Machine assisted reaction optimization: A self-optimizing
reactor system for continuous-flow photochemical reactions
Item Type Article
Authors Poscharny, K.; Fabry, D.C.; Heddrich, S.; Sugiono, E.; Liauw, M.A.; Rueping, Magnus
Citation Poscharny K, Fabry DC, Heddrich S, Sugiono E, Liauw MA, et al. (2018) Machine assisted reaction optimization: A self-optimizing reactor system for continuous-flow photochemical reactions. Tetrahedron. Available: http://dx.doi.org/10.1016/ j.tet.2018.04.019.
Eprint version Post-print
DOI 10.1016/j.tet.2018.04.019
Publisher Elsevier BV
Journal Tetrahedron
Rights NOTICE: this is the author’s version of a work that was accepted for publication in Tetrahedron. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Tetrahedron, 7 April 2018. DOI: 10.1016/j.tet.2018.04.019. © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http:// creativecommons.org/licenses/by-nc-nd/4.0/
Machine Assisted Reaction Optimization: A Self-Optimizing Reactor
System for Continuous-Flow Photochemical Reactions
Konstantin Poscharny, David C. Fabry, Steffen Heddrich,
Erli Sugiono, Marcel A. Liauw, Magnus Rueping
Sampling was performed at steady state:after a minimum of three retention times and a standard deviation of ≤ 7·10-4
. After the IR analysis using ReactIR® (Mettler Toledo)[1] was complete, the MSIM-algorithm[2] calculated the next parameter set and forwarded this information to the relevant system components.
Experimental Setup: HPLC Pump Knauer K-120 (Dr. Ing. Herbert Knauer GmbH)[3], autosampler AutoSam200 (HiTec Zhang GmbH)[4] and Upchurch Scientific (IDEX Health & Science LLC)[5] connectors. MSIM-algorithm implemented as Matlab 7 plugin to LabView 2010 based on [4]; valve and autosampler controlled by LabView 2010 via serial RS-232 connections. The starting tetragon was created with one starting point P1 and an edge length c based on a method of [6].
P1 starting point (vector: flow rate, temperature, pressure) Pi other points of starting tetragon (i = 2 – 4)
c edge length
a corrector value [25 1 0.75]
Setup of photoreactor
• Tube length = 2x10 m (less 60 cm from photoreactor to IR cell) • Tube length between photoreactors = 15 cm
• Tube diameter (inside) = 0.8 mm, (outside) = 1.58 mm Rotilabo®
- FEP-tube transparent Carl Roth®
• Tube volume at reactor = 5 mL
• Tube volume at reactor (self-optimization) = 10 mL • One check valve after each pump
• Volume (IR cell) = 50µL
• Effective height of tube at photoreactor = 16 cm
• Knauer Smartline 100 pumps (deviation of 2.7% for 16 h at 0.05 mL/min)
• 2x TQ150 lamps with Pyrex-coat + Pyrex-shaft, T(cooling) = 25 °C, T(real, distant to lamp 2 cm) = 33 °C
• Furan degased and filtered
• 1:1 mixture of furan to benzophenone in furan c(Benzophenone) = 0.1 M
Hg-lamp emission, in decreasing intensity order: 365, 334, 312-13, 297-302 and 254 nm (Handbook of Photochemistry, 3rd Edition, 2006, pp. 588).
Pyrex transmission http://www.quartz.com/pxprop.pdf
Table 1: Comparison of batch and flow conditions.
Entry[a] Time (min) Yield[b] (%) GC[c] (%)
1 (batch) 80 3 3
2 (batch) 120 9 9
3 (batch) 240 17 15
4 (batch) 320 18 18
5[d] (flow) 83 97[e] 98
[a] Batch reaction conditions: 2a (2.05 mmol), furan (15 mL). [b] Calculated yield from NMR. [c] GC conversions [d] Flow reaction conditions: 2 (2.73 mmol), furan (20 mL), flow rate 60 μL/h. [e] Yield after purification by column chromatography.
