Personal Account
THE CHEMICAL RECORD
Continuous Flow Photochemistry Kerry Gilmore[a] and Peter H. Seeberger[a,b]* [a] Department for Biomolecular Systems, Max-Planck Institute for Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam (Germany) [b] Institute for Chemistry and Biochemistry, Freie Universität Berlin, Arnimallee 22, 14195 Berlin (Germany) E-mail: [email protected]
Received: April 6, 2014 Published online: ■■
ABSTRACT: Due to the narrow width of tubing/reactors used, photochemistry performed in micro- and mesoflow systems is significantly more efficient than when performed in batch due to the Beer-Lambert Law. Owing to the constant removal of product and facility of flow chemical scalability, the degree of degradation observed is generally decreased and the productivity of photochemical processes is increased. In this Personal Account, we describe a wide range of photochemical transformations we have examined using both visible and UV light, covering cyclizations, intermolecular couplings, radical polymerizations, as well as singlet oxygen oxygenations. DOI 10.1002/tcr.201402035 Keywords: continuous flow, photochemistry, radical polymerization, single electron transfer, singlet oxygen
Introduction In 1834, Hermann Trommsdorff reported several observations regarding the explosive structural changes crystals of a sequiterpene lactone, isolated from the leaves of artemesia plants, undergo upon exposure to sunlight.[1] These changes resulted from the absorption of energy from a hitherto chemically benign substance: photons. The use of this traceless reagent, providing the necessary activation energy for otherwise “forbidden” transformations, has allowed organic chemists to synthesize numerous complex structures[2] and natural products,[3] as well as to control reaction pathways.[4] Still, widespread use of photochemistry in synthetic organic chemistry beyond the academic community[5] is lacking. Several contributing factors are summarized in an excellent recent review by Booker-Milburn and co-workers:[6] besides a lack of knowledge
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regarding equipment, safety with regards to high operating temperatures of mercury (Hg) lamps and potentially damaging UV radiation, difficulties in scale up with classic immersionwell reactors are mainly to blame. This difficulty arises from the logarithmic decrease with path length of the transmission of light through a liquid medium (Beer-Lambert law). As such, large-scale photoreactions have been generally found to be inefficient and slow, and often result in decomposition of products due to over-irradiation. In 2005, Booker-Milburn developed and popularized a solution to this limiting issue on the mesoscale;[7] a simple, continuous flow photochemical system comprising a medium pressure Hg lamp with a cooling well, around which is wrapped a variable length of FEP tubing (Figure 1).[8] A similar
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transforming a given starting material, or direct excitation of a starting material that bears a suitable chromophore, resulting in either an inter- or intramolecular reaction. Over the last few years, we have taken advantage of both of these approaches over a wide range of transformations, from polymerizations to ruthenium-catalyzed transformations, from intramolecular rearrangements/cyclizations to the synthesis of anti-malarial medicines. We will begin our discussion with the classical approach to photochemistry—the direct excitation of chromophores/functional groups within the given starting material and will then move on to more complex systems where light is utilized to form reactive species capable of transforming substrates.
Utilization of Light for the Excitation of Starting Materials Fig. 1. The intensity of light (red line) decreases logarithmically with respect to path length (left), making flow chemical systems more efficient.
system had been developed by Birr in 1972 for the removal of photolabile protecting groups in peptide chemistry, but was published in a way such that it was hidden from search engines.[9] The system is highly advantageous compared to batch irradiation, due not only to the large surface-to-volume ratio which ensures efficient irradiation of the entire solution,[10] but also to the continuous removal of product from the irradiation window, reducing the degree of degradation resulting from over-irradiation of the desired material. Photochemistry gives us access to potential energy surfaces generally inaccessible under thermal conditions that can be utilized by chemists in two different ways: either a reactive species (e.g. a radical initiator) is generated that is capable of
Kerry Gilmore was born in Brewster, Massachusetts, USA in 1984. He received his Ph.D. in 2012 from Florida State University under Professor Igor V. Alabugin, where he studied the cyclizations of alkynes and was a Fulbright Scholar. He then moved to the MaxPlanck Institute for postdoctoral work under Professor Seeberger, and in 2014 was promoted to group leader. His current research interests include the development of sequential flow reactions creating chemical assembly line systems for the synthesis of customizable small molecules and APIs.
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If a substrate bears a suitable chromophore, it can absorb solar energy—providing the opportunity for a photochemical transformation in either an intra- or intermolecular fashion. We will discuss each of these in turn, beginning with intramolecular H-atom abstractions and cyclizations before moving on to coupling reactions. Intramolecular Reactions: Bond Cleavage: The Seeberger group continuous to improve the automated oligosaccharide synthesizer it pioneered.[11] By improving from instrument generation to generation we have developed a machine capable of synthesizing a variety of large[12] and complex[13] oligosaccharides on a solid support. The ultimate challenge in this context was the sequential extension of glycosaminoglycans (GAGs) including on-resin sulfation. Our search for a linker drew us to the utilization of light as a traceless reagent for the cleavage from the solid support.[14] 2-Nitrobenzyl chromophores have been found to undergo intermolecular H-atom abstraction
Peter H. Seeberger studied chemistry and biochemistry in Erlangen (Germany) and Boulder (CO) where he completed his Ph.D. After performing research at the Sloan-Kettering Cancer Center Research in New York, he built an independent research program at MIT where he was promoted to Firmenich Associate Professor of Chemistry with tenure after just four years. After six years as Professor at the Swiss Federal Institute of Technology (ETH) Zurich he assumed positions as Director at the Max-Planck Institute for Colloids and Surfaces in Potsdam and Professor at the Free University of Berlin. His research interests span from synthetic chemistry to the glycosciences, immunology and the development of diagnostics and vaccines.
