(2,2,2-trichloroethanol or 2,2,2-trifluoroethanol), propane was pumped as a single stream, and then directly combined
could be functionalized to provide aminated products with and mixed with the gaseous alkane feedstock in the micro-
high efficiency, though in a nonselective manner (Table 1, reactor. Using a flow setup of 10 parallel micro-reactors (4.5
entries 6 and 7). Using methanol as the HAT catalyst, the mL internal volume in total), at a pressure of 1500 kPa for
regioselectivity improved to 1:3.9 (Table 1, entry 8), favoring the ethane gas and a flow rate of 0.75 mL/min for the liquid
the methylene position, although the reaction proceeded at solution stream, amination product was furnished in 90%
a much lower rate. This selectivity could arise from the elec- yield with a residence time of 6 min and a production
tronic difference in the electrophilic nature of methoxy rad- throughput of 2 mmol/h. Under similar conditions, propane
ical compared to halogenated ethoxy radicals. In a similar and butane were functionalized with good yield (76% and
vein, butane could be functionalized with high efficiency, 56%) and productivity (1.7 mmol/h and 1.3 mmol/h). In our
and the regioselectivity could be tuned with different choice attempts to use methane in this mixed liquid/gas flow reac-
of alcohol catalysts to favor the methylene positions. When tion setting, we were hampered by the pressure limits of our
using isopropanol as the HAT catalyst, the 1°/2° product commercial micro-reactors (1800 kPa), leading to a some-
ratio could be increased to 1:4 (Table 1, entry 10); the lower what diminished, but promising, 15% yield. As for higher
efficiency was likely due to the decomposition of the isopro- alkanes, such as cyclohexane, the scaled-up amination could
panol catalyst via alkoxy radical mediated β-scission, as the be conveniently performed with simple liquid injection
side-product of methyl radical coupling with DBAD was ob- mode, affording remarkable productivity of 4.2 mmol/h.
served in the reaction (table S14, entry 5). Methanol proved
Further studies were performed to provide additional
to be a selective HAT catalyst, providing 1:8 selectivity for evidence for the intermediacy of alkoxy radicals under this
the methylene C–H bonds (Table 1, entry 11), validating the catalytic manifold. As shown in fig. S11, methoxy, trichloro-
hypothesis that enhancement of regioselectivity could be ethoxy and trifluoroethoxy radicals could each be trapped
accomplished through electronic tuning of the alcohol HAT by styrene, to generate 1,2-alkoxyamination products (80%,
catalyst. Pleasingly, liquid hydrocarbons such as cyclohex- 25% and 59% yield, respectively). In the case of 2,2,2-
ane could be aminated with high efficiency employing this trifluoroethanol, a small amount of trifluoromethylated
inexpensive photocatalytic platform at a low cerium loading product was also observed, indicative of a β-scission path-
(Table 1, entry 12).
way and trapping of trifluoromethyl radical.
We next applied this photocatalytic protocol to radical
This photocatalytic platform has enabled several direct
alkylation reactions using methane and ethane as alkylating transformations of methane and other simple hydrocarbons,
feedstocks. As shown in Fig. 3, the alkoxy-mediated methyl- including amination, alkylation, and arylation, and offers
ation and ethylation of electron-deficient alkene 1 using intriguing opportunities for further functionalizations of
methane and ethane delivered the desired product with feedstock alkanes.
high efficiency (56% and 90% yield, respectively). Further-
more, methane and ethane proved viable pro-nucleophiles
in Minisci arene alkylation reactions. The acidic conditions
employed diminished product overfunctionalization by elec-
tronically deactivating the benzylic C–H bonds through pro-
REFERENCES AND NOTES
1
. N. J. Gunsalus, A. Koppaka, S. H. Park, S. M. Bischof, B. G. Hashiguchi, R. A.
tonation of the N–heterocycle (39). With ammonium 2. U.S. Energy Information Administration, International Energy Outlook 2017;
www.eia.gov/outlooks/ieo/pdf/0484(2017).pdf.
persulfate as an economical oxidant, methylated and ethyl-
ated isoquinoline could be produced at room temperature.
Photocatalytic reactions in batch reactors are typically
limited to small scale applications, due to the attenuation
effect of superficial light penetration (40). In addition to the
increase of the light utilization efficiency through glass mi-
cro-reactors, the development of continuous-flow photocata-
lytic systems for large volume reactions could further
4
. R. A. Periana, D. J. Taube, S. Gamble, H. Taube, T. Satoh, H. Fujii, Platinum
5. R. A. Periana, O. Mironov, D. Taube, G. Bhalla, C. J. Jones, Catalytic, oxidative
benefit from the ease of handling gaseous reactants and the 6. A. D. Sadow, T. D. Tilley, Synthesis and characterization of scandium silyl
complexes of the type Cp*
2
ScSiHRR'. σ-Bond metathesis reactions and catalytic
enhanced mass transfer between gas and liquid phases,
which are crucial for the utilization of gaseous alkanes. Giv-
en the attractiveness of flow chemistry for mixed phase
gas/solution reactions, we investigated the C–H functionali-
zation of gaseous alkanes in continuous-flow micro-reactors
(
7
. M. V. Kirillova, M. L. Kuznetsov, P. M. Reis, J. A. L. da Silva, J. J. da Silva, A. J. L.
Pombeiro, Direct and remarkably efficient conversion of methane into acetic
acid catalyzed by amavadine and related vanadium complexes. A synthetic and a
theoretical DFT mechanistic study. J. Am. Chem. Soc. 129, 10531–10545 (2007).
(Fig. 4). An acetonitrile solution of reagents and catalysts
First release: 26 July 2018
(Page numbers not final at time of first release)
3