A Small-Footprint, High-Capacity Flow Reactor for UV Photochemical Synthesis on the Kilogram Scale

Article abstract of DOI:10.1021/acs.oprd.6b00277

The development of a highly compact and powerful reactor for synthetic organic photochemistry is described enabling a 10-fold reduction in reaction times, with up to 30% more power efficiency than previous fluorinated ethylene propylene tube reactors. Two

Full text of DOI:10.1021/acs.oprd.6b00277

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Full Paper
A Small Footprint, High Capacity Flow Reactor for
UV Photochemical Synthesis on the Kilogram Scale
Luke D. Elliott, malcolm berry, bashir harji, david klauber, John Leonard, and Kevin I. Booker-Milburn
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00277 • Publication Date (Web): 15 Sep 2016
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A Small Footprint, High Capacity Flow Reactor for UV
Photochemical Synthesis on the Kilogram Scale
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Luke D. Elliott,*† Malcolm Berry,§ Bashir Harji,# David Klauber,¥ John Leonard,¥ and Kevin I.
Booker-Milburn*†
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†School of Chemistry, University of Bristol, Cantock's Close, Bristol, UK, BS8 1TS
§GlaxoSmithKline, Gunnels Wood Road, Stevenage, UK, SG1 2NY
¥Pharmaceutical Sciences, AstraZeneca, Silk Road Business Park, Macclesfield, UK, SK10 2NA
#Cambridge Reactor Design Ltd, Unit D2 Brookfield Business Centre, Twentypence Road,
Cottenham, UK, CB24 8PS
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ABSTRACT
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The development of a highly compact and powerful reactor for synthetic organic photochemistry
is described enabling a 10 fold reduction in reaction times, with up to 30% more power
efficiency than previous FEP tube reactors. Two reactions gave over 1kg of product in 24 hours.
Two other reactions had productivities of 4 and 8 kg in 24h. The reactor consists of a succession
of quartz tubes connected together in series and arranged axially around a variable power
mercury lamp. This compact and relatively simple device can be safely operated in a standard
fumehood.
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Keyword
Flow reactor; photochemistry; ultra-violet; scale-up; kilogram productivity; cycloaddition;
cyclobutane
Introduction
Over the last ten years there has been a very significant increase in the use of continuous flow
reactors in organic synthesis.1 A variety of reactors have been developed for numerous organic
reactions in both academic and industrial labs. In many cases these offer an alternative to classic
batch reactors and can often display significant advantages in heat and mass transfer, efficient
mixing, scale-up, safety and cost. In 2005 we reported2 the development of a practical flow
reactor for photochemical synthesis on scales of up to a few hundred grams per day. This reactor
consisted of a single length of UV transparent fluorinated ethylene propylene (FEP) tubing
wrapped closely around a high power UV source. One to three layers of FEP could be coiled
around the UV source to give a reactor of high surface area and excellent UV capture (Figure
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1a). Many labs worldwide3,4 have adopted this reactor and variants thereof and a commercial
version5 is now available based on the original concept. Key to the success of the FEP reactor is
its ability to totally encapsulate the UV emitting source and as such photon capture by the
circulating substrate is near optimal.
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A key brief of a recent collaboration6 was to design a higher capacity reactor to enable
photochemistry to be carried out on the kg/day scale. Initially we considered building larger FEP
reactors with more powerful UV sources. However, this raised some issues that would be
exacerbated by simply 'scaling-up'. For example, although FEP is a versatile material it is not
completely UV transparent and any kinks or abrasions leads to weak spots that can rupture under
pressure requiring the whole length of FEP tubing to be replaced. Neither is FEP immune to
foul-up and blockage. In our experience a blocked FEP tube can sometimes be reversed by a
short flush of solvent. On other occasions, especially if there is photochemical damage to the
FEP, the whole tubing has to be replaced and the reactor rewound (see SI, Fig. 1-3 for
examples).
With this experience behind us we set out to design a higher capacity flow reactor meeting the
following specifications:
• Capable of delivering ≥ 1kg per day productivity
• Encapsulate UV as effectively as in FEP reactors
• Small footprint to fit within a standard fumehood
• Replace FEP with durable and more UV transparent tubing
• Safe containment of high-power (1-5 kW) UV source
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Figure 1. Comparison of reactor types: (a) FEP photoreactor for 400W Hg-lamp; (b) prototype
parallel tube flow reactor (PTFR) for 400W Hg-lamp; (c) final design of PTFR for 1.5-5 kW Hg-
lamp (Firefly reactor); (d) kilogram quantities of product from Firefly reactor.