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Continuous Flow Photochemistry
Fig. 2. Top: Schematic of the flow system for the photo-induced cleavage of oligosaccharides from a resin. Bottom: The photolabile linker used.
upon irradiation, resulting in cleavage/release of the chromophore from the molecule[15] and have been utilized as photolabile linkers,[16] both from resins[17] and in biological systems.[18] Utilizing a medium pressure mercury lamp set-up, we found that a novel 2-nitrobenzyl ether-based linker was efficiently cleaved in a mixture of DCM/MeOH following manual transfer from the automated synthesizer (Figure 2).[19,20] This work represents the first demonstration of a synthesis system that combines a highly efficient photochemical reaction in continuous flow with solid-phase chemistry. Intramolecular Reactions: Decomposition and Ring Expansion: Other nitrogen-containing functional groups yield reactive intermediates upon irradiation as well. It has been well established that the photolysis of aryl azides yield singlet nitrenes, a valuable transformation for the synthesis of heterocycles[21] and the photoaffinity labeling of proteins.[22] Upon formation, these reactive intermediates can undergo a cyclization/ring-expansion event to yield, for example, didehydroazepines. These intermediates are rapidly trapped by nucleophiles, providing a convenient synthetic route to azepines.[23] The utility of this route is limited, however, due to long reaction times as well as low yields arising from poor selectivity and product decomposition. We thought this process to be well suited to flow photochemistry as the short path length is expected to expedite the reaction and constant removal of the product from the irradiation window should minimize its decomposition. We identified the major product decomposition pathway as a photochemical disrotary electrocyclization to a [3.2.0]bicyclolactam. The formation of this byproduct could be minimized by careful control of the residence time and under our optimized conditions, we were able to obtain moderate yields (35–74%) of a variety of azepines (Figure 3).[24]
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Fig. 3. By optimizing the residence time, product formation can be maximized while product decomposition (from over-irradiation) can be minimized.
Intramolecular Reactions: Photoelectrocyclization: The photoinduced electrocyclization can be a destructive pathway as demonstrated for the previous example; however, it is also a powerful and effective tool for the construction of polycyclic systems. Pyridocarbazoles have been shown to exhibit high affinities and selectivities for individual protein kinases,[25] and the key step in their synthesis is a 6π-photoelectrocyclization/ elimination. At wavelengths >300 nm, the cyclization proceeds directly, as determined by a clean isosbestic point in the UV trace. While the production of azepines (vide supra) was hindered by degradation of the product, here we observed a competing pathway via cyclization of the pyridyl nitrogen. However, as the amount of this product decreases over time, its formation is believed to be reversible under the reaction conditions, and again with careful control of the residence time, high yields of the desired pyridocarbazoles were able to be obtained faster (20 vs. 280 mins) and cleaner than via traditional batch irradiation (Figure 4).[26] Intermolecular Reactions: Thio-ene Coupling for the Defined Adornment of Polymers with Oligosaccharides: With control over concentration, reactive species generated upon photolysis can be made to react intermolecularly. Thiol-ene coupling (TEC) is a well-established method of intra- and intermolecular coupling that proceeds via anti-Markovnikov addition of a thiyl radical generated either thermally or photolytically. Building on our previous work in batch,[27] we turned to this mode of coupling as an orthogonal method of both adorning preformed precision polymers[28] as well as prefunctionalized monomer building blocks (Figure 5). As TEC proceeds more rapidly at 254 nm than 366 nm, and
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standard fluorinated ethylene polymer (FEP) tubing decomposes at high UV, we envisioned a Birr/Booker-Milburn design using Teflon AF-2400 tubing surrounding a water-jacketed In/Hg lamp. The model coupling between O-allyl glycosides and L-cysteine provided good yields (71–80%) of the desired thio-ethers after 10 minute residence times. These conditions nicely translated to the synthesis of homologously glycolsubstituted pentamers, where complete decoration was observed. We next sought to create heterogeneously substituted poly/oligo(amidoamine) structures; however, we quickly found
our olefin-containing monomer unit (diethylenetriamine succinic acid) was not stable under irradiation at 254 nm, presumably due to the FMOC protecting group. By changing to a medium pressure mercury lamp (λmax = 366 nm) and extending the reaction time to 30 minutes, a variety of glycosylated building blocks were synthesized[29,30] with good productivity (34 mmol/day, 29.6 g/day).[29] Intermolecular Reactions: [2 + 2] Chemistry: Another well-established method for late-stage introduction of functionalities to polymers utilizes photochemical [2 + 2] cycloadditions. This mode of coupling served as a prototype of macroflow photochemistry,[32] with efficient (19.7 mmol/h) intermolecular coupling of hexyne and maleimide.[9] Following this initial disclosure, both inter-[31] and intramolecular[33] [2 + 2] couplings, even of biphasic systems,[34] have been reported.[6] We explored this reaction as a means of late-stage decoration of a poly-L-lysine decorated with N-maleimide with nonapod dendrimers bearing either galactose or mannose and terminated by an aliphatic alkyne (Figure 6). Irradiation of an aqueous solution of the two species using a medium pressure mercury lamp with a residence time of 40 minutes resulted in complete conversion of the maleimido groups to the desired cyclobutene adducts. The resulting glyco-dendronized polylysine was successfully utilized to both bind and detect E. coli.[35]
Utilization of Light for the Excitation of Reagents
Fig. 4. Byproduct formation was minimized for the photoelectrocyclization by careful control of the residence time.
When substrates lack a sufficient chromophore to render photochemical transformations by direct excitation possible, a separate reagent is required that can either decompose to form a reactive intermediate or transfer its energy to the substrate. We will discuss each of these examples separately: the utilization of a particular radical initiator allowing for the generation
Fig. 5. Thiol-ene coupling was utilized for the efficient and complete late-stage introduction of sugar moieties to our precision polymers.