Batch type reactions were conducted in a commercially available Rayonet® reactor with
indicated bulbs for corresponding emission wavelength. During the irradiation, the vials were stirred using magnetic stirrer bars. The reactor interior was cooled using pressured air.
Experimental procedures and characterization of compounds.
General: Unless otherwise noted, all commercially available compounds were used as provided without further purification. Solvents for chromatography were technical grade and distilled prior to use. Analytical thin-layer chromatography (TLC) was performed on Merck silica gel 60 aluminium plates with F-254 indicator, visualised by UV irradiation. Column chromatography was performed using Macherey-Nagel silica gel (particle size 0.040-0.063 mm). 1H-NMR and 13C-NMR were recorded on a Varian Mercury 300, Varian Inova 400 or Inova 600 spectrometer in CDCl3 with residual proton signal of the deuterated solvents as the
internal reference (δH = 7.26 ppm and δC = 77 ppm for CDCl3). Data are reported in the
following order: chemical shift (δ) in ppm; multiplicities are indicated s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), ddd (doublet of doublets of doublets), dt (doublet of triplets); coupling constants (J) are in Hertz (Hz). (MS-EI, 70 eV) were conducted on Finnigan SSQ 7000. IR spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR spectrometer and are reported in terms of frequency of absorption (cm
-1
). Melting points were measured on a Büchi B-540 apparatus and are reported in Celsius degrees. All experiments were performed by using an Original Hanau TQ 150 medium-pressure 150 W mercury lamp with a Pyrex-glass cooling shaft, wrapped with a transparent Rotilabo®-FEP-tube with an inner diameter of 0.8 mm and a total length of 10 m. The flow rate was controlled using a Knauer K-120 pump.
General procedure for the Paternò-Büchi Photocycloaddition.
Preparation of exo-6-Phenyl-2,7-dioxabicyclo[3.2.0]hept-3-ene (3a)
A solution of benzaldehyde (2.73 mmol) in 20 mL of degassed furan was pumped through a 5 mL loop with a flow rate of 60 μL min-1 while being irradiated with a medium-pressure Hg lamp at 25 °C. The solvent was evaporated and the crude product was purified by column chromatography (SiO2, n-hexane/ethyl acetate 20:1).
exo-6-(p-Tolyl)-2,7-dioxabicyclo[3.2.0]hept-3-ene (3b) colorless solid, mp: 43-45 °C; 1H-NMR (300 MHz, CDCl3): δ = 7.34 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 6.73–6.70 (m, 1H), 6.55 (d, J = 4.4 Hz, 1H), 5.55 (d, J = 3.1 Hz, 1H), 5.47 (t, J = 2.9 Hz, 1H), 3.68–3.63 (m, 1H), 2.38 (s, 3H); 13C-NMR (75 MHz, CDCl3): δ = 148.4, 138.2, 138.0, 129.4, 125.4, 108.2, 104.4, 92.8, 52.6, 21.2; IR (KBr): ν = 3104, 2922, 1608, 1512, 1205, 1041, 936, 803, 743, 683, 561; MS-EI: m/z (%): 188 (M+, 1), 159 (10), 145 (11), 131 (13), 119 (75), 91 (37), 68 (M–119, 100); HRMS: calcd. for C12H12O2 [M]+ 188.08318; found 188.08338. exo-6-(o-Tolyl)-2,7-dioxabicyclo[3.2.0]hept-3-ene (3c)[7] colorless solid, mp: 37-38 °C; 1H-NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 7.5 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.23 (td, J = 7.4 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 6.74–6.73 (m, 1H), 6.45 (d, J = 4.5 Hz, 1H), 5.71 (d, J = 3.3 Hz, 1H), 5.49 (t, J = 2.9 Hz, 1H), 3.60–3.55 (m, 1H), 2.18 (s, 3H); 13 C-NMR (100 MHz, CDCl3): δ = 148.8, 139.3, 133.4, 130.1, 127.6, 126.2, 123.5, 107.9, 104.0, 90.5, 51.7, 18.5; IR (KBr): ν = 2971, 2918, 1605, 1462, 1277, 1206, 1133, 1036, 943, 895, 751, 722, 672; MS-EI: m/z (%): 188 (M+, 1), 171 (2), 159 (8), 145 (9), 131 (9), 119 (77), 91 (36), 68 (M–119, 100); HRMS: calcd. for C12H12O2 [M]+ 188.08318; found 188.08341.
