A Highly Efficient Single-Chain Metal-Organic Nanoparticle Catalyst for Alkyne-Azide "click" Reactions in Water and in Cells

Article abstract of DOI:10.1021/jacs.6b04477

We show that copper-containing metal-organic nanoparticles (MONPs) are readily synthesized via Cu(II)-mediated intramolecular cross-linking of aspartate-containing polyolefins in water. In situ reduction with sodium ascorbate yields Cu(I)-containing MONPs that serve as highly efficient supramolecular catalysts for alkyne-azide "click chemistry" reactions, yielding the desired 1,4-adducts at low parts per million catalyst levels. The nanoparticles have low toxicity and low metal loadings, making them convenient, green catalysts for alkyne-azide "click" reactions in water. The Cu-MONPs enter cells and perform efficient, biocompatible click chemistry, thus acting as intracellular nanoscale molecular synthesizers.

Full text of DOI:10.1021/jacs.6b04477

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Communication
A Highly Efficient Single-Chain Metal-Organic Nanoparticle
Catalyst for Alkyne-Azide “Click” Reactions in Water and in Cells
Yugang Bai, Xinxin Feng, Hang Xing, Yanhua Xu, Boo Kyung Kim, Noman Baig,
Tianhui Zhou, Andrew A. Gewirth, Yi Lu, Eric Oldfield, and Steven C. Zimmerman
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b04477 • Publication Date (Web): 16 Aug 2016
Downloaded from http://pubs.acs.org on August 16, 2016
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A Highly Efficient Single-Chain Metal-Organic Nanoparticle Catalyst
for Alkyne-Azide “Click” Reactions in Water and in Cells
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Yugang Bai,1 Xinxin Feng,1 Hang Xing,1,2 Yanhua Xu,1 Boo Kyung Kim,1 Noman Baig,1 Tianhui Zhou,1 Andrew
A. Gewirth,1 Yi Lu,1,2 Eric Oldfield1 and Steven C. Zimmerman1,*
1 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
2 Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
Supporting Information Placeholder
ABSTRACT: We show that copper-containing metal-organic
nanoparticles (MONP) are readily synthesized via Cu(II)-mediated
intramolecular crosslinking of aspartate-containing polyolefins in
water. In situ reduction with sodium ascorbate yields Cu(I)-containing
MONP that serve as highly efficient supramolecular catalysts for
alkyne-azide “click chemistry” reactions, yielding desired 1,4-adducts at
low parts-per-million catalyst levels. The nanoparticles have low
toxicity and low metal loadings, making them convenient, green
catalysts for alkyne-azide “click” reactions in water. The Cu-MONP
enter cells and perform efficient, biocompatible click-chemistry, thus
acting as intracellular nanoscale molecular synthesizers.
The key role played by transition metal catalysts in chemical
reactions1,2 has led to their integration into a wide array of more
complex structures. Indeed, several types of macromolecular metal
catalysts have been developed to increase catalyst selectivity, stability,
and recyclability. For example, metal organic frameworks (MOFs) are
heterogeneous lattices where the metal is integral to the 3D structure.3
As catalysts, MOFs’ highly organized structures represent one end of
the spectrum4 whereas at the other are homogenous or heterogeneous,
polymer-supported catalysts that are much less defined structurally
with one or more metal complexes attached to the side-chain or the
end of a random coil polymer.5 A new macromolecular motif was
reported recently by Lemcoff and coworkers, which they named
Scheme 1. Schematic illustration of the synthesis of the
organometallic nanoparticles (OMNPs).6-8 The OMNPs are single-
copper-containing MONP, and a cartoon showin g the
chain linear polymers (SCNPs)9 controllably “folded” by the formation
of carbon-metal bonds into denser structures that contain metal
internal structure of the cross-linkage.
centers and cavities, resembling metalloenzymes. Indeed, both Rh(I)
by Sharpless,15 with significantly improved catalysts reported later.16-19
and Ir(I) OMNPs showed catalytic activity in organic solvents.
