Rapid Chemical Reaction Monitoring by Digital Microfluidics-NMR: Proof of Principle Towards an Automated Synthetic Discovery Platform

Article abstract of DOI:10.1002/anie.201910052

Microcoil nuclear magnetic resonance (NMR) has been interfaced with digital microfluidics (DMF) and is applied to monitor organic reactions in organic solvents as a proof of concept. DMF permits droplets to be moved and mixed inside the NMR spectrometer t

Full text of DOI:10.1002/anie.201910052

A Journal of the Gesellschaft Deutscher Chemiker
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International Edition Chemie
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Accepted Article
Title: Rapid Chemical Reaction Monitoring by Digital Microfluidics-
NMR: Proof of Principle Towards an Automated Synthetic
Discovery Platform
Authors: Bing Wu, Sebastian von der Ecken, Ian Swyer, Chunliang
Li, Amy Jenne, Franck Vincent, Daniel Schmidig, Till Kuehn,
Falko Busse, Henry Stronks, Ronald Soong, Aaron R.
Wheeler, and Andre J Simpson
This manuscript has been accepted after peer review and appears as an
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content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201910052
Angew. Chem. 10.1002/ange.201910052
Link to VoR: http://dx.doi.org/10.1002/anie.201910052
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Angewandte Chemie International Edition
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Rapid Chemical Reaction Monitoring by Digital Microfluidics-
NMR: Proof of Principle Towards an Automated Synthetic
Discovery Platform
Bing Wu, Sebastian von der Ecken, Ian Swyer, Chunliang Li, Amy Jenne, Franck Vincent, Daniel
Schmidig, Till Kuehn, Falko Busse, Henry Stronks, Ronald Soong, Aaron R. Wheeler*, André
Simpson*
Abstract: Microcoil Nuclear magnetic resonance (NMR) has been
interfaced with digital microfluidics (DMF) and is applied to monitor
organic reactions in organic solvents as a proof of concept. DMF
permits droplets to be moved and mixed inside the NMR to initiate
reactions while using sub-microliter volumes of reagent, opening up
the potential to follow the reactions of scarce or expensive reagents.
By setting up the spectrometer shims on a reagent droplet, data
acquisition can be started immediately upon droplet mixing and is
only limited by the rate at which NMR data can be collected, allowing
the monitoring of fast reactions. Here we report a cyclohexene
high field NMR. The first demonstrated the concept but was
limited as the DMF device was placed on top of an existing NMR
microcoil and the one-plate DMF device was limited to basic
[8]
droplet movements . The second paper introduced a two-plate
DMF device that is much more versatile, with reagents dissolved
[9]
in water aimed at biological applications . However, DMF-NMR
holds great promise for organic chemistry research. For example,
in digital microfluidics discrete droplets are moved and
measured directly, the elimination of capillary dead volumes in
connectors and tubing means the entire available volume can be
placed over the NMR coil. In turn, this allows very small samples
to be analyzed directly, important if expensive chemicals or
precious samples need to be reacted and monitored.
Furthermore, in the future it is possible to envision large DMF
carbonate hydrolysis in dimethylformamide and
a Knoevenagel
condensation in methanol/water. This is to our knowledge the first
time rapid organic reactions in organic solvents have been
monitored by high field DMF-NMR. The study represents a key first
step towards larger DMF-NMR arrays that could in future serve as
discovery platforms, where computer controlled DMF automates
mixing/titration of chemical libraries and NMR is used to study the
structures formed and kinetics in real time.
[10]
arrays that have the potential to screen reactions from various
combinations of substrates under automation. In many ways
such an approach would turn DMF-NMR from an analytical tool
into a discovery platform. In this study two basic questions are
asked; 1) As DMF-NMR has yet to be demonstrated with an
organic reaction in an organic solvent, is this feasible? (i.e. can
organic solvents, which have considerably less surface tension
than water, be held and moved vertically (along the NMR
magnet bore), against gravity, when sandwiched between the
plates of a DMF device ?) 2) Can DMF-NMR be used to follow a
rapid reaction? (i.e. a reaction that completes faster than
loading/match-tuning/shimming in conventional NMR (~5 mins)
would allow). To address these questions a simple hydrolysis of
a cyclic carbonate in dimethylformamide is monitored, as-well
as a Knoevenagel condensation in methanol/water (see SI)
(Note as “digital microfluidics” and “dimethylformamide” have
the same acronym, in this paper “DMF” is used for digital
microfluidics while dimethylformamide is written in full.)
