Towards use of floricil-based molecular Batch Molecular Reactors for conventional free radical chemistry

Article abstract of DOI:10.2174/157017811795371377

Floricil (60-100nm, activated)-based Batch Molecular Reactors have been assembled and used in a variety of conventional synthetically useful free radical transformations (Hydrogen Transfer Reactions, Radical Cascade Reactions and Addition to C=C and C=N bonds). Reactions proceeded smoothly in all cases in good to excellent yields at ambient temperature in aqueous and organic media. The advantages of newly assembled setup are ease of setup, recyclability of the solid media, flexibility and scope of the transformations to be performed and ease of scale-up of methodology.

Full text of DOI:10.2174/157017811795371377

292
Letters in Organic Chemistry, 2011, 8, 292-294
Towards use of Floricil-Based Molecular Batch Molecular Reactors for
Conventional Free Radical Chemistry
Victoria T. Perchyonok*
VTPCHEM PTY. LTD, 3163, Melbourne, Australia
Received July 07, 2010: Revised March 11, 2011: Accepted March 11, 2011
Abstract: Floricil (60-100nm, activated)-based Batch Molecular Reactors have been assembled and used in a variety of
conventional synthetically useful free radical transformations (Hydrogen Transfer Reactions, Radical Cascade Reactions
and Addition to C=C and C=N bonds). Reactions proceeded smoothly in all cases in good to excellent yields at ambient
temperature in aqueous and organic media. The advantages of newly assembled setup are ease of setup, recyclability of
the solid media, flexibility and scope of the transformations to be performed and ease of scale-up of methodology.
Keywords: Free radicals, batch reactors, floricil, aqueous.
Increasing emphasis has been placed on producing
synthetic organic compounds faster and more efficiently
using conventional methodology [1]. It has been often
observed that tried and true methods for performing
synthesis, work up on individual and low number of
reactions do not scale up well even to modest level of
parallel synthesis. In nature, however, biological machines
perform tasks that enable life to proceed [2, 3]. In the pursuit
of nanoscale machines, chemists are inspired to mimic
nature, to produce synthetic structures that perform tasks at
our discretion.
zeolites. Several examples of zeolite catalysis in organic
synthesis have been reported previously, however the
application of florisil molecular reactors is unknown in
radical transformations as functional reaction media [8,9].
The advantage of radical over ionic reactions lies in chemo-
selectivity, tolerance of
a wide range of chemical
functionalities without the need for protecting groups, the
general absence of solvent effect, and the kinetically
controlled reaction outcomes.
In line with our continous interest in development and
utilization of molecular reactors in organic synthesis, we
decided to examine the performance of the florisil-filled
molecular reactors under batch conditions for investigation
of free radical hydrogen transfer reactions and radical
cascade reaction in aqueous and organic media.
Free radicals are ubiquitous, reactive chemical entities.
Free radical reactions are an important class of synthetic
reactions that have been traditionally performed in organic
solvents [4]. In recent years, the number of reports of free
radical reactions that use water and alternative media such as
supercritical CO2, ionic liquids, fluorous solvents and solid
state have been increased [5]. Radical reaction is one of the
most useful and flexible methods for organic reactions in
alternative media, because most of the organic radicals
species are stable and not reactive with the alternative media
itself.
Batch Molecular Reactors
Floricil
Molecular reactors are miniature reaction vessels that
control the assembly of reagents to affect the outcomes of
chemical reactions at the molecular level [6]. In many ways,
they are analogous to common laboratory glassware with the
unique advantage that after the chemical reaction has taken
place, the products are removed and the reaction vessel can
be reused [6,7].
Floricil + R
Reaction Types:
a. Hydrogen Atom Transfer Reaction
b. Radical Cascade Reactions
c. Radical Addition Reactions
Floricil + P
Zeolites are crystalline aluminosilicate with highly
ordered crystalline structure. Cavities of a defined size are
formed in the rigid, three-dimensional networks composed of
SiO4- and AlO4- tetrahedral. The lattice contains cavities of
varying diameters, depending on the type of zeolite [6, 7]. A
distinction is made between large-, medium- and small pore
Floricil + P
Where: R=reagent
P=product
Fig. (1). Schematic representation of the prototype molecular
device under investigation.
