Anal Bioanal Chem (2017) 409:7223–7234
https://doi.org/10.1007/s00216-017-0686-y

RESEARCH PAPER

Desktop NMR spectroscopy for real-time monitoring of an
acetalization reaction in comparison with gas chromatography
and NMR at 9.4 T
Kawarpal Singh 1

1& Ernesto Danieli & Bernhard Blümich

1

Received: 11 July 2017 / Revised: 18 September 2017 / Accepted: 29 September 2017 / Published online: 13 October 2017
# Springer-Verlag GmbH Germany 2017

Abstract Monitoring of chemical reactions in real-time is indemand for process control. Different methods such as gas chromatography (GC), mass spectroscopy, infrared spectroscopy,
and nuclear magnetic resonance (NMR) are used for that purpose. The current state-of-the-art compact NMR systems provide a useful method to employ with various reaction conditions
for studying chemical reactions inside the fume hood at thechemical workplace. In the present study, an acetalization reaction was investigated with compact NMR spectroscopy in realtime. Acetalization is used for multistep synthesis of the varietyof organic compounds to protect particular chemical groups. A
compact 1 T NMR spectrometer with a permanent magnet was
employed to monitor the acid catalyzed acetalization of the pnitrobenzaldehyde with ethylene glycol. The concentrations ofboth reactant and product were followed by peak integrals insingle-scan 1H NMR spectra as a function of time. The reaction
conditions were varied in terms of temperature, agitation speed,
catalyst loading, and feed concentrations in order to determine
the activation energy with the help of a pseudo-homogeneous
kinetic model. For low molar ratios of aldehyde and glycol, theequilibrium conversions were lower than for the stoichiometricratio. Increasing catalyst concentration leads to faster conversion. The data obtained with low-field NMR spectroscopy werecompared with data from GC and NMR spectroscopy at 9.4 T
Electronic supplementary material The online version of this article(https://doi.org/10.1007/s00216-017-0686-y) contains supplementarymaterial, which is available to authorized users.

acquired in batch mode by extracting samples at regular timeintervals. The reaction kinetics followed by either method
agreed well. The activation energies for forward and backward
reactions were determined by real-time monitoring with compact NMR at 1 T were 48 ± 5 and 60 ± 4 kJ/mol, respectively.
The activation energies obtained with gas chromatography forforward and backward reactions were 48 ± 4 and 51 ± 4 kJ/mol.
The equilibrium constant decreases with increasing temperature
as expected for an exothermic reaction. The impact of dense
sampling with online NMR and sparse sampling with GC wasobserved on the kinetic outcome using the same kinetic model.
Keywords Compact NMR spectroscopy . Reaction
monitoring . Acetalization . Kinetic model . Gas
chromatography . Activation energy . High-field NMR

Abbreviations
1D
One-dimensional
CDCl3 Deuterated chloroform
EG
Ethylene glycol
FID
Free induction decayGC
Gas chromatographymM
Millimolar
NMR
Nuclear magnetic resonanceppm
Parts per million
PTFE Polytetrafluoroethylene
RPM
Rotations per minute
RTD
Residence time distribution* Kawarpal Singh
Singh@itmc.rwth-aachen.de

Introduction
1

Institut für Technische Chemie und Makromolekulare Chemie,
RWTH Aachen University, Worringerweg 1,52074 Aachen, Germany

Optimization of chemical processes is of central importance inprocess engineering. Efficiency, stability, information content,

7224

economy, etc. are the parameters which are normally desiredfor choosing an analytical method. Depending upon the typeof information required, different methods such as chromatography, mass spectrometry, calorimetry, gravimetric analysis,
spectroscopy, etc. are used for chemical process engineering.
Nuclear magnetic resonance (NMR) is a unique analyticaltechnique, because it is quantitative [1]. No calibration is required under correct acquisition conditions. This makes it particularly interesting for reaction monitoring. NMR spectroscopy is generally used for determining the structure, conformation, purity, percentage yield, and kinetic isotope ratio of
the reaction products in synthetic as well as in natural productchemistry [2]. Usually, a chemical reaction can be monitored
in three ways: (a) at-line, (b) batch wise, and (c) online. In atline reaction monitoring, the chemical reaction proceeds inside the NMR tube as a batch following addition of the reaction components and mixing them by simply shaking the tube
for a while. After insertion into the spectrometer, the reaction
mixture needs to settle for some time to avoid convection
before the NMR observation can begin. Spectra of the reaction
mixture are then recorded in regular time intervals to follow
the reaction progress. In batch mode reaction monitoring, thechemical reaction is conducted outside the analytical instrument such as the NMR spectrometer. Aliquots are taken fromthe reaction mixture in suitable time intervals and prepared assolutions for analysis in a laboratory, for which NMR spectrometers are normally distant from the chemical synthesis
laboratory. In online monitoring, the chemical reaction is performed outside the magnet and the reaction mixture is flown
continuously through the magnet using the suitable tubing at adesired flow rate. Spectra of the flowing mixture are recorded
in regular time intervals depending upon the T1 relaxation
time of the slowly decaying component in the reaction mixture
to obtain the spectrum under equilibrium conditions.
Monitoring a reaction in batch mode has two disadvantages;
one is the limitation of the time resolution by the rate ofcollecting aliquots, and the other is the need to quench thereaction in the aliquots. Quenching often demands particularsolvents, reagents, and separation processes such as centrifugation. None of these applies to online monitoring as long as
sensitivity and speed of measurement are compatible with thereaction. Special setups have been designed for reaction monitoring using high-field NMR spectroscopy in dedicated laboratories. These setups include rapid injection [3] and stopped
flow operations [4] in order to transfer the reaction mixture
quickly into the magnet. In recent years, reaction monitoring
techniques have been developed by which a reaction mixture
can be passed through conventional 5-mm-diameter sample
tubes inside a superconducting magnet [5–7].
Today’s state-of-the-art spectrometers provide superiorsensitivity and resolution so that a wider range of chemical
reactions can be studied. Until recently, all modern NMR
spectrometers were equipped with superconducting magnets,

