nucleophilic reaction.8 However, in no cases were the
proposed addition products isolated, making it difficult to
verify the suggested mechanism of action. Given this
uncertainty, we felt it would be advantageous to develop a
cyanide-driven reaction that (i) operates at room temperature,
(ii) has a clear mechanistic signature, and (iii) could be
exploited for the development of off-the-shelf indicators9 for
this toxic agent. We now report such a reaction. It involves
the optimized trapping of a single product from a hitherto
little-explored, cyanide-induced transformation called the
benzil rearrangement.
Table 1. Products from the Benzil Rearrangementa
The benzil rearrangement, and the mechanistically related
benzil-cyanide reaction (Scheme 1), is believed to proceed
Scheme 1. Proposed Mechanisms of the Benzil-Cyanide
a All reactions were run in chloroform on a 20 mg scale (diketone
substrate). Tetrabutylammonium cyanide (1.2-2 equiv) was added to a
solution of substrate (6 mL, CHCl3) at 25 °C. The reaction was deemed
complete after 20 min (cf. Supporting Information). b Isolated yields.
Reaction and the Benzil Rearrangement Reaction
yield from benzil analogues; cf. Table 1. Our results thus
provide direct support for intermediate C in benzil-cyanide-
type reactions.
An interesting feature of the rearrangement of 1 to 1a is
that it serves to sever the conjugation pathway between the
two aryl carbonyl groups originally present in benzil. We
thus imagined that this rearrangement could be used to
produce a specific, cyanide-mediated color change, provided
a suitably colored benzil derivative could be obtained. To
test this hypothesis, the π-extended system 3 was prepared;
it was synthesized in 70% yield via the Sonogashira coupling
of dibromobenzil with N,N-diethyl-4-ethynylbenzenamine
(cf. Supporting Information).13
The benzil rearrangement reaction of 3 was monitored by
UV-vis spectroscopy, as shown in Figure 1. In the absence
of an added anion, the absorption maximum of 3 (dissolved
in ethyl acetate appears at 412 nm). After the addition of 3
equiv of tetrabutylammonium cyanide, a large bathochromic
shift was observed (∆λmax ) 56 nm), with all spectral
changes being complete within 1 min (Figure 1a). This blue
shift is reflected in a change in the color of the solution from
yellow to colorless (Figure 1b), allowing for facile qualitative
analysis.14 The fact that 3a is fluorescent also allowed the
cyanide-mediated conversion to be followed using a labora-
tory UV lamp (Figure 1c), with the limit of detection [LoD]
being ca. 20 µM in organic solution.
through intermediate C.10 While this intermediate represents
a species whose existence is widely accepted, to the best of
our knowledge, the corresponding protonated mandelonitrile
benzoate product 1a has yet to be isolated as a major product
from benzil.11 As detailed below, this species may be
obtained in good yield via the appropriate choice of condi-
tions. Moreover, the use of benzil analogues permits the
dosimeter-type detection of the cyanide anion in organic
media.
Intermediate C has long been considered to be unstable
under typical benzil-cyanide-type reaction conditions. In
fact, in alcoholic solvents, intermediate C undergoes scission
to produce benzaldehyde and the alcohol-derived benzoate
ester, whereas in DMSO, the stilbenediol benzoate diester
1b is formed.12 However, we have now found that the use
of aprotic solvents (i.e., acetonitrile, CHCl3, and EtOAc), as
well as a more organic soluble cyanide source (tetrabutyl-
ammonium cyanide, TBA‚CN), allows the protonated form
of intermediate C (compound 1a) to be isolated in decent
(7) Chen, C.-L.; Chen, Y.-H.; Chen, C.-Y.; Sun, S.-S. Org. Lett. 2006,
8, 5053-5056.
(8) An interesting reaction-based approach to developing fluorescent (but
non-colorimetric) cyanide anion receptors, involving the use of ammonium
boranes, was reported during the time this work was being written up for
publication. See: Hudnall, T. W.; Gabbai, F. P. J. Am. Chem. Soc. 2007,
129, 11978-11986.
To evaluate the selectivity of receptor 3, 3 equiv of various
potentially competing anions (studied as the corresponding
tetrabutylammonium salts), including OH-, F- (as the
-
-
-
trihydrate), N3 , AcO-, Cl-, HSO4 , and H2PO4 , were each
(9) Miyaji, H.; Sessler, J. L. Angew. Chem., Int. Ed. 2001, 40, 154-
157.
(10) (a) Kwart, H.; Baewky, M. J. Am. Chem. Soc. 1958, 80, 580-588.
(b) Kuebrich, A. W.; Schowen, R. L. J. Am. Chem. Soc. 1971, 93, 1220-
1223. (c) Bwgstahler, A. W.; Walker, D. E., Jr.; Kuebrich, J. P.; Schowen,
R. L. J. Org. Chem. 1972, 37, 1272-1273. (d) Okimoto, M.; Itoh, T.; Chiba,
T. J. Org. Chem. 1996, 61, 4835-4837.
(11) Previous workers isolated 1a in 18% yield while recovering benzil
in 60% yield: Clerici, A.; Porta, O. J. Org. Chem. 1994, 59, 1591-1592.
(12) Trisler, J. C.; Frye, J. L. J. Org. Chem. 1965, 30, 306-307.
(13) N,N-Dimethyl-4-ethynylbenzenamine is commercially available.
N,N-Diethyl-4-ethynylbenzenamine was synthesized according to a literature
procedure: Miki, Y.; Momotake, A.; Arai, T. Org. Biomol. Chem. 2003,
1, 2655-2660.
(14) (a) Miyaji, H.; Sato, W.; Sessler, J. L. Angew. Chem., Int. Ed. 2000,
39, 1777-1780. (b) Anzenbacher, P., Jr.; Jursikova, K.; Sessler, J. L. J.
Am. Chem. Soc. 2000, 122, 9350-9351. (c) Sessler, J. L.; Cho, D.-G.;
Lynch, V. J. Am. Chem. Soc. 2006, 128, 16518-16519.
74
Org. Lett., Vol. 10, No. 1, 2008
Sessler, Jonathan L.