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Continuous Flow Photochemistry
Fig. 6. [2 + 2] Coupling was used to decorate poly-L-lysine bearing N-maleimides with dendrons bearing terminal alkynes.
of multiple growing radicals within a polymerization process, as well as a variety of visible light-initiated Ru(bpy)32+ chemistry. We will conclude by combining these two concepts with the efficient generation of singlet oxygen, by excitation of oxygen with a dye, and the broad scope of this powerful reagent’s use. Excitation of Radical Precursors: While styrene is a classical monomer displaying zero-one kinetics in radical emulsion polymerization,[36] we have found that when using a particular photoinitiator (2-(bis(2,4,6-trimethylbenzoyl)phosphoryl) acetic acid (BAPO-AA)), styrene polymerizes in a novel polymerization process. Our reaction set-up consisted of two syringes containing the monomer and a water/emulsifier/initiator mixture, which met in a Standard Slit Interdigital Micro Mixer (SSIMM), which resulted in mean drop sizes of about 50–100 μm. These droplets then entered the 2.7 mL photoreactor, with a medium pressure mercury lamp, with a residence time of 36.5 seconds. The polymerization was quenched by flowing the post-reaction solution into THF, providing latex particles with average diameters below 50 nm. We noted, however, that chain sizes were significantly larger than predicted based on the propagation and chain transfer frequency values, with number average molecular weights up to 30 times higher than the respective batch processes. Interestingly, we noted that a five-fold increase of BAPO-AA concentration results in about 20 radicals per growing chain, yielding a high degree of cross-linked products. This forced us to develop a new conceptual framework to quantitatively evaluate our results, taking into account the kinetic and geometric constraints. The observed results are likely the result of phosphine oxide incorporation into the polymer backbone, resulting in repeated “snowballing” radical generation upon photolysis (Figure 7).[37] Excitation of a Catalyst: Single electron transfer (SET) is a powerful method to affect a variety of organic transformations under relatively mild conditions. While Ru(bpy)32+ has emerged as a promising tool for these transformations, particularly attractive as it is activated by visible light.[38] However, these reactions are traditionally too slow (3–72h) to be consid-
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Fig. 7. The radical initator BAPO-AA is capable of multiple photo-induced decompositions, leading to multiple growing radicals within a polymerizing chain.
ered practical, and while UV-mediated photochemistry has been shown to be accelerated under continuous conditions, no visible-light-driven continuous flow systems existed to facilitate these organic transformations.[39] We were thus inspired to develop a visible-light flow photoreactor to investigate a range of Ru(bpy)32+-catalyzed transformations. A 4.7 mL photoreactor of FEP tubing wrapped around two vertical metal rods was suspended between two 17 W cold white LED lamps (Figure 8). These powerful and energy efficient lamps generate a high photon flux at 452 nm, bisecting the metal to ligand charge transfer (MLCT) band of the Ru(II) photocatalyst. We first investigated the reduction of aryl azides. Contrary to previous literature results,[40] we found that our flow photoreduction proceeded without Hantzsch ester and full conversion (89% yield) was observed after only a 20 minute residence time in the presence of only 1% Ru(bpy)32+.[41] This result represents a 12-fold increase in reactivity as compared to the corresponding batch process. Similarly encouraging results were obtained for the tin-free reduction of activated C-Cl bonds, phosphine free conversion of 1° and 2° alcohols to the resultant bromines, as well as the reductive opening of epoxides. Overall, 10–50 fold rate
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Fig. 8. A homemade photoreactor, irradiated on two sides by cold white LED lamps (visible light), was used to conduct ruthenium-catalyzed SET chemistry.
enhancements were observed with respect to the batch processes. We were able to remove expensive and redundant activators (Hantzsch ester) from the system as well as lower catalyst loadings, and all transformations proceeded cleanly and efficiently in less than 30 minutes.[41] Generation of Singlet Oxygen: Additions to Alkenes: Thus far we have looked at direct excitation of reagents to generate reactive intermediates as well as the excitation of catalysts capable of transforming our substrates. Both of these are onestep processes which lead to modifications of the starting materials. However, some reactive intermediates are more difficult to generate and require a two-step process to induce the desired transformation. Singlet oxygen (1O2) is a powerful reagent and capable of a variety of synthetically useful transformations including ene reactions, cycloadditions ([2 + 2] and [4 + 2]), as well as heteroatom oxidations.[42] It is generated via dyesensitized photoexcitation of triplet oxygen (3O2), but the rate of mass transfer of oxygen gas into solution is low. This can be improved using supercritical CO2 as solvent, but highly specialized reaction set-ups are required.[43] While flow reactors have been explored for the photochemical generation of 1O2,[44] the productivity of these systems was traditionally very low (10.8 μmol/h).[44a] With this in mind, we envisioned that a mesoflow 450W medium pressure mercury photoreactor could continuously generate singlet oxygen in close proximity to our substrates under biphasic
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Fig. 9. Our continuous flow singlet oxygen generator has facilitated a number of transformations.
O2/liquid plug flow conditions, and the solubility of oxygen could be enhanced by using a back-pressure regulator (Figure 9). We initially chose to investigate the oxidation of citronellol at 25 °C using tetraphenylporphyrin (TPP) as a dye (1 mol% loading). Satisfyingly, we observed 85% conversion after only a 0.8 minute residence time, equating to a productivity of 60.4 mmol/h.[45] As hypothesized, the conversion/productivity increased upon pressurization (6.9 bar BPR) due to the increase in oxygen concentration at saturation (Henry’s Law). We also
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Fig. 10. The product composition resulting from 1O2 oxygenation of primary amines on primary carbon atoms is controlled by temperature, with complete oxidation observed at −50 °C.
