A benchtop NMR spectrometer as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four organic transformations

Article abstract of DOI:10.1039/c6ra19662d

An approach is reported for monitoring continuous-flow reactions by means of a low-field benchtop NMR spectrometer. The spectrometer is interfaced with a mesofluidic reactor and used as a tool for optimising four organic transformations, namely an acid-catalysed esterification, a Knoevenagel condensation, a Diels-Alder reaction, and an alkylation. Reactions need to be performed either solvent-free or at relatively high concentration in order to monitor them effectively using the NMR spectrometer, but this allows for the leveraging of one of the key advantages of flow processing, namely process intensification.

Full text of DOI:10.1039/c6ra19662d

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A Benchtop NMR Spectrometer as a Tool for Monitoring
Mesoscale Continuous-Flow Organic Synthesis: Equipment
Interface and Assessment in Four Organic Transformations
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Cynthia M. Archambault and Nicholas E. Leadbeater*
www.rsc.org/
An approach is reported for monitoring continuous-flow reactions by means of a low-field benchtop NMR spectrometer.
The spectrometer is interfaced with a mesofluidic reactor and used as a tool for optimising four organic transformations,
namely an acid-catalysed esterification, a Knoevenagel condensation, a Diels-Alder reaction, and an alkylation. Reactions
need to be performed either solvent-free or at relatively high concentration in order to monitor them effectively using the
NMR spectrometer, but this allows for the leveraging of one of the key advantages of flow processing, namely process
intensification.
is that the signals observed are proportional to the concentration
of the analytes. It is therefore possible to calculate conversion
Introduction
By using continuous-flow processing, reactions can often be
streamlined, multiple steps can be linked together, and reactions
that were challenging in batch are now available for chemists to
and yields without needing first to derive calibration curves or
apply other post-analysis corrections. Traditionally, the
compounds are dissolved in a deuterated solvent, placed into a
sample tube and the spectrum recorded. The combination of
chromatography and NMR has also made its way into the
analytical laboratory. A liquid-chromatography (LC) system
can be coupled directly to an NMR unit, the sample being
1
,2
use. There is also better control of heating and mixing,
allowing for reactions to be performed under very precise and
reproducible conditions. For these reasons, flow processing is
seeing increasing interest both in academic and industrial
settings. When evaluating the outcome of reactions performed
using flow chemistry and optimizing reaction conditions, the
best option is to employ in-line analytical tools. This opens the
avenue for fast, reliable assay in comparison with the traditional
approach in which performance is evaluated based on off-line
product analysis. To this end, in-line analysis of flow processes
has taken significant strides in recent years, particularly when
14
transferred into the spectrometer “as is”. That is, it arrives at
the concentration and in the (non-deuterated) solvent supplied
by the LC. This in essence is the genesis of NMR analysis of
15
flow chemistry. A range of NMR spectrometers have been
interfaced with microfluidic equipment for real-time analysis of
16
chemical reactions and biological processes. The majority,
however, require complex engineering either on the part of the
spectrometer or the flow cell used. Traditional high-field NMR
spectrometers have been used for real-time analysis of batch
3
,4
interfaced with microfluidic devices.
Spectroscopic tools
5
6
7,8
such as infrared,
UV-visible,
Raman,
and mass
9
spectroscopy have all been successfully employed. Other
reaction assay tools are also attracting attention, such as the use
reactions by means of a flow system removing aliquots over
17
time for analysis.
More recently, a benchtop NMR
1
0
11
of digital cameras, or analytical balances. By putting the
available tools either individually or together, it is possible for
flow processes to be self-optimizing.
spectrometer comprising of a permanent magnet and operating
at 43 MHz has been used in a similar way to monitor a transfer
4
,12,13
In essence, this
18
hydrogenation reaction. The NMR spectrometer was installed
involves performing the reaction and then varying parameters
such as stoichiometry, temperature and residence time, until
optimal conditions are found. These iterations can be performed
automatically by means of feedback loops between in-situ
reaction monitoring tools and the flow apparatus.
Of all the analytical techniques available to organic
chemists on a day-to-day basis, NMR spectroscopy is probably
the most widely used. A key advantage of NMR spectroscopy
directly next to a Schlenk tube containing the reaction mixture
and a peristaltic pump used to pass the solution through the
magnet and back to the tube.
