Kremsner and Kappe
as polymer synthesis,5 material sciences,6 nanotechnology,7 and
biochemical processes.8
run on a small scale (1 mmol) in toluene at 150 °C, a solvent
change to the significantly more polar trifluoromethylbenzene
was required for carrying out the same reaction on a larger scale
in the same microwave instrument (max power 300 W) due to
the poor microwave coupling characteristics of toluene (tan δ
) 0.040).10
Microwave chemistry generally relies on the ability of the
reaction mixture to efficiently absorb microwave energy, taking
advantage of “microwave dielectric heating” phenomena such
as dipolar polarization or ionic conduction mechanisms.9 In most
cases this means that the solvent used for a particular transfor-
mation must be microwave absorbing. The ability of a specific
solvent to convert microwave energy into heat at a given
frequency and temperature is determined by the so-called loss
tangent (tan δ), expressed as the quotient, tan δ ) ꢀ′′/ꢀ′, where
ꢀ′′ is the dielectric loss, indicative of the efficiency with which
electromagnetic radiation is converted into heat, and ꢀ′ is the
dielectric constant, describing the ability of molecules to be
polarized by the electric field.9 A reaction medium with a high
tan δ at the standard operating frequency of a microwave
synthesis reactor (2.45 GHz) is required for good absorption
and, consequently, for efficient heating.
Alternatively, instead of switching entirely to a polar solvent
it sometimes suffices to add small quantities of a strongly
microwave absorbing (polar) solvent to an otherwise low
absorbing solvent or reaction mixture to achieve similar effects.
As has been demonstrated by Ondruschka and co-workers,11
a
20% solution of 2-propanol in hexane absorbs microwave
irradiation with an efficiency that is comparable to that of pure
2-propanol (tan δ ) 0.799), with hexane being nearly microwave
transparent (tan δ ) 0.020). Similarly, dilute solutions of
standard inorganic salts can be used to dramatically improve
the comparatively moderate microwave absorbance of water (tan
δ ) 0.123).9,12,13
One of the most elegant techniques in this context is the use
of room temperature ionic liquids, which are very strongly
microwave absorbing, as heating aids. As has been demonstrated
by Ley and co-workers in 2001, the addition of only small
amounts of an ionic liquid (ca. 5%) sufficed to modify the
dielectric properties of toluene to an extent that superheating
to high temperatures (200-220 °C) by microwaves in a sealed
vessel reactor became possible.14 Subsequent detailed studies
by Leadbeater,15 Ondruschka,16 and others17 established the
general usefulness of this methodology for microwave-assisted
organic synthesis employing nonpolar solvents.18
It is obvious, however, that all of the above-mentioned
“invasive” methods have a severe disadvantage in that the
polarity of the original solvent system is inadvertently being
modified. Clearly, there are situations where it is desirable or
even a necessity to perform a particular reaction in a genuinely
nonpolar solvent in the absence of any polar additives. In
particular, the use of ionic liquids is sometimes incompatible
with certain reaction types and even small amounts of an ionic
liquid may prevent specific reaction pathways (see below).15,19
Furthermore, recent evidence suggests that under high-temper-
ature microwave irradiation conditions some ionic liquids will
decompose in the presence of nucleophiles.20
In general, solvents used for microwave synthesis can be
classified as high (tan δ > 0.5, for example: ethanol, DMSO,
methanol, formic acid), medium (tan δ 0.1-0.5, for example:
acetic acid, 1,2-dichlorobenzene, NMP, DMF, water), and low
microwave absorbing (tan δ < 0.1, for example: chloroform,
ethyl acetate, THF, dichloromethane, toluene, hexane).2,9 Other
common solvents without a permanent dipole moment such as
carbon tetrachloride, benzene, and dioxane are more or less
microwave transparent. Therefore, microwave synthesis in low-
absorbing or microwave-transparent solvents is often not
feasible, unless either the substrates or some of the reagents/
catalysts are strongly polar and therefore microwave absorbing,
raising the overall dielectric properties of the reaction medium
to a level that allows sufficient heating by microwaves. Since
this is not always the case, many nonpolar solvents, that have
proven to be very useful and are popular in conventional
chemistry, are potentially precluded from use as solvents in
microwave synthesis.
To overcome the problem of low microwave absorption, the
original solvent choice for a particular reaction sometimes has
to be compromised, requiring a change to a more polar, better
microwave absorbing solvent instead. A recent example was
reported by Maes and co-workers in the context of a scale-up
study involving a microwave-assisted Buchwald-Hartwig ami-
nation.10 While the amination was successfully optimized and
Looking for noninvasive alternatives, we have explored the
use of passive heating elements (PHEs) as additives to poorly
(4) For reviews, see: (a) Larhed, M.; Hallberg, A. Drug DiscoVery Today
2001, 6, 406. (b) Wathey, B.; Tierney, J.; Lidstro¨m, P.; Westman, J. Drug
DiscoVery Today 2002, 7, 373. (c) Al-Obeidi, F.; Austin, R. E.; Okonya, J.