investigated the use of heterogeneous catalysts, conjugated benzothiadiazole polymers, for the generation of 1O2. While these catalysts could easily be separated and reused with only a small drop (3.6%) in conversion, the reaction rates and efficiencies of citronellol oxidation were less than those of homogeneous catalysts.[46] Generation of Singlet Oxygen: Oxidation of Heteroatoms: Returning to TPP, we investigated the oxidation of a series of alkenes and dienes, observing high conversions and good yields of the oxidized products (68–88%). This system could also be used to oxidize thioethers, with a 95% yield of the corresponding sulfide and sulfone (3:1).[45] This prompted the question as to whether other heteroatoms could also be oxidized using our photooxidation system. There are select cases of benzylic 2° amines being oxidized using 1O2 to the N-substituted imines, for example using TPP (8–14 h)[47] or an organogold(III) complex (1.5 h).[48] We had adapted our photoflow system to utilize a 420 nm LED lamp for efficiency of TPP excitation and to minimize side reactions of broad-band irradiation. We modeled the reactor after that used for the ruthenium chemistry, wrapping 7.5 mL of FEP tubing around a glass plate. The temperature of the reactor could be maintained and controlled by submerging the tubing in an ethylene glycol/water mixture (3/2 v/v). Upon introduction of a 0.5 M solution of dibenzylamine and TPP (0.1 mol%) in dichloromethane to the photooxidation system, we observed quantitative oxidation to the imine (N-benzylidene-1-phenylmethanamine) in just 90 seconds at room temperature.[49] Due to the synthetic value of α-aminonitriles,[50] we envisioned that an oxidation silent cyanide source could trap the in situ formed imine. Excitingly, when 1.1 equivalents of trimethylsilyl cyanide (TMSCN) was added to the amine/TPP solution and passed through the photooxidation reactor, quantitative conversion to the α-aminonitrile was observed. While secondary amines worked well under these conditions, all primary amines we examined gave N-substituted α-aminonitriles, the product of an oxidative coupling with the starting material prior to trapping with cyanide. We hypothesized that, while both oxidation of the
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amine and amine addition to the imine were fast, that oxidation could outcompete the undesired pathway if the temperature were significantly reduced. Gratifyingly, when the temperature was lowered to −50 °C and with the addition of a sub-stoichiometric amount of tetrabutylammonium fluoride, 73–92% yields of monoalkylated α-aminonitriles could be obtained (Figure 10). This represents the first example of the formation and utilization of primary aldamines.[49] Utilization in Drug Manufacturing: The facility of connecting sequential flow reactions is one of the major benefits of this technique, and we have examined the subsequent reactions of other 1O2 oxidations as well. The first step of artemisinin biosynthesis is an ene reaction with dihydroartemisinic acid (DHAA), similar to our model reactions described above.[45] The intermediate organo-peroxide then undergoes an acidmediated Hock cleavage, followed by the addition of triplet oxygen—triggering a series of condensation reactions to yield the desired compound.[51] We thought that our biphasic oxidation conditions would be perfect for this multi-step cascade, as the excess oxygen present from the first step can be utilized in the third. We initially examined this transformation using a 20 mL Birr/Booker-Milburn photoreactor followed by a two reactors (16 mL and 10 mL) held at 25 °C and 60 °C, respectively. We first examined the photooxidation of dihydroartemisinic acid to yield the allylic hydroperoxide. Using TPP (0.5 mol%) as a photosensitizer, we were able to obtain 75% of the desired compound with 91% conversion when a 0.2 M solution of DHAA in methylene chloride (DCM) was passed through the photoreactor, yielding a productivity of 1.5 mmol/min. The best selectivities for the subsequent Hock cleavage/triplet oxygen-induced condensation cascade were obtained using one equivalent of trifluoroacetic acid (TFA). The fully integrated continuous-flow synthesis, where a biphasic oxygen/DCM solution containing DHAA and TPP passed through the Birr/ Booker-Milburn photoreactor and was subsequently mixed with TFA before flowing through the second two-part reactor, has a residence time of only 4.5 minutes and provides artemisinin in 39% yield.[52]
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[6] Fig. 11. The formation of byproducts in the first step of artemisinin formation, an ene reaction with 1O2, is minimized at low temperature.
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This process, however, was further improved, particularly with respect to the photooxidation. After exchanging the Birr/ Booker-Milburn reactor for our 420 nm LED set-up (vide supra), we examined the effect of decreased temperature on the selectivity of allylic oxidation. While essentially full consumption of DHAA was observed throughout, the reaction temperature had a significant effect on the outcome of the reaction; the highest yields being obtained at −20 °C (Figure 11). By exchanging the dye from TPP to one with similar reactivity (9,10-dicyanoanthracene (DCA)), we were able to add the acid to the initial DHAA solution and thus eliminated the need for a second HPLC pump. We also examined the effect of byproduct formation with respect to solvent, prompting us to change to toluene. The optimized continuous system increased the yield of artemisinin to 65%,[53] albeit with a longer residence time (11.5 minutes) when compared to the previous set-up (39% yield in 4.5 min).
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Acknowledgements We gratefully acknowledge financial support from the MaxPlanck Society and the hard work and dedication of all current and past members of our flow chemistry team.