Results & Discussion
Replacing FEP with a more durable material, with at least equal performance characteristics,
was non-trivial. Although a spiral quartz reactor would be ideal, and have been described7,
obtaining the necessary compact, multi-layer coiled quartz device on the scale required for this
project was not feasible. A multi-tube reactor system has been reported8a,b but in these designs
the reactor tubes were isolated from each other and acting independently and no synthetic
photochemistry was described. We therefore designed a modular reactor comprised of an array
of quartz tubes linked in series and arranged axially around a high power UV source so that they
effectively operate as one single tube with a large surface area. We proposed that such a reactor
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could encapsulate light just as effectively as the previous FEP reactors. At the centre of the
concentric reactor array would be placed a standard, high power medium pressure Hg-lamp,
although this would be able to accommodate different types of lamps and light sources (eg
LEDs) to suite a broad range of photochemistry. The reaction solution would enter through an
end-cap, flow through one tube, into the opposite end-cap, then back through the adjacent tube in
the opposite direction. Thus a relatively thin profile of solution would get high UV exposure by
the time it had passed through the entire reactor assembly. Any UV that passes through or
between the tubes would be reflected back in very close proximity to the reaction solution.
Initially we built a prototype for a 400 W Hg-lamp contained in a water-cooled jacket (Fig 2).
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Figure 2. A Parallel Tube Flow Reactor (PTFR), 20 cm (l) x 7 cm (d)
Initial screening with a [2+2] reaction between N-methyl maleimide and hex-1-yne gave a
productivity of 3.41g/h, which approached that of an optimized 3-layer FEP reactor2d (3.62 g/h).
Similarly maleimide and propargyl alcohol gave a productivity of 2.13 g/h vs 2.35 g/h for the
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FEP reactor (Table 1). These were surprising initial results, especially considering that they were
obtained using the reactor without the metal reflector. However, when the metal reflector was
placed around the reactor significant overheating was encountered. It was clear that the stagnant
hot air between the water jacket and the reactor tubing was overheating. It was conceived that
this could be prevented by encapsulating the reactor tubes within a fluid-cooled annular cavity.
In addition, a fan installed at one end of the reactor would simultaneously remove the stagnant
hot air. This dual mode of cooling should be effective at negating the heating effects produced by
the powerful UV source (Figure 3a). The lamp would not require containment within a cooling
jacket, thus simplifying the design. The inner boundary could also serve as an exchangeable UV
filter. A highly polished and earthed outer metal tube would serve to reflect any transmitted UV
back into the reactor tubes and to protect the user from intense radiant energy.
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Table 1. Comparison of maleimide [2+2] in 400 W FEP and PTFR reactors
O
O
R'
R'
(1.5 eq.)
NR
NR
400W
MeCN (0.1 M)
O
O
Reactor
R/R'
mL/min
Yield [%]
g/h
3-layer FEP
Me/nBu
Me/nBu
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49
64
58
3.62
3.41
2.35
2.13
400W PTFRa
3-layer FEP
400W PTFRa
6
4
4
H/CH2OH
H/CH2OH
aResults obtained without metal reflector
The reactor (Fig. 3b) was constructed to these specifications, with interlocks put in place to
protect against overheating, electrical and coolant failures. A sophisticated variable power supply
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meant that the lamp could be run at powers ranging from 1.5 - 5 kW to match the photochemical
reaction productivity. The footprint of this reactor was not much larger than a rotary-evaporator
condenser, which is remarkable considering the power of the device. Although mains water
could be used for cooling, our results were obtained using a commercial recirculating chiller
(water/glycol - see SI). The final operational design9 of the reactor was named The Firefly.
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Figure 3: Schematics and operational pictures of an Immersion-Cooled Parallel Tube Flow
Reactor - The Firefly: a) Diagram of reactor; b) Firefly reactor in operation. Internal volume of
the reactor = 120 mL.
After trialing a few reactions we soon found 3 kW to be a convenient power setting. At this
power the reactor gave approximately 10 times greater productivity than the corresponding three-
layer FEP flow reactor with a 400 W lamp. For example, the [2+2] cycloaddition of N-methyl
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maleimide and trichloroethene 2d (Table 2, entry 2) gave 2.85 g/h (68%) in a 400 W FEP reactor.
At 3 kW the Firefly reactor gave a productivity of 28.8 g/h (66%), enabling the isolation of 64 g
of product in just 2 h 10 min (400 W FEP, 62 g in 22 h).
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The [2+2] cycloaddition of maleimide and propargyl alcohol2d (Table 2, entry 3) can be
problematic on account of formation of insoluble by-products (see SI). When using the quartz
tube reactor at 3 kW, we were able to process 2.5 L of a 0.1 M solution at 36 ml/min and still
maintain almost complete conversion with a productivity of 24.6 g in 70 min (64%, 21.2 g/h).
We believe the high flow rate in this case prevents significant foul-up.
