Instantaneous Click Chemistry by a Copper-Containing Polymeric-Membrane-Installed Microflow Catalytic Reactor

Article abstract of DOI:10.1002/chem.201503178

The copper(I)-catalyzed Huisgen cycloaddition (azide-alkyne cycloaddition) is an important reaction in click chemistry that ideally proceeds instantaneously. An instantaneous Huisgen cycloaddition has been developed that uses a novel catalytic dinuclear c

Full text of DOI:10.1002/chem.201503178

DOI: 10.1002/chem.201503178
Full Paper
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Click Chemistry |Hot Paper|
Instantaneous Click Chemistry by a Copper-Containing Polymeric-
Membrane-Installed Microflow Catalytic Reactor
Yoichi M. A. Yamada,*[a] Aya Ohno,[a] Takuma Sato,[a] and Yasuhiro Uozumi*[a, b]
Abstract: The copper(I)-catalyzed Huisgen cycloaddition
(azide–alkyne cycloaddition) is an important reaction in click
chemistry that ideally proceeds instantaneously. An instanta-
neous Huisgen cycloaddition has been developed that uses
a novel catalytic dinuclear copper complex-containing poly-
meric membrane-installed microflow device. A polymeric
membranous copper catalyst was prepared from poly(4-vi-
nylpyridine), copper(II) sulfate, sodium chloride, and sodium
ascorbate at the interface of two laminar flows inside micro-
channels. Elucidation of the structure by XANES, EXAFS, and
elemental analysis, as well as second-order Møller–Plesset
perturbation theory (MP2) calculations and density function-
al theory (DFT) calculations assigned the local structure near
Cu as a m-chloro dinuclear CuI complex. The microflow
device promotes the instantaneous click reaction of a variety
of alkynes and organic azides to afford the corresponding
triazoles in quantitative yield.
Introduction
mer-encapsulated micellar Cu catalyst for the cycloaddition
with a catalytic turnover number of 510000.[7]
Instantaneous production of organic materials is important for
quick supply of lead compounds for pharmaceutical, biochemi-
cal, and material science as well as effective positron emission
tomography (PET) for nuclear medical imaging.[1] The click re-
action is one of the most promising means. The copper-cata-
lyzed Huisgen 1,3-dipolar cycloaddition of organic azides and
terminal alkynes (copper(I)-catalyzed azide–alkyne cycloaddi-
tion) is a typical click reaction for the preparation of bioactive
compounds, pharmaceutical lead compounds, bio-probes, and
functional soft materials, as well as for bioconjugation.[2] In par-
ticular, development of immobilized copper catalysts for this
purpose with high catalytic activity and reusability without
leaching of metal species is important.[3] In 2006, Lipshutz re-
ported a pioneering work in heterogeneous click chemistry by
using Cu/C.[4] Recently, some researchers have reported excel-
lent heterogeneous Cu catalysts for this reaction with high
turnover numbers (up to 1000).[5] Our group developed
a highly active, insoluble, amphiphilic polymeric imidazole–Cu
catalyst, which, with 4.5”10À4–4.5”10À3 mol% Cu, catalyzed
the Huisgen 1,3-dipolar cycloaddition of alkynes and organic
azides.[6] Recently, Astruc and co-workers reported a dendri-
We envisioned that, by installing highly active heterogene-
ous catalysts inside a microchannel, the click reaction could be
instantaneously accomplished. Accordingly, we attempted to
develop a microflow reactor system in which an insoluble
membranous catalyst was installed at the interface of two lam-
inar flows by using our previously reported molecular convolu-
tion methodology.[8] Microflow reactor systems provide many
fundamental and practical advantages and have been devel-
oped as novel devices for rapid organic transformations.[9] Mi-
croflow Huisgen cycloaddition using immobilized copper cata-
lysts is a promising application for which the efficiency of vari-
ous catalytic reactions has been found to increase due to the
vast interfacial area and the short distance of the molecular dif-
fusion path within the narrow space of the microflow reac-
tor.[10] Herein, we report the development of the first polymeric
membranous copper catalyst-installed microflow reactor, and
its applicability to Huisgen cycloaddition of alkenes and organ-
ic azides. A variety of triazoles were quantitatively produced
within a residence time of a few seconds by using the mem-
branous copper catalyst-installed microflow reactor.