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(a) A. Ajayaghosh, V. N. Rajasekharan Pillai, Tetrahedron 1988, 44, 6661–6666. (b) A. Ajayaghosh, V. N. Rajasekharan Pillai, J. Org. Chem. 1990, 55, 2826–2829. (a) C. H. Self, S. Thompson, Nature (Medicine) 1996, 2, 817–820. (b) A. K. Singh, P. K. Khade, Bioconjugate Chem. 2002, 13, 1286–1291. (c) D. Mendel, J. A. Ellman, P. G. Schultz, J. Am. Chem. Soc. 1991, 113, 2758–2760. S. Eller, M. Collot, J. Yin, H. S. Hahm, P. H. Seeberger, Angew. Chem. Int. Ed. 2013, 52, 5858–5861. M. W. Weishaupt, S. Matthies, P. H. Seeberger, Chem. Eur. J. 2013, 19, 12497–12503. (a) S. Bräse, C. Gil, K. Knepper, V. Zimmermann, Angew. Chem. Int. Ed. 2005, 44, 5188–5240. (b) B. Iddon, O. Meth-Cohn, E. F. V. Scriven, H. Suschitzky, P. T. Gallagher, Angew. Chem. Int. Ed. Engl. 1979, 18, 900–917. (a) F. Kotzyba-Hilbert, I. Kapfer, M. Goeldner, Angew. Chem. Int. Ed. Engl. 1995, 34, 1296–1312. (b) M. O. Sydnes, I. Doi, A. Ohishi, M. Kuse, M. Isobe, Chem. Asian J. 2008, 3, 102– 112. (c) P. E. Nielsen, O. Buchardt, Photochem. Photobiol. 1982, 35, 317–323. Other synthetic routes are represented here: (a) K. Knobloch, W. Eberbach, Org. Lett. 2000, 2, 1117–1120. (b) Y. Endo, K.-i. Kataoko, N. Haga, K. Shudo, Tetrahedron Lett. 1992, 33, 3339–3342. (c) H.-U. Reissig, G. Böttcher, R. Zimmer, Can. J. Chem. 2004, 82, 166–176. F. R. Bou-Hamdan, F. Lévesque, A. G. O’Brien, P. H. Seeberger, Beilstein J. Org. Chem. 2011, 7, 1124–1129. (a) E. Meggers, Angew. Chem. Int. Ed. 2011, 50, 2442–2448. (b) H. Bregman, D. S. Williams, E. Meggers, Synthesis 2005, 1521–1527. (c) N. Pagano, J. Maksimoska, H. Bregman, D. S. Williams, R. D. Webster, F. Xue, E. Meggers, Org. Biomol. Chem. 2007, 5, 1218–1227. D. T. McQuade, A. G. O’Brien, M. Dörr, R. Rajaratnam, U. Eisold, B. Monnanda, T. Nobuta, H.-G. Löhmannsröben, E. Meggers, P. H. Seeberger, Chem. Sci. 2013, 4, 4067–4070. N. Merbouh, F. Wallner, O. M. Cociorva, P. H. Seeberger, Org. Lett. 2007, 9, 651–653. (a) F. Wojcik, S. Mosca, L. Hartmann, J. Org. Chem. 2012, 77, 4226–4234. (b) L. Hartmann, Macromol. Chem. Phys. 2011, 212, 8–13. F. Wojcik, A. G. O’Brien, S. Götze, P. H. Seeberger, L. Hartmann, Chem. Eur. J. 2013, 19, 3090–3098. F. Wojcik, S. Lel, A. G. O’Brien, P. H. Seeberger, L. Hartmann, Beilstein J. Org. Chem. 2013, 9, 2395–2403. T. Horie, M. Sumino, T. Tanaka, Y. Matsushita, T. Ichimura, J. Yoshida, Org. Process Res. Dev. 2010, 14, 405–410. Alkene [2+2] cycloadditions had previously been reported in microreactor systems; see: F. Fukuyama, Y. Hino, N. Kamata, I. Ryu, Chem. Lett. 2004, 33, 1430–1431.
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THE CHEMICAL RECORD
Continuous Flow Photochemistry Kerry Gilmore[a] and Peter H. Seeberger[a,b]* [a] Department for Biomolecular Systems, Max-Planck Institute for Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam (Germany) [b] Institute for Chemistry and Biochemistry, Freie Universität Berlin, Arnimallee 22, 14195 Berlin (Germany) E-mail: [email protected]
Received: April 6, 2014 Published online: ■■
ABSTRACT: Due to the narrow width of tubing/reactors used, photochemistry performed in micro- and mesoflow systems is significantly more efficient than when performed in batch due to the Beer-Lambert Law. Owing to the constant removal of product and facility of flow chemical scalability, the degree of degradation observed is generally decreased and the productivity of photochemical processes is increased. In this Personal Account, we describe a wide range of photochemical transformations we have examined using both visible and UV light, covering cyclizations, intermolecular couplings, radical polymerizations, as well as singlet oxygen oxygenations. DOI 10.1002/tcr.201402035 Keywords: continuous flow, photochemistry, radical polymerization, single electron transfer, singlet oxygen
Introduction In 1834, Hermann Trommsdorff reported several observations regarding the explosive structural changes crystals of a sequiterpene lactone, isolated from the leaves of artemesia plants, undergo upon exposure to sunlight.[1] These changes resulted from the absorption of energy from a hitherto chemically benign substance: photons. The use of this traceless reagent, providing the necessary activation energy for otherwise “forbidden” transformations, has allowed organic chemists to synthesize numerous complex structures[2] and natural products,[3] as well as to control reaction pathways.[4] Still, widespread use of photochemistry in synthetic organic chemistry beyond the academic community[5] is lacking. Several contributing factors are summarized in an excellent recent review by Booker-Milburn and co-workers:[6] besides a lack of knowledge
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regarding equipment, safety with regards to high operating temperatures of mercury (Hg) lamps and potentially damaging UV radiation, difficulties in scale up with classic immersionwell reactors are mainly to blame. This difficulty arises from the logarithmic decrease with path length of the transmission of light through a liquid medium (Beer-Lambert law). As such, large-scale photoreactions have been generally found to be inefficient and slow, and often result in decomposition of products due to over-irradiation. In 2005, Booker-Milburn developed and popularized a solution to this limiting issue on the mesoscale;[7] a simple, continuous flow photochemical system comprising a medium pressure Hg lamp with a cooling well, around which is wrapped a variable length of FEP tubing (Figure 1).[8] A similar
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transforming a given starting material, or direct excitation of a starting material that bears a suitable chromophore, resulting in either an inter- or intramolecular reaction. Over the last few years, we have taken advantage of both of these approaches over a wide range of transformations, from polymerizations to ruthenium-catalyzed transformations, from intramolecular rearrangements/cyclizations to the synthesis of anti-malarial medicines. We will begin our discussion with the classical approach to photochemistry—the direct excitation of chromophores/functional groups within the given starting material and will then move on to more complex systems where light is utilized to form reactive species capable of transforming substrates.
Utilization of Light for the Excitation of Starting Materials Fig. 1. The intensity of light (red line) decreases logarithmically with respect to path length (left), making flow chemical systems more efficient.
system had been developed by Birr in 1972 for the removal of photolabile protecting groups in peptide chemistry, but was published in a way such that it was hidden from search engines.[9] The system is highly advantageous compared to batch irradiation, due not only to the large surface-to-volume ratio which ensures efficient irradiation of the entire solution,[10] but also to the continuous removal of product from the irradiation window, reducing the degree of degradation resulting from over-irradiation of the desired material. Photochemistry gives us access to potential energy surfaces generally inaccessible under thermal conditions that can be utilized by chemists in two different ways: either a reactive species (e.g. a radical initiator) is generated that is capable of
Kerry Gilmore was born in Brewster, Massachusetts, USA in 1984. He received his Ph.D. in 2012 from Florida State University under Professor Igor V. Alabugin, where he studied the cyclizations of alkynes and was a Fulbright Scholar. He then moved to the MaxPlanck Institute for postdoctoral work under Professor Seeberger, and in 2014 was promoted to group leader. His current research interests include the development of sequential flow reactions creating chemical assembly line systems for the synthesis of customizable small molecules and APIs.
