Fe/ppm Cu nanoparticles as a recyclable catalyst for click reactions in water at room temperature

Article abstract of DOI:10.1039/c7gc00883j

New iron-based nanoparticles doped with ppm levels of CuOAc are capable of catalyzing cycloadditions between alkynes and azides to afford triazole-containing products. These reactions take place in water at ambient temperatures, enabled by the presence of

Full text of DOI:10.1039/c7gc00883j

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Fe/ppm Cu nanoparticles as a recyclable catalyst
for click reactions in water at room temperature†
Cite this: DOI: 10.1039/c7gc00883j
a
Aurélien Adenot,a Evan B. Landstrom,a Fabrice Galloub and Bruce H. Lipshutz
*
Received 22nd March 2017,
Accepted 28th April 2017
DOI: 10.1039/c7gc00883j
rsc.li/greenchem
New iron-based nanoparticles doped with ppm levels of CuOAc product.12 In this Letter, we present new NPs that contain ppm
are capable of catalyzing cycloadditions between alkynes and levels of copper13 that are not only trivial to prepare, but can
azides to afford triazole-containing products. These reactions take be either used directly in water at room temperature, or can be
place in water at ambient temperatures, enabled by the presence isolated and stored in an aqueous mixture at room tempera-
of nanomicelles that function as a delivery mechanism. The NPs ture for future use.
can be easily recycled within the same reaction vessel. Low levels
Previously, we disclosed new NPs that feature an iron-based
platform containing ppm levels of palladium which catalyze
Suzuki–Miyaura cross-couplings in water between rt and 45 °C.14
This technology is enabled by the presence of aqueous nanomi-
celles derived from TPGS-750-M15 (1, Scheme 1), where the PEG
component serves as the delivery mechanism bringing the sub-
strates, housed within, to the metal NP catalyst. This “nano-to-
of residual copper are found in the product.
Copper-based nanoparticles (NPs) continue to be the subject
of several recent reports.1 Much of the driving force behind
this popular area of research lies in the base (i.e., inexpensive)
metal status of copper for use in catalysis, as well as the accent
on heterogeneous reagents that enable facile product isolation
and catalyst recycling. Moreover, their application to click
chemistry is of value in multiple arenas (e.g., drug discovery,2
combinatorial chemistry,3 chemical biology,4 material
science,5 etc.). From the green chemistry perspective, several
studies describe reagents that reduce their metal content to
ppm levels of copper embedded within NPs.6–13 Some can be
utilized in a purely aqueous setting,6,13 avoiding in large
measure organic solvents and, thereby, minimizing organic
waste. While these approaches are meritorious in this regard,
those that result in cycloadditions to triazoles at ambient
temperatures7,10 typically require some degree of water solubil-
ization of the educts, and therefore, face obvious limitations.
Others involve procedures for reagent preparation that can be
lengthy, and/or rely on starting materials that can be costly or
esoteric, and the procedures for catalyst recycling can involve
several steps.7,9 Typically, these reports focus heavily on ana-
lyses of these newly fashioned NPs (e.g., by SEM, TEM, EDX,
etc.), and oftentimes are concerned with the extent of copper
leaching from the solid support. Few, however, address the key
question as to how much residual copper is to be found in the
aDepartment of Chemistry & Biochemistry, University of California, Santa Barbara,
CA 93106, USA. E-mail: lipshutz@chem.ucsb.edu
bNovartis Pharma A6, Basel, Switzerland
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c7gc00883j
Scheme 1 Preparation of Fe/ppm Cu NPs and their use in click
chemistry.
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nano” phenomenon14,16 is non-operative in organic solvents, 24, respectively, under these aqueous conditions (Scheme 2).
and is presumably responsible for the mild conditions under In the absence of TPGS-750-M en route to 2 (i.e., “on water”),18
which these heterogeneous couplings take place. Replacing the there was no reaction under otherwise identical conditions.
Pd doped into these NPs with copper is especially straight-
As an alternative to in situ formation and use of these Fe/
forward; thus, treatment of FeCl3, together with CuOAc ppm Cu NPs, removal of the THF in vacuo after Grignard
(1000 ppm, or 0.1 mol%), in THF with MeMgCl (also in THF; 2.0 addition and trituration with dry pentanes followed by further
equiv.) at room temperature (22 °C) leads to active Fe/ppm Cu
NPs. Removal of the THF under vacuum affords the catalyst
ready for use in click chemistry. Introduction of an aqueous solu-
tion containing two weight percent of 1, followed by the alkyne,
an azide (1.2 equiv.), and Et3N (0.5 equiv.) leads (with vigorous
stirring at room temperature) to the corresponding triazole.
A variety of substrate combinations could be used to arrive
at 1,4-disubstituted triazoles. As illustrated in Table 1, alkyl