Results and Discussion
[a] Dr. Y. M. A. Yamada, A. Ohno, Dr. T. Sato, Dr. Y. Uozumi
RIKEN Center for Sustainable Resource Science
Wako, Saitama 351-0198 (Japan)
Four different polymeric membranous copper catalysts (A–D)
were installed within microflow devices. The polymeric Cu
membranes were formed with a glass microchannel reactor
bearing a Y-junction and a channel pattern 100 mm wide,
40 mm deep, and 40 mm long (Figure 1). Poly(4-vinylpyridine)
(PVPy, 1) in ethyl acetate/methanol (3:1 v/v; 5.0 mm in pyri-
dine; flow rate=50 mLminÀ1; from inlet A1), aqueous copper(II)
sulfate solution (4.0 mm; flow rate=25 mLminÀ1; from inlet B1),
and an aqueous solution of sodium ascorbate (NaAsc; 0.80m)
Fax: (+81)48-467-1423
E-mail: ymayamada@riken.jp
[b] Dr. Y. Uozumi
Institute for Molecular Science (IMS)
Myodaiji, Okazaki, Aichi 444-8787 (Japan)
E-mail: uo@ims.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503178.
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Figure 1. Preparation of copper-containing polymeric membrane-installed microdevices A-D.
and sodium chloride (20 mm; flow rate=25 mLminÀ1; from
inlet B2) were installed in the microchannel at 258C for 60 s,
determination of these structures, see the Supporting Informa-
tion, Figures S1–S8). The polymeric membrane D was also pre-
pared from CuCl2 2b (in place of CuSO4 2a), PVPy 1, NaCl and
NaAsc.
and then 2% methanolic ethyl acetate (flow rate=1 mLminÀ1
;
from inlet A2) and an aqueous solution of NaAsc (0.80 m) and
NaCl (20 mm) (flow rate=1 mLminÀ1; from inlet B2) were instal-
led at 508C for 10 min. Instantaneously, a two-phase parallel
laminar flow formed under the flowing conditions and a poly-
meric copper membrane A of approximately 10 mm thickness
precipitated out at the interface of the laminar flows. Analysis
by energy-dispersive X-ray spectroscopy (EDX) and scanning
electron microscopy (SEM) showed that Cu and Cl species
were dispersed uniformly throughout the membrane and S
species were not detected (Figure 2). X-ray absorption near-
edge structure (XANES) and extended X-ray absorption fine
structure (EXAFS) spectroscopies and elemental analysis, as
well as second-order Møller–Plesset perturbation theory (MP2)
and density functional theory (DFT) calculations suggested
that the local structure near the Cu complex is a m-chloro dinu-
clear copper complex [CuI2(m-Cl)(py)4]+ (py=pyridine unit in
PVPy 1; for details, see the Supporting Information, Figures S1–
S8 and Table S1). When a catalytic Cu membrane was prepared
without NaCl, a polymeric Cu membrane B readily formed, the
local structure of which near the CuI complex is a mononuclear
copper complex [CuI(py)3]+ (Figure 1). Similar complexation
without NaCl and NaAsc afforded the membranous CuII com-
plex C, for which the local structure near Cu was composed of
a mixture of [CuII(py)2(OH2)2]2+ and [CuII(py)3(OH2)]2+ (for the
With the copper-containing polymeric membrane-installed
microflow devices A–D in hand, the Huisgen cycloaddition of
an organic azide and an alkyne, that is, the click reaction, was
conducted under microflow conditions inside these microflow
devices (Scheme 1). When an acetone/water solution of benzyl
azide (3a), phenylacetylene (4a), and NaAsc was injected from
one inlet, and an acetone/water solution was installed from
the other inlet at 508C, we were pleased to find that the reac-
tion with the microflow device A smoothly proceeded in 8 s to
give 1-benzyl-4-phenyl-1H-1,2,3-triazole (5a) with 99% yield,
and leaching of Cu species was found by inductively coupled
plasma mass spectrometry (ICP-MS) to be less than 50 ppb. Mi-
croscopic snapshots of the microdevice A before and after use
(0 h vs. 24 h) exhibited the stability of the catalytic membrane
during the reaction (Figure 3). The reaction with the microde-
vice B under similar conditions gave 5a with 86% yield, where-
as that with the microdevices C and D afforded 5a with 26%
and 48% yield, respectively.