Singh K. et al.

which enable high magnetic fields, for high sensitivity andhigh chemical-shift dispersion. Most of these magnets are
too large and delicate to operate within an ordinary chemical
synthesis laboratory. Moreover, they demand expert training
for operation and maintenance, as well as the budget for cryogenic cooling. Apart from operational complexity, these large
magnets necessitate long tubes to loop the reactant from thereactor through the magnet, which delay the time between
reaction and measurement, and limit the time resolution byflow dispersion. As a partial solution to these problems, flow
cells which are optimized to the flow regime and NMR relaxation times [8] can be used to obtain spectra with the best
possible sensitivity and resolution. Nevertheless, due to thelong time delay of the fluid looping through the magnet, thedifference in reaction parameters for the reaction mixture inside the reactor and the reaction mixture inside the NMR magnet can impact the information derived from the NMR spectra.
Consequently, mostly slow reactions are monitored at ambientconditions with such instruments [9]. Multiphase reactions
present a particular challenge, because they need to be continuously agitated to remove the mass transfer resistance. While
there is no general solution to these issues today, small andcompact NMR spectrometers with permanent magnets aremaintenance free, can be set up in the chemistry laboratory,
and require much shorter feed lines [10]. Despite their lower
field strength, they give sufficient sensitivity and spectral dispersion and bear promise to alleviate many of the challenges
mentioned above.
With desktop NMR spectrometers, the delay from sample
preparation to spectrum analysis can be shortened to a few
minutes when setting up the spectrometer in the chemistrylaboratory. As an alternative to thin-layer and gas chromatography, compact NMR spectroscopy [11] can serve to monitor
chemical reactions in a simple and accurate way [12, 13],
especially when the initial reaction rates are critical. Because
the measurement happens in real time, the NMR parameters
can be employed to control the reaction conditions andkinetics.
Gas chromatography (GC) is a very stable, sensitive, andstandard method used in process engineering where very few
microliters of the sample are required to perform the measurement [14]. Helium or nitrogen need to be used as a carrier gas
for the mobile phase. The stationary phase has to be chosen tosuit the particular samples in order to avoid detrimental chemical interactions with the sample. The measurement times of
the GC can be long depending upon the retention time of thereactants, products, and intermediates. On the other hand, thechemical shift range for 1H nuclei lies within the range of 0 to
12 ppm which is usually sufficient for detecting the 1H nuclei
from reactants, products, and intermediates using 1H NMR
spectroscopy. The sensitivity of table top NMR spectrometers
suffices to acquire a 1H NMR spectrum in a single shot in 15 s.
Online NMR provides densely sampled data compared to GC

Desktop NMR spectroscopy for real-time monitoring of an acetalization reaction in comparison with gas...

