Scratching the catalytic surface of mechanochemistry: A multi-component CuAAC reaction using a copper reaction vial

Article abstract of DOI:10.1039/c3gc36720g

Herein we report the first copper vial catalysed CuAAC reaction. Under solvent-free mechanochemical conditions the reaction is complete in as little as 15 minutes and the triazole product isolated straight from the reaction vial with no further purification.

Full text of DOI:10.1039/c3gc36720g

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Scratching the catalytic surface of mechanochemistry: A multi-component CuAAC reaction
using a copper reaction vial
Teresa L. Cook, James A. Walker Jr., and James Mack*
5
Herein we report the first copper vial catalysted CuAAC reaction. Under solvent-free
mechanochemical conditions the reaction is complete in as little as 15 minutes and the triazole product
isolated straight from the reaction vial with no further puriifcation.
One of the primary examples of Sharpless’s coined “Click” reaction is the copper catalysed
azide-alkyne cycloaddition (CuAAC). This powerful reaction is viable for the synthesis of polymers,
10 natural products and a host of synthetically important molecules which is a testament to its utility
and versatility.1 One of the many appeals of CuAAC reactions is the ability to conduct the reaction in
an aqueous environment with the use of a copper catalyst. Although this reaction is designed to be
performed using an environmentally benign medium such as water, many reactions need to use
complimentary solvents such as DMF due to the insolubility of many organic reagents in water.2
15 Mechanochemistry is a solventless method that lends itself quite naturally to “click” type reactions.
Although historically this methodology has been used for metal-alloying, our group and others have
extended this novel methodology to the field of organic synthesis.3 Stolle and co-workers
demonstrated the CuAAc reaction can be conducted under mechanochemical conditions using
traditional catalytic systems such as copper sulfate and sodium ascorbate.4 We previously
20 demonstrated that the surface of the milling vial can be used in lieu of traditional organometallics
catalyst to perform catalytic reactions.5 Our thought was conducting CuAAC reactions under
mechanochemical conditions not only would allow us to conduct the reaction without a solvent, but
also use a copper vial in place of other copper catalyst traditionally used in the CuAAC reaction.
Additionally since the reaction occurs on the surface of the vial the isolation of the product from the
25 catalytic material would be more efficient compared to traditional solution based methods. The use
of elemental copper as a catalyst in CuAAc reactions are known in solution but these reactions
require long reaction times to reach completion.6 Herein, we demonstrate our ability to conduct a
multicomponent CuAAC reaction simply by milling an alkyne in the presence of an alkyl azide in an
elemental copper vial, in the absence of any ligands or additives.
30
To test our hypothesis, we charged a copper reaction vessel with phenylacetylene,
benzylazide and a copper milling ball. After only 15 minutes of milling we observed the expected 1-
benzyl-4-phenyltriazole as the only product formed in quantitative yield (Figure 1).
35

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Cu vial
N
N
1a
+
3/16" Cu ball
15 min
N
N3
3a
40
2a
>95%
Figure 1. Phenylacetylene and benzylazide milled in a copper vial for fifteen minutes.
In order to be sure that copper was the active catalytic species, we attempted the same reaction in a
Teflon reaction vial with a Teflon ball. After milling for 16 hours we only observed unreacted starting
45 materials. We also conducted the reaction using a stainless steel vial and a stainless steel ball; after
16 hours of milling we observed only unreacted starting materials suggesting copper is the active
catalytic species in this reaction. We have previously demonstrated that we can form alkyl azides
under mechanochemical conditions,7 therefore we decided to generate the benzylazide in situ for the
purpose of developing a single step multicomponent synthesis of triazoles. We envisioned milling
50 sodium azide, benzylbromide and phenylacetylene in our copper vial to afford the benzylazide in situ
which would then subsequently react with the phenylacetylene to give our desired triazole product.
Milling sodium azide, phenylacetylene and bromobenzyl bromide in our copper vial for one hour gave
the desired triazole in a modest 8% conversion. Given the fact that our initial CuAAC reaction is
complete in 15 minutes and the fact that formation of the alkyl azide is known to be sluggish,8 we
55 hypothesized the nucleophilic addition step is the rate determining step for this reaction. Changing
the alkali metal salt of a nucleophile or adding crown ethers can increase the rate of nucleophilic
substitution reaction under mechanochemical conditions.9 However neither of these approaches
was able to significantly increase the nucleophilicity of the azide. Milling phenylacetylene,
benzylbromide and sodium azide for 16 hours afforded the desired 1-benzyl-4-phenyltriazole in
60 quantitative yield (Figure 2.). By comparison Alonso, Yus and co-workers recently demonstrated the
multicomponent CuAAC reaction using elemental copper gives the desired triazole product in only
52% yield after heating for 24 hours.10 We tested the scope of the one-step multicomponenet CuAAC
reaction on various compounds listed in Table 1. Most of the substrates tested provided very high
yields of the desired products. We noticed all reactions went to completion after 24 hours of
65 milling.11 Similarly to what is observed in solution, we found that internal alkynes are unreactive
using our conditions even in a step wise fashion.
Given the shock sensitive nature of many alkyl azides we were concerned that these azides would
be unstable under the violent milling conditions.12 However, at no point during any of these
reactions did we observe any explosion or increased exothermicity due to milling azides. Further,
70 upon milling sodium azide for 16 hours we observed no noticeable changes and completely

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recovered the sodium azide. Additionally, due to the fact that these reactions are conducted in a
sealed metal container as compared to a round bottomed flask, we believe azide reactions under
mechanochemical conditions are much safer conducting then under traditional solution based
chemistry with glass apparatus.
75
Figure 2. Phenylacetylene, benzylbromide and sodium azide in a solvent-free
multicomponent “Click” reaction.
80
We wanted to determine if any copper metal was leached into the isolated product. This
would be particularly important if this methodology were to be applied to the synthesis of
pharmaceuticals. We conducted ICP-MS experiments to determine the level of copper present in our
product after isolation. According to our ICP-MS results our product contains 4.61 mg/g of copper in
85 the product. This level is well below the levels of copper need to make a person ill. 13
Insert Table #1 Here
There have been many studies on the mechanism of the CuAAC reaction. It is hypothesized
that in solution the activated copper species is in the first oxidation state. In previous reports which
use elemental copper as a catalyst for the CuAAC reaction it was theorized that the elemental copper
90 undergoes a comproportionation of copper in the second oxidation state and copper in the zero
oxidation state to give the active copper catalyst in the first oxidation state.6a,14 We believe that the
reaction is occurring on the surface of the copper vial starting with a copper metal in the zero
oxidation state. We are unsure if the suggested comproportionation pathway is available under
mechanochemical conditions but we are in the process of trying to discover the active catalytic
95 copper species. In all of the reactions presented in Table 1 we used the same reaction vial and did
not observe any significant changes in yield or reaction rate over that period of time. Additionally,
we massed the vial before and after the reaction and observed no measurable change in the total
mass of the copper vial or the copper balls, strongly suggesting the reaction is occurring on the
surface of the vial or ball.

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100
To conclude we have demonstrated that a copper vial and copper ball can be used in lieu of a
traditional homogenous copper catalyst to conduct the CuAAc reaction. We have tested a number of
different azide substrates and the reaction proceeds in very high yields within 15 minutes of milling
time. We have also demonstrated that the alkyl azide can be generated in situ as a three component
reaction to generate the desired triazole however these reactions are sluggish due to the slow nature
105 of alkyl azide formation. The copper vial can be used repeatedly as the active surface has been used
at this point for over 100 different reactions yet we have observed no decrease in yield or reaction
rate. Mechanochemistry is not only a novel solvent-free method that has the potential to lead to
environmentally benign reactions but the vial surface of these reactions can be used in lieu of a
powder catalyst. Conducting reactions in this method allows for the ability recycle the metal catalyst
110 and isolated product in a simple and environmentally benign manner.
Acknowledgements
This research is supported by the National Science Foundation grant number CHE-1058627, and the
University of Cincinnati Research Counsel (URC). We would also like to thank the Ronald McNair
Scholars program for financial support for James A. Walker Jr.
115
Notes and references
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