Microreactors for oxidations using fluorine

Article abstract of DOI:10.1016/S0022-1139(02)00244-0

Continuous flow gas-liquid thin film microreactors have been effectively used for the oxidation of alcohols and Baeyer-Villiger oxidation of ketones using elemental fluorine.

Full text of DOI:10.1016/S0022-1139(02)00244-0

Journal of Fluorine Chemistry 119 (2003) 81±82
Preliminary communication
Microreactors for oxidations using ¯uorine
Richard D. Chambers*, Darren Holling, Anthony J. Rees,
Graham Sandford1
Department of Chemistry, University of Durham, South Road,
Durham DH1 3LE, UK
Received 11 June 2002; received in revised form 6 July 2002; accepted 3 August 2002
Dedicated to Professor Tatlow on the occasion of his 80th birthday.
Abstract
Continuous ¯ow gas±liquid thin ®lm microreactors have been effectively used for the oxidation of alcohols and Baeyer±Villiger oxidation
of ketones using elemental ¯uorine.
# 2002 Elsevier Science B.V. All rights reserved.
Keywords: Microreactors; Oxidation of ketones; Fluorine
For a long period, the use of elemental ¯uorine as a
reagent for organic synthesis was considered impractical,
due to its highly reactive nature, but this perception has
now changed [1±3]. Fluorine can now be used not only for
the selective introduction of ¯uorine atoms into organic
molecules but also as a mediator for a variety of other
transformations that do not involve ¯uorination, including
iodination [4,5], bromination [5,6], oxidation [7], and depro-
tection [8] methodologies.
Recently, we reported the use of a continuous ¯ow thin
®lm gas±liquid microreactor device as a reaction vessel for
carrying out direct ¯uorination reactions [9,10]. Many
advantages associated with miniaturizing chemical pro-
cesses have been documented [11±13] such as high through-
put, automation, reduced waste products and high
performance, and the advantages of using a continuous ¯ow
reactor rather than batch-wise techniques have long been
recognized, especially by industry. Furthermore, microreac-
tors offer particularly suitable technology for performing
reactions that involve highly reactive reagents because of the
low inventory of reagent in the reaction vessel, thus increas-
ing operational safety.
Oxidation reactions can be mediated by ¯uorine, either by
the generation of the oxygen transfer reagent HOFÁMeCN by
reaction of ¯uorine with wet acetonitrile developed by
Rozen [14], or by the use of ¯uorine alone [7]. A range
of oxidations including transformation of alcohols to
ketones and Baeyer±Villiger processes [7,15], have been
reported that do not require the use of toxic heavy metal
oxidants. Furthermore, the only by-product of oxidations
using ¯uorine is hydrogen ¯uoride which, in principle, could
be recycled by electrolysis in a very environmentally benign
process. Such oxidations may be easily controlled simply by
adjusting the ¯ow-rate of ¯uorine into the reaction vessel,
thus preventing any reaction `run-away'.
In this communication, we report the use of a micro-
reactor for selective and controlled oxidation processes
mediated by ¯uorine.
A single channel microreactor device, constructed essen-
tially by cutting a 0.5 mm-wide groove into a solid nickel
block, was assembled as described previously (Fig. 1) [10].
The substrate, in an appropriate solvent (acetonitrile or
formic acid) was injected at a controlled rate by a syringe
pump into the reaction channel. Simultaneously, ¯uorine in
nitrogen was introduced into the reaction channel via a
second inlet. Both gas and liquid phases progress down
the reaction channel by `pipe ¯ow' (Fig. 2), which max-
imizes the mixing between the phases, to emerge from the
product outlet.
* Corresponding author. Tel.: ‡44-191-374-3120;
fax: ‡44-191-384-4737.
E-mailaddresses: r.d.chambers@durham.ac.uk (R.D. Chambers),
graham.sandford@durham.ac.uk (G. Sandford).
1 Co-corresponding author.
For example, a mixture consisting of cyclohexanol in
acetonitrile was injected into the micro-reactor channel at a
0022-1139/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 2 4 4 - 0

82
R.D. Chambers et al. / Journal of Fluorine Chemistry 119 (2003) 81±82
Fig. 1. Single channel microreactor.
Scheme 1. Oxidation using fluorine in a microreactor.
Acknowledgements
We thank EPSRC (ROPA Award to AJR and QUOTA
studentship to D. Holling) for funding and the Royal Society
(University Research Fellowship to G. Sandford).
Fig. 2. Pipe flow.
rate of 0.94 mmol of substrate per hour whilst a mixture of
10% ¯uorine in nitrogen was introduced into the channel at a
controlled rate of 2.6 mmol/h. After passage of both the
phases down the micro-reactor channel, the liquid products
were collected and gaseous waste products were passed
through a scrubbing tower. The organic mixture was added
to water and extracted by dichloromethane to give a crude
product which contained cyclohexanone in high yield and
conversion (Scheme 1). Puri®cation was achieved by col-
umn chromatography on silica gel or distillation. Similarly,
diols were oxidised to mono- and di-ketones, respectively
(Scheme 1).
Baeyer±Villiger oxidation of cyclohexanone was
achieved using ¯uorine and wet formic acid (5% water
(v/v)) as the reaction medium, giving the lactone by a
mechanism discussed previously [7].
For both the types of oxidation process, yields and con-
versions to products were comparable, or better, when using
a microreactor compared to batch-wise techniques [7].
In summary, continuous ¯ow gas±liquid microreactors
can be used for controlled, ef®cient ¯uorine mediated
oxidation of alcohols and ketones in an environmentally
friendly process.
References
[1] S.T. Purrington, B.S. Kagen, T.B. Patrick, Chem. Rev. 86 (1986) 997.
[2] S. Rozen, Acc. Chem. Res. 21 (1988) 307.
[3] J. Hutchinson, G. Sandford, in: R.D. Chambers (Ed.), Top. Curr.
Chem., vol. 193, Springer-Verlag, Berlin, 1997, p. 1.
[4] S. Rozen, D. Zamir, Y. Menachem, M. Brand, J. Org. Chem. 53
(1988) 1123.
[5] R.D. Chambers, C.J. Skinner, M.J. Atherton, J.S. Moilliet, J. Chem.
Soc., Perkin Trans. 1 (1996) 1659.
[6] S. Rozen, M. Brand, R. Lidor, J. Org. Chem. 53 (1988) 5545.
[7] R.D. Chambers, J. Hutchinson, G. Sandford, A. Shah, J.F.S.
Vaughan, Tetrahedron 53 (1997) 15833.
[8] R.D. Chambers, G. Sandford, M.E. Sparrowhawk, M.J. Atherton, J.
Chem. Soc., Perkin Trans. 1 (1996) 1941.
[9] R.D. Chambers, R.C.H. Spink, Chem. Commun. (1999) 883.
[10] R.D. Chambers, D. Holling, R.C.H. Spink, G. Sandford, Lab on a
Chip 1 (2001) 132.
[11] S.J. Haswell, V. Skelton, Trends Anal. Chem. 19 (2000) 389.
[12] S.J. Haswell, R.J. Middleton, B. O'Sullivan, V. Skelton, P. Watts, P.
Styring, Chem. Commun. (2001) 391.
[13] O. Worz, K.P. Jackel, T. Richter, A. Wolf, Chem. Eng. Sci. 56 (2001)
1029.
[14] S. Rozen, Acc. Chem. Res. 29 (1996) 243.
[15] S. Rozen, Y. Bareket, M. Kol, Tetrahedron 49 (1993) 8169.