which provides sparsely sampled data, therefore densely sampled data can provide more reliable kinetic information thansparsely sampled data. NMR is a calibration-free method because of the linearity between the absolute signal area to thenumber of spins and sample concentration. Compact NMR
systems do not require any helium filling. In terms of stability
and sensitivity, GC measurements are similarly stable andaccurate b ut more sensitive t han compact NMR
measurements.
Acetalization reactions are used in a variety of chemical
syntheses to protect functional groups in the chemistry of carbonyl compounds and intermediate products [15]. Aldehydes
are unstable in alkaline conditions and the carbonyl groups
need to be protected against the reduction from nucleophilicgroups. Carbonyl compounds can be converted via
acetalization into many other functional groups, such as acyclic and cyclic acetals (1, 3-dioxolanes), which serve as intermediates in chemical and biochemical syntheses [16].
Acetalization reactions produce major intermediates in thepolymer, fragrance, and pharmaceutical industries. Many biologically active compounds, which have aryl, alkyl, imidazole, triazole, pyrazole, benzimidazole, benzotriazole,oxypurine, pyrimidinyl, and naphtyl groups linked to a 1, 3dioxolane ring at positions 2, 4, or 5 are important to thepharmaceutical industry, because of their use in antifungal,
antibacterial, antineoplastic, and antiviral drugs [17].
Depending on the structure of the substrate molecule, eachcompound exhibits different properties. Acetals are used forincreasing the cetane number of fuel, for example as diesel
additives, in order to improve the combustion by shortening
the ignition delay [18]. Moreover, 1,3-dioxolanes are used inelectrolytes of batteries [19]. Different methods and strategies
have been followed to produce 1,3-dioxolanes and monitor
their syntheses [20, 21]. 1,3-Dioxolanes (cyclic acetals) areusually formed from benzaldehyde or other aromatic aldehydes by reaction with ethylene glycol in the presence of acidcatalysts [22]. This path involves a cyclic ring formation,
which favors formation of the product rather than return tothe reactant.
Reliable kinetic and thermodynamic data are available for
acetalization reactions, studied with gas chromatography [23,24]. This work reports the kinetics of an acetalization reaction
monitored with a compact NMR spectrometer at 1 T in comparison with gas chromatography and NMR at 9.4 T. An efficient and easy way is presented to monitor the acetalization
reaction and analyzing it by controlling different reaction parameters, such as temperature, catalyst concentration, initial
reactant concentrations, and agitation speed. The reaction kinetics, order, equilibrium conversion, equilibrium conditions,and activation energy are interpreted in terms of a pseudohomogeneous kinetic model. The results obtained are compared with results from gas chromatography and NMR spectroscopy at 9.4 in batch mode, showing very good agreement.

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Materials
Ethylene glycol, p-nitrobenzaldehyde, p-toluenesulphonic acid, sodium bicarbonate, and sodium chloride were purchasedfrom Sigma Aldrich Chemie GmbH, Steinheim, Germany.
Toluene was purchased from Th. Geyer GmbH and Co. KG,
Renningen, Germany. Acetone and isopropanol were obtained
from the chemical shop of RWTH Aachen University. 2-(4Nitrophenyl)-1, 3-dioxolane was synthesized by performing
the acetalization reaction in the laboratory at ITMC. The synthetic procedure is given in the supplementary information.

Experimental
Acetalization reaction
The acid-catalyzed acetalization of p-nitrobenzaldehyde (1) with
ethylene glycol (2) (Scheme 1) was studied in the temperature
range from 333 to 370 K for the synthesis of 2-(4-nitrophenyl)1, 3-dioxolane (3). In each experiment, p-nitrobenzaldehyde(0.55 mol L−1) and p-toluene sulfonic acid monohydrate
0.2 wt% were dissolved in 150 ml toluene (solvent) containedin a 500 ml three-necked round-bottom flask. After proper
mixing, ethylene glycol (0.55 mol L−1) was added with a syringe. The solution was refluxed with a condenser. The reaction
mixture was stirred at a rate of 200 RPM with the mechanicalstirrer to avoid mass transfer effects due to the viscous behaviorof ethylene glycol at room temperature and at lower stirring
speeds. During each measurement, 2 ml of sample were takenwith a syringe after different time intervals at 2, 5, 10, 15, 25, 35,
45, 60, 90, 100, 150, 210, 270, 360 min and so on depending
upon the reaction time. Each sample was quenched with 4 ml ofsaturated solution of sodium bicarbonate. The resultant solution
was shaken for a while and then added to the separating funnel.
In the separating funnel, saturated solution of sodium chloride(4 ml) was added and then shaken again. After some time, thesolution separates into two phases. The lower layer contains theunreacted ethylene glycol and water, and upper layer contains
toluene, unreacted reactant (p-nitrobenzaldehyde), and product(2-(4-nitrophenyl)-1, 3-dioxolane). The lower layer was taken
away and the upper layer was used for the batch analysis withgas chromatography and NMR spectroscopy at 9.4 T.

Online NMR setup for compact NMR spectroscopy
A compact NMR spectrometer (Magritek Spinsolve) was
employed for studying the acetalization of the pnitrobenzaldehyde with ethylene glycol to yield 2-(4-nitrophenyl)-1, 3-dioxolane at different temperatures ranging from 333
to 370 K (Fig. S1).

7226

Singh K. et al.

Scheme 1 Overall reaction
between p-nitrobenzaldehyde andethylene glycol

Flow setup and temperature
The reaction mixture was circulated through the NMR magnet(Fig. 1a) with a specially designed flow cell of 5 mm outer
diameter in the center near the sensitive volume and 1 mm
outer diameter away from the center (Fig. 1b). The flow cell
was connected to PTFE (polytetrafluoroethylene) tubing of
1/16″ OD and 1 mm ID. The tubing was inserted into thereactor and connected to a peristaltic pump forming a closed
loop through the NMR spectrometer. The reactants which are
not completely miscible when present in the reactor require
rigorous stirring. The rigorous stirring cannot be performed
using at-line NMR procedures, which are usually employedwith high-field NMR. Therefore, online NMR involving thereactor outside the magnet enables complete dispersion andmixing of the reaction mixture. The reaction mixture wasflowing inside the magnet at the magnet temperature of
301.5 K, while the reactor temperature was set at the desired
temperature range with the aid of heater. The temperaturefluctuation in the reactor was 0.9 K due to fluctuation in thetemperature of the heater from the surroundings. The reaction
mixture was cooled down to the temperature of the magnet bymaking 2 cm diameter coils of the PTFE tubing and immersing them in cold water. Because the reaction time was longcompared to the time required for the measurement after lowering the temperature, it can be assumed that the reaction
kinetics are hardly affected. The data obtained from gas

