Azide-alkyne cycloadditions in a vortex fluidic device: Enhanced "on water" effects and catalysis in flow

Article abstract of DOI:10.1039/d0cc04401f

The Vortex Fluidic Device is a flow reactor that processes reactions in thin films. Running the metal-free azide-alkyne cycloaddition in this reactor revealed a dramatic enhancement of the "on water"effect. For the copper-catalyzed azide-alkyne cycloaddit

Full text of DOI:10.1039/d0cc04401f

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Azide-Alkyne Cycloadditions in a Vortex Fluidic Device: Enhanced
“On Water” Effects and Catalysis in Flow
Gabriela Oksdath-Mansilla,a,b Renata L. Kucera,b Justin M. Chalker*b and Colin L. Raston*b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
The Vortex Fluidic Device is a flow reactor that processes reactions the safety profile because the local scale of the reaction would
in thin films. Running the metal-free azide-alkyne cycloaddition in be small with scalability a matter of continuous or parallel
this reactor revealed a dramatic enhancement of the “on water” processing. Finally, we wanted to explore new strategies in
effect. For the copper-catalyzed azide-alkyne cycloaddition, catalysis for this reaction and report a method that integrates
stainless steel or copper jet feeds were effective reservoirs of a copper jet feed and a photoredox process to generate the
active copper catalyst.
active catalyst in flow.
The azide-alkyne cycloaddition is a mainstay in the chemical,
biological, and material sciences.1-3 Indeed, the widespread
use of both the copper-catalyzed4, 5 and uncatalyzed6 variants
of this transformation position it as a model example in the
click chemistry philosophy.7 Yet, even with the broad utility of
these reactions, there is intense interest in delivering more
versatile and reactive catalysts,8 as well as safe processing
10
methods for the handling of azides.9,
In this study, we
examined these issues in the context of flow chemistry.
Specifically, we explored both the copper-catalyzed and
uncatalyzed azide-alkyne cycloaddition in a unique reactor: the
Vortex Fluidic Device (VFD, Figure 1 and S5).11-13 In this reactor,
reagents are added to a rapidly spinning tube and react in a
thin film. In the confined mode, the reaction mixture remains
in the tube. In continuous mode the products exit the top of
the tube while more reagents are delivered through feed jets
under the control of a syringe pump. We hypothesized that the
thin film processing in the VFD might impart some advantage
to the azide-alkyne cycloaddtion, potentially enhancing “on
water” effects when hydrophobic starting materials are
reacted in aqueous media.14-16 This hypothesis relates to the
fluid flow in the VFD that promotes high surface area contact
between immiscible liquids and the centrifugal force that
layers liquids of different density. Additionally, for azide-alkyne
cycloadditions that proceed at elevated temperature,
continuous processing in the VFD was anticipated to increase
Figure 1. A schematic representation of the Vortex Fluidic Device (VFD). Digital
images of the reactor are provided in the Electronic Supplementary Information.
The uncatalyzed reaction between benzyl azide (1) and
disubstituted alkyne 2 was studied first to determine any
advantages of the VFD and the effect of water on the reaction.
While the tilt angle of the rotating tube in the VFD can be
varied (θ, Fig. 1), the optimal value for a diversity of
applications is 45o,11-13 so this angle was used in this study.
When the reaction between 1 and 2 was run in confined mode
o
in the VFD at 80 C in acetonitrile, the conversion to triazole
never exceeded 30%, even at a range of rotational speeds
(Scheme 1 and S6). Similarly, conversion to the triazole was a
mere 23% when the reaction was run neat, with no solvent
(Scheme 1 and S10). However, when water was present in the
reaction under otherwise identical conditions, reaction
1
conversions increased up to 70%, as determined by H NMR
spectroscopic analysis of the reaction mixture (Scheme 1 and
S11). The conversion also correlated with the rotational speed
of the tube, with 8000 rpm identified as optimal for this
reaction (S6). Importantly, the conversion to triazole in water
was always higher in the VFD than when the azide and alkyne
were simply stirred in the glass reaction tube at 80 oC (a
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“batch” reaction, S4 and S7). For example, while the reaction entering the tube through stainless steel jet feeds. For these
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of 1 and 2 reached 70% conversion in the VFD, the experiments, mixtures of water and aceDtoOnI:it1r0i.l1e03w9/eDr0eCuCs0e4d40s1oF
corresponding batch reaction only reached 27%. We attribute that homogenous solutions of the reagents could be delivered
this difference to an enhanced “on water” effect for this in a controlled fashion. Under such conditions we did not
reaction in the VFD in comparison to batch processing. “On expect to observe the “on water” effect, but the homogenous
water” azide-alkyne cycloadditions have been previously conditions were helpful in controlling stoichiometry when
described15 and we attribute the enhancement of this effect in using the syringe pump. In the first experiments (run at 80 oC,
the VFD to the aforementioned high proportion of reagents at Table 2), no copper was added to the reaction and the result
the organic-water phase boundary. In contrast to running the was a surprise: near quantitative conversion to the triazole
reaction in a thin film, traditional batch processing has a much was observed with the exclusive formation of the 1,4-isomer.