D
igital microfluidics is a powerful technique in which droplets
[1]
are moved over an open array of electrodes. The approach
permits a wide range of applications including, proteomic sample
[2]
[3]
[4]
preparation, immunoassays, organic synthesis, as well as
[5]
cell culture and analysis. As such, interfacing with high field
NMR, one of the most powerful analytical detectors for chemical
[
6]
[7]
structure and interactions, holds exciting promise. To date,
two papers have been published on the interface of DMF and
[
[
[
[a]
b]
c]
Dr. B. Wu, A. Jenne, Dr. R. Soong, Prof. A. Simpson
Department of Chemistry
University of Toronto Scarborough,
1256 Military Trail, Toronto, ON, M1C 1A4 (Canada)
E-mail: andre.simpson@utoronto.ca
Dr. S. von der Ecken, Dr. I. Swyer, Prof. A. Wheeler
Department of Chemistry
It is necessary to probe reaction kinetics in real-time to gain a
[11]
thorough understanding of their mechanisms.
Traditionally,
optical spectroscopies (e.g. UV-vis, IR, fluorescence, Raman
spectroscopy) have been used to monitoring chemical reaction
University of Toronto
80 St. George St., Toronto, ON, M5S 3H6 (Canada)
[12]
E-mail: aaron.wheeler@utoronto.ca
Dr. C. Li
kinetics because of their widespread availability.
However,
such approaches only offer limited chemical information
Laboratory of Physical Chemistry
Eindhoven University of Technology
P.O. Box 513, 5600 MB Eindhoven (The Netherlands)
Dr. F. Vincent, Dr. D. Schmidig, Dr. T. Kuehn
Bruker BioSpin AG.
Industriestrasse 26, 8117 Fällanden, Switzerland
Dr. F. Busse
Bruker BioSpin GmbH
[13]
compared to NMR.
Alternatively, mass spectrometry (MS)
can be employed, but MS faces other challenges, including, the
[14]
[
[
[
d]
e]
f]
inability to distinguish between isomers. The "Achilles' heel" of
NMR its relatively low mass sensitivity. However, as the defined
droplets used for DMF are generally quite small (i.e., pL to µL)
NMR microcoils can be used to increase mass sensitivity. This
approach leverages the fact that the magnetic flux density
induced by a unit current (and therefore the voltage induced in
the coil by nuclear spins) increases at a greater rate than the
resistive noise (due to sample proximity), leading to improved
signal-to-noise ratios. Despite the fact that planar microcoils are
Silberstreifen 4, 76287 Rheinstetten (Germany)
Dr. H. Stronks
Bruker Canada Ltd, 2800 High Point Drive, Milton, Ontario, L9T 6P4
(Canada)
Supporting information for this article is given via a link at the end of
the document.
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relatively well developed and give excellent NMR mass
sensitivity ], they have not found routine application because of
difficulties in sample handling for such small volumes of liquid.
Interestingly, DMF solves the sample handling aspect,
while the increased mass sensitivity of micro-coils opens up the
future potential for routine analysis of tiny samples.
[
15
Figure 1. Functional principle of Digital Microfluidics (DMF) and it’s integration with NMR. (a.1) Schematic side-view of a DMF device. The bottom-plate features an
array of actuation electrodes (chromium, grey) on a bottom-substrate (glass, light blue), which are covered by a dielectric layer (Parylene, green) and a
hydrophobic coating (Fluoropel, yellow). The top-plate features a ground electrode (copper, orange), and a hydrophobic layer (Fluoropel, yellow). (a.2) Schematic
side-view, illustrating how a force can be induced on the droplet by applying a voltage between an actuation and a ground electrode. (a.3) Schematic top-views,
illustrating how activating the electrodes in specific patterns allows the basic fluid operations moving, splitting/dispensing, merging, and mixing. (b) Photographs of
NMR coil and DMF top-plate. (b.1) A 500 μm (I.D.) 980 μm (O.D.) planar microcoil is integrated into the ground electrode on the top-substrate, which is mounted
on a holder. (b.2) shows the open holder (top), which functions as the top-plate, and the DMF bottom-plate with the actuation electrode array (bottom). A detailed
[
1]
description of the hardware setup can be found in our previous work. (b.3) Frames from a video of a DMF experiment in which two droplets are dispensed from
reservoirs and then merged and mixed on the array of electrodes. Artificial colour has been added to the droplets to aid in visualization. (c) Schematic top-view of
the positioning of actuation electrode array of the bottom-plate, NMR coil of the top-plate, and droplets sandwiched in between. (c.1) Reactants are loaded into the
device. (c.2) Reactant “blue” is moved over the coil for shimming and moved back to its starting position. This is repeated with reactant “orange”. (c.3) Both
reactants are mixed and moved into the detection site over the coil. (c.4) The previously acquired shims are used for measurement permitting acquisition to be
started immediately. Note that for clarity in (c.3) the droplets are shown to be mixed in a large circle but in practice they are mixed over the NMR coil to permit NMR
data to be acquired during the mixing process, as described below.