chromatography and NMR spectroscopy at 9.4 T validate thisassumption. The reaction mixture was pumped with the aid ofa three-channel peristaltic pump (ISMATEC® Relgo) at aflow rate of 0.65 ml/min. After each reaction, the tubing waswashed with acetone to remove residual reaction mixture adhering to the walls. Subsequently, the tubes were rinsed withtoluene to ensure the removal of any droplets of acetone.
Delay times
The time between a change in the composition of the reaction mixture in the reactor and corresponding change in thesignal amplitude of the NMR signal is the important parameter that needs consideration for monitoring the reaction
kinetics. The time which the reaction mixture takes fromthe reactor to the active region is the transfer time denotedby ttrans. The reaction mixture fills the active volume staring
from its tracer concentration to the stationary value. The
time it takes is denoted by tdelay. The difference between
ttrans and tdelay is called dwell time tdwell [25]. For obtaining
the reliable NMR data, it is required to completely replace
the solution in the NMR probe with the fresh sample. The
transfer time ttrans was determined to be 66.4 s. The delay
time of 126.5 s and dwell time of 60.5 s was used for thepresent reaction which is very short compared to the reaction time.
Non-ideal flow of the sample from the chemical reactor
to the sensitive volume of the NMR results from backmixing, stagnant regions, and spreading of the sample atdifferent positions during the flow (Fig. S2). This behaviorof the liquid in the pipes is described by the residence time
distribution (RTD) profile. The RTD profile was determined at 0.65 ml/min flow rate using the step tracer experiment with acetone and isopropanol solution where 3% acetone solution in isopropanol was replaced with pureisopropanol to see the concentration step produced in thereactor and the NMR signal. The mean residence time t res
was determined to be 96.6 s. The tdwell can also be determined from the relation of tres and tdwell following Eq. 1.
t res ¼ t trans þ tdwell=2

Fig. 1 Experimental setup. a Compact 1 T NMR spectrometer andreaction set-up inside the fume hood. b Flow cell to pass the reaction
mixture though the magnet

ð1Þ

From the knowledge of the RTD function, the timedependent concentration changes in the reactor Sreact(t)Desktop NMR spectroscopy for real-time monitoring of an acetalization reaction in comparison with gas...

7227

can be reconstructed from the NMR signal SNMR (t) byfollowing Eq. 2.
S react ðt Þ ¼ S NMR ðt þ t res Þ

ð2Þ

The data lost before the first measurement within t̄res = 2 minwere extrapolated from seven measurements with an accuracyof ± 2%.
Polarization length
The pre-polarization volume of the reaction mixture needs tobe studied for the reaction optimization. Pre-polarization volume is the volume of the reaction mixture inside the magnet
which should be pre-polarized enough to monitor the reaction
under equilibrium conditions depending upon the longitudinalrelaxation times of the components of the reaction mixture.
The variation of signal amplitude of the mixture of pnitrobenzaldehyde and 2-(4-nitrophenyl)-1, 3-dioxolane intoluene was studied with different flow rates. The T1 relaxation times of the different components of the reaction mixture
were evaluated (Figs. S3 and S4). The pre-polarization lengthof 170 mm was determined by simulating Eq. 3 [26].


Lpol
S
ð3Þ
¼ 1−exp −vT 1
S0
S0 is the signal amplitude under equilibrium conditions when
(tr → ∞, V → 0), i.e., at longer pulse repetition time and at zeroflow rate. The flow rate under equilibrium conditions was
0.65 ml/min under the maximum T1 time of 3.3 s which belongs to 1,3-dioxo protons in the 2-(4-nitrophenyl)-1, 3dioxolane (Fig. S5). The pre-polarization length Lpol was determined from the change in signal amplitude of the –CH3
isopropanol with flow rate (Fig. S6).

Fig. 2 1D 1H NMR spectra of pure components of the acetalization
reaction at 1 T. a para-Nitrobenzaldehyde (1). b Ethylene glycol (2). c
2-(4-nitrophenyl)-1, 3-dioxolane (3)acquisition times of several hours without substantial change
in the signal amplitude (Fig. S7).
Data acquisition
A single-scan free induction decay (FID) was measured every
15 s from the beginning to the end of the reaction using a43.2 MHz (1 T) Magritek Spinsolve NMR spectrometer.
Each spectrum used a π/2 excitation pulse of 7 μs, an acquisition time of 6.6 s, an acquisition bandwidth of 5 kHz, anddwell time of 200 μs with 32,768 data points.
Data processing
The original FID data were recorded and saved by the spectrometer software. The saved data were processed andShim procedure and shimming stability
Protonated solvent with 10 wt% of water in D2O was used as
shimming sample to shim the spectrometer with the automatic
shimming procedure given in the spectrometer software. Theline width observed after shimming was 0.5 Hz. When usedevery day, it takes 2.5 min to shim the magnet with the loworder shims. When used only occasionally, shimming all orders may take 40 min. Shimming can also be performed during the reaction on representative large peaks in the reaction
mixture. The B0 field is stabilized by an external lock together
with the software lock which adjusts the ppm scale following
the field drift. The shim was stable during all the reactions
performed. No drift was observed during either experiment.
The system was monitored by continuously flowing methanol
for 24 h to see the drift in the field and change in the signal
amplitude. The magnetic field B0 was stable enough to realize