smaller proportion of the reagents at this interface so the “on
Table 1. Comparison of VFD processing and batch processing in the azide
alkyne cycloaddition. All reactions were run at 80 ºC for 1 h using 0.25 mmol
azide, 0.30 mmol alkyne and 0.5 mL water (unless otherwise specified). VFD
processing was carried out at 8000 rpm in confined mode at a 45º tilt angle.
Batch reactions were run in the same glass reaction tube with magnetic stirring.
water” effect is less pronounced. Similar conclusions were
made by Huck and co-workers17 and also Song and co-
workers18 for other “on water” reactions in biphasic,
VFD conversions are reported as the average of triplicate experiments. Isolated
yields are reported in the bottom four examples.
continuous flow systems.
O
F3C
CF3
CF3
Azide
Ph N3
Alkyne
Product[a]
Batch[b]
VFD
O
+
O
80 ºC
1 hr
N3
+
CO2Me
CO2Me
N
N
N
N
1
2
50%
91 ± 2%[b]
N
N
Ph
N
N
N
Conditions
Solvent
MeCN
Conversion to triazole
VFD confined mode, thin film, 3000-9000 rpm
VFD confined mode, thin film, 8000 rpm
< 30%
23%
CO2Me
CO2Me
CO2Me
14%
41%
82 ± 1%[b]
82 ± 3%[b]
none (neat)
H2O
Ph N3
N
N
VFD confined mode, thin film, 8000 rpm
VFD tube, magnetic stirring, batch reaction
70%
27%
Ph
N
H2O
F
CO2Me
F
Scheme 1. Thin film processing in the VFD enhances the “on water” effect for the
azide alkyne cycloaddition. 0.25 mmol azide, 0.30 mmol alkyne and 0.5 mL
solvent were used in all reactions, except for the neat reaction in which no
solvent was used. The tilt angle for all VFD reactions was 45o. Conversions,
determined by 1H NMR spectroscopy, are the average of triplicate experiments.
N3
N
N
N
F
F
F
F
O
F3C
42 ± 2%[b]
O
F
31%
N3
CF3
N
N
Ph
N
This phenomenon was observed for a range of azides and
alkynes (Table 1). Notably, this enhanced “on water” effect
F
MeO2
C
CO2Me
CO2Me
CO2Me
CO2tBu
[c]
N3
Ph
provided
excellent
conversions
where
the
same
53%
87%[d]
82%[d]
90%[d]
MeO2
C
C
Ph
N
N
transformations in other solvents were previously reported to
require high pressures and far higher temperatures to achieve
comparable results.19 In fact, the reaction between benzyl
azide and methyl propiolate even occurred at room
temperature in water in the confined mode of the VFD, with
up to 49% conversion observed in a mere 2.5 hours (S16-S17).
No reaction was observed at room temperature under batch
conditions for this reaction, illustrating the dramatic rate
enhancement enabled by the thin film processing in the VFD.
The “on water” effect was also apparent for the reaction of
benzyl azide with dimethyl acetylenedicarboxylate, which was
run at room temperature, with batch processing providing 53%
conversion and VFD processing resulting in an 87% isolated
yield. Additionally, the last four entries in Table 1 indicated
that confined mode processing could be used on a preparative
scale, with 300-500 mg of triazole obtained in excellent
isolated yields (S18-S24). It was also shown that the azide in
these reactions could be generated in situ in the VFD followed
by direct reaction with the alkyne (S19-S24). The “on water”
effect was still observed under such conditions and the water
could extract the salts, facilitating clean isolation of the
product triazole.
