In order to increase the scale of the reaction, a 1 g “batch” reaction was attempted in a 50 mL round bottom flask (25 mm in diameter) using our light-mediated radical conjugate addition into
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acrolein (Scheme 5.13).91 While 85% conversion was obtained, the reaction required 24 hours of irradiation on this scale for a net turnover frequency (TOF) of 3.5 h-1. A comparable reaction on a 25 mg-scale reaction in a 5 mm diameter NMR tube afforded 73% conversion after only one hour of irradiation, a TOF of 70 h-1 (Scheme 5.13). This is a general trend we have observed in our investigations; thinner reaction vessels generally result in faster reaction rates. For a potential explanation of this, we considered the absorption profile of these reaction mixtures at relevant concentrations. The molar extinction coefficients for RuL3
2+
complexes are high, in the range of 14000 M-1cm-1 for L = bpy to 170000 M-1cm-1 for L = dmb, and we considered the possibility the reactions were light-starved. This is consistent with our previous observations as described in Chapter 4. In this scenario, the light source fails to provide sufficient photons to irradiate the entire reaction volume. A simple analysis of the absorption profile at relevant concentrations of Ru(dmb)3
2+
at increasing vessel diameters using the Beer-Lambert law is shown in Figure 5.1.
Figure 5.1: % Transmittance vs distance (d) from the Wall from the Beer-Lambert law. Circle = 0.5 mM Ru(dmb)3 2+ , triangle = 1 mM Ru(dmb)3 2+ , square = 2 mM Ru(dmb)3 2+ .
From this analysis, it can be concluded the vast majority of the reaction volume receives negligible light. At 1 mM catalyst loading, 98% of the incident light is absorbed within 1 mm of the vessel wall. Since the absorption of photons is required to generate “active catalyst” (i.e. RuL3
+
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reductant), this 1 mm volume represents the “active volume” of the vessel. The remaining volume in the vessel only serves to dilute the concentration of the reagents, which in turn decreases the forward rate of the reaction. This is consistent with lower TOFs observed in larger diameter vessels. By extension, continually thinner vessels should provide increased rates of reaction by increasing the concentration of the reagents within the “active volume”. However, thinner reaction vessels would decrease the overall scale of the reaction and limit the amount of material produced in a given “batch” reaction. Our solution to obtaining sufficiently thin reaction vessel diameters without sacrificing reaction volume was a photo-flow reactor, which allows for the reaction mixture to be continuously flowed through tubing around a light source. In this manner, the rate of the reaction is rendered independent of the reaction scale, which is opposite of “batch” reactions.
The basic design principle for photoflow reactors was initially reported by Booker-Milburn in 2005 for large-scale UV-initiated cycloadditions.122 Since this time, several more examples of photo- flow reactor designs have been reported,123 the most recent of which was reported by Lévesque and Seeberger.124 In the report, the authors detail the large-scale synthesis of the anti-malarial drug artemisinin through a continuous-flow reactor that incorporated multiple synthetic steps, including a photo-mediated step, into a single reactor. With this reactor design, the authors estimated the reactor was capable of synthesizing 200 g of artemisinin per day and that 1500 of these relatively simple and
122 Hook, B. D. A.; Dohle, W.; Hirst, P. R.; Pickworth, M.; Berry, M. B.; Booker-Milburn, K. I., J. Org. Chem.
2005, 70, 7558-7564.
123 a) Vaske, Y. S. M.; Mahoney, M. E.; Konopelski, J. P.; Rogow, D. L.; McDonald, W. J., J. Am. Chem. Soc.
2010, 132, 11379-11385. b) Laurino, P.; Kikkeri, R.; Azzouz, N.; Seeberger, P. H., Nano Lett. 2011, 11, 73-78. c) Lévesque, F.; Seeberger, P. H., Org. Lett. 2011, 13, 5008-5011. d) Gutierrez, A. C.; Jamison, T. F., Org. Lett.
2011, 13, 6414-6417. e) Bourne, R. A.; Han, X.; Poliakoff, M.; George, M. W., Angew. Chem., Int. Ed. 2009,
48, 5322-5325.