Fig. 3 1D 1H NMR spectra of pure components of the acetalization
reaction at 9.4 T. a para-Nitrobenzaldehyde (1). b Ethylene glycol (2).
c 2-(4-nitrophenyl)-1, 3-dioxolane (3)7228Singh K. et al.

Fig. 4 Stack plot of spectra
acquired during 100 min of thereaction of p-nitrobenzaldehyde(0.55 mol L−1) and p-toluene
sulfonic acid monohydrate
0.2 wt% dissolved in toluene(solvent) and ethylene glycol(0.55 mol L−1) at a temperature of
370 K with an agitation speed of
200 RPManalyzed with MestreNova® (Mestrelab Research S. L.,
Santiago de compostela Spain) 11.0 software. All the spectra
were aligned using the reference alignment tool in MNova.
The –CH3 peak of toluene at 2.3 ppm was used as a reference
to align the NMR spectra. The integration range was set byconsidering the line width and neighboring peaks of the desired signal using sum method. The exponential apodizationof 0.6 Hz was used to increase the resolution. The values
obtained for the signal amplitude as a function of the reaction
time were transferred to Origin® 9.0 to plot the graphs. The
different values of the reaction rate constants for real-time
NMR and gas chromatography were evaluated with theRunge-Kutta fourth-order method using Matlab.

nitrobenzaldehyde and 1,3-dioxolane. The lower layer was
removed and the upper layer was used for quantification.
Each NMR sample was prepared in a 5 mm NMR tube byadding 0.05 ml of sample into 0.5 ml of deuterated chloroform. Each sample was measured at 9.4 T with 16 scans in
1.5 min.
The calibration samples were prepared with knowledge oflimits of detection and quantification at 1 (Fig. S8) and 9.4 T(Fig. S9) with known concentrations of p-nitrobenzaldehyde
and 1,3-dixolane. Data for the calibration curves are given in
the supplementary information.

Gas chromatography
High-field NMR spectroscopy at 9.4 T
During the course of the reaction, aliquots of 2 ml were extracted with a syringe at different time intervals. The samples
obtained were quenched with saturated solution of sodium
bicarbonate (NaHCO3). The resultant solution was shaken
for 5 min before transferring to the separating funnel for separating the aqueous and organic layers. The solution waswashed with brine. The lower aqueous layer contained ethylene glycol and water, and upper layer contained unreacted p-

Fig. 5 Variation of 1H NMR peak integrals with time at 370 K for
300 min. The reactant signal of the aldehyde proton decreases while theproduct signal of the acetal proton increases

The same samples obtained by quenching the reaction mixture
were used for the gas chromatographic measurements withhigh-purity helium at a flow rate of 1.5 ml/min. A ThermosScientific TRACE 1 gas chromatograph with flame ionization
detector (FID) was used with CP-Sil-Pona column capillary of
50 m length. The retention time of p-nitrobenzaldehyde and1,3-dioxolane were 12.6 and 18.1 min, respectively.
The calibration samples were prepared with known concentrations of p-nitrobenzaldehyde and 1,3-dixolane with given concentration of each component and area (Fig. S10). The

Fig. 6 Repeatability measurements after intervals of days and months forthe acetalization reaction at 333 K

Desktop NMR spectroscopy for real-time monitoring of an acetalization reaction in comparison with gas...

7229

complete agreement with each other. Peaks corresponding todifferent chemical groups can be easily distinguished at 1 T in
spite of low field strength.
Real-time monitoring of the acetalization reaction with 1D
1
H NMR spectroscopy

Fig. 7 Effect of catalyst loading on the concentration of the product interms of the concentration of the acetal proton versus the reaction timedetails of calibration curves are given in the supplementary
information.

