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Organic & Biomolecular Chemistry
Scheme 3 Proposed fluxionality in 2.
arsenous oxide suggests that its exchange rates may be con-
siderably faster than those reported here. In what may be a
helpful analogy, the facile dimethylarsenium transfer reactions
discovered here have many parallels with the trans-nitrosyl-
ation chemistry of the nitrosylated thiolates, RSNO, which
have been more extensively studied.15
Fig. 3 Dependence of coalescence temperature upon (a) the pH of a 5 mM
solution of 2 and (b) concentration of 2 in 5 mM phosphate buffer.
Support from NSERC, FQRNT, and CRC is gratefully
acknowledged.
site exchange, with most obvious, a formal inversion of the
arsenic geometry, being unlikely. Experimentally, arsenic(III)
pyramidal inversion through a trigonal planar transition state
has a high barrier, 176 kJ mol−1 for PhEtMeAs.12 Theoretical
calculations13 also suggest these transition states should be in
excess of 150 kJ mol−1, which is much higher than our experi-
mentally determined barrier of 80 kJ mol−1. Surprisingly facile
racemisation at arsenic of the diastereomeric methylphenyl-
arsinic acid adduct with glutathione was observed by
Edmonds et al., and interpreted in terms of an unexpected
and unaccountably low inversion barrier.14
To account for the rapid methyl site exchange in 1 and 2 we
note that As(III) species are of course ambiphilic being potent
nucleophiles and ligands as well being as metalloids with
latent Lewis acidity. It is this latter character which would
allow for an associative chelation of the amine to the arsenic
to give a net five coordinate intermediate with four substitu-
ents and a stereochemically active lone pair, Scheme 3. For
this geometry Berry pseudorotation barriers are expected to be
low, and their action will lead to rapid methyl site exchange.
This mechanism is in accord with the negative entropy of acti-
vation and the rate enhancement at higher pH. The increase
in rate at lower pH may be due to a separate acid catalyzed
exchange, but the generally low of solubility of these species
limits a more extensive study under these conditions.
Notes and references
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of Chemistry, 2008, pp. P001–P412.
2 G. Q. Chen, X. G. Shi, W. Tang, S. M. Xiong, J. Zhu, X. Cai,
Z. G. Han, J. H. Ni, G. Y. Shi and P. M. Jia, et al., Blood,
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3 D. J. Thomas, J. Li, S. B. Waters, W. Xing, B. M. Adair,
Z. Drobna, V. Devesa and M. Styblo, Exp. Bio. Med., 2007,
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4 (a) V. Lallemand-Breitenbach, J. Zhu, Z. Chen and H. de
Thé, Trend Mol. Med., 2012, 18, 36–42; (b) A. M. Spuches,
J. Am. Chem., 2008, 2, 8148–8149; (c) A. M. Spuches,
H. G. Kruszyna, A. M. Rich and D. E. Wilcox, Inorg. Chem.,
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5 N. Rey and O. Howarth, J. Inorg. Biochem., 2004, 98, 1151–
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6 (a) M. Delnomdedieu, M. M. Basti, J. D. Otvos and
D. J. Thomas, Chem. Res. Toxicol., 1993, 6, 598–602;
(b) K. Dill, E. R. Adams, R. J. O’Connor, S. Chong and
E. L. McGown, Arch. Biochem. Biophys., 1987, 257, 293–301;
(c) D. E. Wilcox, Inorg. Chim. Acta, 2008, 361, 857–867.
7 M. Delnomdedieu, M. M. Basti, J. D. Otvos and
D. J. Thomas, Chem.-Biol. Interact., 1994, 90, 139–155.
8 W. R. Cullen, B. C. McBride and J. Reglinski, J. Inorg.
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In conclusion, we have shown that the As–S bond is kineti-
cally labile and can be interact with other thiols in aqueous
solutions. In addition to being more stable to oxidation, 1 is
1.4 kJ mol−1 more stable than 2 in aqueous solutions. This
type of facile thiol exchange has important implications for
the activity of methylarsenic species in cells and proteins. Also
given the enhanced electrophilicity of the AsO2 moiety in
9 K. K. Mann, B. Wallner, I. S. Lossos and W. H. Miller,
Expert Opin. Invest. Drugs, 2009, 18, 1727–1734.
10 J. Sandström, J. Mol. Struct., 1983, 102, 417–420.
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