The application of NMR spectroscopy for real-time
monitoring reactions performed using mesofluidic (flow rates
of 0.5-10 mL / min) equipment is less explored. In our
laboratory we have had success interfacing a simple benchtop
7,19
Raman spectrometer with a mesoflow unit.
This has allowed
us to monitor reactions from both a qualitative and quantitative
perspective. Cronin and co-workers recently described the use
1
8
of the aforementioned benchtop NMR spectrometer for
2
0
monitoring continuous-flow reactions.
They performed
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reactions using a flow cell inside the spectrometer as the
reactor. The approach works well and can be extended to self-
optimization by means of feedback loops. However, using this
configuration, reactions need to be performed at room
temperature. A Grignard reaction has also been monitored
2
1
using this NMR unit. These reports sparked our interest in
interfacing a basic NMR spectrometer that we use primarily in
teaching settings with one of our continuous-flow units and
employing it for in-line reaction monitoring of a number of
organic transformations both at ambient and elevated
temperatures. Our results are presented here.
Figure 1 A continuous-flow unit interfaced with a benchtop NMR spectrometer
Results and discussion
Apparatus
As our NMR spectrometer, we selected a benchtop unit Test reactions
containing a 2 Tesla magnet and operating at 80 MHz
With an experimental design established, we decided on four
test reactions to probe its application as a reaction monitoring
tool (Scheme 1).
2
2
(picoSpin™ 80 Series II). It operates in a lock-free manner
and therefore can be employed with non-deuterated organic and
aqueous solvents. This instrument and its 45 MHz analog have
been used with success previously as a teaching tool as well as
for rapid analysis of reaction mixtures in a research and
Acid-catalysed esterification reaction
3.48 ppm
3
.72 ppm
O
O
2
3
+
development environment. In these settings, samples are
manually injected into the inlet of the spectrometer using a
[H ]
+
MeOH
2
+ H O
OH
flow
OMe
syringe (100
system is contained within a cartridge and has a working
volume of 40 L. Material is injected through the cartridge and
µL glass or 1 mL plastic). The fluid capillary
Base-catalysed Knoevenagel reaction
2
.48 ppm (E)
O
2. 39 ppm (Z)
O
O
H
µ
O
O
NH
flow
OEt
H
+
then out of a drain tube. Solvent can be passed through to clean
the system. What drew our attention was that both the inlet and
drain assemblies on the instrument are compatible with the
standard PEEK nuts used on mesoscale flow equipment. We
therefore envisaged we could connect our flow unit directly to
the spectrometer with no modification required to either
apparatus (Figure 1). We decided initially to operate in a bypass
mode whereby we would briefly divert the stream exiting the
flow unit through the spectrometer. We could then record the
NMR spectrum of the sample while the material was static.
When we were ready to take another sample, we planned to use
that to push out the prior one and refill the spectrometer with
new analyte. Also, we decided to place the spectroscopic
interface just after the back-pressure regulator assembly. This
meant that we did not need to engineer a flow cell capable of
holding significant pressure and also we were able to record the
NMR spectra at room temperature, the product mixture having
cooled by the time it reached the spectrometer.
OEt
10.11 ppm
Diels-Alder reaction
3.57 ppm
O
O
H
H
flow
+
O
O
7.26 ppm
O
O
Alkylationreaction
O
O
10.42 ppm
H
DBU
flow
H
+
Br
OH
O
4
.18 ppm
Scheme 1 Test reactions selected
(i) Acid-catalysed esterification reaction
We selected the acid-catalysed esterification of acetic acid with
methanol as our first test reaction. We envisaged monitoring the
disappearance of the signal due to the protons on the methyl
group of methanol (3.48ppm) and growth of that due to the
methyl group attached to the oxygen of the methyl acetate
product (3.72ppm). Product conversion could then be obtained
by integrating the two signals selected for monitoring. We
prepared two stock solutions, one of acetic acid (solution A)
and one of methanol and sulfuric acid (solution B). Pumping
from solution A at a flow rate of 0.34 mL/min and from
solution B at a flow rate of 0.66 mL/min and combining them
by means of a T-piece, we passed the reaction mixture through
a 10 mL capacity coil (1 mL/min combined flow rate; 10 min
2
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residence time) at room temperature. At these flow rates, the Knoevenagel reaction. With an eye to obtaining spectra with
reagent stoichiometry was such that there was a 1:2 molar ratio good signal-to-noise ratio in a timely manner, we set about
of acetic acid to methanol and a sulfuric acid catalyst loading of determining what the optimal reagent concentration at which to
2
.5 mol%. We recorded the NMR spectrum of the product operate. We prepared a series of stock solutions of
mixture, making sure that at least one coil volume had passed benzaldehyde and ethyl acetoacetate in ethyl acetate at analyte
before we sent a sample in to our bypass loop and the concentrations up to 2 M and recorded their NMR spectra. We
spectrometer. Without stopping the flow of reagents, we raised focused attention on the aldehyde signal from benzaldehyde at
the reactor coil temperature in 20 °C increments, recording the 10.11 ppm and the methylene group in ethyl acetoacetate at
NMR spectrum of the product mixture at each point. Again we 3.55 ppm. Being able clearly to see these signals would be key
ensured that at least one coil volume of reagents had passed to reaction monitoring. As shown in Figure 3, a reagent
through the reactor at the desired temperature before we concentration at least 1M would be needed to be able to
recorded the NMR spectrum. A plot of product conversion vs monitor the reaction reliably.