Results and discussion
1D 1H NMR spectra at 1 and 9.4 T for the acetalization
In the acetalization reaction, the 1D 1H NMR spectra of pnitrobenzaldehyde (1) at 1 (Fig. 2a) and 9.4 T (Fig. 3a) showed
the peaks of the aldehyde proton at 10.4 ppm. The two aromatic protons close to the –NO2 group showed a multiplet centeredat 8.3 ppm and the other two protons close to the -CHO group
appeared at 8 ppm (Fig. 2). 1D 1H NMR spectrum of ethylene
glycol (2) showed a single peak corresponding to the hydroxyl
proton at 5.4 ppm and a single peak for the –CH2-CH2- groupat 3.7 ppm at 1 (Fig. 2b) and 9.4 T (Fig. 3b). The 1D 1H NMR
spectrum of 2-(4-nitrophenyl)-1, 3-dioxolane (3) showed a single peak corresponding to the acetal proton at 5.8 ppm. A
single peak corresponding to the four protons in the 1,3-dioxogroup appeared at 4 ppm at 1 T (Fig. 2a) while a multiplet
centered at 4 ppm was observed at 9.4 T (Fig. 3a). The two
aromatic protons adjacent to the 1, 3-dioxo group appeared at
7.56 ppm and the two protons near to the –NO2 group at
8.14 ppm. The 1D 1H NMR spectra at 1 and 9.4 T are in

Fig. 8 Variation of the reaction
rate for different molar ratios of
the reactants. a The ethylene
glycol concentration was varied
and the p-nitrobenzaldehyde
concentration was kept constant.
b The ethylene glycol
concentration was kept constantand the p-nitrobenzaldehyde
concentration was varied

The concentrations of reacting components in the mixture
vary as the reaction progresses. This variation is followed ina stack of spectra (Fig. 4), where each spectrum was acquiredin 15 s one after the other. Corresponding to the low-field
NMR spectra of the reactants and products described in the
B1D 1H NMR spectra at 1 and 9.4 T for the acetalization^section, the real-time NMR data reveal that the peak integrals(concentration) of the aldehyde proton in the pnitrobenzaldehyde (reactant) at 10.4 ppm decrease, and thepeak integrals of the 1,3-dioxo and acetal protons near 4 and
5.8 ppm, respectively, increase with the formation of the product (Fig. 5). Their time dependence can be modeled to extract
the parameters describing the reaction kinetics.
Toluene is used as a solvent whose concentration is 19
times higher than the other analytes. Reactions, which proceed
in protonated solvents at high concentrations, are very difficult
to monitor at low field due to low chemical shift resolution.
But because the lines are narrow due to the excellent field
homogeneity of the instrument, the changing peak integralsof the prominent acetal and carbonyl protons can readily befollowed in the stack of spectra acquired during the course of
the reaction as a function of the reaction time in addition to theslight changes in chemical shift of the peaks corresponding to
the aromatic protons in the p-nitrobenzaldehyde and 2-(4-nitrophenyl)-1, 3-dioxolane near 8 ppm which are occurring
during the reaction.
Repeatability: effect of system stability
Stability of the system is essential for quality control in process engineering applications. The acetalization reaction was
repeated at 333 K in the interval of days and months in order7230

Singh K. et al.

Fig. 9 Kinetic model fitted withthe experimental results
calculated by following theconcentration of the acetal protonof the 2-(4-nitrophenyl)-1, 3dioxolane (product). a Online
NMR at 1 T. b Gas
chromatography

to see the impact of system stability on reaction kinetics. The
NMR spectrometer was shimmed every time before starting
the reaction using the automatic shim routine given in the
instrument software. The system showed excellent repeatability (Fig. 6).

Mass transfer resistance: effect of stirring speed
Low stirring speeds and viscous mixtures are most unfavorable candidates responsible for resistance to external masstransfer. Vigorous stirring was necessary to achieve a homogeneous mixture of the reaction components which could not
be obtained at lower stirring speeds because of the viscosity of
ethylene glycol. Also, elimination of mass transfer resistanceis important for studying the reaction rate in order to ensurethat the rate of the reaction is not influenced by energy required for transfer of molecules from one phase to the other.
The reaction mixture was stirred mechanically at rates varying
from 200 to 400 RPM at a reaction temperature of 333 K with
0.2 wt% of p-toluene sulphonic acid as catalyst. The reaction
rate turned out to be essentially independent of the stirring
speed above 200 RPM. After ensuring the absence of masstransfer resistance, all experiments were carried out at
200 RPM (Fig. S11).

Effect of catalyst loading
The amount of catalyst is an important parameter which influences the conversion rate of the reaction. The impact of catalyst concentration was studied by varying the amount of ptoluene sulphonic acid (catalyst) from 0.2 to 1.6 wt%. With
increasing amount of catalyst, the reaction rate increases. The
more active catalyst sites are available to assist the protonationof the carbonyl oxygen of p-nitrobenzaldehyde, the faster isthe reaction. Because the protonation of the carbonyl carbon iscontrolled by the proton in the p-toluene sulphonic acid catalyst, the concentration of the 1,3-dioxo group of the productincreases with increasing catalyst amount at a particular time
(Fig. 7). The higher the catalyst loading, the higher is the rateof conversion.
Effect of feed composition
The impact of the reactant concentrations on the reaction
kinetics was studied by varying the ratios of the initialconcentrations of p-nitrobenzaldehyde and ethylene glycol
as 0.5:1, 0.75:1, and 1:1 as well as 1:0.5, 1:0.75, and 1:1.
The reaction rate decreases as the concentrations deviate
from the stoichiometric ratio of the reactants (Fig. 8). As aresult, the equilibrium conversion decreases from 90 to
65.6 to 49.4% for decreasing the initial concentration of
p-nitrobenzaldehyde while keeping the concentration of
ethylene glycol constant equal to its stoichiometric concentration. Similarly, the equilibrium conversion decreases
Table 1 Rate constants for the reaction at temperatures ranging from333 to 370 K using real-time NMR at 1 T
T[K]

