5
6
P. Vogel et al. / Tetrahedron Letters 50 (2009) 55–56
We observed that the nucleophilicity of the anion was strongly
while in the absence of 18- crown-6 the reaction needs to be milled
for 48 h to achieve comparable yield.
dependent on the counter cation. Sodium and potassium fluoride
did not give the corresponding p-bromobenzyl fluoride, but cesium
fluoride provided a 50% yield of the desired product. Likewise, we
noticed that potassium iodide gave much higher yield than sodium
iodide, demonstrating again that the counterion is crucial under
HSBM conditions.
Br
X
MX
HSBM
Br
18-Cr-6
Br
It has been shown that with many solvent-free reactions the
reagents need to create a eutectic melt in order for a reaction to
X= F, Cl, I, CN, OAc
1
2
occur. We wanted to examine how a eutectic melt influences
the product yield of the various nucleophiles. Takacs showed while
milling that a Spex Mixer/Mill 5000 M reaches a global tempera-
Entry
Metal
Nucleophile
% Conversion
% Yield
1
3
ture of about 60 °C. Due to the fact that the melting point of
p-bromobenzyl bromide is also about 60 °C, it is very possible that
the success of these reactions is dependent on the mixture of p-
bromobenzyl bromide and the desired nucleophile causing a phase
change. When the reagents are added to the vial we do not observe
a phase change; however, the reagents may reach a eutectic melt
once ball milling is initiated.14 To further explore this possibility,
1
2
3
4
5
K
K
K
K
K
F
80
90
70
>99
>99
80
90
70
90
90
Cl
I
OAc
CN
we used
a
freezer mill in
a
liquid nitrogen environment
In conclusion we have demonstrated environmentally benign
method for conducting heterogeneous mixtures in the absence of
a phase transfer catalyst using HSBM. We look to further study
HSBM in various organic reactions to further demonstrate its util-
ity in organic synthesis.
(
ꢁ196 °C) to determine if these reactions occur in low temperature
conditions. We milled sodium iodide and p-bromobenzyl bromide
1
for 1 h under a liquid nitrogen environment. Both H NMR and GC–
MS confirmed the presence of the expected p-bromobenzyl iodide.
We also produced the nucleophilic addition product of the thio-
cyanate using the freezer mill; therefore, given the low tempera-
tures that these reactions were conducted, we do not believe a
phase change is a requirement for these solvent-free hetero-
geneous ball-milled reactions. Currently, we are in the process of
exploring the effect of a phase change on the success of other ball
milled organic reactions.
We thought that we could increase the nucleophilicity of the
reagents through the addition of 18-crown-6 (1.0 mmol) for the
potassium salt nucleophiles. The addition of 18-crown-6 led to
an increase in yield and conversion for all of the potassium salt
nucleophiles including those which were previously unsuccessful
such as fluoride, acetate, and cyanide. 18-crown-6 is typically used
as a phase transfer catalyst in solution. Therefore, we wanted to
examine whether it acts as a phase transfer catalysts under our
conditions. We ball milled p-bromobenzyl bromide and potassium
chloride for 1 h with and without 18-crown-6. Both reactions pro-
duce the desired p-bromobenzyl chloride demonstrating that the
crown ether is not a necessity for these heterogeneous reactions.
The addition of the crown ether greatly increased the reaction rate;
References and notes
1.
2.
3.
Anastas, P.; Warner, J. Green Chemistry: Theory and Practice 1998.
Suryanarayana, C. Prog. Mater. Sci. 2000, 46, 1–184.
Takacs, L. Prog. Mater. Sci. 2002, 47, 355–414.
4. Balema, V. P.; Wiench, J. W.; Pruski, M.; Pecharsky, V. K. Chem. Commun. 2002,
606–1607.
Balema, V. P.; Wiench, J. W.; Pruski, M.; Pecharsky, V. K. J. Am. Chem. Soc. 2002,
24, 6244–6245.
1
5.
1
6. Balema, V. P.; Wiench, J. W.; Pruski, M.; Pecharsky, V. K. Chem. Commun. 2002,
724–725.
7.
8.
9.
Mack, J.; Shumba, M. Green Chem. 2007, 9, 328–330.
Mack, J.; Fulmer, D.; Stofel, S.; Santos, N. Green Chem. 2007, 9, 1041–1043.
Yadav, G. D. Top. Catal. 2004, 29, 145–161.
10. Yadav, G. D. Chem. Indus. Digest 2005, 18, 49–62.
1
1
1. Yadav, G. D.; Badure, O. V. Ind. Eng. Chem. Res. 2007, 46, 8448–8458.
2. Rothenberg, G.; Downie, A. P.; Raston, C. L.; Scott, J. L. J. Am. Chem. Soc. 2001,
1
23, 8701–8708.
13. Takacs, L.; McHenry, J. S. J. Mater. Sci. 2006, 41, 5246–5249.
1
4. In all cases, the p-bromobenzylbromide appears to have melted under the
reaction conditions, while the nucleophilic salt seems to remain solid
throughout the milling process. An oily-solid is present at the conclusion of
all of these reactions.