Organic Process Research & Development
Article
Hegetschweiler, K.; Abram, U.; Bernhardt, P. V.; Schubiger, P. A.
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(Syrris). The two streams were mixed using a standard T-mixer
(0.5 mm inner diameter) and entered coil 1 (PFA tubing, 75
μL volume, 0.8 mm i.d. and 1.59 mm o.d.). The second part of
the reactor, coil 2, consisted of a 1 mL PFA tubing with 0.8 mm
i.d. and 1.59 mm o.d. The water bath was preheated at 40 °C,
and the sonication (35 kHz, ultrasonic peak output = 160 W)
was activated during the processing. The crude reaction mixture
was diluted with a stream of distilled water. For this purpose, a
wider T-mixer (1.5 mm i.d.) was employed. The diluted
solution was used for the next step without purification.
Continuous-Flow Hydrogenation of TNPG. TNPG (5
mmol, 1.31 g) was dissolved in a mixture of 15 mL of MeOH
and 100 mL of 0.5 M sulfuric acid, which resulted in a
homogeneous yellow substrate mixture (substrate concen-
tration 0.05 M). The hydrogen level of the H-Cube Pro was set
to “full H2” mode; the reactor containing a PtO2/PTFE
cartridge was preheated to 50 °C, and the flow rate was set to 3
mL/min. The reaction mixture was processed in two cycles.
The second reaction cycle resulted in a clear reaction mixture
with full conversion of TNPG. The solvent was evaporated
under reduced pressure to a volume of approximately 5 mL.
Addition of 20 mL of MeOH led to precipitation of an off-
white solid which was filtered and dried in a drying oven at 50
°C overnight, providing 1.469 g (92%) of TAPG × 1.5 H2SO4
(characterization data are given below).
Sequential Continuous-Flow Nitration/Hydrogena-
tion of Phloroglucinol. Using the setup depicted in Figure
3, 5 mmol of the substrate was processed by running the
combined instruments for approximately 150 min. The
ultrasound bath was preheated at 40 °C, and the sonication
activated during the complete process. Then, 5 mL of a 1 M
solution of PG in sulfuric acid (feed A, 33 μL/min) was
pumped through the reactor. The feed B containing NH4NO3
(1.5 M in sulfuric acid) was set to 66 μL/min, and the water
stream (feed C) was set to 2.9 mL/min. The H-Cube Pro
pump was set to 3 mL/min, and the instrument was adjusted to
50 °C and “full H2” mode. The crude reaction mixture collected
from the output (ca. 500 mL) was evaporated under reduced
pressure to approximately 10% of the initial volume, and then
ca. 200 mL of ethanol was added to the residue. The
crystallized white solid was filtered, washed with a small
amount of cold ethanol, and dried in a desiccator, yielding 1.31
g (82%) of pure TAPG × 1.5 H2SO4:27 mp 190−195 °C (dec)
(lit.8 190−200 °C dec.); 13C NMR (75 MHz, DMSO-d6) δ
135.0, 111.9; IR (ATR) v 2934, 2636, 1643, 1596, 1543, 1503,
1334; m/z (LS-MS/ESI-pos) 172.
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(10) For a detailed description of a fatal accident involving TNPG,
including a discussion of its safety profile, see the following source:
Tinsley, J. E. System failure case study details: Mishap at an explosives
R&D laboratory, 2006. NASA Safety Center Home Page; http://nsc.
March, 2014). Relevant safety data for TNPG are also discussed in
ref 9c..
ASSOCIATED CONTENT
* Supporting Information
Additional experimental information and supplementary
figures. This material is available free of charge via the Internet
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AUTHOR INFORMATION
Corresponding Author
Notes
(11) Ducry, L.; Roberge, D. M. Angew. Chem., Int. Ed. 2005, 44,
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7972−7975.
(12) Barton, J.; Rogers, R. Chemical Reaction Hazards; IChemE:
Trowbridge, 1997.
(13) For a recent review on continuous-flow nitrations, see: Kulkarni,
A. A. Beilstein J. Org. Chem. 2014, 10, 405−424.
The authors declare no competing financial interest.
(14) For recent selected reviews on continuous-flow/microreactor
chemistry, see: (a) Hessel, V.; Kralisch, D.; Kockmann, N.; Noel, T.;
Wang, Q. ChemSusChem 2013, 6, 746−789. (b) Baxendale, I. R. J.
Chem. Technol. Biotechnol. 2013, 88, 519−552. (c) Newman, S. G.;
Jensen, K. F. Green Chem. 2013, 15, 1456−1472. (d) Wiles, C.; Watts,
REFERENCES
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dx.doi.org/10.1021/op5001435 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX