Paper
The generally high yields, absence of any detectable diyne by-
RSC Advances
products and lack of degradation of the materials post reaction
suggested that our products were indeed pure, but to rigorously
test our copper acetylides and the validity of our method, we
performed a simple Huisgen-type reaction (the most famous of
the ‘Click’ reactions)17 to form a 1,2,3-triazole product via Cu-
promoted azide–alkyne coupling (CuAAC) which proceeds
through a copper(I) acetylide intermediate. This reaction is
a good exemplar because it is so widely-used, especially in
pharmaceutical chemistry where many drug molecules,
biomaterials and polymers are routinely produced using this
chemistry.18 It is also a reaction known to be efficient and relies
upon a CuI-based catalytic cycle, meaning that if our copper
acetylides were in a mixed oxidation state, this would be high-
lighted clearly. We therefore adapted conditions from Shao
et al.,19 deliberately selecting a method without a reducing agent
such as sodium ascorbate to remove the possibility of CuII being
converted into CuI mid-reaction (Fig. 3).
Scheme 4 One-pot electrochemical CuAAC reaction.
These results suggest that the presence of acetate anions
permits the generation of a potent copper acetate catalyst,
indeed, control reactions using Cu(I)OAc and Et3N produced 5,
but in lower yields than the electrochemical method. Further-
more, trace amounts of diyne 2 were also produced (presumably
from Cu(II) contamination of the Cu(I)OAc catalyst) which was
not observed in any of the electrochemical tests where Cu(I) is
generated in situ.
To our delight, we found that the yields and spectral data for
5 produced using 1a from both the traditional method (syn-
thesised using CuI in NH3–H2O–EtOH8) and our new electro-
chemical method matched very well, reaffirming that our new
method for producing copper acetylides is robust. We also
noted that when 1a of questionable oxidation state, i.e.
a possible mixture of CuI and CuII acetylides as in picture B of
Fig. 3 was used, a signicantly lower yield of 48% was obtained
for 5. Emboldened by these results, we attempted to integrate
our electrochemical copper(I) acetylide formation with the Click
reaction to produce a sustainable, one-pot electrochemical
process, as shown in Scheme 4. Previously, groups have carried
out electro-assisted CuAAC-type reactions on electrode surfaces
coated with either alkyne or azide functional groups, where
Cu(II) salts added to solution are electrochemically reduced to
Cu(I), initiating the Click reaction.20 Another approach involving
the generation of the alkyne moiety on the surface of electrodes
through the reduction of Co2(CO)6 has also been demon-
strated,21 but to our knowledge this is the rst example of both
an electro-oxidised Cu(0) to Cu(I) approach and of such a reac-
tion on preparative-scale. We obtained yields of 49% for 5 with
Et4NO3SC6H4CH3 and 79% with Et4NOAc$4H2O (control reac-
tions with no potential applied yielded 2% and 0% respectively).
Conclusions
In summary, we have successfully improved the efficiency and
sustainability of copper(I) acetylide synthesis using electro-
chemistry in an undivided cell. This decreased the amount of
solvent required, the base was generated from the background
electrolyte and regenerated electrochemically to make it cata-
lytic and halogen waste was completely eliminated from the
process. We rigorously assessed the delity of our products
through a ‘Click test’ (CuAAC reaction) and we successfully
integrated the two reactions into a sustainable, one-pot elec-
trochemical process, which serves as a promising initial
demonstration of this approach in a pharmaceutically-relevant
reaction.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
We thank UCL for nancial support via a studentship awarded
to PWS and Dr D. MacMillan (UCL) for MS support.
Notes and references
1 Y. Kamamoto, Y. Nitta, K. Kubo, T. Mizuta and S. Kume,
Chem. Commun., 2016, 52, 10486–10489.
2 P. W. Seavill, K. B. Holt and J. D. Wilden, Green Chem., 2018,
20, 5474–5478.
3 B. Wang, J. Zhang, X. Wang, N. Liu, W. Chen and Y. Hu, J.
Org. Chem., 2013, 78, 10519–10523.
4 R. D. Stephens and C. E. Castro, J. Org. Chem., 1963, 28,
3313–3315.
5 D. H. Ryu and E. J. Corey, J. Am. Chem. Soc., 2003, 125, 6388–
6390.
6 G. Evano, K. Jouvin, C. Theunissen, C. Guissart, A. Laouiti,
C. Tresse, J. Heimburger, Y. Bouhoute, R. Veillard,
M. Lecomte, A. Nitelet, S. Schweizer, N. Blanchard,
Fig. 3 (A) Picture of 1a that matches literature physical descriptions.
(B) Picture of 1a that is of questionable oxidation state. (C) ‘Click test’ of
copper acetylides to assess product purity.19
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RSC Adv., 2019, 9, 29300–29304 | 29303