(10), 91 (12), 77 (7), 68 (18); HRMS: calcd. for C14H16O2Na [M+Na]+ 239.10425; found
239.10420.
exo-6-(4-(t-Butyl)phenyl)-2,7-dioxabicyclo[3.2.0]hept-3-ene (3f)
pale yellow oil; 1H-NMR (600 MHz, CDCl3): δ = 7.46 (d, J = 8.2 Hz,
2H), 7.38 (d, J = 8.2 Hz, 2H), 6.73–6.71 (m, 1H), 6.56 (d, J = 4.4 Hz, 1H), 5.56 (d, J = 3.1 Hz, 1H), 5.47 (t, J = 2.9 Hz, 1H), 3.71–3.67 (m, 1H), 1.35 (s, 9H); 13C-NMR (150 MHz, CDCl3): δ = 151.4, 148.5, 138.3, 125.8, 125.3, 108.4, 104.4, 92.9, 52.5, 34.8, 31.5; IR (KBr): ν = 3454, 3107, 2961, 2727, 1914, 1701, 1605, 1465, 1364, 1218, 1130, 1045, 955, 827, 737, 680, 552; MS-EI: m/z (%): 230 (M+, 1), 201 (3), 187 (6), 161 (M–68, 44), 147 (100), 119 (18), 91 (31), 77 (6), 68 (99), 57 (18); HRMS: calcd. for C15H18O2 [M]+ 230.13013; found 230.13041.
exo-6-(2-Cyanophenyl)-2,7-dioxabicyclo[3.2.0]hept-3-ene (3g) colorless solid, mp: 69-71 °C; 1H-NMR (300 MHz, CDCl3): δ = 7.87–7.81 (m, 1H), 7.73–7.66 (m, 2H), 7.46–7.39 (m, 1H), 6.75–6.73 (m, 1H), 6.50– 6.47 (m, 1H), 5.87 (d, J = 3.0 Hz, 1H), 5.64 (t, J = 2.9 Hz, 1H), 3.75–3.70 (m, 1H); 13C-NMR (75 MHz, CDCl3): δ = 148.9, 145.4, 133.5, 133.0, 128.4, 125.3, 116.9, 108.9, 108.2, 104.7, 90.0, 52.9; IR (KBr): ν = 2928, 2224, 1725, 1602, 1479, 1451, 1278, 1188, 1124, 1041, 1000, 939, 856, 768, 710, 677; MS-EI: m/z (%): 199 (M+, 1), 170 (1), 143 (7), 142 (4), 130 (2), 115 (13), 102 (4), 89 (4), 77 (3), 68 (M–131, 100), 52 (3); HRMS: calcd. for C12H9O2NNa [M+Na]+ 222.05255; found 222.05188.