Fig. 10 Evolution of the acetal protons of product peaks with time fortemperatures ranging from 333 to 370 K at 200 RPM agitation speed and
0.2 wt% catalyst concentration

k1* 10−3 95% confidence k2 × 10−5 95% confidence R2interval × 10−3interval × 10−6

333 1.89
345 4.51
358 7.04
370 11.5[1.86, 1.91][4.37, 4.56][6.83, 7.17][11.2, 11.8]

1.52
3.86
6.81
1.47

[1.51, 1.55][2.64, 3.96][5.15, 7.10][13.8, 15.0]

0.9576
0.97180.9461
0.9846

Desktop NMR spectroscopy for real-time monitoring of an acetalization reaction in comparison with gas...

7231

Fig. 11 Arrhenius plots of therate constants of the forward (a)and backward (b) reactions using
online NMR at 1 T from which
the activation energies were
determinedfrom 90 to 70.9 to 47.4% when varying the initial concentration of ethylene glycol while keeping the initial concentration of p-nitrobenzaldehyde constant to stoichiometricconcentration.
Modeling of the kinetic data
After ensuring the absence of mass transfer resistance, a kinetic model [27, 28] can readily be developed to extract thereaction rate constants from which the activation energy canbe estimated by fitting model expressions to the timedependent concentration data of the acetal protons present in
the 2-(4-nitrophenyl)-1,3-dioxolane product (Fig. 9). From thedata obtained by varying the temperature between 333 and370 K, the activation energy of the reaction was estimated.
A pseudo-homogeneous kinetic model was used for
obtaining the rate constants. The overall reaction between pnitrobenzaldehyde (C7H5O3N) and ethylene glycol (EG) in
the presence of toluene as a solvent and p-toluene sulphonicacid as a catalyst (Scheme 1) yields 2-(4-nitrophenyl)-1, 3dioxolane (DIOX) and water (H2O). Considering the timedependent reactant concentrations [C7H5O3N] and [EG], andthe initial product concentrations½DIOX0 ¼ 0 ¼ ½H2 O0ð4Þ

where [] is the concentration of the compound Bi^ in mol L−1,
w is the catalyst concentration in wt%−1
cat , and k1 and k2 are thereaction rate constants for the forward and the backward reactions in L2 mol−1 min−1 wt%−1
cat . In the absence of side reactions,the concentrations of the other species are calculated by massbalance as½EG ¼ ½EG0 −½DIOX;ð6Þ½C7 H5 O3 N ¼ ½C7 H5 O3 N0 −½DIOX;ð7Þ

½H2 O ¼ ½DIOX:ð8Þ

The differential Eq. (5) was solved by fourth-order RungeKutta integration along with the initial conditions (4) and themass balances (6, 7, and 8) using MATLAB.
The validity of the mass balance was verified by integrating
the peaks of both reactants and products and forming the sum,which remained constant during the whole course of the reaction. The rate constants were determined by minimizing thesum of the square of the difference between the experimental
and predicted concentrations. The 95% confidence intervals
for the rate constants of each reaction were calculated from1000 iterations to estimate the variation in the reaction kinetics
following a Monte-Carlo approach.

and the formation rate of the dioxolane product is written as
d½DIOX
¼ wk 1 ½EG½C7 H5 O3 N−wk 2 ½DIOX½H2 O;
dt

ð5Þ

Table 2 Rate constants for the reaction at temperatures ranging from333 to 370 K using gas chromatographyT
k1 × 10−3 95% confidence k2 × 10−5 95% confidence R2[K]interval × 10−3interval × 10−5
333 1.86
345 4.10
358 6.84
370 10.7[1.82, 1.99][4.06, 4.13][6.71, 6.88][10.6,10.8]

1.38
3.19
5.13
9.33

[1.30, 1.47][2.73, 3.27][4.45, 5.45][8.24, 9.41]

0.99150.98730.98030.9832

Fig. 12 Comparison of online NMR at 1 T, batch NMR at 9.4 T, and gas
chromatography for the acetalization reaction at 370 K

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Singh K. et al.