*Address correspondence to this author at the VTPCHEM PTY. LTD, 3163,
Melbourne, Australia; Tel/Fax: +61414596304:
E-mail: tamaraperchyonok@gmail.com
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

Towards use of Floricil-Based Molecular Batch Molecular Reactors
Letters in Organic Chemistry, 2011, Vol. 8, No. 4 293
Atom Transfer Reactions
Radical Cascade Reactions
Radical Addition Reactions
-
(Bu4N)+H2PO2
O
-
(Bu4N)+H2PO2
O
N
Br
Ph
N
Ph
N
Br
H2O, 45min
Et3B/air
b-CD
H2O,1h
Et3B/air
florisil
I
batch 1 75%
batch 2 78%
batch 3 72%
batch 1 45%
batch 2 42%
batch 3 38%
-
(Bu4N)+H2PO2
H2O,1h
Et3B/air
florisil
O
I
O
Br
O
TMS3SiH
TMS3SiH
OH
OH
HN
H2O, 45min
Et3B/air
b-CD
H2O,1h
Et3B/air
florisil
O
iPr
batch 1 76%
batch 2 72%
batch 3 74%
batch 1 82%
batch 2 80%
batch 3 76%
batch 1 63%
batch 2 70%
batch 3 65%
Scheme 1. Selected Free Radical Transformations performed in the floricil batched molecular reactors.
CONVENTIONAL FREE RADICAL CHEMISTRY
FLORICIL AS MOLECULAR BATCH REACTOR
further exciting developments and applications and further
uses in chemically important transformations.
We chose to investigate the 3 types of synthetically
useful free radical transformations: hydrogen transfer
reaction and carbon-carbon bond formations via radical
cascade reaction and radical addition to C=C and C=N
bonds. All reactions were performed in aqueous and organic
media in order to expand the applicability of the proposed
methodology and results of the investigations are
summarized in Scheme 1.
CONCLUSION
In this short communication we have demonstrated for
the first time, excellent performance of the floricil-based
molecular reactors under batch conditions in organic and
aqueous media to expand the scope and application of
conventional free radical chemistry in modern, potentially
high-throughput conditions suitable to broad range of
applications and future developments.
Floricil (60-80nm) activated have shown to be a powerful
experimental set-up as a molecular batch reactor suitable for
the range of synthetically useful transformations, such as
atom transfer reactions, radical cascade reactions and
additions to C=C and C=N double bonds reported in Scheme
1 with the following advantages being observed in broad
scope of fundamental synthetic transformations with added
advantage of a homogeneous distribution of substrate,
reactants and products over the molecular reactor, reliable
operation and recyclability for 2-3 cycles at present and
stable conditions under substrate-limiting conditions as well
as unexplored and novel aspects of the transformations. In
parallel, transformations were repeated in organic media
(benzene and cyclohexane, for comparison) in order to
provide comparison of the system performance in organic
and aqueous media, with isolated yields being excellent in
both solvent systems. The floricil was recycled and reused
after thorough washing with hexane/ethyl acetate (50:50)
mixture and drying, performance of zeolite was not altered.
These outcomes demonstrate for the first time successful
application of natural floricil as a functional molecular
reaction media which is suitable for the use as a molecular
batch reactor, which is commercially available, cheap and in
some instances recyclable and undoubtedly will lead to
REFERENCES
[1]
Zhang, S., Chen, J., Lykakis, I. N., Perchyonok, V. T, Streamlining
Organic Free Radical Synthesis through Modern Molecular
Technology: from Polymer Supported Synthesis to Microreactors
and beyond, Current Organic Synthesis, 2010, 7, 177-188 and
references sited therein.
[2]
[3]
Easton C, Onagi H, Dawson R, Maniam S, Coulston R, Zhang J,
Lincoln S Cyclodextrin nanoscale devices, Chem. Aust., 2009,
76(1), 8-12, 22.
a. Dawson R. E, Lincoln S. F, Easton C. J The foundation of a light
driven molecular muscle based on stilbene and ꢀ-cyclodextrin.
Chem.
Commun.