Entries 1-3 were invaluable benchmarks for testing the Firefly reactor as their
performances were well understood. However, in terms of scale-up to kg quantities they were
limited as the starting maleimides were relatively expensive and chromatography was required.
We therefore sought to test the Firefly with low-cost readily available starting materials that
produced complex, structurally diverse molecules that could be easily purified on kg scales.
Previously10 we had shown that 3,4,5,6-tetrahydrophthalic anhydride (THPA, 1) and cis-
2-butene-1,4-diol undergo an efficient batch [2+2] cycloaddition-lactonisation sequence to
tricyclic lactone 2 upon direct UV irradiation. Repeating the batch irradiation at 0.4 M with just
1% of isopropythioxanthone (iTHX) as sensitizer gave an impressive 15-fold increase in
productivity. Use of the parent THX4p,q led to equally good productivity, however due to the
insoluble nature of THX it was more difficult to remove from the crystallized product 2. This
demonstrates how previously optimized, but scale-limited reactions can be made dramatically
more productive by judicious choice of sensitizer and solvent. Transferring these newly
optimized conditions to the Firefly (0.4 M @ 36 mL/min) gave a staggering 1,538 g of pure 2 in
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just 9.26 h of irradiation, with the product crystalizing out in the receiving flask. In a 24 hour
run this productivity would enable the synthesis of almost 4 kg of 2 at this power setting.
'Cookson's Dione' 411 (table 2, entry 5) is produced by an intramolecular [2+2] of the ene-dione
3, and was previously shown to be highly productive in our FEP reactors with a UVA lamp.2d In
the Firefly we found that at just 1.5 kW a single 140 min run of a 0.5M solution (5 L, 36
mL/min) gave 387g of pure 4 (89%). Increasing the concentration to 1.0 M and power to 3kW
gave 385g (8 kg/24 h) in just 1.16 h (36 mL/min) - the product crystalizing in the receiving flask.
Using these conditions we carried out a 'kilo-run' and were able to produce 1,165g of pure 4 in a
single 3.5 h run. It is important to highlight that these three results demonstrate complete
linearity in productivity with respect to power as might be expected e.g. doubling the power from
1.5 kW to 3 kW gave an exact doubling in productivity. In a certified process lab it can be
confidently predicted that at the full 5 kW power rating the Firefly could deliver over 13 kg of 4
in 24 h.
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Table 2. Scale-up of synthetic organic photochemistry in a Parallel Tube Flow Reactor (The Firefly)
entry reaction
run
timea
(h)
lamp
power
(kW)
M
flow rate
(mL/min
)
yield
(%)
g/hh
isolated
(g)
g/24h
(projected)
1
9
1.16
3
0.1b
36
65
25.2
29.3
605
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2
3
1.16
2.22
9.26
3
3
3
0.1b
0.2b
0.4c
36
15
36
64
66
80
21.2
28.8
166
24.6
64.0
509
691
4g
5
1,538
3984
2.31
1.16
3.47
1.5
3
0.5c
1.0
36
36
36
89
88
89
167
331
335
387
385
4,008
7,944
8,058
3
1.0d
1,165
6g
7
22.22
3
0.4e
9
86
48.9
1,082
1,174
17.78
3
0.2f
30
85
57.9
1,032
1,390
aTotal reaction volume/flow rate, MeCN; EtOAc; d10% MeCN in EtOAc; e10% H2O in MeCN; 50% H2O in MeCN;
b
c
f
g1% isopropyl thioxanthone (iTHX); Hourly productivity (g/h) = Conc. (M) x Flow Rate (L/h) x MW x Yield (%) /100.
Note:
h
Following the work of Piotrowski12 we developed a highly scalable route to the bridged
pyrrolidine 6 by a 'crossed' [2+2] cycloaddition of the enamine 5 (table 2, entry 6). After
extensive screening in batch, we again found iTHX a most productive sensitizer. In batch
(400W, 0.4 M) the reaction proceeded with a productivity of 17 mmol/h with just 1% iTHX.
Using these optimized conditions a total of 4.8 moles of 5 in 12 L of MeCN was irradiated in the
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Firefly at 9 ml/min to give 1,082 g (86% yield) of pure 6 in 22.2 h. This represents an 11-fold
increase in productivity over the batch reactor.