temperature shown in Figure 2. The product conversion begins
to plateau at around 85 °C, this being as expected since the
reaction reaches equilibrium in the sealed system. We repeated
the reaction at a catalyst loading of 5 mol%, the data also being
shown in Figure 3. Again, product conversion is seen to
plateau, equilibrium being reached slightly faster in this case.
These results showed that we were able to monitor the reaction
effectively using our apparatus.
Figure 3 NMR spectrum of benzaldehyde and ethyl acetoacetate in ethyl acetate
as solvent, recorded across a range of analyte concentrations
Deciding to proceed at reagent concentration of 1M, we
took an approach similar to that for the esterification reaction,
performing the Knoevenagel condensation at a series of
temperatures. In one reservoir we placed an ethyl acetate
solution of benzaldehyde and ethyl acetoacetate (2M in each)
and in another we placed a 0.2 M ethyl acetate solution of
Figure 2 Monitoring an acid-catalysed esterification
piperidine (10 mol%). Each solution was flowed at 0.5 mL /
min giving a combined flow rate of 1 mL / min through the
reactor coil. To quantify the outcome of the reaction, we
(ii) Base-catalysed Knoevenagel reaction
focused attention on the signal from unreacted benzaldehyde
10.11 ppm) and the signal for the CH moiety of the acetyl
group in the product. Using this signal, we were able to
differentiate between the - and -isomers of the product (2.48
With the results of the esterification reaction in hand, we turned
next to a transformation performed using a solvent. We selected
the Knoevenagel condensation reaction between benzaldehyde
and ethyl acetoacetate catalyzed by piperidine. This is a
reaction we had monitored previously using Raman
(
3
E
Z
ppm vs. 2.39 ppm respectively). A superimposition of the
spectra recorded is shown in Figure 4 and product conversion
data shown in Table 1. Increasing the temperature from 40 °C
to 85 °C led to a concomitant increase in product conversion.
However, moving to 105 °C resulted in a slight decrease,
perhaps due to the competitive decomposition of the product.
There is a correlation between these results and those obtained
7
,24
spectroscopy.
When performing a reaction in a non-
deuterated solvent and recording spectra on a low-field
benchtop NMR spectrometer, reagent concentration and the
number of scans taken are key factors to take in to account. If
the reaction mixture is too dilute, signals from the reagents and
products will be swamped by those of the solvent and make
quantification of reaction progress significantly challenging.
This can be overcome by increasing the reagent concentration,
increasing the number of scans taken, or a combination of the
two. In the case of the esterification reaction, we had set the
instrument to record 10 scans, this taking around 90 s. We did
not want to increase the acquisition time when moving to the
7
using Raman monitoring for the same reaction.
Table 1 Product conversion as a function of temperature in the base-catalysed
Knoevenagel reaction of benzaldehyde and ethyl acetoacetate
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Temperature (°C) Product conversion (%)
anhydride), and using acetonitrile as the solvent, we performed
the reaction across a series of reactor temperatures, keeping the
residence time constant at 10 min. To assay the reaction, we
focused attention on a signal from unreacted maleic anhydride
1
2
3
4
5
40
50
26
43
53
63
55
65
85
(
7.26 ppm) and one that is unique to the product (3.57 ppm). As
105
shown in Figure 5, at 75 °C the conversion to product plateaus
at 75%.
