Pavlinac et al.
SCHEME 1
one substrate is soluble in water and the other is completely
insoluble. Breslow and co-workers used water in combination
with antihydrophobic additives as a mechanistic tool for
obtaining information about the nature and structure of transition
states in transformations of molecules that are almost completely
soluble in water.4 Mayr and co-workers have recently found an
important influence of water on the reactivity of organic
molecules, enabling alkylation of aromatic molecules with
benzyl halides in a water-acetonitrile mixture without the use
of a Friedel-Crafts catalyst.5 Very recently, Sharpless and co-
workers6 reported the important observation that some organic
molecules can react on the surface of water, and in some cases,
a very strong enhancement in reaction rates was noticed in
comparison to reactions without the solvent. This is particularly
the case when at least one molecule bears a polar group enabling
some degree of solubility (carboxylic ether, amine, etc.). The
authors also suggested that water could be a useful reaction
medium for reactions where no acceleration of rate was
observed, especially in cases of exothermic reactions because
of the high heat capacity of water. This concept of organic
reactions on water has been recently confirmed by Bose et al.
as well.7
Water as a reaction medium has not been extensively used
in connection with the introduction of halogens into organic
molecules. However, we recently reported that fluorination8 with
F-TEDA-BF4 and iodination9 with the I2/H2O2 tandem of
various types of organic compounds could be effectively
performed in water. To obtain some additional information about
the role of water in these functionalizations, we decided to study
(11)) or the propan-2-onyl functional moiety (1-(4-methoxyphen-
yl)propan-2-one (12)) was introduced to obtain some information
about the regioselectivity of such functionalizations.
reactions of substituted anisoles with iodine in the presence of
10,11
F-TEDA-BF4
or hydrogen peroxide (H2O2) as an envi-
ronmentally more convenient oxidant.12 The basic model
compound was chosen because of the known fact that the
activated aromatic ring in such molecules can readily form ion
radicals with various oxidizing reagents.13 The hydroxymethyl
(p-methoxy benzyl alcohol (5)) and aldehyde (p-methoxy
benzaldehyde (6)) functionalities were additionally introduced
into the aromatic ring because of their sensitivity toward
oxidants, and the acetyl group (1-(4-methoxyphenyl)ethanone
Results and Discussion
In studying the effect of water on the functionalization of
organic molecules in or on water, one must carefully analyze
where the reactions take place. For this reason, we chose a rather
complex reaction system, where the oxidant (F-TEDA-BF4,
1, or H2O2, 2) is completely soluble in water, the organic
substrates are partially soluble, and solubility is dependent on
the temperature; iodine is partly soluble both in water and in
organic substrates (Scheme 1). Finally, we also used the anionic
surface active compound sodium lauryl ether sulfate (Genapol
LRO), which can enhance the solubility of the substrate or partly
mycellize the substrate in the water. Benzyl alcohols are soluble
in water, whereas other substrates form emulsions with various
degrees of solubility.
As we studied the functionalization of anisole (3), we found
that neither F-TEDA-BF4 nor iodine by itself reacts with it
in acetonitrile or methanol at room temperature. The triad
anisole/iodine/F-TEDA-BF4 readily exchanged electrons at
room temperature, and after 3 h in acetonitrile, almost complete
conversion to 4-iodo anisole (8) occurred (entry 1, Table 1).
The molar ratio of substrate to iodine to mediator/oxidant plays
an important role, and almost quantitative conversion was
achieved at the ratio 2:1:1.2, respectively, which means that
F-TEDA-BF4, besides activating the reaction system, also
oxidized the iodide anion to iodine. The introduction of a more
hydrophilic solvent (MeOH or H2O) demanded the prolongation
of the reaction time to 17 h for comparable efficiency of the
transformation (entries 3 and 4), with methanol being the worse
choice (entry 2).
(4) (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159-164. (b) Breslow,
R. Acc. Chem. Res. 2004, 37, 471-478. (c) Breslow, R.; Groves, K.; Mayer,
M. U. J. Am. Chem. Soc. 2002, 124, 3622-3635.
(5) (a) Hofmann, M.; Hampel, N.; Kanzian, T.; Mayr, H. Angew. Chem.,
Int. Ed. 2004, 43, 5402-5405. (b) Minegishi, S.; Kobayashi, S.; Mayr, H.
J. Am. Chem. Soc. 2004, 126, 5174-5181. For further reading on the role
of the acceptor and donor on the reactivity of organic molecules, see: (c)
Mayr, H. Angew. Chem. 1990, 102, 1415-1428. (d) Mayr, H.; Patz, M.
Angew. Chem. 1994, 106, 990-1010. (e) Mayr, H.; Kempf, B.; Ofial, A.
R. Acc. Chem. Res. 2003, 36, 66-77.
(6) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275-3279.
(7) (a) Bose, A. K.; Manhas, M. S.; Ganguly, S. N.; Pednekar, S.;
Mandadi, A. Tetrahedron Lett. 2005, 46, 3011-3013. (b) Bose, A. K.;
Manhas, M. S.; Pednekar, S.; Ganguly, S. N.; Dang, H.; He, W.; Mundadi,
A. Tetrahedron Lett. 2005, 46, 1901-1903.
(8) Stavber, G.; Zupan, M.; Jereb, M.; Stavber, S. Org. Lett. 2004, 6,
26, 4973-4976 and references therein.
(9) Jereb, M.; Zupan, M.; Stavber, S. Chem. Commun. 2004, 2614-
2615.
(10) (a) Singh, R. P.; Shreeve, J. M. Acc. Chem. Res. 2004, 37, 31-44.
(b) Nyffeler, P. T.; Gonzalez Duro´n, S.; Burkart, M. D.; Vincent, S. P.;
Wong, C.-H. Angew. Chem., Int. Ed. 2005, 44, 192-212.
(11) Stavber, S.; Zupan, M. Acta Chim. SloV. 2005, 52, 13-26.
(12) Noyori, R.; Aoki, M.; Sato, K. Chem. Commun. 2003, 1977-1986.
(13) (a) Kochi, J. K. Angew. Chem. 1988, 100, 1331-1372. (b) Bockman,
T. M.; Kochi, J. K. J. Phys. Org. Chem. 1994, 7, 325-351. (c) Hubig, S.
M.; Jung, W.; Kochi, J. K. J. Org. Chem. 1994, 59, 6233-6244. (d) Eberson,
L.; Hartshorn, M. P.; Radner, F.; Persson, O. J. Chem. Soc., Perkin Trans.
2 1998, 59-70.
A typical experiment in water was carried out in the following
way: to a mixture of 1 mmol of substrate in 10 mL of water
1028 J. Org. Chem., Vol. 71, No. 3, 2006