7
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9
Griesbeck and Oelgemöller13 had previously reported the useful photo-decarboxylative
cyclisation of the phthalimide-potassium salt 7 to the hydroxy lactam 8 in the presence of
acetone as a triplet sensitizer. When a 3 kW excimer lamp (XeCl, 308 nm) was employed within
a falling film reactor14 the reaction proceeded with a productivity of 7 g/hr. More recently
Oelgemöller reported15 a 4.56 mmol/h (2.89 g, 3.3h, 76%) productivity of 8 using the Vapourtec-
UV150 (10 ml/min, 0.01M, 82 W lamp power). This reaction was attractive to us to test on kg
scales as 7 was readily available in large quantities. Interestingly we found that the acetone
solvent sensitizer was not necessary and acetonitrile was a more convenient alternative co-
solvent with water. Thus irradiation of a 0.2 M solution of 7 in a 150 ml quartz batch reactor
(125 W) gave full conversion to 8 in just 2 h (4.6 g, 81%, 12.2 mmol/h). By increasing the
concentration 20-fold, purification of 8 was made considerably more efficient as the product
precipitated on solvent evaporation. This enabled us to test, for the first time, the exchangeable
inner glass filter (Fig. 2a), by simply swapping the pyrex inner tube for quartz. Ultimately a total
of 6.4 moles of 7 in 32 L of MeCN/H2O was irradiated over a total of 18 h at 3kW @ 30 ml/min,
giving 1,032 g of pure 8 in 85% overall yield with a productivity of 57.9 g/h (Table 2, entry 7)
Entries 4-7 have all proved to be excellent low-cost reactions with greater than 1-
kilogram productivities in a 24 h processing period. It is perhaps surprising that with the high-
powers and concentrations involved that foul-up of the reactor was much less than expected in
long runs. In general, we found that as long as the starting material was pure, and the reactor
clean to start-with, then foul-up proved not to be an issue for the examples studied. For example,
in entry 5 colored impurities carried over from the preparation of a particular batch of 3 had a
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deleterious effect on productivity and product quality as well as resulting in minor fouling of the
reactor. These unidentified impurities were likely chromophoric quinone derivatives from the
previous Diels-Alder step. Although in this specific case substrate 3 was ≥ 95% pure by NMR it
does highlight that in photochemistry it is important that substrates are not contaminated with
small quantities of compounds that may act as quenchers of the reaction or sensitizers of
undesired side reactions. For all other reactions in this study substrate quality of ≥ 95% purity
was tolerated without issue.
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The Firefly reactor would appear to be significantly more efficient than any of the FEP
reactors that we have previously designed. For example entry 2 gave 10.1 times the productivity
of the 400W FEP result using only 7.5 times the UV power, making the Firefly almost 30% more
power efficient. Although we can only speculate at this stage, this performance enhancement is
likely due to the superior UV transparency of the quartz tubing vs. FEP combined with the
efficiency of UV capture and reflection of the device.
Conclusions
In summary, we have developed a powerful new flow reactor that enables complex
photochemical synthesis to be carried out on a variety of scales whilst reducing reaction times
10-fold compared to previous FEP reactors. The fact that such a small photo-reactor can
routinely produce over a kilogram of product, and more, in a 24 h processing period is
unprecedented. The small footprint enables the device to be operated in a standard (1.5 m)
research lab fumehood. The versatility of the device was demonstrated by successful scale-up of
reactions at UVA (Table 2, entry 4-6), UVB (entries 1-3) and UVB/UVC (entry 7) - all using the
same Hg-lamp. As the UV lamp is not an integral part of the reactor, it could easily be removed
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and replaced with sources of different wavelengths such as visible light LEDs to match other
types of photochemistry. As UV LED's continue to develop, we expect high-power, compact
devices to eventually exceed the productivity and efficiency of the medium pressure lamp
presented and such UV sources will be easily accommodated within the Firefly reactor. We hope
these formidable capabilities can make significant contributions to synthetic photochemistry in
research and process labs within universities and industry and encourage others to use this
technology as an enabling synthetic tool. Current work is concerned with developing a
commercial version of the prototype Firefly reactor in order to realize these ambitious goals.
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Experimental Section
General
For photolysis, standard reagent grade solvents were used without further purification. For all
photochemical reactions, solvents were “degassed” by evacuating under vacuum and re-filling
with N2. For the duration of the reaction, N2 was bubbled through the solution in the holding
flask. When photochemical reactions were followed for their duration by NMR, 1,3,5-
trimethoxybenzene was used as an internal standard. In all cases, a stock solution of this was
added to aliquots of the reaction mixture prior to NMR sample preparation.
For flow reactions, when the full volume of solution had been taken up, the reactor was flushed
out with a reactor volume of neat solvent and the reactor cleaned with recirculating DMSO/water
(ca. 10 mins) prior to irradiating the next volume. The 5 kW variable power supply (JA5000
VPXi) and the 350 mm mercury lamp were purchased from Jenton International, Whitchurch.
For the Firefly reactor, an FMI Q-series valveless piston pump was used along with an FMI
pulse dampener (Cole-Parmer). The reactor was cooled with a Huber Unichiller 025-MPC,
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purchased from Radleys, Saffron Walden. Large-scale evaporations were assisted using a
Heidolph Distimatic automatic module in conjunction with a standard rotary evaporator.