N
MeO2
C
CO2Me
[c,e]
N3
Ph
-
-
MeO2
Ph
N
N
N
tBuO2
C
CO2tBu
Ph
N3
tBuO2
C
Ph
N
N
N
tBuO2
C
CO2tBu
CO2tBu
[e]
N3
Ph
-
83%[d]
tBuO2
C
Ph
N
N
N
[a] Only one regioisomer is shown for asymmetric alkynes [b] Conversions
based on 1H NMR spectroscopy. [c] Reaction run at 20 ºC [d] Isolated yield for
VFD processing with reaction scale >300 mg. [e] Azide generated in situ in the
VFD by reaction of benzyl bromide and sodium azide in water.
The exquisite regioselectivity strongly suggested that a copper
contaminant was present and indeed ICP-MS indicated 9 ppb
copper in the product solution. We suspect that the trace
copper was leaching from the stainless steel jet feed. The Milli-
Q water used in the reaction did not contain sufficient copper
to account for these results because the confined mode
resulted in a mixture of regioisomers (S27). The same reaction
run in continuous mode at room temperature resulted in no
reaction. This result suggests that catalyst leaching from the
stainless steel required elevated temperature. The results in
In scaling up reactions in the VFD, continuous mode is
required. In this setting, the azide and alkyne are added to the
rotating reaction tube via two separate syringe pumps,
2 | J. Name., 2012, 00, 1-3
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Table 2 are remarkable because of the very low copper levels steel jet feed and methyl propiolate was delivered to the
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required to catalyze this reaction. The low levels of copper will reaction tube through the copper jeDtOfIe: 1e0d.1.03T9h/De0CrCe0a4c4ti0o1nF
also help meet heavy metal regulatory limits when, for occurred at room temperature and the flow rate was 0.1
instance, these reactions are used in the preparation of active mL/min, which corresponds to a residence time of 11.7
pharmaceutical ingredients. Furthermore, using the jet feed as minutes. Analysis of the product solution under these
a reservoir for the copper is a convenient and technically conditions revealed a copper concentration of 4.4 ppm (S34).
simple method for delivering catalyst to the reaction.
Notably, these conditions consistently provided higher
conversions of the triazole than when copper sulfate and
ascorbic acid were used as the catalyst in confined mode (S30).
This finding suggests that the catalyst generated from the
copper jet feed is highly active. We also note that this method
is distinct from other flow chemistry reports in which the
reaction occurs in a copper tube.10 In the VFD setup in Table 3,
the copper jet feed is a reservoir for catalyst, which is leached
into the reaction zone in the glass tube.
Table 2. Continuous mode operation of the VFD provided full conversion to a
single regioisomer. Trace copper was leached from the steel jet feeds, resulting
in a final concentration of 9 ppb.
Table 3. A copper jet feed leaches sufficient metal to catalyze the azide-alkyne
cycloaddition in flow at room temperature. Ascorbic acid is required for high
conversions. The tabulated results were all run on >200 mg scale.
Azide
Alkyne
Product[a]
Conversion[b]
CO2Me
CO2Me
Ph
N3
99%
Ph
N
N
N
CO2Me
CO2Me
Ph N3
99%
99%
N
N
Ph
N
F
CO2Me
CO2Me
F
N3
N
N
N
F
F
Azide
Ph
Alkyne
Product
Isolated yield
CO2Me
CO2Me
N3
N3
N3
80%
Ph
N
N
[a] A single regioisomer was produced in these reactions [b] Conversions based
on 1H NMR spectroscopy
N
CO2Et
CO2Et
Ph
Ph
82%
90%
Inspired by the results above, it occurred to us that using a
copper jet feed might be a useful reservoir of catalyst,
especially for reactions that might require catalyst loading
higher than low ppb levels generated from the stainless
steel.20 Additionally, the higher copper concentration might
allow the reactions to proceed at room temperature—a
capability not realized using the stainless steel jet feeds.