We then performed the reaction, keeping the temperature
constant at 75 °C and varying the flow rate. By decreasing the
flow rate to 0.5 mL / min, hence increasing the residence time
from 10 min to 20 min, the product conversion rose to 98%.
Figure 5 Monitoring a Diels-Alder reaction
(iv) Alkylation reaction
Given the wide use of alkylation reactions in synthetic
chemistry, we selected this class of transformation as our final
example of a to probe in this study, Our inspiration again came
from
a reaction previously performed at high reagent
concentration using a microcapillary flow disc reactor, namely
the alkylation of salicylaldehyde using allyl bromide. In that
case, a twofold excess of allyl bromide was used and the
process performed at room temperature. We decided to focus
our attention on the less reactive 1-bromobutane so that we
could probe the reaction across a range of temperatures. We
Figure
4 NMR spectra of the base-catalysed Knoevenagel condensation,
recorded across a range of reactor coil temperatures: Top – full spectrum,
bottom – aldehyde signal from benzaldehyde and methyl signal from alkene
product.
(iii) Diels-Alder reaction
We selected the Diels-Alder reaction as a further test reaction operated at a salicylaldehyde to 1-bromobutane stoichiometric
for our study. We again would need to operate at high reagent ratio of 1:2 and employed DBU (1.5 equiv.) as a base to remove
concentration. We selected isoprene as the diene and maleic the HBr byproduct. We decided to operate at a concentration of
anhydride as the dienophile. A test reaction, even at room 2M in salicylaldehyde and 3M in 1-bromobutane. As in the
temperature, showed the significantly exothermic nature of the case of the Diels-Alder reaction, this alkylation is exothermic
process when performed at high concentration in common when performed at such high concentration in batch on scale.
organic solvents. This is not unexpected, given the previous Focusing on the aldehyde signal from the salicylaldehyde
reports on the significantly exothermic nature of solvent-free starting material (10.42 ppm) and the triplet from the methylene
Diels-Alder reactions. An advantage of continuous-flow group of the alkyl chain next to the oxygen atom in the product
processing is that it is often possible to mitigate the problems (4.18 ppm), we monitored the reaction over a range of reactor
associated with performing reactions that are potentially coil temperatures. The results are shown in Figure 6. While at
2
5
exothermic in nature. The same Diels-Alder reaction has been room temperature there was no product formation observed, by
successfully performed in a microcapillary flow disc reactor. In the time we reached 100 °C, full conversion was obtained. To
that case, the reagents are dissolved in acetonitrile and passed probe the effects of varying the reagent stoichiometry, we
through the disc reactor at 60 °C with a residence time of 28- changed the salicylaldehyde to 1-bromobutane ratio from 1:2 to
1
13 min. Operating with a slight excess of dienophile 1:1.5 and recorded spectra over the same temperature range.
(concentrations of 5.9 M in isoprene and 6.3 M in maleic There was little difference in product conversion, showing that
4
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the reaction can be effectively performed at the lower software provided with the instrument. The data was then
stoichiometric ratio.
processed using Mnova NMR (Mestrelab Research, S.L.).
Acid-catalysed esterification reaction
Two stock solutions were prepared – Solution A: acetic acid
(
43 mL, 750 mmol, 1 equiv.); Solution B: concentrated sulfuric
acid (2 mL, 37.5mmol, 0.05 equiv.) in methanol (61 mL, 1506
mmol, 2 equiv.). Two pumps were employed (pump A and
pump B), the outlets of which were joined to a T-piece and the
outlet of the T-piece attached to the “reagent in” port of the 10-
mL capacity reactor coil. The “reagent out” port of the second
reactor coil was directly interfaced with a variable back
pressure regulator set to 4 bar, after which there was a short
length of tubing leading to the waste / collect switch. The flow
system was primed using the equipment manufacturer’s
suggested start-up sequence. The entire system was flushed
with methanol for 5 min at a flow rate of 1 mL / min on each
pump. The flow rate of pump A was then decreased to 0.34 mL
Scheme 2 Monitoring an alkylation reaction
/
min and that of pump B decreased to 0.66 mL / min (giving a
combined flow rate of 1.0 mL / min) and the reactor coil heated
to 20 °C. Once at the target temperature, the flow was then
changed from solvent to reagents by means of a switch on the
flow unit. Solution A was pumped by pump A and solution B
by pump B. The reaction mixture was then flowed through the
reactor coil. After 15 min, an aliquot of the product stream was
diverted to the spectrometer and the NMR spectrum recorded.