Since microdevice A provided the fastest transformation in
the click reaction, the reaction of a variety of substituted ben-
zylic azides 3 and alkynes 4 was carried out (Table 1). The cy-
cloaddition of an electron-deficient 4-nitrobenzyl azide (3b)
and 4a proceeded smoothly to give the triazole 5b in 99%
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Figure 2. a) SEM image of A; b) EDX/SEM images of A (SEM, Cu, Cl and S); c) XANES spectra of A–D, Cu2O, and CuSO4·5H2O; d) k3-weighted FT-EXAFS of mi-
crodevice A and the best fit
Scheme 1. Huisgen cycloaddition of 3a and 4a promoted by microdevices
A–D.
yield in 13 s (entry 2). A fluoro compound, 4-fluorobenzyl azide
(3c), was readily converted under similar conditions to afford
the triazole 5c in 99% yield in 13 s (entry 3). The more elec-
tron-rich 4-methylbenzyl azide (3d) and 4-methoxybenzyl
azide (3e) led to efficient conversion, giving the corresponding
triazoles 5d and 5e in 94% and 86% yield in 19 s (entries 4
and 5). The reaction of a naphthyl substrate, 2-naphthylmethyl
Figure 3. Snapshots of microdevice A in the reaction of 3a with 4a (top:
0 h, bottom: 24 h).
azide (3 f), for 13 s gave the triazole 5 f in 92% yield (entry 6).
The reaction of 3a with less reactive electron-rich alkynes,
p-tolylacetylene (4b) and p-anisylacetylene (4c), was also per-
formed, affording the corresponding triazoles 5g and 5h in
98% and 90% yield, respectively (entries 7 and 8). The micro-
device was also applied to the cycloaddition of less reactive ali-
phatic azides and alkynes: the reaction of 1-azidodecane (3g)
with 4a in 2-propanol took 38 s, affording 1-decyl-4-phenyl-
1H-1,2,3-triazole (5i) in 83% yield (entry 9). An aliphatic alkyne,
1-heptyne (4d), readily reacted with 3a within 13 s, giving the
triazole 5j in 91% yield (entry 10). An alkynol, 5-hexyn-1-ol
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Table 1. Huisgen cycloaddition of organic azides 3 and alkynes 4 mediat-
ed by microdevice A to give triazoles 5.[a]
Entry
3 (R1)
4 (R2)
5
Yield [%]
1
2
3
4
5
6
7
8
9[b]
10
11
12[b]
3a (PhCH2)
3b (4-NO2C6H4CH2)
3c (4-FC6H4CH2)
3d (4-CH3C6H4CH2)
3e (4-OMeC6H4CH2)
3 f (2-C10H7CH2)
3a
3a
4a (Ph)
4a
4a
4a
4a
4a
4b (4-CH3C6H4)
4c (4-OMeC6H4)
4a
4d (C5H11)
4e (CH2(OH)(CH2)3)
4e
5a
5b
5c
5d
5e
5 f
5g
5h
5i
99
99
99
94
86
92
98
90
83
91
99
98
3g (C10H21)
3a
3a
3g
5j
5k
5l
Scheme 3. Proposed reaction mechanism of the A-promoted Huisgen cyclo-
addition.
[a] Conditions: [Inlet A] organic azide 3 (20 mm), alkyne 4 (22 mm) and
NaAsc (20 mm) in acetone/water (3:1 v/v); [Inlet B] acetone/water (1:1 v/
v); flow rate=0.1–0.5 mLminÀ1, residence time=8–38 s, 508C; [b] condi-
tions: [Inlet A] organic azide 3 (10 mm), alkyne 4 (11 mm) and NaAsc
(20 mm) in 2-propanol/water (3:1 v/v); [Inlet B] 2-propanol/water (1:1 v/
v); flow rate=0.1 mLminÀ1, residence time=38 s, 708C.