Control experiments indicated that copper was easily leached
from the copper jet feed, as determined by ICP-MS of the
solvent flow through (S30). Water alone provided copper in a
concentration of 75 ppb in the outflow, while mixtures of
water and acetonitrile consistently provided copper
concentrations of 2-7 ppm copper (S30-S31). Unfortunately,
the conversion for the reaction of benzyl azide and methyl
propiolate were relatively low in continuous mode, never
exceeding 23% (Table 3, top). In contrast to recent reports
where sufficient active catalyst was leached into solution from
a copper reaction tube in flow,21 we suspected that the
leached copper in our system might not be in the right
oxidation state. Therefore, we simply included ascorbic acid in
the azide solution. In doing so, quantitative conversion to the
triazole was observed in continuous mode where the azide and
ascorbic acid were delivered to the tube through a stainless
Ph
N
N
N
OMe
OMe
Ph
N
N
N
MeO
OMe
OMe
N3
93%
OMe
N
N
N
MeO
MeO
OMe
OH
N3
OH
82%
73%
N
N
N
MeO
OMe
N3
OMe
N
N
N
This protocol was also adapted to a preparative scale in which
the methyl propiolate and benzyl azide solutions were
delivered into the VFD at 80 oC at a 10 fold higher
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concentration and increased flow rate (1.0 mL/min). The
reaction resulted in complete consumption of starting
materials and could provide gram-scale quantities of triazole
per hour of continuous processing (S37). To further assess the
scope of this method, several additional azide-alkyne
cycloadditions were processed in flow (Table 3). All reactions
were run on at least 200 mg in scale and isolated yields were
good to excellent. Notably, these reactions using the copper
tubing as the catalyst reservoir have been reproducible for at
least 30 experiments, indicating the leaching process
consistently provided active catalyst.
The requirement of ascorbic acid in generating the active
catalyst led us to explore other methods of copper reduction
in the VFD. Taking advantage of the transparent reaction tube,
we considered photochemical reduction of the leached
copper. In the event, eosin Y was used as a photoredox
catalyst at a loading of 0.15 mol%.22 The eosin was delivered to
the rotating tube in the same solution as the benzyl azide
through a stainless steel jet feed while methyl propiolate was
added through the copper jet feed, all at room temperature.
Green LEDs (525 nm) were positioned around the outside of
the reaction tube (see pages S53-S54 for details including a
digital image and schematic of the equipment). Running in
continuous mode at a flow rate of 0.1 mL/min resulted in
quantitative conversion to the triazole. The full conversion was
consistent in the product outflow over a total run time of 3.5
hours. If eosin Y was not contained in the reaction, the
conversion dropped to 21%. If the LEDs were not used, the
conversion dropped to 33% (S53). And while there have been
reports of photochemically promoted copper-catalyzed azide-
alkyne cycloadditions,22-24 our method is a simple way to
deliver and maintain an active copper catalyst in flow.
Furthermore, the transparent tube and the thin film in the VFD
reactor helps ensure efficient irradiation of the reaction
mixture.25
Conflicts of interest
There are no conflicts to declare.
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DOI: 10.1039/D0CC04401F
Notes and references
The authors thank the National Scientific and Technical
Research Council of Argentina and the Australian Research
Council (DP170100452) for financial support. Dr Kasturi
Vimalanathan is thanked for technical assistance.
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free cycloadditions. This is an important new addition to other
advantages imparted by thin film processing in the VFD such as
efficient heat dissipation,26, 27 rapid gas exchange and mass
transfer,27 and accelerated multi-phase reactions.27 In
continuous mode, the metallic jet feeds served as a convenient
reservoir of catalyst in the copper-catalyzed azide-alkyne
cycloadditions. To maintain the active copper catalyst, a
reducing agent such as ascorbic acid was required for efficient
reactions at room temperature. Alternatively, reducing
conditions could be maintained photochemically using eoisin Y
and green LEDs, which promoted a highly efficient copper-
catalyzed azide-alkyne cycloaddtion in flow. Together, these
results illustrate how novel processing techniques can reveal
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catalysis. Furthermore, the integration of azide-alkyne
28, 29
cycloaddition into flow chemistry platforms10,
is an
important capability as this reaction continues to be adopted
in industrial and pharmaceutical endeavors.2,20
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC04401F
TOC Graphic:
Azide-alkyne cycloadditions in a Vortex Fluidic Device benefit from enhanced “on water” effects and
copper jet feeds provide a convenient method of highly active catalyst delivery for flow chemistry.