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[
20]
The schematics in Fig. 1 illustrate (a) the principle of digital
microfluidics, (b) the NMR-DMF integration, and (c) the
experimental protocol. The DMF-NMR assembly (Fig. 1b) is
described in the supporting information and in our previous
work.[9] Briefly, the top plate and bottom plate are assembled
along with an electrical manifold and housing to connect to a
standard MIC-5 imaging probe, and then loaded into an 11.7 T
Bruker Avance III spectrometer. The plates are separated by
using cutting edge ultrafast 2D NMR. In such applications the
mixing on chip and pre-shimming are key steps which permit
NMR data collection to start at exactly the same time as the
reaction is initiated. For example, a recent pioneering study that
developed tapered stripline NMR coils to follow rapid reactions
in a capillary, cited that the rapid mixing of the reagents in a
narrow capillary was the limiting factor rather than the NMR
[
21]
detection itself.
0
.18 mm such that unit-droplets of reagents (covering one
driving electrode) were ~911 nL and the volume of sample within
the field lines of the microcoil (0.98 mm OD) was ~136 nL. As
[
9]
previously demonstrated , during NMR acquisition the droplets
are actively stretched along the B direction (direction of the
N
0
O
external magnetic field) to produce an elongated shape that is
more amenable to shimming using the vertically orientated
shims on standard NMR spectrometers. Shimming can be
N
N
H
HO
OH
O
O
TBD
+
2
H O
+
CO
2
[9]
performed on either a dummy reaction as previously described
or by shimming on one of the reactant droplets; the latter was
used for the data reported here. Before the probe is inserted into
the NMR system different chemical reagents are loaded on the
bottom-plate in separate droplets (Fig. 1-c.1). Figure 1-c.2
shows how the two droplets (orange, blue) are moved on the
device, while being inside the NMR system. The pre-shimming is
also performed on the first droplet (blue) at this stage. After the
shimming is complete the reactants are merged, mixed (Fig. 1-
c.3) and brought over the microcoil to monitor the reaction (Fig.
rac-CHC
c-CHDO
Scheme 1. TBD-catalyzed hydrolysis of racemic cyclohexene carbonate (rac-
CHC) to cis-1,2-cyclohexanediol (c-CHDO).
1
-c.4). The DMF device is controlled using an open-source
[16]
Dropbot control-system. The voltage for droplet actuation was
set to 145-165 Vrms at 10 kHz.
A model reaction was used to test the capability of the
DMF-NMR system for carrying out organic reactions in organic
solvents.
A hydrolysis reaction in dimethylformamide was
selected, in part because optically active diols are important
intermediates for synthesizing natural products as well as
[
17]
biologically active compounds.
Scheme
1
shows the
[
18]
cyclohexene carbonate hydrolysis reaction
studied here. To
increase the reaction rate, triazabicyclodecene (TBD) was
employed as a strong nucleophilic reagent to catalyze this
reaction and to create the basic condition required for rapid
[19]
conversion.
The model reaction studied here has rapid kinetics, and thus
following its progress is out of reach for conventional NMR
systems. Specifically, loading, matching/tuning and automated
shimming protocols take many minutes, such that reactions like
the one in Scheme 1 can proceed to completion prior to the first
measurement. With DMF-NMR, reagents can be injected and
reacted without moving the reaction vessel, such that the
matching and tuning remains constant throughout the process.
After pre-shimming, on initialization of the reaction (including a
Figure 2. DMF-NMR for fast reaction analysis. (a) Representative spectra
collected during the rac-CHC hydrolysis reaction ([rac-CHC]=4M) to c-CHDO
10 s mixing step in which the merged droplet is manipulated
across the array, Fig 1 c.3-4), data can be collected without
delay. In typical experiments, spectra were collected every 5
seconds, providing sufficient temporal resolution to follow the
progress of the reaction evaluated here. This sampling
frequency is much faster than that reported in previous DMF-
7
in dimethylformamide-d , with peaks highlighted that represent CHC protons
(green, blue), c-CHDO protons (red), and IPA protons (turquoise); (b)
Concentrations as a function of time extrapolated from peaks correlated to rac-
CHC (blue triangles and green circles), c-CHDO (red triangles), IPA (turquoise
triangles) (see the detailed chemical shift assignments in SI); (c)
Concentrations as a function of time for pure rac-CHC (4 M). Insets are
magnified regions at the beginning (left) and in the middle (right) of the
experiment.