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inexpensive reactors could satisfy the annual global demand for this drug. This example clearly demonstrates the potential of photo-flow reactors not only in small-scale laboratory experiments but also in large-scale process chemistry for the synthesis of advanced therapeutics. We hoped to contribute to this thriving area of research through the development of reactors for highly-absorbing photosensitizers to compliment photoreactors designed for the poorly-absorbing sensitizers typically employed in these UV-light mediated processes.
Figure 5.2: Diagram of the Designed Photo-flow Reactor.
Our reactor design utilizes fluorinated ethylene propylene (FEP) tubing coiled around the outside of a Liebigs condenser with three 12” blue LED strips on the inside (Figure 5.2). FEP tubing is versatile, flexible, and chemically resistant and has excellent light transmission properties. In order to mitigate the thermal output of the LEDs, cooling water is passed through the water jacket of the condenser. A prep-HPLC pump precisely controls the flow rate of the reaction mixture through the tubing in order to control the reaction time. As opposed to the Booker-Milburn design, only a single layer of tubing can be used, as the extra layers would receive negligible light. The ends of the tubing were fitted with Swagelok connectors to allow for several “modules” to be connected in series to increase the residence time without decreasing flow rate, which would decrease the amount of product produced per hour.
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Evaluation of Photo-Flow Reactor.
Figure 5.3: TOF vs [Ru(dmb)32+] at Two Tubing Diameters;circle=1/32”IDFEPtubing,triangle=1/16”FEP tubing.
The efficiency of this flow reactor design was evaluated at three concentrations of catalyst and two diameters of tubing. At 1.6 mm I.D. tubing and 1.1 mM [Ru(dmb)3
2+
], a 30 h-1 net TOF was observed for one module at a flow rate of 0.1 mL/min (Figure 5.3). Increasing the photocatalyst concentration to 2.2 mM resulted in lower TOFs (17 h-1), and decreasing the photocatalyst concentration to 0.5 mM increased the observed rate of reaction (TOF = 50 h-1). As predicted by the analysis in Figure 5.1, we found thinner reaction tubing significantly increased the rate of the reaction. At 1.1 mM [Ru(dmb)3
2+
] in 0.8 mm I.D. tubing, a TOF of 72 h-1 was observed, a two-fold increase in rate. A similar inverse relationship between catalyst concentration and conversion was observed for the thinner tubing, and 0.5 mM of catalyst resulted in the highest observed TOFs for this
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reaction (120 h-1). From these results, it is clear the photoflow reactor resulted in significantly higher TOFs than observed in “batch” reactions, with thinner tubing diameters resulting in higher TOFs. These observations support the analysis presented in Figure 5.1 and our hypothesis that higher rates of reaction can be obtained in thinner reaction vessels.
Table 5.1: 24-hour Continuous Flow Reaction for Ac- and Piv-Protected Sugars.
For our final reactor design, we chose 1.6 mm I.D. FEP tubing and 1 mM Ru(dmb)3 2+
concentrations, as these conditions led to the highest yields based on remaining starting material. On an 18.2 mmol scale with two modules connected in series, we were able to obtain full conversion and a 70% yield (4.5 g) of 43 after 24 hours of continuous flowing (Table 5.1, entry 1). The yields were unexpectedly low for this reaction, but higher yields (85%) were observed by increasing the concentration of the alkene to provide 5.5 g of 43 (Table 5.1, entry 2). This is significantly higher than the previous theoretical best of 0.8 g of 43 in the 24 hour “batch” reaction (vide supra).
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Figure 5.4: Experimental Setup for the Synthesis of Acetate-Protected C-Glycosides.
Pivaloate protected substrate 60 was slower to react, reaching only 75% conversion with two modules of the flow reactor (Table 5.1, entry 3). Simply attaching a third module to the reactor allowed for full conversion of the substrate, which demonstrates the flexibility of the reactor design (Figure 5.5).
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Synthesis of C-Glycoconjugates.
With substantial quantities of 43 in hand, we turned our attention to synthesis of C-linked serines. One-pot asymmetric Strecker cyanation of 43 with Jacobsen thiourea 48 at low temperatures provided the aminonitrile 62 in good yields and diastereoselectivities (Scheme 5.14). Pivaloate- protected 61 reacted more sluggishly in these reactions and required warmer temperatures to reach full conversion but afforded higher diastereoselectivities, providing only one diastereomer (63). The stereoselectivity of cyanation in these reactions was assigned by analogy to the original report.119