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If a substrate bears a suitable chromophore, it can absorb solar energy—providing the opportunity for a photochemical transformation in either an intra- or intermolecular fashion. We will discuss each of these in turn, beginning with intramolecular H-atom abstractions and cyclizations before moving on to coupling reactions. Intramolecular Reactions: Bond Cleavage: The Seeberger group continuous to improve the automated oligosaccharide synthesizer it pioneered.[11] By improving from instrument generation to generation we have developed a machine capable of synthesizing a variety of large[12] and complex[13] oligosaccharides on a solid support. The ultimate challenge in this context was the sequential extension of glycosaminoglycans (GAGs) including on-resin sulfation. Our search for a linker drew us to the utilization of light as a traceless reagent for the cleavage from the solid support.[14] 2-Nitrobenzyl chromophores have been found to undergo intermolecular H-atom abstraction
Peter H. Seeberger studied chemistry and biochemistry in Erlangen (Germany) and Boulder (CO) where he completed his Ph.D. After performing research at the Sloan-Kettering Cancer Center Research in New York, he built an independent research program at MIT where he was promoted to Firmenich Associate Professor of Chemistry with tenure after just four years. After six years as Professor at the Swiss Federal Institute of Technology (ETH) Zurich he assumed positions as Director at the Max-Planck Institute for Colloids and Surfaces in Potsdam and Professor at the Free University of Berlin. His research interests span from synthetic chemistry to the glycosciences, immunology and the development of diagnostics and vaccines.
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Fig. 2. Top: Schematic of the flow system for the photo-induced cleavage of oligosaccharides from a resin. Bottom: The photolabile linker used.
upon irradiation, resulting in cleavage/release of the chromophore from the molecule[15] and have been utilized as photolabile linkers,[16] both from resins[17] and in biological systems.[18] Utilizing a medium pressure mercury lamp set-up, we found that a novel 2-nitrobenzyl ether-based linker was efficiently cleaved in a mixture of DCM/MeOH following manual transfer from the automated synthesizer (Figure 2).[19,20] This work represents the first demonstration of a synthesis system that combines a highly efficient photochemical reaction in continuous flow with solid-phase chemistry. Intramolecular Reactions: Decomposition and Ring Expansion: Other nitrogen-containing functional groups yield reactive intermediates upon irradiation as well. It has been well established that the photolysis of aryl azides yield singlet nitrenes, a valuable transformation for the synthesis of heterocycles[21] and the photoaffinity labeling of proteins.[22] Upon formation, these reactive intermediates can undergo a cyclization/ring-expansion event to yield, for example, didehydroazepines. These intermediates are rapidly trapped by nucleophiles, providing a convenient synthetic route to azepines.[23] The utility of this route is limited, however, due to long reaction times as well as low yields arising from poor selectivity and product decomposition. We thought this process to be well suited to flow photochemistry as the short path length is expected to expedite the reaction and constant removal of the product from the irradiation window should minimize its decomposition. We identified the major product decomposition pathway as a photochemical disrotary electrocyclization to a [3.2.0]bicyclolactam. The formation of this byproduct could be minimized by careful control of the residence time and under our optimized conditions, we were able to obtain moderate yields (35–74%) of a variety of azepines (Figure 3).[24]
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Fig. 3. By optimizing the residence time, product formation can be maximized while product decomposition (from over-irradiation) can be minimized.
Intramolecular Reactions: Photoelectrocyclization: The photoinduced electrocyclization can be a destructive pathway as demonstrated for the previous example; however, it is also a powerful and effective tool for the construction of polycyclic systems. Pyridocarbazoles have been shown to exhibit high affinities and selectivities for individual protein kinases,[25] and the key step in their synthesis is a 6π-photoelectrocyclization/ elimination. At wavelengths >300 nm, the cyclization proceeds directly, as determined by a clean isosbestic point in the UV trace. While the production of azepines (vide supra) was hindered by degradation of the product, here we observed a competing pathway via cyclization of the pyridyl nitrogen. However, as the amount of this product decreases over time, its formation is believed to be reversible under the reaction conditions, and again with careful control of the residence time, high yields of the desired pyridocarbazoles were able to be obtained faster (20 vs. 280 mins) and cleaner than via traditional batch irradiation (Figure 4).[26] Intermolecular Reactions: Thio-ene Coupling for the Defined Adornment of Polymers with Oligosaccharides: With control over concentration, reactive species generated upon photolysis can be made to react intermolecularly. Thiol-ene coupling (TEC) is a well-established method of intra- and intermolecular coupling that proceeds via anti-Markovnikov addition of a thiyl radical generated either thermally or photolytically. Building on our previous work in batch,[27] we turned to this mode of coupling as an orthogonal method of both adorning preformed precision polymers[28] as well as prefunctionalized monomer building blocks (Figure 5). As TEC proceeds more rapidly at 254 nm than 366 nm, and
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standard fluorinated ethylene polymer (FEP) tubing decomposes at high UV, we envisioned a Birr/Booker-Milburn design using Teflon AF-2400 tubing surrounding a water-jacketed In/Hg lamp. The model coupling between O-allyl glycosides and L-cysteine provided good yields (71–80%) of the desired thio-ethers after 10 minute residence times. These conditions nicely translated to the synthesis of homologously glycolsubstituted pentamers, where complete decoration was observed. We next sought to create heterogeneously substituted poly/oligo(amidoamine) structures; however, we quickly found
our olefin-containing monomer unit (diethylenetriamine succinic acid) was not stable under irradiation at 254 nm, presumably due to the FMOC protecting group. By changing to a medium pressure mercury lamp (λmax = 366 nm) and extending the reaction time to 30 minutes, a variety of glycosylated building blocks were synthesized[29,30] with good productivity (34 mmol/day, 29.6 g/day).[29] Intermolecular Reactions: [2 + 2] Chemistry: Another well-established method for late-stage introduction of functionalities to polymers utilizes photochemical [2 + 2] cycloadditions. This mode of coupling served as a prototype of macroflow photochemistry,[32] with efficient (19.7 mmol/h) intermolecular coupling of hexyne and maleimide.[9] Following this initial disclosure, both inter-[31] and intramolecular[33] [2 + 2] couplings, even of biphasic systems,[34] have been reported.[6] We explored this reaction as a means of late-stage decoration of a poly-L-lysine decorated with N-maleimide with nonapod dendrimers bearing either galactose or mannose and terminated by an aliphatic alkyne (Figure 6). Irradiation of an aqueous solution of the two species using a medium pressure mercury lamp with a residence time of 40 minutes resulted in complete conversion of the maleimido groups to the desired cyclobutene adducts. The resulting glyco-dendronized polylysine was successfully utilized to both bind and detect E. coli.[35]
Utilization of Light for the Excitation of Reagents
Fig. 4. Byproduct formation was minimized for the photoelectrocyclization by careful control of the residence time.