[8-9]
NMR analyses.
In theory, in future applications with ultrafast
reactions (sensitivity permitting) it should be possible to collect
NMR data in even shorter time frames; for example, collection of
even full 2D datasets have been reported in as little as 100 ms
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1
Figure 2 shows the H DMF-NMR data for the model
as above, and then analyzed for a longer period of time (Fig. 2c).
As shown, there is (again) a small signal increase observed in
the first ~minute, with negligible changes observed for the
remainder of the experiment (>50 min). The signal stability over
this long duration suggests that evaporation is not causing
appreciable changes to the signal. More work is needed to
explore, but regardless of the mechanism, the inclusion of the
internal standard allowed for reactant and product integrals to be
corrected to obtain precise kinetic parameters.
hydrolysis reaction and corresponding concentration plots. First,
it is important to note here that data are plotted from 15 seconds
onwards. In the first 10 seconds the data are being actively
mixed after which the droplet takes a 5 seconds to stabilize. As
such during this time the integrals are less stable as the droplet
content is changing dynamically, making it challenging to extract
kinetic data. However, it is still possible to collect NMR data
during this initial window (see Fig. S2) which would be important
to monitor rapid qualitative changes (i.e. new products formed,
intermediates formed) as soon as the droplets are brought
together. After the first 15 seconds the data show a steady
consumption of starting material rac-CHC (green and blue), with
a corresponding increase in concentration of product cis-1,2-
cyclohexendiol (c-CHDO) (red) (detailed NMR spectral
assignments are shown in Figure S3-S7, including diffusion
ordered spectroscopy (DOSY) which is a powerful tool for
separating products and studying non-covalent interactions).
The corrected reagent and product concentration data for
the model hydrolysis reaction (Fig. 2b) exhibit exponential
behaviour with time that is consistent with simple 1st order
[23]
reaction kinetics. As outlined previously , TBD is a basic
catalyst that acts as a proton bridge because of the synergistic
action of its two N atoms. Therefore, the promotion of proton
transfer results in a base-catalyzed reaction that follows pseudo-
[
24]
first order reaction kinetics.
As shown in Figure 3, this was
tested in the DMF-NMR system for different concentrations of
reagent, while maintaining a constant ratio of reagent:catalyst.
For example, the calculated reaction rate constant is k’ =
2
Note that water ([H O] = 8 M) was included in the CHC reagent
droplet to accelerate the reaction and to suppress the cyclic ring
polymerization on
-
1
0
.0127±0.0011s for initial rac-CHC concentration = 4 M, which
is similar to what was reported from alkaline hydrolysis of cyclic
0.05
0.04
0.03
0.02
0.01
[25]
0
0
0
0
.015
.010
.005
.000
carbonate using conventional apparatus. This indicates that at
sub-μL volumes, the reaction follows the same chemical kinetics
[
26]
observed with larger volumes. As reported previously,
the
second-order rate constant k for base-catalyzed reactions can
be obtained by dividing k’ by base concentration. Using [TBD]
as an approximation, k was calculated here to be around
-1 -1
0
.014±0.002 M ꞏs for rac-CHC again consistent with previous
[26a]
reports . In summary, Figure 3 demonstrates that DMF-NMR
can be used to explore features of chemical reactions while only
consuming small volumes of reagents.
0.00
Finally, a reaction in a methanol/water solvent was
0
1
2
3
4
5
evaluated to test the performance of the DMF-NMR system with
volatile constituents. The Knoevenagel condensation and
Michael addition between dimedone (DIM) and benzoic acid
[
rac-CHC] (M)
[27]
Figure 3. DMF-NMR hydrolysis reaction kinetics. Plot of the pseudo-first order
reaction constant k’ (black circles, left axis), and the second order reaction
constant k (red boxes, right axis) as a function of the concentration of reactant
rac-CHC. (The ratio between reactant and catalyst concentration in all the
cases held at 10:1). Error bars represent ± standard deviation for n = 6 (see
text for details).