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Flow procedure: Table1, Entry 1
A solution of maleimide CAS: 541-59-3 (24.3 g, 250 mmol) and 1-hexyne CAS: 693-02-7 (43
ml, 374 mmol) in degassed MeCN (2.5 L) was irradiated with the Firefly reactor fitted with a
Pyrex inner filter and lamp at 3 kW at 36 ml/min. The mixture was concentrated in vacuo and
chromatography on silica (30% EtOAc in hexane) yielded the product as a pale yellow oil (29.3
g, 65%). Analytical data as previously reported.2d
Flow procedure: Table1, Entry 2
A solution of maleimide (24.3 g, 250 mmol) and propargyl alcohol CAS: 107-19-7 (22 ml, 378
mmol) in degassed MeCN (2.5 L) was irradiated with the Firefly reactor fitted with a Pyrex inner
filter and lamp at 3 kW at 36 ml/min. The mixture was concentrated in vacuo and
chromatography on silica (100% EtOAc) yielded the product as an off white solid (24.6 g, 64%).
Analytical data as previously reported.2d
Flow procedure: Table1, Entry 3
A solution of NMe maleimide CAS: 930-88-1 (44.4 g, 400 mmol) and trichloroethene CAS: 79-
01-6 (180 ml, 2 mol) in degassed MeCN (0.2 M) was irradiated with the Firefly reactor fitted
with a Pyrex inner filter and lamp at 3 kW at 15 ml/min. The mixture was concentrated in vacuo
and chromatography on silica (10% Et2O in DCM) yielded the product as a mixture of
diastereomers (64.0 g, 66%). Analytical data as previously reported.2d
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Representative Procedure: Table1, Entry 4
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A solution of THPA16 1 CAS: 2426-02-0 (608 g, 4 mol), cis-2-butene-1,4-diol CAS: 6117-80-2
(500 ml, 6.1 mol) and isopropylthioxanthone CAS: 75081-21-9 (10.2 g, 40 mmol) in degassed
EtOAc (0.4 M) was irradiated with the firefly reactor fitted with a Pyrex inner filter and lamp at
3 kW at 36 ml/min. The mixture was concentrated in vacuo to a slurry which was filtered,
washing with EtOAc and Et2O and dried to give product 2 as a colourless crystalline solid (769
g, 80%): m.p. 188 -189°C (MeOH); 1H NMR (400 MHz, DMSO) δ 12.25 (br. s, 1H), 4.45 (br. s,
1H), 4.21 (dd, J = 9.2, 4.8 Hz, 1H), 4.13 (d, J = 9.2 Hz, 1H), 3.54 – 3.44 (m, 2H), 2.83 (dd, J =
8.5, 4.8 Hz, 1H), 2.64 (dt, J = 8.5, 7.2 Hz, 1H), 1.94 – 1.25 (m, 8H) ppm; 13C NMR (100 MHz,
DMSO) δ 179.9, 174.4, 70.3, 59.4, 48.4, 45.7, 42.7, 37.3, 26.1, 26.1, 21.5, 20.9 ppm
Two additional runs yielded 577g (3.47 hr) and 192g (1.16 hr) of 2 (Total = 1,538g in 9.26 h).
Although no drop off in productivity was observed during each run, the reactor was flushed with
DMSO/water as a precaution before the next run was commenced. This allowed for safe
evaporation of three successive volumes of solvent in a research lab setting. All three runs were
completed in a single working day. This strategy was adopted for other reactions where large
volumes of flammable solvents were involved. In a certified process lab, where real-time
evaporation of bulk solvent is routine, it is likely that the Firefly could be run continuously with
continuous evaporation of solvent. Any drop in productivity detected by online monitoring could
initiate a brief automated shutdown of the reactor, flush with DMSO/water followed by start-up
of the reactor.
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Representative flow procedure: Table1, Entry 5
A solution of Diels-Alder adduct17 3 CAS: 51175-59-8 (1,307 g, 7.5 mol) in degassed solvent
(10% MeCN in EtOAc, 1.0 M) was irradiated with the firefly reactor fitted with a Pyrex inner
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filter and lamp at 3.0 kW at 36 ml/min. The mixture was concentrated in vacuo to a slurry to
which was added hexane. The mixture was filtered, washing with petroleum ether and the solid
dried to give pure Cookson’s dione 4 CAS: 2958-72-7 as a colourless crystalline solid (1,165 g,
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89%): m.p. 242 - 243°C; H NMR (400 MHz, CDCl3) δ 3.19 – 3.14 (m, 2H), 2.95 – 2.90 (m,
2H), 2.82 – 2.78 (m, 2H), 2.72 – 2.68 (m, 2H), 2.04 (app. d, J = 11.4 Hz, 1H), 1.88 (app. d, J =
11.4 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) 212. 2, 54.9, 44.8, 43.9, 40.6, 38.9 ppm
Representative flow procedure: Table1, Entry 6
To a solution of enamine 512 (421 g, 1.6 mol) and isopropylthioxanthone (4.1 g, 16 mol) in
degassed MeCN (3 L) was added water (380 ml) and further MeCN to make up to 4 L (0.4 M).