We show herein that the easily synthesized Cu-MONPs have low
Pomposo and coworkers described copper containing SCNPs that
toxicity and promote the regioselective ligation of terminal alkynes and
catalyze coupling reactions and polymerizations, including in water.10,11
azides with high efficiency at low parts-per-million (ppm) levels in
We recently reported several types of covalently cross-linked
water.
polymers termed organic nanoparticles (ONPs) that present an array
For maximum utility, MONPs should have three key properties:
of functional groups and enter cells in a controllable manner.12-14 Here
water solubility, catalytically active metal centers, and the ability to
we describe water-soluble, copper-cross-linked single-chain, metal-
bind hydrophobic substrates. To install these properties, the ring-
organic nanoparticles (MONPs), as nanoscale catalysts. As with the
opening metathesis polymerization (ROMP)20 of monomers M1 and
Lemcoff and Pomposo systems, our Cu-containing MONPs were
M2 (Scheme 1) was performed using Grubbs 3rd generation catalyst21
designed to share some structural similarity with metalloenzymes and
using a M1:M2:Cat = 100:20:1 ratio to give 1 (Scheme 1). Gel
in our case, to promote the copper-catalyzed alkyne-azide
permeation chromatography (GPC) indicated a molecular weight
cycloaddition (CuAAC). The CuAAC “click” reaction was pioneered
close to the calculated value, and a low polydispersity index (1.04) for
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Table 1. “Click” reactions of benzyl azide and
phen ylacetylene with Cu-MONP or CuSO 4.
1
2
3
4
5
6
7
8
9
T
(
Cu-MONP
level (ppm)
Cu Level
(ppm)
time
(h)
Yieldb
(%)
o
NaAsca
C)
50
50
50
50
25
25
25
50
50
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1.0
2.5
5.0
10
2.5
0
2.5
0
0
10
25
50
100
25
25d
25
0
+
+
+
+
+
+
-
24
24
24
24
58c
>99
>99
>99
>99
9e
72
336
336
24
9e
Figure 1. AFM characterization of the Cu-MONP (bottom) and its
parent linear polymer (top) in (a) normal (height) mode, (b) adhesion
mode and (c) deformation mode.
-
+
6e
25d
24
6e
aReactions marked “+” contained 2.5 mg of sodium L(+)-ascorbate (NaAsc).
bBy NMR integration (see procedure in Supporting Information). cReaction was
performed in 0.25 mL of water. dBecause no Cu-MONP was used, the
corresponding copper level was reached by adding CuSO4 solution. eNMR yield
of the 1,4-isomer. Crude product also contained approximately the same
amount of 1,5-isomer for these entries.
the parent linear polymer (see Figure S2). The polymer was
quaternized with N-butylimidazole to give 2, which was purified by
precipitation. The imidazolium groups in 2 provide water solubility,22
whereas the alkyl chains provide a hydrophobic interior to the MONP
for substrate binding.
Amino acids form stable coordination complexes with Cu(II)23 and
Cu(I),24,25 so 2 was prepared with a few aspartate-bearing co-monomer
M2, allowing a limited number of copper ion mediated intra-chain
crosslinks. Polymer 2 was deprotected with trifluoroacetic acid to give
linear polymer 3, which was intramolecularly crosslinked at high
dilution in water using 0.5 equivalents of CuSO4 per amino acid residue
yielding Cu-MONP 4. Dynamic light scattering showed the products
to have slightly smaller radii of gyration (Rg, Figure S6) with no
evidence of interchain crosslinking. The minimally reduced particle
size is consistent with a small contraction from a few intrachain cross-
links on a hydrophobically collapsed random-coil polynorbornene.