exo-6-(4-Fluorophenyl)-2,7-dioxabicyclo[3.2.0]hept-3-ene (3h)
pale yellow oil; 1H-NMR (600 MHz, CDCl3): δ = 7.41 (dd, J = 5.3, 8.4
Hz, 2H), 7.10 (t, J = 8.4 Hz, 2H), 6.72–6.70 (m, 1H), 6.53 (d, J = 4.4 Hz, 1H), 5.54 (d, J = 3.1 Hz, 1H), 5.47 (t, J = 2.7 Hz, 1H), 3.66–3.60 (m, 1H); 13C-NMR (150 MHz, CDCl3): δ = 162.5 (d, JCF = 246.9 Hz), 148.7, 137.0, 127.2 (d, JCF = 8.2 Hz), 115.6 (d, JCF = 21.7 Hz), 108.3, 104.2, 92.3, 52.8; 19 F-NMR (282 MHz, CDCl3): δ = 113.86 (F); IR (KBr): ν = 3455, 2937, 2739, 1902, 1698, 1600, 1509, 1296, 1228, 1154, 1092, 951, 837, 757, 599, 508; MS-EI: m/z (%): 192 (M+, 14), 175 (42), 163 (54), 149 (22), 135 (54), 123 (M–68, 100), 109 (59), 95 (64), 86 (36), 75 (28), 68 (20), 58 (39); HRMS: calcd. for C11H9O2F [M]+ 192.05811; found 192.05834.
exo-6-(2,4-Difluorophenyl)-2,7-dioxabicyclo[3.2.0]hept-3-ene (3i)
pale yellow oil; 1H-NMR (400 MHz, CDCl3): δ = 7.57 (dt, J = 6.4, 8.6
Hz, 1H), 6.98–6.91 (m, 1H), 6.83 (ddd, J = 10.5, 8.8, 2.5 Hz, 1H), 6.73– 6.70 (m, 1H), 6.48 (d, JF = 4.4 Hz, 1H), 5.68 (d, JF = 3.2 Hz, 1H), 5.50 (t, J = 2.9 Hz, 1H), 3.75–3.69 (m, 1H); 13C-NMR (100 MHz, CDCl3): δ = 162.9 (dd, JCF = 249.3, 11.8 Hz), 159.8 (dd, JCF = 249.4, 12.1 Hz), 148.8, 128.1 (dd, JCF = 9.8, 5.9 Hz), 124.6 (dd, JCF = 13.8, 3.7 Hz), 111.5 (dd, JCF = 21.2, 3.6 Hz), 108.4, 104.3, 104.1 (dd, JCF = 25.6, 24.8 Hz), 87.3 (d, JCF = 2.5 Hz), 52.0; 19F-NMR (282 MHz, CDCl3): δ = 110.28 (F), 114.78 (F); IR (KBr): ν = 3444, 3108, 3082, 2980, 2920, 2852, 1607, 1502, 1429, 1272, 1137, 1047, 965, 853, 725, 678; MS-EI: m/z (%): 210 (M+, 1), 181 (7), 165 (4), 151 (14), 141 (16), 133 (15), 127 (19), 113 (7), 83 (6), 75 (4), 68 (M–142, 100), 57 (3); HRMS: calcd. for C11H8O2F2 [M]+ 210.04869; found 210.04866.
exo-6-(3-(Trifluoromethyl)phenyl)-2,7-dioxabicyclo[3.2.0]hept-3-ene (3j) colorless oil; 1H-NMR (300 MHz, CDCl3): δ = 7.71–7.67 (m, 1H), 7.65–7.51 (m, 3H), 6.74– 6.73 (m, 1H), 6.55 (d, J = 4.4 Hz, 1H), 5.63 (d, J = 3.2 Hz, 1H), 5.50 (t, J = 2.9 Hz, 1H), 3.69–3.64 (m, 1H); 13C-NMR (75 MHz, CDCl3): δ = 148.9, 142.3, 131.3 (q, JCF = 32.4 Hz), 129.4, 128.6, 125.0 (q, JCF = 3.8 Hz), 124.1 (q, JCF = 272.5 Hz), 122.1 (q, JCF = 3.8 Hz), 108.3, 104.1, 91.8, 52.8; 19F-NMR (282 MHz, CDCl3): δ = 62.65 (CF3); IR (KBr): ν = 3463, 3110, 2973, 2922, 1707, 1607, 1449, 1330, 1170, 1127, 1047, 959, 803, 701, 661, 558; MS-EI: m/z (%): 242 (M+, 2), 225 (15), 213 (4), 185 (3), 173 (12), 145 (16), 69 (8), 68 (M–174, 100), 57 (3); HRMS: calcd. for C12H9O2F3 [M]+ 242.05492; found 242.05518.
