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Organic & Biomolecular Chemistry
DOI: 10.1039/C4OB01350F
ARTICLE
catalyst in parentheses). C. Reactions between benzylazide and phenylacetylene without catalyst. D. Visualization of the modeled transition states TSꢀ1 and
TSꢀ2 on catalyst model 6.
F.V. would like to express his deep appreciation to State Key Lab
The free energy contributions between the different states of the
catalytic cycle can be split in enthalpy and entropy contributions
(Supplementary table S7). The click reaction is very exergonic
with reaction free energy differences around ꢀ305 kJ/mol. To
quantify the relative rates between catalysts 6 and 8, one can look
to the difference in activation free energy for the global barrier.
Therefore, a reduced catalytic cycle is constructed withonly the
major states (right part, figure 6.A), omitting the (de)protonation
transition states. Right now, the largest free energy barrier of
both catalytic cycles can easily be compared. The global free
energy barrier from F amounts to 141.6 kJ/mol and 145.7 kJ/mol,
for catalyst 6 and 8 respectively. This gives a rate acceleration of
5.3 between both complexes, which is in agreement with the
experimentally observed rate acceleration of 4 between catalyst 5
and 7 (figure 2). As these catalysts have only one CH2 group less
compared to catalyst 6 and 8, the difference in rate between
catalyst 6 and 8 will be similar, and thus, is in very good
agreement with the computationally predicted acceleration.
Without catalyst the free energy barrier would be 132.9 kJ/mol,
which is larger than the barrier measured from complex A (90.9
and 95.8 kJ/mol, Supplementary table S8) but still lower than the
barrier from complex F (141.6 and 145.7 kJ/mol).
of Advanced Technology for Materials Synthesis and Processing
(Wuhan University of Technology) for financial support. F.V.
acknowledges the Chinese Central Government for an “Expert of
the State” position in the program of “Thousand talents”. H.D.V.
appreciates the financial support from Mexican Council of
Science and Technology (CONACYT, Ph. D. grant,). M.V. is a
PostꢀDoctoral Fellow with the FWO. Y.R. is indebted to the
Marie Curie ITN with grant agreement number 238679.
Computational resources and services were provided by Ghent
University (Stevin Superꢀcomputer Infrastructure). We would
also like to thank prof.dr.ir. Veronique Van Speybroeck for
reading the manuscript and scientific discussions.
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Conclusion and Outook
We have presented for the first time the synthesis of sulfonate
functionalized bisꢀNHCꢀCu(I) complexes and their application in
Click reactions for a variety of reaction conditions, illustrating
the high versatility of these compounds, for the synthesis of
triazoles with different substitution patterns. We haver further
shown the use of these waterꢀsoluble complexes in
bioconjugation experiments, attaining for the first time the
functionalization of an unprotected 25ꢀaminoacid chain peptide
using low catalyst loading, which otherwise would need a much
higher amount of Cu(I) to achieve high efficiency due to the
chelating properties of certain aminoacid residues. We could take
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ligand and used this feature to ionically immobilize these
complexes on an anion exchange resin. Moreover, both, the
homogeneous and heterogeneous catalysts even performed Click
reactions by using acetylene gas as the alkyne source. Exploiting
tosyl azide as substrate generated tosylꢀacetamide as the sole
product and thus broadens the scope of the newly developed
catalysts. Mechanistic analysis of the Cu(I) catalysts bearing
sulfonate functionalized NHC ligands shows that the sulfonate
group allows internal deprotonation and protonation steps of the
alkyne and formed reaction product, respectively. Comparison of
energy barriers quantitatively confirmed that the complexes with
saturated ligands are more active than the complexes with
unsaturated ligands toward Click reactions, which is in good
agreement with the experiments.
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Acknowledgements
This journal is © The Royal Society of Chemistry 2013
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