(path a) or alkyl (aryl) group from the aldehyde (path b)
leading to 2 mol of acid 4 (path a) or 1 mol of acid 4
and 1 mol of formate 5 (path b). Generally, path a
dominates and the carboxylic acid is the main pro-
duct. The ratio of hydride to alkyl (aryl) migration
was found to depend critically on the structure of
aldehydes, temperature, and solvent among others.7
Furthermore, from Scheme 1, one can see that molecu-
lar oxygen is obviously an ideal oxidant for such a
transformation since both oxygen atoms in O2 are
utilized for oxidation (100% atom efficiency).8
Recently, flow chemistry has opened new, exciting
opportunities in fundamentalstudies of chemical reactions.11
In particular, flow chemistry demonstrated safety advan-
tages in conducting highly reactive chemical processes12
and, among them, oxidation processes.13
In the case of aldehyde oxidation, the flammability
hazard associated with the oxygen and the organic vapor
mixture could be mitigated by the reduction of the explosion
region.14 Furthermore, continuous flow gasÀliquid pro-
cesses offer advantages of large and well-defined interfacial
areas, fast mixing, and reduced mass-transfer limitations.15
Among the different flow modes, Taylor flow is a special
case of slug flow where the liquid slugs are separated by
elongated bubbles. Taylor flow has been shown to increase
heat and mass transfer compared to single phase laminar
flow because of the recirculation within the liquid slugs.15
Thus, we investigated the possibility of utilizing Taylor flow
for the oxidation of aliphatic aldehydes using pure oxy-
gen. In designing our continuous flow reactor (Figure 1),
we sought to make it as simple as possible using cheap,
disposable PFA tubing (internal diameter of 1 mm) that
allows simple visual monitoring (see the Supporting
Information).
Scheme 1. Stepwise Aerobic Oxidation of Aldehydes
In many of the processes used commercially or described
in the literature for the liquid phase aldehyde oxidation,
the reaction rate is limited by oxygen transfer.5 Oxygen is
typically introduced into the liquid through air bubbles.
Since oxidation reactions occur in the liquid phase, either
in the bulk liquid phase or in the film which surrounds air
bubbles, adequate mass transfer of oxygen is critical because
the oxygen solubility in common solvents is low.9 The
driving force for oxygen mass transfer could be significantly
improved by replacing air with oxygen. However, in a
conventional stirred reactor and a bubble column reactor,
the oxygen partial pressure of the exiting waste air stream
must be maintained below a practical safety limit of 5% in
order to prevent formation of flammable gas mixtures in the
reactor head space.10
Figure 1. Experimental setup for the aldehyde oxidation under
Taylor flow conditions with online GC analysis, back pressure
controller, and sampling system.
Initial tests were carried out on 1a, an industrially
important aldehyde produced worldwide on a large scale
(Table 1, entry 1).16 Preliminary experiments were started
(7) (a) Lehtinen, C.; Nevalainen, V.; Brunow, G. Tetrahedron 2001,
57, 4741–4751. (b) Lehtinen, C.; Brunow, G. Org. Process Res. Dev.
2000, 4, 544–549.
(13) For selected papers on oxidation processes in a microreactor,
ꢀ
see: (a) Levesque, F.; Seeberger, P. H. Org. Lett. 2011, 13, 5008–5011.
(8) An excess of O2 was used in the publication in order to minimize
the variation of the superficial velocity owing to the bubble shrinking. A
complete conversion of O2 has already been observed in microreactors in
our laboratory; see: Leclerc, A.; Alame, M.; Schweich, D.; Pouteau, P.;
Delattre, C.; de Bellefon, C. Lab Chip 2008, 8, 814–817. The reaction can
also be performed using pressurized air. Nevertheless P(O2) decreases
during the course of the reaction which has a strong effect on the rate.
(9) Battino, R.; Rettich, T. R.; Tominaga, T. J. Phys. Chem. Ref.
Data 1983, 12, 163–178.
(10) Chen, J.-R.; Chen, S.-K. J. Loos Prevent. Proc. 2005, 18, 97–106.
(11) (a) Wegner, J.; Ceylan, S.; Kirschning, A. Chem. Commun. 2011,
47, 4583–4592. (b) Wiles, C.; Watts, P. Green Chem. 2012, 14, 38–54. (c)
Hartman, R. L.; McMullen, J. P.; Jensen, K. F. Angew. Chem., Int. Ed.
2011, 50, 7502–7519.
(b) Irfan, M.; Glasnov, T. N.; Kappe, C. O. Org. Lett. 2011, 13, 984–987.
(c) Greene, J. F.; Hoover, J. M.; Mannel, D. S.; Root, T. W.; Stahl, S. S.
Org. Process Res. Dev. 2013, 17, 1247–1251. (d) Hamano, M.; Nagy,
K. D.; Jensen, K. F. Chem. Commun. 2012, 48, 2086–2088. (e) Pieber, B.;
Kappe, C. O. Green Chem. 2013, 15, 320–324.
(14) (a) Liebner, C.; Fischer, J.; Heinrich, S.; Lange, T.; Hieronymus, H.;
Klemm, E. Process Saf. Environ. Prot. 2012, 90, 77–82. (b) Chattopadhyay,
S.; Veser, G. AIChE J. 2006, 52, 2217–2229.
(15) (a) Kreutzer, M. T.; Kapteijn, F.; Moulijn, J. A.; Heiszwolf, J. J.
Chem. Eng. Sci. 2005, 60, 5895–5916. (b) Shao, N.; Gavriilidis, A.;
Angeli, P. Chem. Eng. Sci. 2009, 64, 2749–2761. (c) Leclerc, A.; Philippe,
R.; Houzelot, V.; Schweich, D.; de Bellefon, C. Chem. Eng. J. 2010, 165,
290–300. (d) Sobieszuk, P.; Aubin, J.; Pohorecki, R. Chem. Eng.
Technol. 2012, 35, 1346–1358.
(16) (a) Raju, R.; Prasad, K. Tetrahedron 2012, 68, 1341–1349. (b)
Seki, T.; Grunwaldt, J.-D.; Baiker, A. Chem. Commun. 2007, 3562–3564.
(17) Solvent effects have been studied (see ref 5c), and heptane was
found to be a rather good compromise between O2 solubility, viscosity,
and vapor pressure.
(12) (a) Heugebaert, T. S. A.; Roman, B. I.; De Blieck, A.; Stevens,
C. V. Tetrahedron Lett. 2010, 51, 4189–4191. (b) Zaborenko, N.; Bedore,
M. W.; Jamison, T. F.; Jensen, K. F. Org. Process Res. Dev. 2011, 15,
131–139. (c) Kleinke, A. S.; Jamison, T. F. Org. Lett. 2013, 15, 710–713.
(d) Webb, D.; Jamison, T. F. Org. Lett. 2012, 14, 568–571.
Org. Lett., Vol. 15, No. 23, 2013
5979