Fig. 13 Evolution of the 1, 3dioxolane product peaks withtime for temperatures ranging
from 333 to 370 K at 200 RPM
agitation speed and 0.2 wt%
catalyst concentration. a Gas
chromatography. b High-field
NMR at 9.4 T

Effect of temperature: NMR spectroscopy at 1 T
To determine the activation energies of the forward and backward reactions, the reaction kinetics were studied at temperatures of 333, 345, 358, and 370 K using the stoichiometricfeed ratio. The reaction rates for both forward and backward
reactions increase with increasing temperature. It is observed
here that the reaction rate increases with increasing temperature (Fig. 10) as expected, but the final equilibrium conversion
is independent of temperature. This observation was associated to heat effects in the reaction. Guemez et al. [23], Agirre
et al. [27], and Silva et al. [28] have observed similar behavior
in the same acetalization studies. This effect implies that thewhole process has very low heat effects. According to thestandard heat of formation, the acetalization reactions are exothermic [23, 27, 28] including the one in the present study.
Nevertheless, it was observed that the heat of mixing between
different reactants aldehyde and glycerol and water (product)
is positive and the enthalpy of mixing between water and theformed acetal (product) is also positive showing endothermic
behavior. The increase in temperature decreases the equilibrium constant of the reaction which revealed the exothermic
behavior of the reaction (Table 1). The activation energies of
the reaction retrieved by real-time monitoring for the forward
and backward reactions turns out to be 48 ± 5 and 60 ± 4 kJ/
mol, respectively (Fig. 11).
Gas chromatography and high-field NMR at 9.4 T
Each reaction was followed simultaneously by real-time monitoring with compact NMR at 1 T and batch monitoring withgas chromatography and high-field NMR at 9.4 T by extracting
the samples after regular time intervals. The samples obtained
were quenched and the organic layer was separated from theaqueous layer. The results obtained with gas chromatography(Table 2) and high-field NMR confirm the reaction kinetics
obtained with the compact NMR at 370 K (Fig. 12) and at othertemperatures also (Fig. 13). The activation energies obtainedwith gas chromatography for forward and backward reactions
were 48 ± 4 and 51 ± 4 kJ/mol (Fig. S12). Each point in the

online-NMR measurement was obtained in 15-s intervals while
for GC, the points were obtained in irregular intervals from
5 min to several hours. Therefore, the data points sampled withNMR (~1200) are much denser than those acquired with GC(~15) and provide more reliable kinetic information thansparsely sampled data. The higher sampling density is particularly important in the beginning of the reaction when concentrations change rapidly. The rate constants evaluated by minimizing the sum of square of the difference between experimental and predicted concentrations are more accurate because theerror minimization is more reliable for a large number of data
points than a low number of data points.

Conclusion
Real-time reaction monitoring by NMR spectroscopy is simplified with compact NMR spectrometers that can be operated
on the laboratory bench. By example of an acetalization reaction, it is shown that the effects of parameters like temperature,
feed composition, catalyst loading, and agitation speed can bedirectly monitored in terms of time-dependent reactant andproduct concentrations with the conclusion, that desktop
NMR spectroscopy is an interesting tool to monitor, model,
and optimize chemical reactions. For the studied acetalization
reaction, the time-dependent concentrations of the various
groups involved during the reaction were followed in orderto estimate the equilibrium conversion in the acetalization
reaction. This knowledge is particularly important for optimizing multistep syntheses. Real-time monitoring serves this purpose and there is no need to extract the reaction mixture,
quench it, and then monitor the concentration of the chemical
constituents involved with off-line gas chromatography andhigh-field NMR methods, which require additional preparation steps such as quenching, phase separation, dissolution, or
centrifugation. Moreover, no deuterated solvents were needed
for the NMR measurements due to the external lock in the
spectrometer, and the magnet remained shimmed without field
drift throughout an entire observation period of over 2 h.
Deuterated solvents can also give rise to kinetic isotope effects

Desktop NMR spectroscopy for real-time monitoring of an acetalization reaction in comparison with gas...

which would lead to changes in reaction kinetics. Gas chromatographic measurements are time consuming due to longer
retention times of the chemical species involved in the reaction both reference methods need cryogenic coolants.
The data from the three methods showed excellent agreement. The experiment at 333 K was repeated three times overthe duration of 15 days and 6 months in order to see therepeatability of the reaction and reproducibility of the instrument. No variation of instrument performance could be detected. The results agreed excellently well. The activation energies for forward and backward reactions that were determined by real-time monitoring were 48 ± 5 and 60 ± 4 kJ/
mol, respectively. The activation energies obtained with gas
chromatography for forward and backward reactions were
48 ± 4 and 51 ± 4 kJ/mol. The kinetic parameters derived fromdensely sampled data and sparsely sampled data showed differences in the rate constants. The data with large number ofpoints provide a more reliable kinetic model than the data withfew points. The equilibrium constant decreases with increasing temperature as expected for an exothermic reaction.
Despite the low resolution and sensitivity, compact NMR
has proven to be a reliable tool for monitoring chemical reactions in process engineering applications as accurate as otherstandard methods.
Acknowledgements The authors gratefully acknowledge financial
support from Deutsche Forschungsgemeinschaft (DFG Gerätezentrum
Pro2NMR) by a joint instrumental NMR facility BL 231/46-1 of
RWTH Aachen University and KIT Karlsruhe. We are also thankful to
GC department of ITMC especially to Elke Biener, Hannelore Eschmann,and Heike Boltz for providing the measurement time and data for the GC
samples. Moreover we thank Sharoff Pon Kumar for helping in providing
the MATLAB codes for running the Runge-Kutta method and optimizing
the kinetic rate constants.

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Compliance with ethical standards
Conflict of interest Bernhard Blümich is on the board of directors of
Magritek Ltd.

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