When substrates lack a sufficient chromophore to render photochemical transformations by direct excitation possible, a separate reagent is required that can either decompose to form a reactive intermediate or transfer its energy to the substrate. We will discuss each of these examples separately: the utilization of a particular radical initiator allowing for the generation
Fig. 5. Thiol-ene coupling was utilized for the efficient and complete late-stage introduction of sugar moieties to our precision polymers.
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Continuous Flow Photochemistry
Fig. 6. [2 + 2] Coupling was used to decorate poly-L-lysine bearing N-maleimides with dendrons bearing terminal alkynes.
of multiple growing radicals within a polymerization process, as well as a variety of visible light-initiated Ru(bpy)32+ chemistry. We will conclude by combining these two concepts with the efficient generation of singlet oxygen, by excitation of oxygen with a dye, and the broad scope of this powerful reagent’s use. Excitation of Radical Precursors: While styrene is a classical monomer displaying zero-one kinetics in radical emulsion polymerization,[36] we have found that when using a particular photoinitiator (2-(bis(2,4,6-trimethylbenzoyl)phosphoryl) acetic acid (BAPO-AA)), styrene polymerizes in a novel polymerization process. Our reaction set-up consisted of two syringes containing the monomer and a water/emulsifier/initiator mixture, which met in a Standard Slit Interdigital Micro Mixer (SSIMM), which resulted in mean drop sizes of about 50–100 μm. These droplets then entered the 2.7 mL photoreactor, with a medium pressure mercury lamp, with a residence time of 36.5 seconds. The polymerization was quenched by flowing the post-reaction solution into THF, providing latex particles with average diameters below 50 nm. We noted, however, that chain sizes were significantly larger than predicted based on the propagation and chain transfer frequency values, with number average molecular weights up to 30 times higher than the respective batch processes. Interestingly, we noted that a five-fold increase of BAPO-AA concentration results in about 20 radicals per growing chain, yielding a high degree of cross-linked products. This forced us to develop a new conceptual framework to quantitatively evaluate our results, taking into account the kinetic and geometric constraints. The observed results are likely the result of phosphine oxide incorporation into the polymer backbone, resulting in repeated “snowballing” radical generation upon photolysis (Figure 7).[37] Excitation of a Catalyst: Single electron transfer (SET) is a powerful method to affect a variety of organic transformations under relatively mild conditions. While Ru(bpy)32+ has emerged as a promising tool for these transformations, particularly attractive as it is activated by visible light.[38] However, these reactions are traditionally too slow (3–72h) to be consid-
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Fig. 7. The radical initator BAPO-AA is capable of multiple photo-induced decompositions, leading to multiple growing radicals within a polymerizing chain.
ered practical, and while UV-mediated photochemistry has been shown to be accelerated under continuous conditions, no visible-light-driven continuous flow systems existed to facilitate these organic transformations.[39] We were thus inspired to develop a visible-light flow photoreactor to investigate a range of Ru(bpy)32+-catalyzed transformations. A 4.7 mL photoreactor of FEP tubing wrapped around two vertical metal rods was suspended between two 17 W cold white LED lamps (Figure 8). These powerful and energy efficient lamps generate a high photon flux at 452 nm, bisecting the metal to ligand charge transfer (MLCT) band of the Ru(II) photocatalyst. We first investigated the reduction of aryl azides. Contrary to previous literature results,[40] we found that our flow photoreduction proceeded without Hantzsch ester and full conversion (89% yield) was observed after only a 20 minute residence time in the presence of only 1% Ru(bpy)32+.[41] This result represents a 12-fold increase in reactivity as compared to the corresponding batch process. Similarly encouraging results were obtained for the tin-free reduction of activated C-Cl bonds, phosphine free conversion of 1° and 2° alcohols to the resultant bromines, as well as the reductive opening of epoxides. Overall, 10–50 fold rate
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Fig. 8. A homemade photoreactor, irradiated on two sides by cold white LED lamps (visible light), was used to conduct ruthenium-catalyzed SET chemistry.
enhancements were observed with respect to the batch processes. We were able to remove expensive and redundant activators (Hantzsch ester) from the system as well as lower catalyst loadings, and all transformations proceeded cleanly and efficiently in less than 30 minutes.[41] Generation of Singlet Oxygen: Additions to Alkenes: Thus far we have looked at direct excitation of reagents to generate reactive intermediates as well as the excitation of catalysts capable of transforming our substrates. Both of these are onestep processes which lead to modifications of the starting materials. However, some reactive intermediates are more difficult to generate and require a two-step process to induce the desired transformation. Singlet oxygen (1O2) is a powerful reagent and capable of a variety of synthetically useful transformations including ene reactions, cycloadditions ([2 + 2] and [4 + 2]), as well as heteroatom oxidations.[42] It is generated via dyesensitized photoexcitation of triplet oxygen (3O2), but the rate of mass transfer of oxygen gas into solution is low. This can be improved using supercritical CO2 as solvent, but highly specialized reaction set-ups are required.[43] While flow reactors have been explored for the photochemical generation of 1O2,[44] the productivity of these systems was traditionally very low (10.8 μmol/h).[44a] With this in mind, we envisioned that a mesoflow 450W medium pressure mercury photoreactor could continuously generate singlet oxygen in close proximity to our substrates under biphasic
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Fig. 9. Our continuous flow singlet oxygen generator has facilitated a number of transformations.