The solution was irradiated with the firefly reactor fitted with a Pyrex inner filter and lamp at 3
kW at 9 ml/min. The photolysate was concentrated to a slurry which was triturated with hexane
and filtered, washing with hexane then cold Et2O to give pyrrolidine 6 as a white crystalline
granular solid (367.3 g, 87%): m.p. 101 – 103 °C; 1H NMR (400 MHz, CDCl3) δ 7.63 – 7.03 (m,
13
10H), 3.70 (br. s, 2H), 2.93 – 2.89 (m, 1H), 2.21 – 2.14 (m, 2H), 2.05 – 1.99 (m, 2H) ppm; C
NMR (126 MHz, DMSO, 80°C) δ 171.8, 139.2, 136.4, 129.6, 127.5, 127.3, 127.1, 125.9, 125.7,
73.9, 54.9, 42.9, 34.2 ppm; HRMS (CI) calcd [M + H]+ for C18H18NO 264.1388, found
264.1380
Three additional runs yielded 361.7g (7.41 hr), 177g (3.7hr) and 176.2g (3.7h hr) of 6 (Total =
1,082g in 22.22 h). As a slight (~2%) drop in productivity was observed towards the end of some
runs, the reactor was flushed with DMSO/water as a precaution before the next run was
commenced.
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Representative flow procedure: Table1, Entry 7
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A mixture of carboxylic acid 718 CAS: 3130-75-4 (233 g, 1.0 mol) and K2CO3 (69 g, 0.5 mol)
was sonicated in deionised water (1 L) until fully dissolved. The solution was diluted to 2.5 L
with more water then made up to 5 L with degassed MeCN (0.2 M). The solution was irradiated
with the firefly reactor fitted with a quartz inner filter and lamp at 3 kW at 30 ml/min. The
MeCN was removed in vacuo to give a white slurry which was washed (water), filtered and the
aqueous filtrate extracted with CHCl3 (4×400 ml). Into the combined organic extracts was
dissolved the wet residue which was separated, dried (MgSO4), filtered through Celite and
evaporated to give product 8 as white solid (167 g, 88%), m.p. 128-130˚C: 1H NMR (400 MHz,
DMSO) δ 7.66 – 7.57 (m, 3H), 7.54 – 7.49 (m, 1H), 6.35 (d, J = 1.6 Hz, 1H), 3.52 (app. dt, J =
11.2, 8.4 Hz, 1H), 3.29 (ddd, J = 11.2, 9.2, 2.9 Hz, 1H), 2.53 – 2.40 (m, 1H), 2.27 – 2.12 (m,
2H), 1.49 – 1.38 (m, 1H) ppm; 13C NMR (100 MHz, DMSO) δ 169.1, 148.3, 132.5, 131.5, 129.3,
122.8, 122.7, 95.6, 41.1, 35.2, 27.4 ppm
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Four additional runs yielded 335g (5.56 hr), 317g (5.56 hr), 147g (2.78 hr) and 66g (1.12 hr) of 8
(Total = 1,032 g in 17.78 hr). Due to the relatively dilute nature of this reaction (0.2 M) it was
split into 5 runs in order to make product extraction and solvent evaporation more manageable.
After one run a small residue build-up on the quartz tubes resulted in 13% drop in yield over the
run. Before the subsequent run 30% water/DMSO was circulated for ca. 10 min (36 ml/min) and
no significant drop in conversion was observed for the next 20 L of reaction solution (see table in
SI).
Corresponding Authors
*E-mail: k.booker-milburn@bristol.ac.uk; luke.elliott@bristol.ac.uk
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Funding Sources
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Financial support from the Engineering and Physical Sciences Research Council (EPSRC;
EP/L003325/1), GlaxoSmithKline and Astra Zeneca is gratefully acknowledged.
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ACKNOWLEDGMENT
We thank Darren Mitchell and Paul Dinham (University of Bristol) for construction of reactor
prototypes; Richard Little and Dr Jaromir Bilek (Jenton International) for technical advice and
Gillian Smith Associates for project coordination
Supporting Information
1H & 13C spectral data for all photochemically prepared compounds, experimental and
optimisation procedures for photoreactions, sensitizer screens, pictures of FEP tubing (PDF).