6,6-Diphenyl-2,7-dioxabicyclo[3.2.0]hept-3-ene (3l)[8] colorless solid, mp: 104-106 °C; 1H-NMR (600 MHz, CDCl3): δ = 7.52 (d, J = 8.4 Hz, 2H), 7.42–7.37 (m, 2H), 7.36–7.26 (m, 5H), 7.23–7.18 (m, 1H), 6.49–6.45 (m, 1H), 6.36 (d, J = 4.2 Hz, 1H), 5.00–4.99 (m, 1H), 4.44–4.42 (m, 1H); 13C-NMR (150 MHz, CDCl3): δ = 148.2, 145.7, 142.7, 128.6, 128.0, 127.5, 127.0, 125.5, 125.3, 105.3, 102.8, 94.6, 56.2; IR (KBr): ν = 3438, 3060, 3028, 2973, 2920, 2851, 1957, 1730, 1605, 1491, 1447, 1280, 1211, 1133, 1048, 1024, 964, 929, 848, 728, 700, 660, 554; MS-EI: m/z (%): 250 (M+, 1), 221 (1), 182 (81), 165 (21), 115 (17), 105 (100), 77 (28), 68 (57), 51 (8). 1-Methyl-6,6-diphenyl-2,7-dioxabicyclo[3.2.0]hept-3-ene (3m)[9] colorless solid, mp: 124-126 °C; 1H-NMR (400 MHz, CDCl3): δ = 7.54– 7.48 (m, 2H), 7.41–7.31 (m, 4H), 7.30–7.23 (m, 3H), 7.20–7.14 (m, 1H), 6.39 (dd, J = 2.9, 1.1 Hz, 1H), 4.90 (t, J = 2.9 Hz, 1H), 4.16 (dd, J = 2.9, 1.1 Hz, 1H), 1.57 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ = 147.9, 145.4, 143.1, 128.4, 128.0, 127.2, 126.8, 125.5, 125.4, 113.0, 102.9, 91.2, 57.5, 23.1; IR (KBr): ν = 3060, 2965, 2928, 1726, 1656, 1601, 1490, 1444, 1383, 1314, 1275, 1210, 1105, 1023, 943, 865, 759, 699; MS-EI: m/z (%): 264 (M+, 1), 221 (20), 183 (71), 165 (26), 115 (21), 105 (87), 82 (M–182, 100), 77 (49), 51 (16). References [1] http://us.mt.com/us/en/home/products/L1_AutochemProducts/L2_in-situSpectrocopy.html [2] Morgan, E.; Burton, K. W.; Nickless, G.; Chemom. Intell. Lab. Syst. 1990, 7, 209–222. [3]
http://www2.knauer.net/e/e_index.html?cf=%27http://www2.knauer.net/cgi-bin/e_prodpage.pl?artnr=A41509&zusatz=10%20ml%20pump%20head%2C%20inert%2C%20with% 20titanium%20inlays&ptype=Pumps%27
[4] http://www.hitec-zang.de/de/liquid-handlinglaborroboter/automatischer-probensammler.html [5] http://webstore.idex-hs.com/
[6] Spendley, W.; Hext, G. R.; Himsworth, F. R. Technometric 1962, 4, 441–461. [7] Griesbeck, A. G.; Stadtmüller, S. Chem. Ber. 1990, 123, 357–362.
[8] Bolívar, R. A.; Doppert, K.; Rivas, C. J. Heterocycl. Chem. 1982, 19, 317–320.
