion 80% 70% 60% 50% 40% 30% 20% 10% 0% y = x R² = Residence time (s) Figure S7 Actinometry; C DPA = 0.1 mm, C cat = 0.1 mm 8

9 4.0E 08 Photonflux (Einstein/s) 3.5E E E E E E E 09 φ = 2.48E 08 Einstein/s 0.0E Residence time (s) Figure S8: Photon flux Finally, the quantum yield for our reaction was calculated according to Equation S2, by considering the first three data points of the conversion curve (Figure S6), the closest to the linear part of the conversion curve. The results are shown in Table S2. The different values obtained for the quantum yield show that the conversion curve is indeed not in the linear part anymore. This means that the actual quantum yield value would be higher, if calculated with values from the linear part of the curve. Table S2 also shows quantum yield values, much larger than 1 (ϕ >> 1), proving that chain propagating single electron transfer steps must be involved in our reaction mechanism. A proposed mechanism for the light-induced perfluoroalkylation of cysteine can be found in Scheme 5 of the manuscript. Table S2: Quantum yield of the trifluoromethylation of cysteine Residence time (s) Yield (%) Quantum yield (%)

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48 References: 1. Straathof, N. J. W.; Su, Y.; Hessel, V.; Noël, T., Nat. Protoc. 2015, 11, Pitre, S. P.; McTiernan, C. D.; Vine, W.; DiPucchio, R.; Grenier, M.; Scaiano, J. C., Sci. Rep. 2015, 5,