catalyst A, followed by deprotonation gives the copper acety-
lide A2. Coordination of organic azide 3 to A2 followed by in-
tramolecular cycloaddition affords dinuclear copper intermedi-
ate A4. Protonation of A4 results in the formation of the tria-
zole 5 and regeneration of the catalyst A. We are still not cer-
tain why catalytic microdevice A was the best for the instanta-
neous cycloaddition. However, it is worth noting that the
addition of NaCl provided complex A as a m-chloro dinuclear
Cu species, whereas B and C were mononuclear Cu complexes
(Figure 1). Based on Fokin’s report,[11,12] A could act as a cooper-
ative catalyst, in which a dinuclear Cu species activated both
an organic azide 3 and an alkyne
(4e), underwent cycloaddition with 3a in 38 sec to afford 5k
in 99% yield (entry 11). The reaction of the aliphatic azide 3g
and the aliphatic alkyne 4e afforded 4-(1-decyl-1H-1,2,3-triazol-
4-yl)butan-1-ol (5l) in 98% yield (entry 12).
To apply the catalytic microdevice for the preparation of
conjugated materials, the Huisgen cycloaddition of a sugar de-
rivative was investigated (Scheme 2). When an N-acetyl-d-glu-
4 synergistically, promoting the
instantaneous click reaction
(Scheme 3). Moreover, D, pre-
pared from CuCl2 (2b), 1, NaAsc,
and NaCl, gave the triazole 5a in
48% yield. This result suggested
Scheme 2. Conjugation of N-acetyl-d-glucosamine (GlcNAc) derivative and a linear alcohol.
that addition of NaCl to CuSO4
(2a) was important for the for-
mation of an active dinuclear
copper complex membrane.
cosamine (GlcNAc) derivative 6, bearing amide and acetal moi-
eties, was connected with the alkyne 4e bearing a terminal al-
cohol, a plausible connector to a variety of proteins and
sugars, by using the copper-containing polymeric membrane-
installed microflow reactor A at 708C in 38 s, the desired tri-
Conclusion
azole carbohydrate 7 was readily obtained in 85% yield.
As shown in Scheme 1, the microdevice A, incorporating a di-
nuclear Cu complex (Figure 1), afforded the triazole 5a in
a higher yield than the microdevices B–D. To rationalize the su-
periority of the dinuclear Cu catalyst-installed microdevice A,
a proposed reaction mechanism is shown in Scheme 3, which
is based on the report by Fokin and co-workers on a homoge-
neous dinuclear copper catalyzed azide–alkyne cycloaddi-
tion.[11] Thus, coordination of alkyne 4 to the dinuclear copper
In conclusion, we have developed the first polymeric membra-
nous copper catalyst-installed microflow device. The microde-
vice was applied to the Huisgen cycloaddition, affording the
corresponding triazoles with quantitative yield within 8–38 s.
Our microdevice system will be useful for bioconjugation, posi-
tron emission tomography for nuclear medical imaging, and
high-throughput screening of pharmaceutical, biochemical,
and material compounds.
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Acknowledgements
We thank Dr. Tetsuo Honma, Dr. Masafumi Takagaki (JASRI,
SPring-8), and Prof. Hikaru Takaya (Kyoto University) for mea-
surement of XAFS (SPring-8, BL14B2, 2012B1868). We also
thank RIKEN for elemental (Dr. Yoshio Sakaguchi), ICP-MS (Dr.
Kazuya Takahashi), and ICP-AES (Ms. Chieko Kariya) analyses.
We gratefully acknowledge financial support from JST ACT-C,
JST ACCEL, JSPS (Nos. 24550126, 20655035, and 15K05510),
Takeda Science Foundation, the Naito Foundation, and RIKEN.
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Keywords: click chemistry
microreactors · polymeric membranes
·
copper
·
cycloaddition
·
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[11] B. T. Worrell, J. A. Malik, V. V. Fokin, Science 2013, 340, 457–460.
[12] Although Fokin’s report is based on homogeneous Cu catalysis, this
catalytic cycle could also fit our heterogeneous dinuclear Cu catalytic
pathway.
Received: August 12, 2015
Published online on October 6, 2015
Chem. Eur. J. 2015, 21, 17269 – 17273
www.chemeurj.org
17273
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