REFERENCES
(1)
a) Mak, X. Y.; Laurino, P.; Seeberger, P. H. Beilstein J. Org. Chem. 2009, 5, 19. b)
Webb, D.; Jamison, T. F. Chem. Sci. 2010, 1, 675–680. c) Hartman, R. L.; McMullen, J. P.;
Jensen, K. F. Angew. Chem. Int. Ed. 2011, 50, 7502-7519. d) Wegner, J.; Ceylan, S.; Kirschning,
A. Adv. Synth. Catal. 2012, 354, 17–57. e) Baxendale, I. R. J. Chem. Technol. Biotechnol. 2013,
88, 519–552. f) Pastre, J. C.; Browne, D. L.; Ley, S. V. Chem. Soc. Rev. 2013, 42, 8849–8869. g)
Gutmann, B.; Cantillo, D.; Kappe, C. O. Angew. Chem. Int. Ed. 2015, 54, 6688–6728. h)
Baumann, M.; Baxendale, I. R. Beilstein J. Org. Chem. 2015, 11, 1194–1219.
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(2)
a) Hook, B. D. A.; Dohle, W.; Hirst, P. R.; Pickworth, M.; Berry, M. B.; Booker-Milburn,
5
6
7
8
K. I. J. Org. Chem. 2005, 70, 7558–7564. b) Lainchbury, M. D.; Medley, M. I.; Taylor, P. M.;
Hirst, P.; Dohle, W.; Booker-Milburn, K. I. J. Org. Chem. 2008, 73, 6497–6505. c) Maskill, K.
G.; Knowles, J. P.; Elliott, L. D.; Alder, R. W.; Booker-Milburn, K. I. Angew. Chem. Int. Ed.
2013, 52, 1499–1502. d) Elliott, L. D.; Knowles, J .P.; Koovits, P.J.; Maskill, K. G.; Ralph, M.
J.; Lejeune, G.; Edwards, L. J.; Robinson, R. I.; Clemens, I. R.; Cox, B.; Pascoe, D. D.; Koch,
G.; Eberle, M.; Berry, M. B.; Booker-Milburn K. I. Chem. Eur. J. 2014, 20, 15226–15232. e)
Ralph, M.; Ng, S.; Booker-Milburn, K. I. Org. Lett. 2016, 18, 968−971.
9
10
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12
13
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17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3)
For reviews on flow photochemistry, see a) Knowles, J. P.; Elliott, L. D.; Booker-
Milburn, K. I. Beilstein J. Org. Chem. 2012, 8, 2025–2052. b) Oelgemöller, M. Chem. Eng.
Technol. 2012, 35, 1144–1152. c) Gilmore K.; Seeberger, P. H. Chem. Rec. 2014, 14, 410–418.
d) Cambie, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noel, T. Chem. Rev. 2016, 116,
DOI: 10.1021/acs.chemrev.5b00707. e) Rehm, T. H. Chem. Eng. Technol. 2016, 39, 66–80. e)
Beeler, A. B.; Corning, S. Photochemistry in Flow in Photochemistry: Volume 43; Royal Society
of Chemistry: Cambridge, 2016, 173-190
(4)
For FEP based flow photochemistry see: a) Bou-Hamdan, F. R.; Lévesque, F.; O’Brien,
A. G.; Seeberger, P. H. Beilstein J. Org. Chem. 2011, 7, 1124–1129. b) Lévesque, F.; Seeberger,
P. H. Org. Lett. 2011, 13, 5008–5011. c) Gutierrez, A. C.; Jamison, T. F. Org. Lett. 2011, 13,
6414–6417. d) Lévesque, F.; Seeberger, P. H. Angew. Chem. Int. Ed. 2012, 51, 1706–1709. e)
Harrowven, D. C.; Mohamed, M.; Gonçalves, T. P.; Whitby, R. J.; Bolien, D.; Sneddon, H. F.
Angew. Chem. Int. Ed. 2012, 51, 4405–4408. f) Andrews, R. S.; Becker, J. J.; Gagné, M. R.
Angew. Chem. Int. Ed. 2012, 51, 4140–4143. g) Yavorskyy, A.; Shvydkiv, O.; Hoffmann, N.;
Nolan, K.; Oelgemöller, M. Org. Lett. 2012, 14, 4342–4345. h) Aida, S.; Terao, K.; Nishiyama,
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7
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Y.; Kakiuchi, K.; Oelgemöller, M. Tetrahedron Lett. 2012, 53, 5578–5581. i) Šterk, D.; Jukič,
M.; Časar, Z. Org. Process Res. Dev. 2013, 17, 145–151. j) Wojcik, F.; O’Brien, A. G.; Götze,
S.; Seeberger, P. H.; Hartmann, L. Chem. Eur. J. 2013, 19, 3090–3098. k) Cludius-Brandt, S.;
Kupracz, L.; Kirschning, A. Beilstein J. Org. Chem. 2013, 9, 1745–1750. l) Cantillo, D.; de
Frutos, O.; Rincon, J. A.; Mateos, C.; Kappe, C. O. J. Org. Chem. 2014, 79, 223–229. m) Do, H.-
Q.; Bachman, S.; Bissember, A. C.; Peters, J. C.; Fu, G. C. J. Am. Chem. Soc. 2014, 136, 2162–
2167. n) Fagnoni, M.; Bonassi, F.; Palmieri, A.; Protti, S.; Ravelli, D.; Ballini, R. Adv. Synth.