Atomic force microscopy (AFM) was used to visualize and probe
the mechanical properties of polymer 3 and Cu-MONP 4. The
uncrosslinked polymers appear larger, less homogeneous than the Cu-
MONPs (Figure 1a), similar to what was observed with ONPs.12 The
relatively narrow size distribution of the MONPs are consistent with a
intramolecular crosslinking. Similar results were observed in adhesion
mode (Figure 1b). Importantly, the adhesion force from the Cu-
MONPs was much smaller than found with the linear polymers. For
uncrosslinked linear polymers with random coil structures, the number
of conformations available during macromolecular extension is high,
leading to a greater adhesive force. In contrast, Cu-MONPs have more
fixed conformations with a smaller entropic elasticity.26 The difference
in adhesion mode AFM further supports the formation of
intramolecular crosslinks in the MONP synthesis. In deformation
mode AFM, the Cu-MONPs show significantly higher rigidity and
resistance to deformation (Figure 1c), consistent with the observation
of previously reported dendritic ONPs,27 providing additional evidence
of crosslinking mediated by Cu(II). Likewise, there is a small increase
in particle height (z) despite the significant diameter reduction
observed in the xy plane after crosslinking (Figure S8).27
1
was calculated based on the integrated intensity of the H NMR signal
of the methylene group in benzyl azide with that in the product. In the
presence of 2.5-10 ppm of Cu-OMNP with respect to benzyl azide at
o
50 C, reactions went to completion in 24 h, with 1,4-triazoles as the
only product. The 1,4-triazole was obtained in 58% yield with just 1
ppm Cu-MONP (Table 1). Without Cu(I), or with CuSO4, only a low
conversion of the starting material to product was observed, with a
mixture of 1,4- and 1,5-triazoles, indicative of an uncatalyzed reaction.
To validate the generality of Cu-MONP catalysis, the cycloaddition
reactions of additional substrate pairs was investigated. As can be seen
in Table 2, seven different terminal alkynes and five different azides
underwent Cu-MONP catalyzed click reaction, with isolated yields
o
ranging from 83% to 98% at 5-30 ppm Cu-MONP after 24 h at 50 C.
For Entry 2 and 3, chloroform was added to improve the reaction
kinetics (see Table S1 and discussion in Supporting Information).
Preliminary data suggests that Cu-MONP is significantly less effective
with highly hydrophilic substrates at preparative scale, such as
propargyl alcohol and 6-azidohexanoic acid (see Supporting
Information for additional detail). These results support the
importance of hydrophobic binding, but further studies are needed to
reach a firm conclusion.
For the examples shown, the catalyst loadings needed for Cu-
MONP were significantly lower than those in most previous reports
and comparable to the lowest catalyst loading reported in water, e.g., by
Astruc,17 and Yamada and Uozumi.19 The fate of the Cu ion during and
after the reaction was not determined. For example, it is beyond the
scope of this study to determine if Cu is lost from the MONP. Even if
metal loss occurs, it would represent a very low level of contamination.
For the reaction catalyzed by the 2.5 ppm Cu-MONP, the 0.5 mL of
water used as solvent contained only 2.5 nmol of Cu, equivalent to 0.32
ppm by weight, lower than the maximum contaminant level goal
(MCLG) for Cu in drinking water (1.3 ppm), defined by the United
States Environmental Protection Agency (EPA).
To compare the activity of the Cu-MONPs to polymeric copper
catalysts reported previously for the Cu(I) catalyzed regioselective
Huisgen ligation,16-19,28-44 i.e., the “click” reaction, the cycloaddition
between phenylacetylene and benzyl azide was investigated as a model
system. Sodium ascorbate was used to reduce Cu(II) to Cu(I) in the
OMNPs in situ,45 and the reaction performed in pure water.
Phenylacetylene was added in slight excess and the yield of the reaction
In addition to their potential utility in chemical synthesis, the low
Cu concentrations needed for a highly reactive catalyst suggest the
possibility of performing “click” reactions under biologically relevant
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Table 2. “Click” reactions between various terminal
alkynes and azides using Cu-MONP as catalysta
1
2
3
4
5
Cu-
MONP
(ppm)
NMR
Yieldb
(%)
Isolated
Yield
(%)
Alkyne
Azide
6
7
8
9
1
5
7.5
5
93
97
95
91
94
94
2c
3c
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12
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15
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4
5
6
10
10
>99
93
95
93
90
7.5
92
7
8
9
15
5
87
84
96
97
>99
>99
5
10
11
5
88
83
98
30
>99
Figure 2. (a) Fluorogenic click compounds 5 and 6. (b) Confocal
microscopy study of intracellular catalysis of 4 (0 or 500 nM) on the
“click” reaction between 5 (100 µM) and 7 (100 µM). (c) Model
study of intracellular synthesis of antimicrobial bisamidine 10 from 8
and 9 in E. coli, catalyzed by 4. NaAsc = sodium L-ascorbate.