F.; Bond, D. R. S. Mini-ReV. Med. Chem. 2003, 3, 449. (d) Shipe, W. D.;
Wolkenberg, S. E.; Lindsley, C. W. Drug DisoVery Today: Technol. 2005,
2, 155. (e) Kappe, C. O.; Dallinger, D. Nature ReV. Drug DiscoVery 2006,
5, 51.
(5) For reviews, see: (a) Bogdal, D.; Penczek, P.; Pielichowski, J.;
Prociak, A. AdV. Polym. Sci. 2003, 163, 193. (b) Wiesbrock, F.; Hoogen-
boom, R.; Schubert, U. S. Macromol. Rapid Commun. 2004, 25, 1739.
(6) For reviews, see: (a) Barlow, S.; Marder, S. R. AdV. Funct. Mater.
2003, 13, 517. (b) Zhu, Y.-J.; Wang, W. W.; Qi, R.-J.; Hu, X.-L. Angew.
Chem., Int. Ed. 2004, 43, 1410.
(7) For a review, see: Tsuji, M.; Hashimoto, M.; Nishizawa, Y.;
Kubokawa, M.; Tsuji, T. Chem. Eur. J. 2005, 11, 440.
(8) (a) Orrling, K.; Nilsson, P.; Gullberg, M.; Larhed, M. Chem. Commun.
2004, 790. (b) Zhong, H.; Zhang, Y.; Wen, Z.; Li, L. Nature Biotechnol.
2004, 22, 1291. (c) Zhong, H.; Marcus, S. L.; Li, L. J. Am. Soc. Mass
Spectrom. 2005, 16, 471.
(11) Nu¨chter, M.; Mu¨ller, U.; Ondruschka, B.; Tied, A.; Lautenschla¨ger,
W. Chem. Eng. Technol. 2003, 26, 1207.
(12) Neas, E.; Collins, M. Introduction to MicrowaVe Sample Prepara-
tion: Theory and Practice; Kingston, H. M., Jassie, L. B., Eds.; American
Chemical Society: Washington, DC, 1988.
(13) Kremsner, J. M.; Kappe, C. O. Eur. J. Org. Chem. 2005, 17, 3672.
(14) (a) Ley, S. V.; Leach, A. G.; Storer, R. I. J. Chem. Soc., Perkin
Trans I 2001, 358. (b) Baxendale, I. R.; Lee, A.-L.; Ley, S. V. Synlett 2001,
1482.
(15) Leadbeater, N. E.; Torenius, H. M. J. Org. Chem. 2002, 67, 3145.
(16) Hoffman, J.; Nu¨chter, M.; Ondruschka, B.; Wasserscheid, P. Green
Chem. 2003, 5, 296.
(17) Van der Eycken, E.; Appukkuttan, P.; De Borggraeve, W.; Dehaen,
W.; Dallinger, D.; Kappe, C. O. J. Org Chem. 2002, 67, 7904.
(18) For recent reviews, see: (a) Leadbeater, N. E.; Torenius, H. M.;
Tye, H. Comb. Chem. High Throughput Screening 2004, 7, 511. (b)
Habermann, J.; Ponzi, S.; Ley, S. V. Mini-ReV. Org. Chem. 2005, 2, 125.
(19) Silva, A. M. G.; Tome´, A. C.; Neves, M. G. P. M. S.; Cavaleiro, J.
A. S.; Kappe, C. O. Tetrahedron Lett. 2005, 46, 4723. In the particular
cycloaddition studied in this paper it was found that small amounts of an
ionic liquid (bmimPF6) used as doping reagent led to complete decomposi-
tion of the starting material and therefore inhibited the desired reaction
pathway.
(9) (a) Gabriel, C.; Gabriel, S.; Grant, E. H.; Halstead, B. S.; Mingos,
D. M. P. Chem. Soc. ReV. 1998, 27, 213. (b) Mingos, D. M. P.; Baghurst,
D. R. Chem. Soc. ReV. 1991, 20, 1. See also refs 1-3.
(10) Loones, K. T. J.; Maes, B. U.; Rombouts, G.; Hostyn, S.; Diels, G.
Tetrahedron 2005, 61, 10338.
(20) Glenn, A. G.; Jones, P. B. Tetrahedron Lett. 2004, 45, 6967.
4652 J. Org. Chem., Vol. 71, No. 12, 2006