and aryl alkynes readily participated, while benzylic azides
serve as excellent reaction partners. Acetylenic derivatives
bearing alkyl residues containing free and protected alcohols,
as well as a terminal chloride, led to products in good isolated
yields, as did a TIPS-protected educt leading to product 7. Aryl
alkynes, e.g., those substituted with either electron-withdraw-
ing F or CF3 moieties, or an electron-donating Me2N group,
were not problematic. Importantly, ICP MS analysis of triazole
2 revealed that <1 ppm of residual copper could be detected,
in line with the reduced levels observed previously for both Pd
(<10 ppm) and Ni (≤1 ppm).
Substrates featuring highly water-insoluble fragments, such
as those represented by alkyne 21 derived from vitamin E, and
the 48-carbon alkyne 23 prepared from solanesol,17 were
Scheme 2 Conditions: Fe/ppm Cu NPs, Et3N (0.5 equiv.),
2 wt%
smoothly converted to their corresponding products 22 and
TPGS-750-M/H2O, rt.
Table 1 Representative substrates for the Fe/Cu NP-catalyzed click reaction. Conditions: Fe/Cu NPs (1000 ppm Cu), Et3N (0.5 equiv.), 2 wt%
TPGS-750-M/H2O, rt
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drying under high vacuum afforded light brown-colored NPs.
This freshly prepared catalyst, stored carefully under argon,
could be used with equal effectiveness over a 2–3 day period.
However, after a week, it loses much of its activity due to
gradual oxidation of copper(I). To maintain these NPs in their
active state, storage is best achieved in an aqueous medium
containing ascorbic acid19 (0.10 equiv. vs. educt). Click reac-
tions using this catalyst over weeks showed no difference in
reaction rates or yields compared to those obtained with
freshly made material (see Table 1).
Nano-to-nano technology14,16 presents opportunities for in-
flask processing, and subsequent recycling of the aqueous
reaction mixture containing the surfactant and the Fe/ppm Cu
NP catalyst. Once a cycloaddition is complete, extraction with
minimal amounts of EtOAc ultimately affords the desired
cycloadduct. To the remaining mixture, in the presence of
added 0.1 equiv. vitamin C, is then introduced an alkyne/azide
pair being either the same or different in nature, leading to
another click reaction. As shown in Scheme 3, this initial
process was repeated three additional times, with each cycle
leading to (in this case) a different triazole. The efficiency of
cycloaddition remained high throughout. An E Factor based
on solvent usage, as originated by Sheldon20 and studied
extensively for this micellar technology,21 was determined to
be 4.1, which is ca. an order of magnitude below values often-
times associated with processes in the fine chemicals area.22
Analyses by cryo-TEM of isolated Fe/ppm Cu NPs placed in
an aqueous medium containing nanomicelles derived from
TPGS-750-M provided the appearance, the sizes, and the nano-
to-nano state in which this catalyst exists. Fig. 1A confirms the
rod-like shape, with sizes that are highly variable (ca. 25 nm
on average), along with the anticipated association of spherical
nanomicelles with the metal NPs. The identical analysis on
used NPs (Fig. 1B) showed NPs that had become larger and
more fibril-like, while their aggregation with surfactant
micelles remains, along with their equivalent activity. An EDX
experiment was also run (Fig. 2), and the results, again, are
akin to those seen previously with Fe/ppm Pd NPs,14 where the
presence of the ppm metal, copper in this case, was undetect-
able. Most of the material is composed of Mg and Cl from the
Fig. 1 cryo-TEM data on Fe/ppm Cu NPs in TPGS-750-M/H2O.
(A) Fresh Fe/ppm Cu NPs in 2 wt% TPGS-750-M/H2O. (B) Used Fe/ppm
Cu NPs in 2 wt% TPGS-750-M/H2O.
Scheme 3 Recycling of Fe/ppm Cu NPs used in aq. TPGS-750-M.
Fig. 2 EDX analysis of Fe/ppm Cu NPs.
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Grignard, along with the THF used as solvent; iron constitutes
only ca. 3% of these NPs.
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In summary, an experimentally simple procedure has been
developed leading to the formation of nanoparticles contain-
ing ppm levels of active Cu(I) that effect click reactions
between azides and alkynes in water at ambient temperatures.
These [3 + 2]-cycloadditions are enabled by the presence of a
surfactant, TPGS-750-M, engineered to maximize reaction
efficiency. All ingredients within these aqueous mixtures are
recyclable within the same reaction vessel: the water, surfac-
tant, and the catalyst, while the product is easily extracted with
minimal amounts of a single organic solvent. Only traces of
residual copper are to be expected in the triazole products
formed in high yields. Further developments of new catalysts
based on Fe/ppm metal NPs containing other base metals
(e.g., Ni), as well as precious metals (e.g., Rh and Ir), will be
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Acknowledgements
We are very pleased to acknowledge the NSF (SusChEM
1561158) for supporting this work.
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