aUnless otherwise noted, all reactions were carried out with 0.10 mmol of azide,
0.12 mmol of alkyne, 2.5 mg of sodium ascorbate in 0.5 mL of water at 50 oC for
24 h. Dosages of Cu-MONP were listed in the table for each reaction. bBy NMR
integration. (see Supporting Information). 50 µL of CDCl3 was added to the
reaction to delay the crystallization of the product and improve the kinetics.
c
revealed an acceptable biocompatibility for the Cu-MONP (Figures
S10, S11 and S12 in the Supporting Information).
conditions. Successful intracellular “click” was pioneered by Ting and
coworkers using copper-chelating azides for biomolecular labeling,46
and such intracellular reactions have also been found to be useful for
the measurement of pH inside E. coli.47 Both studies used >100 µM of
ligands analogous to tris-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-
amine (TBTA) developed by Sharpless and Fokin,16 and copper
concentrations of at least 40 µM.
The apparent intracellular click reaction described above suggests
the potential utility of MONP in the intracellular synthesis of more
complex molecules. As a proof of concept, the modular assembly of an
antimicrobial agent inside E. coli was tested. This experiment used
amidine-containing alkyne 8 and azide 9, which each showed minimal
antimicrobial activity against E. coli (MIC > 300 µg/mL). The click
product of the two, bisamidine 10, showed much higher activity (MIC
= 11 µg/mL).49 Thus, E. coli with or without MONP 4 pretreatment
and washing were treated with various combinations of 8, 9 and
sodium ascorbate. Strong inhibition of bacterial cell growth was
observed in the experiment containing MONP, 8, 9 and sodium
ascorbate, whereas all other treatment combinations showed little
inhibitory effect (Figure 2c). These data suggest the intracellular
formation of 10 mediated by the Cu-MONP, and subsequent growth
inhibition.
In summary, we developed a Cu-containing organic nanoparticle
that catalyzes the CuAAC click reaction with high efficiency in water.
Beyond their utility in chemical synthesis in water, our results
demonstrate that Cu-MONPs can effect intracellular click reactions
inside both bacteria as well as mammalian cells. The intracellular
examples featured simple azides and alkynes, but more complicated
modular assembly of complex molecules may be possible using
appropriate MONP and bio-orthogonal reaction partners. Indeed, it
may be possible to selectively synthesize inside cells, compounds that
would otherwise be difficult to deliver.
To test the Cu-MONP for activity at low substrate and catalyst
concentrations, 3-azido-7-coumarin (5) and 7-ethynyl-coumarin (6)
were used as well-known fluorogenic coumarin derivatives that “light
up” upon alkyne-azide cycloaddition. Results for two pairs of
compounds are given in Figure S8 in the Supporting Information. The
click efficiency for both pairs of compounds were similar with ≥90%
conversion in 60 min at 1 µM Cu-MONP. The potential for
intracellular Cu-MONP catalysis of the reaction between 5 and 7 was
tested in live cells using confocal microscopy. Thus, NCI-H460
(human non-small cell lung carcinoma) and MDA-MB-231 (human
breast cancer) cells were pre-incubated with PBS or Cu-MONP (0.5
µM in PBS) for 1 h. The PBS was removed and the cells washed three
times. The substrates (100 µM) were added along with sodium
ascorbate (2 mM) to effect Cu(II) reduction. As seen in Figure 2b,
only weak fluorescence, likely from unreacted azidocoumarin, could be
observed in the absence of Cu-MONP, whereas cells were intensely
fluorescent in the presence of the catalyst. Cytotoxicity, hemolytic, and
Amplex-Red/horseradish peroxidase48 assays were performed and
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Detailed synthetic procedures and characterization data of the OMNP,
“click” substrates and products were provided in the Supporting
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http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*sczimmer@illinois.edu
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Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the National Science Foundation (CHE-
1307404), the Binational Science Foundation (2014116), the U.S.
National Institutes of Health (ES016865, GM65307 and CA158191),
the Office of Science (BER), the U.S. Department of Energy (DE-
FG02-08ER64568). Dr. Yang Liu is acknowledged for assistance with
the confocal microscope studies.
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