O2/liquid plug flow conditions, and the solubility of oxygen could be enhanced by using a back-pressure regulator (Figure 9). We initially chose to investigate the oxidation of citronellol at 25 °C using tetraphenylporphyrin (TPP) as a dye (1 mol% loading). Satisfyingly, we observed 85% conversion after only a 0.8 minute residence time, equating to a productivity of 60.4 mmol/h.[45] As hypothesized, the conversion/productivity increased upon pressurization (6.9 bar BPR) due to the increase in oxygen concentration at saturation (Henry’s Law). We also
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Fig. 10. The product composition resulting from 1O2 oxygenation of primary amines on primary carbon atoms is controlled by temperature, with complete oxidation observed at −50 °C.
investigated the use of heterogeneous catalysts, conjugated benzothiadiazole polymers, for the generation of 1O2. While these catalysts could easily be separated and reused with only a small drop (3.6%) in conversion, the reaction rates and efficiencies of citronellol oxidation were less than those of homogeneous catalysts.[46] Generation of Singlet Oxygen: Oxidation of Heteroatoms: Returning to TPP, we investigated the oxidation of a series of alkenes and dienes, observing high conversions and good yields of the oxidized products (68–88%). This system could also be used to oxidize thioethers, with a 95% yield of the corresponding sulfide and sulfone (3:1).[45] This prompted the question as to whether other heteroatoms could also be oxidized using our photooxidation system. There are select cases of benzylic 2° amines being oxidized using 1O2 to the N-substituted imines, for example using TPP (8–14 h)[47] or an organogold(III) complex (1.5 h).[48] We had adapted our photoflow system to utilize a 420 nm LED lamp for efficiency of TPP excitation and to minimize side reactions of broad-band irradiation. We modeled the reactor after that used for the ruthenium chemistry, wrapping 7.5 mL of FEP tubing around a glass plate. The temperature of the reactor could be maintained and controlled by submerging the tubing in an ethylene glycol/water mixture (3/2 v/v). Upon introduction of a 0.5 M solution of dibenzylamine and TPP (0.1 mol%) in dichloromethane to the photooxidation system, we observed quantitative oxidation to the imine (N-benzylidene-1-phenylmethanamine) in just 90 seconds at room temperature.[49] Due to the synthetic value of α-aminonitriles,[50] we envisioned that an oxidation silent cyanide source could trap the in situ formed imine. Excitingly, when 1.1 equivalents of trimethylsilyl cyanide (TMSCN) was added to the amine/TPP solution and passed through the photooxidation reactor, quantitative conversion to the α-aminonitrile was observed. While secondary amines worked well under these conditions, all primary amines we examined gave N-substituted α-aminonitriles, the product of an oxidative coupling with the starting material prior to trapping with cyanide. We hypothesized that, while both oxidation of the
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amine and amine addition to the imine were fast, that oxidation could outcompete the undesired pathway if the temperature were significantly reduced. Gratifyingly, when the temperature was lowered to −50 °C and with the addition of a sub-stoichiometric amount of tetrabutylammonium fluoride, 73–92% yields of monoalkylated α-aminonitriles could be obtained (Figure 10). This represents the first example of the formation and utilization of primary aldamines.[49] Utilization in Drug Manufacturing: The facility of connecting sequential flow reactions is one of the major benefits of this technique, and we have examined the subsequent reactions of other 1O2 oxidations as well. The first step of artemisinin biosynthesis is an ene reaction with dihydroartemisinic acid (DHAA), similar to our model reactions described above.[45] The intermediate organo-peroxide then undergoes an acidmediated Hock cleavage, followed by the addition of triplet oxygen—triggering a series of condensation reactions to yield the desired compound.[51] We thought that our biphasic oxidation conditions would be perfect for this multi-step cascade, as the excess oxygen present from the first step can be utilized in the third. We initially examined this transformation using a 20 mL Birr/Booker-Milburn photoreactor followed by a two reactors (16 mL and 10 mL) held at 25 °C and 60 °C, respectively. We first examined the photooxidation of dihydroartemisinic acid to yield the allylic hydroperoxide. Using TPP (0.5 mol%) as a photosensitizer, we were able to obtain 75% of the desired compound with 91% conversion when a 0.2 M solution of DHAA in methylene chloride (DCM) was passed through the photoreactor, yielding a productivity of 1.5 mmol/min. The best selectivities for the subsequent Hock cleavage/triplet oxygen-induced condensation cascade were obtained using one equivalent of trifluoroacetic acid (TFA). The fully integrated continuous-flow synthesis, where a biphasic oxygen/DCM solution containing DHAA and TPP passed through the Birr/ Booker-Milburn photoreactor and was subsequently mixed with TFA before flowing through the second two-part reactor, has a residence time of only 4.5 minutes and provides artemisinin in 39% yield.[52]
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[5]
[6] Fig. 11. The formation of byproducts in the first step of artemisinin formation, an ene reaction with 1O2, is minimized at low temperature.
[7]
[8]
This process, however, was further improved, particularly with respect to the photooxidation. After exchanging the Birr/ Booker-Milburn reactor for our 420 nm LED set-up (vide supra), we examined the effect of decreased temperature on the selectivity of allylic oxidation. While essentially full consumption of DHAA was observed throughout, the reaction temperature had a significant effect on the outcome of the reaction; the highest yields being obtained at −20 °C (Figure 11). By exchanging the dye from TPP to one with similar reactivity (9,10-dicyanoanthracene (DCA)), we were able to add the acid to the initial DHAA solution and thus eliminated the need for a second HPLC pump. We also examined the effect of byproduct formation with respect to solvent, prompting us to change to toluene. The optimized continuous system increased the yield of artemisinin to 65%,[53] albeit with a longer residence time (11.5 minutes) when compared to the previous set-up (39% yield in 4.5 min).
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Acknowledgements We gratefully acknowledge financial support from the MaxPlanck Society and the hard work and dedication of all current and past members of our flow chemistry team.
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