2008,
34,
3980-
3982.http://dx.doi.org/10.1039/b809014a, b. Dawson R. E, Maniam
S, Lincoln S. F, Easton C. J Synthesis of ꢀ-cyclodextrin [2]-
rotaxanes using chlorotriazine capping reagents. Org. Biomol.
Chem.
2008,
6(10),
1814-1821.
http://dx.doi.org/10.1039/b802229a. (c) Maniam S, Cieslinski M.
M, Lincoln S. F, Onagi H, Steel P.J, Willis A.C, Easton C.J
Molecular fibers and wires in solid-state and solution self-
assemblies of cyclodextrin [2]rotaxanes. Org. Lett., 2008,
10(10),1885-1888.http://dx.doi.org/10.1021/ol8002145.
[4]
(a)Radicals in Organic Synthesis, Vol. 1; Renaud, P.; Sibi, M. P.,
Eds. Wiley-VCH: Weinheim, 2001. (b) Postigo, A.; Ferreri, C.;
Navacchia, M.L.; Chatgilialoglu, C. The radical-based reduction
with (TMS)3SiH on water. Synlett, 2005, 2854-2856. (c) Postigo,
A.; Ferreri, C.; Navacchia, M.L.; Chatgilialoglu, C. The radical-

294 Letters in Organic Chemistry, 2011, Vol. 8, No. 4
Victoria Tamara Perchyonok
based reduction with (TMS)3SiH on water. Synlett, 2005, 2854-
2856. (d) Chatgilialoglu, C; Ferreri, C.; Mulazzani, Q.C.; Ballestri,
M.; Landi, L. Cis-trans isomerization of monounsaturated fatty acid
residues in phospholipids by thiyl radicals. J.Am.Chem.Soc., 2000,
122, 4593-4601 (e) Yorimitsu, T.; Nakamura, H.; Shinokubo, K.;
Oshima, K.; Fujimoto, H. Powerful solvent effect of water in
radical reaction: triethylborane-induced atom-transfer radical
cyclization in water. J.Am.Chem.Soc., 2000, 122, 11041-11047.
catalysis, Applied Catalysis. 2000, 18, 127-132. (b) Pitchumani,
K.; Corbin, D. R., Ramamurthy, V., Electron Transfer Reactions
with Zeolites: Radical Cations from Benzonorbornadienes. J. Am.
Chem. Soc., 1996, 118(34), 8152-8153 . (c) Turro, N., From
Boiling Stones to Smart Crystals: Supramolecular and Magnetic
Isotope Control of Radical-Radical Reactions in Zeolites, Acc.
Chem. Res., 2000, 33, 637-646 and references sited therein.
a. Perchyonok, V. T. Radical Reactions in Aqueous Media, RSC,
2010, http://www.rsc.org/Shop/books/2009/9781849730006.asp b).
Johnson, A. E., Zhang, S., Chen, J. and Perchyonok, V. T, On the
[8]
[9]
[5]
a) Perchyonok, V. T.; Lykakis, I. N. Radical reactions in aqueous
media: origins, reason and applications. Curr. Org. Chem., 2009,
13, 573; b) Perchyonok, V. T.; Lykakis, I. N.; Tuck, K. L. Recent
use of ꢁ-cyclodextrins as molecular reactors for the radical
cyclizations under tin free conditions, Current Organic Chemistry,
advances in CꢀH bond formation in aqueous media: a mechanistic
perspective Green Chem., 2008, 10, 153; c) Perchyonok, V. T.;
Tuck, K. L.; Langford, S. J.; Hearn, M. W. On the scope of radical
reactions in aqueous media utilizing quaternary ammonium salts of
phosphinic acids as chiral and achiral hydrogen donors
Tetrahedron Lett., 2008, 49, 4777; d) Li, C.-J.; Chen, L. Organic
chemistry in water Chem. Soc. Rev., 2006, 35, 68 and references
therein; e) Yorimitsu, H.; Nakamura, T.; Shinokubo, H.; Oshima,
K., Omoto, K.; Fujimoto, H. Powerful solvent effect of water in
radical reaction: triethylborane-induced atom-transfer radical
cyclization in water J. Am. Chem. Soc., 2000, 122, 11041. For an
interesting example of use of supercritical CO2, see: f) Hadida, S.;
Super, M. S.; Beckman, E. J.; Curran, D. P. Radical reactions with
alkyl and fluoroalkyl (fluorous) tin hydride reagents in supercritical
CO2 J. Am. Chem. Soc., 1997, 119, 7406; see also: g) Tanko, J. M.,
"Free-Radical Chemistry in Supercritical Carbon Dioxide", in
Green Chemistry using Liquid and Supercritical Carbon Dioxide,
Joseph M. DeSimone and William Tumas, Ed.s; Oxford University
Press: New York, 2003; chp. 4, p. 64. (h) Lykakis, I. N.,
Perchyonok, V. T., Thiols as an efficient hydrogen atom donor in
free radical transformations in aqueous media, Current Organic
Chemistry, 2010, in print. k). Johnson, A. E., Perchyonok, V. T.
