Communication
Organic & Biomolecular Chemistry
at 5 mol%) in the presence of 100 mol% sodium chloride, CuAAC in the many scenarios in which halides are
sodium bromide or sodium iodide (Scheme 4B). THPTA encountered.
offered no benefit in the presence of iodide, as 1 was not
formed with or without THPTA. Apparently, THPTA cannot
compete with iodide in binding to copper and the catalyst is
completely deactivated. A modest benefit was observed in the
Acknowledgements
case of bromide, with a 45% conversion to triazole 1 with The authors acknowledge financial support from the Tulsa
THPTA, compared to 25% when THPTA was omitted. In the Undergraduate Research Challenge (R.M.M. and M.B.C.). The
case of chloride, THPTA did protect the copper from inhi- authors thank Dr Gordon Purser for valuable discussions and
bition, as triazole 1 was formed in 95% conversion in the pres- Jennifer Holland for assisting with mass spectrometry.
ence of 100 mol% NaCl (Scheme 4B). In the control reaction
without THPTA, the triazole was formed in 17% conversion.
These results suggest that THPTA can compete with chloride
in binding to the copper catalyst and promote the cyclo-
Notes and references
addition. As a practical measure, we therefore suggest that
THPTA be considered as a ligand for the CuAAC when the reac-
tion is carried out in buffered saline. This recommendation is
of particular importance when using the CuAAC in bioconjuga-
tion reactions.10,17,27
1 V. V. Rostovtsev, L. G. Green, V. V. Fokin and
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Conclusions
In this study, several important effects of halides on the
CuAAC have been revealed. First, inhibition by chloride was
observed at less than 300 mM sodium chloride when using a
copper(II) sulphate pre-catalyst. This chloride effect is an
important consideration when employing the CuAAC in
buffered saline, as is common in bioconjugation reactions.
Finn has recommended 500 mM sodium chloride as an upper
limit for buffers in this context,17 and our results suggest that
5 B. M. Trost, Science, 1991, 254, 1471–1477.
6 R. A. Sheldon, Pure Appl. Chem., 2000, 72, 1233–1246.
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this is the first report of sodium bromide inhibiting the
CuAAC in water. Lal and Díez-González have noted that 12 R. Berg and B. F. Straub, Beilstein J. Org. Chem., 2013, 9,
sodium bromide can inhibit the CuAAC in organic solvents 2715–2750.
when using [CuBr(PPh3)3] as a catalyst, but that this effect was 13 K. Fagnou and M. Lautens, Angew. Chem., Int. Ed., 2002, 41,
not observed in water.16 In contrast, the copper(II) sulphate
26–47.
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was observed. As iodide is often used as a nucleophilic catalyst 2373.
in substitution reactions, its inhibition of the CuAAC must be 17 V. Hong, S. I. Presolski, C. Ma and M. G. Finn, Angew.
taken into account to successfully execute one-pot SN2-CuAAC Chem., Int. Ed., 2009, 48, 9879–9883.
sequences such as the one in Scheme 3. Finally, this study 18 S. Löber, P. Rodriguez-Loaiza and P. Gmeiner, Org. Lett.,
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the CuAAC reaction mixture. For instance, silver nitrate was 19 A. Gheorghe, T. Chinnusamy, E. Cuevas-Yañez, P. Hilgers
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was also demonstrated as an effective halide scavenger that 20 A. Schätz, T. R. Long, R. N. Grass, W. J. Stark, P. R. Hanson
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In a similar vein, we have demonstrated that the tris-triazole 21 C. Shao, X. Wang, Q. Zhang, S. Luo, J. Zhao and Y. Hu,
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technical considerations will facilitate the application of the
88, 1511–1517.
Org. Biomol. Chem.
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