(BA) to form tetraketones (TKs) (Scheme S1) was selected as
a model system for this test, in recognition of the role of TKs as
key intermediates for synthesizing heterocycles. Figure 4a and
4b show NMR data and associated kinetics for the model
reaction, with assignments provided in the supporting materials
(
Figures S8-S9). We expected that evaporation might be more
significant in this system (with a volatile solvent) than the one
described above; thus, an internal standard, tetramethylsilane
[
19, 22]
mixing with TBD
, although a trace amount of polymer still
formed (Fig. S5). Likewise, a reference standard, isopropyl
alcohol (IPA), was included in the TBD reagent droplet to permit
normalization between runs and correct for changes not caused
by the reaction. Concentrations as a function of time were
calculated for all species. As shown in Figure 2b, the internal
standard/IPA signal appears to increase for the first minute of
the analysis, after which it plateaus. We hypothesize that this
may reflect a subtle droplet shape change that takes effect in the
first minute of incubation above the coil. Another potential
explanation is that it is related to evaporation of solvent. To
investigate this effect further, a control study was carried out in
(TMS) was used and its signal was evaluated as a function of
time (Fig 4c). As shown, in 25 min the internal standard
concentration increases by ~10%, suggesting that a similar
amount of solvent evaporates during the reaction. In the future
(
if needed), this effect might be diminished by sealing the device.
For the purposes described here, however, it was sufficient to
simply correct the data shown in Fig. 4b for evaporation effect,
-
1
allowing calculation of the reaction rate constant of 0.0011 s ,
based on a first order reaction mechanism proposed by previous
[
28]
studies.
To our knowledge, this is the first reaction rate
which droplets of reagent (rac-CHC dimethylformamide-d
solution) and solvent (pure dimethylformamide-d ) were treated
7
constant reported for this reaction.
7
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only tiny amounts of reagents. Given that DMF can automate
reactions and NMR provide unparalleled de novo structure
elucidation, it is more a question of when DMF-NMR with
become an everyday tool in organic chemistry research rather
than if.
Experimental Section
Details are provided in the supporting information
Acknowledgements
We would like to thank the National Science and Engineering
Research Council (NSERC) (STPGP 494273-16), the Canada
Foundation for Innovation (CFI), the Ontario Ministry of
Research and Innovation (MRI), and the Krembil Foundation for
providing funding. A.S. would like to thank the Government of
Ontario for an Early Researcher Award. A.R.W. thanks the
Canada Research Chairs (CRC) Association for a CRC.
Figure
4. DMF-NMR for analysis of reactions in volatile solvents. (a)
Keywords: Digital Microfluidics • reaction monitoring • NMR •
Representative spectra collected during the Knoevenagel condensation and
Michael addition of BA ([BA] = 0.1 M) to form TKs, with peaks highlighted that
represent BA protons (red) and TK protons (blue). (b) Concentrations as a
function of time extrapolated from peaks BA (red squares) and TK (blue
circles). (Detailed chemical shift assignment in Fig. S8-9.) (c) The integrated
peak area as a function of time I(t) relative to the initial integrated peak area
I(0) for the peak corresponding to the internal standard TMS as a function of
time.
hydrolysis • rapid reaction
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volumes inherent to DMF allow the use of tiny amounts of
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condensation and Michael addition, each unit-droplet covering a
single electrode (911 nL) contained 6.3 µg of DIM and 9.4 µg of
BA, while in the active volume above the coil (136 nl) only 0.94
µg and 1.4 µg were needed for NMR detection. As such this
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using NMR, even with limited or precious reagents. Here the
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with literature values indicating the rate determined at μL-volume,
still follows the expected chemical kinetics observed with larger
volumes.
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Angewandte Chemie International Edition
10.1002/anie.201910052
COMMUNICATION
COMMUNICATION
Automated Discovery: When
Bing Wu, Sebastian von der Ecken, Ian
Swyer, Chunliang Li, Amy Jenne, Franck
Vincent, Daniel Schmidig, Till Kuehn,
Falko Busse, Henry Stronks, Ronald
Soong, Aaron R. Wheeler*, André
Simpson*____________________
combined
microcoil
nuclear
magnetic resonance (NMR) and
digital microfluidics (DMF) allow
sub-microliter volumes of reagents
to be moved and mixed inside the
NMR to initiate reactions. This
permits monitoring reactions of
scarce or expensive reagents and
opens up the potential for future
Rapid Chemical Reaction Monitoring
by Digital Microfluidics-NMR: Proof of
Principle Towards an Automated
Synthetic Discovery Platform
automated synthetic
platforms.
discovery
This article is protected by copyright. All rights reserved.