Recent Advances in Free Radical Chemistry in unconventional
medium: ionic liquids, microwaves and solid state to the rescue,
review article, Current Organic Chemistry, 2009, 13(17), in print,
l). Postigo, A.; Kopsov, S.; Zlotsky, S.S.; Ferreri, C.;
Chatgilialoglu, C. Hydrosilylation of C-C multiple bonds using
(Me3Si)3SiH in water. Comparative study of the radical initiation
step. Organometallics, 2009, doi: 10.1021/om900086m.
2010, in print. c). Johnson, A. E. Perchyonok, V. T., ꢁ -
cyclodextrin based molecular reactors for free radical chemistry in
aqueous media. Current Organic Chemistry, 2009, 13(9), 914-918.
For recent reviews of microreactor-based synthesis, see: (a)
Ehrfeld, W.; Hessel, V.; Lowe, H. Microreactors: New Technology
for Modern Chemistry, John Wiley & Sons Inc., Weinheim, 2000;
(b) Jahnisch, K.; Hessel, V.; Lowe, H.; Baerns, M. Chemistry in
microstructured reactors. Angew. Chem., Int. Ed., 2004, 43, 406-
446; (c) Watts, P.; Wiles, C. Recent advances in synthetic micro
reaction technology. Chem. Commun., 2007, 443-467; (d) Mason,
B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D.
T. Greener approaches to organic synthesis using microreactor
technology. Chem. Rev., 2007, 107, 2300-2318; (e) Ahmed-Omer,
B.; Brandt, J. C.; Wirth, T. Advanced organic synthesis using
microreactor technology. Org. Biomol. Chem., 2007, 5, 733-740;
(f) Geyer, K.; Codee, J. D. C.; Seeberger, P. H. Microreactors as
tools for synthetic chemists - the chemists' round-bottomed flask of
the 21st century? Chem. Eur. J., 2006, 12, 8434-8442; (g)
Fukuyama, T.; Rahman, M. T.; Sato, M.; Ryu, I. Adventures in
inner space: microflow systems for practical organic synthesis.
Synlett, 2008, 151, (e) Fukuyama, T.; Kobayashi, M.; Taifur
Rahman, Md.; Kamata, N.; Ruy, I. Spurring radical reactions of
organic halides with tin hydride and ttmss using microreactors.
Org. Lett., 2008, 10, 533-536. (f) Sugimoto, A.; Takagi, M.;
Sumito, Y.; Fukuyama, T.; Ryu, I. The barton reaction using a
microreactor and black light. Continuous flow synthesis of a key
steroid intermediate for an endothelin receptor antagonist.
Tetrahedron Lett., 2006, 47, 6197-6200, (j) Iwasaki, T.; Yoshida, J.
Free radical polymerization in microreactors significant
improvement in molecular weight distribution control.
Macromolecules, 2005, 38, 1159-1163.
[6]
[7]
Holderich W., Hesse M., Naumann F., Zeolites: Catalysis for
Organic Synthesis, Angew. Chem. Int. Ed. Engl., 1988, 27, 226-246
and references sited therein.
Selected references: (a) Navratilova, M.; Sporka, K.; Muller, A.,
Synthesis of adamantine on commercially available zeolitic