The temperature was then increased to 40 °C and, once at
temperature and after at least one reactor volume of reagents
had passed through the coil, the NMR spectrum was again
recorded. The process was repeated across a range of
temperature values. Once the trial was complete, the flow was
changed back to solvent and the system run until the remainder
of the reaction mixture has passed through the entire
configuration. Once all the product had exited the unit, heating
was ceased and, once the reactor coil had returned to room
temperature, the flow of methanol solvent was stopped.
Conclusions
In summary, we have interfaced a low-field benchtop NMR
spectrometer with a mesofluidic reactor, allowing us to monitor
reactions and optimize reaction conditions in a streamlined
manner. We show the application of the apparatus in four
synthetic organic transformations. Reactions need to be
performed at relatively high concentration in order to be able to
monitor them effectively using the NMR spectrometer. This
however allows us to leverage one of the key benefits of flow
chemistry, namely process intensification. By positioning the
NMR spectrometer directly after the back pressure regulator,
we are not only able to monitor reactions without the need for a
specially engineered flow cell but also can probe the effect of
temperature on the outcome of the reaction without issue. In
future work we will explore further the application of this
benchtop NMR spectrometer for process control and
optimization of a broader range of medicinally and industrial
relevant transformations performed using flow approaches.
Base-catalysed Knoevenagel reaction
Two stock solutions were prepared – Solution A: benzaldehyde
Experimental section
(
21.224 g, 200 mmol, 2 M) and ethyl acetoacetate (26.028 g,
00 mmol, 2 M) in ethyl acetate (total volume 100 mL);
2
Apparatus configuration
Solution B: piperidine (1.703 g, 20 mmol, 0.2 M) in ethyl
acetate (total volume 100 mL). An identical approach to that for
the esterification was taken with the exceptions that ethyl
acetate was used in the place of methanol for priming and
flushing the system, and that the flow rate of pumps A and B
was set at 0.5 mL / min (combined flow rate of 1.0 mL / min)
for the trials across a range of temperatures.
The benchtop NMR spectrometer used was a Thermo Scientific
picoSpin 80 Series II tuned at 82.699017 MHz for H with the
permanent magnet at 36 °C. Spectra were recorded using 10
scans, 3072 data points, 8 s relaxation delay, and a -8.6° pulse
1
of 45
µs. The continuous-flow unit used was a Vapourtec E-
series equipped with three pumps and, in the configuration used
here, interfaced with one PFA reactor coil of total internal
volume of 10 mL. The spectrometer was interfaced with the
flow unit after the back-pressure regulator by attaching to the
Diels-Alder reaction
Two stock solutions were prepared – Solution A: maleic
anhydride (47.718 g, 487 mmol, 6.3 M) in acetonitrile (total
volume 77 mL); Solution B: isoprene (65 mL, 650 mmol, 5.9
M) in acetonitrile (total volume 110 mL). Given the low boiling
point of isoprene, solution B was kept in an ice bath. An
identical approach to that for the esterification was taken with
“
waste” port of the waste / collect valve using 1mm i.d. PFA
tubing. Material was loaded in to the spectrometer by diverting
the flow from “collect” to “waste”. During a reaction, spectral
data was recorded at pre-determined time intervals using
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the exception that acetonitrile was used in the place of methanol
for priming and flushing the system, and that the flow rate of
pumps A and B was set at 0.5 mL / min (combined flow rate of
1
.0 mL / min). When probing the effect of flow rate on the
reaction, the temperature of the reactor coil was set constant at
5 °C.
7
Alkylation reaction
Two stock solutions were prepared
–
Solution A:
salicylaldehyde (21 mL, 197 mmol, 2.0 M) and DBU (45 mL,
01 mmol, 3.0 M) in acetonitrile (total volume 100 mL);
3
Solution B: 1-bromobutane (32 mL, 298 mmol, 3.0 M) in
acetonitrile (total volume 100 mL). An identical approach to
that for the esterification was taken with the exception that
acetonitrile was used in the place of methanol for priming and
flushing the system, and that the flow rate of pumps A and B
was set at 0.5 mL / min (combined flow rate of 1.0 mL / min).
C. V. Stevens, Org. Process. Res. Dev. 2013, 17, 760-791. (e) D. T.
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1
4583-14609. (c) W. Ferstl, T. Klahn, W. Schweikert, G. Billeb, M.
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We gratefully acknowledge financial support from the National
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