Catal. 2014, 356, 753–758. o) Hurevich, M.; Kandasamy, J.; Ponnappa, B. M.; Collot, M.;
Kopetzki, D.; McQuade, D. T.; Seeberger, P. H. Org. Lett. 2014, 16, 1794–1797. p)
Kumarasamy, E.; Raghunathan, R.; Jockusch, S.; Ugrinov, A.; Sivaguru, J. J. Am. Chem. Soc.
2014, 136, 8729–8737. q) Junkers, T. Eur. Polym. J. 2015, 62, 273–280. r) Halperin, S. D.;
Kwon, D.; Holmes, M.; Regalado, E. L.; Campeau, L.- C.; DiRocco, D. A.; Britton, R. Org. Lett.
2015, 17, 5200–5203. s) Blanco-Ania, D.; Gawade, S. A.; Zwinkels, L. J. L.; Maartense, L.;
Bolster, M. G.; Benningshof, J. C. J.; Rutjes, F. P. J. T.; Org. Process Res. Dev. 2016, 20, 409–
413.
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23
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25
26
27
28
29
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31
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
(5)
(6)
Fang, Y.; Tranmer, G. K. Med. Chem. Commun. 2016, 7, 720–724
Factory in a Fumehood: Reagentless Flow Reactors as Enabling Techniques for
Manufacture: EPSRC EP/L003325/1
(7) a) Birr, C.; Lochinger, W.; Stahnke, G.; Lang, P. Justus Liebigs Ann. Chem. 1972, 763,
162–172. b) Braun, A. M.; Maurette, M-T.; Oliveros, E. Photochemical Technology. Chapter 4,
Wiley, Chichester, 1991. c) Chaignon, P.; Cortial, S.; Guerineau, V.; Adeline, M. T.; Giannotti,
C.; Fan, G.; Ouazzani, J. Photochem. Photobiol. 2005, 81, 1539–1543. d) Gutierrez, A. C.;
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Page 22 of 22
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2
3
4
5
6
Jamison, T. F. Org. Lett. 2011, 13, 6414–6417. e) Shen, B.; Bedore, M. W.; Sniady, A.; Jamison,
T. F. Chem. Commun. 2012, 48, 7444–7446.
7
8
9
(8)
a) Tymoschuk, A. R.; Alfano, O. M.; Cassano, A. E. Ind. Eng. Chem.
10
11
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
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55
56
57
58
59
60
Res. 1993, 32,1328–1341. b) Tymoschuk, A. R; Negro, A. C.; Alfano, O. M.; Cassano, A. E. Ind.
Eng. Chem. Res. 1993, 32,1342–1353. c) A similar concept was tested in water purification -
Natarajan, K.; Natarajan, T.S.; Bajaj, H. C.; Tayade, R. J. Chem. Eng. J. 2011, 178, 40–49.
(9)
UK Patent Application number GB1612034.7
(10) Booker-Milburn, K. I.; Cowell, J. K.; Jimenez, D.; Sharpe, A.; White, A. J. Tetrahedron,
1999, 55, 5875–5888
(11) Cookson, R. C.; Crundwell, E.; Hill, R. R.; Hudec, J. J. Chem. Soc. 1964, 3062–3075
(12) Piotrowski, D. W. Synlett, 1999, 7, 1091–1093
(13) Griesbeck, A. G.; Henz, A.; Kramer, W.; Lex, J.; Nerowski, F.; Oelgemöller, M. Helv.
Chim. Acta, 1997, 80, 912–933
(14) Griesbeck, A. G.; Maptue, N.; Bondocka, S; Oelgemöller, M. Photochem. Photobiol.
Sci., 2003, 2, 450–451
(15) Josland, S.; Mumtaz, S.; Oelgemöller, M. Chem. Eng. Technol. 2016, 39, 81–87
(16) Bailey, M. E.; Amstutz, E. D. J. Am. Chem. Soc. 1956, 78, 3828–3830
(17) Mao, J.; Xie, H.; Bao, W. Org. Lett. 2015, 17, 3678 – 3681
(18) Guenin, E.; Monteil, M.; Bouchemal, N.; Prange, T.; Lecouvey, M. Eur. J. Org. Chem.
2007, 3380 - 3391
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