Application Note 9: Benchtop NMR
Reaction Monitoring for Kinetic
Profiling
The Spinsolve high-resolution NMR spectrometer has been used to study the hydrolysis of acetic anhydride bywater. Rate constants can easily and reliably be obtained by plotting the peak height or integral of a characteristic
peak as a function of reaction time. The activation energy of the process can be determined by carrying out thereaction at different temperatures.

Reaction Scheme for Hydrolysis of Acetic Anhydride

60 Minutes

5 Minutes

Acetic Anhydride

Acetic Acid

7.0

6.5

6.0

5.5

5.04.54.0

3.5
f1 (ppm)

3.0

2.5

2.0

1.5

1.0

0.5

0.0

Experiment
Acetic anhydride (0.05 mL) and water (10 mL) weremixed in a 25 mL reaction flask to make a 0.05% v/v
solution. The reaction was monitored in real time byconnecting the reactor to the flow cell with PTFE
tubing of 1 mm I.D. as shown in Figure 1. The reaction
mixture was circulated through the PTFE tubing using
a flow rate of 0.9 mL/min and spectra were acquired
every 15 seconds. With this set-up the reaction mixture
reached the sensitive volume in less than 50 seconds.
Temperature variations in the reactor (5 - 50°C)
were achieved using a hot plate and an ice bath. A
mechanical stirrer was used to ensure that the mixture
was homogeneous. It is important to note that these
conditions are difficult and costly to achieve withinconventional 5 mm NMR tubes typically used at highfield.

Figure 1. Spinsolve NMR spectrometer set in a fume
hood to monitor the hydrolysis of acetic anhydride.

Hydrolysis of acetic anhydride
The area containing the peaks corresponding to the reactants and products in the stacked NMR spectrum and thecorresponding kinetic curves acquired from the signal amplitude of the described peaks is shown in Figures 2A and2B, respectively.

ABFigure 2. (A) Stacked spectrum from 1.0 ppm to 7.0 ppm. The growing peak near 2.04 ppm corresponds to acetic
acid and the decreasing peak near 2.19 ppm corresponds to acetic anhydride. (B) Profile of the reaction, showing themass balance and peak height of the reactant (red) and product (blue).

Kinetic model
The amount of H2O is in excess compared to the concentration of the acetic anhydride, thus a pseudo-first order
reaction is expected. Consequently, a first order kinetic model was used to fit the experimental data and to calculate
the rate constant.
Equation 1: [OAc2] = [OAc2]0 e-kt
Where [OAc2] is the concentration of acetic anhydride, which is measured by the height of the methyl peak near
2.19 ppm in the 1H NMR spectrum (Figure 3A), and ‘k’ is the pseudo-first order rate constant of the reaction. The
negative sign in Equation 1 indicates that the concentration of acetic anhydride is decreasing with elapsed time, as
shown in the reaction scheme.
A plot of the peak height against time yields an exponential curve. The fit of the curve (red line, Figure 3B) has adecay constant of k according to Equation 1, hence the rate constant of the reaction at 296 K is 0.8 x 10-3 s-1. Thereis a strong correlation between the fit and experimental data (Figure 3C), thus the data is consistent with a pseudofirst order reaction mechanism.

ACB

k = 0.8 x 10-3 s-1

Figure 3. (A) Stacked spectrum showing decreasing acetic anhydride peak at 2.19 ppm that was measured. (B) Plotof acetic anhydride peak height against time, with the fit of the curve shown in red. (C) Residual plot of the fit showing
the fit quality.

Effect of temperature
The reaction was performed at different temperatures and it was observed that the rate constant is temperaturedependant (Figure 4A). The activation energy of the reaction was determined by the Arrhenius equation (Equation 2).
A plot of the natural logarithm of the rate constant against 1/T yields a straight line, the gradient of which gives theactivation energy according to Equation 2 (Figure 4B).
Equation 2:
Where A is a pre-exponential factor, Ea is the activation energy, R is the universal gas constant (1.98 kcal mol-1) and T
is the temperature.

AB
Ea = 6.79 kcal mol-1

Figure 4. (A) Reaction profiles at various temperatures, showing the effect of temperature on the rate of the reaction(B) Arrhenius plot.
These results show that reactants diluted in protonated solvents at concentrations less than 1% can be measured
with accuracy using the Spinsolve spectrometer set inside the fume hood. For reactions whose products do notprecipitate at lower temperatures, it is possible to monitor the effect of temperature in the reactor provided that thesampling volume represents a small fraction of the reactor volume. This condition is met due to the small scale of thecompact NMR system.

Flow Setup Specifications
The setup required for on-line monitoring is shown below (Figure 5). A dewar (5 mm O.D. and 2.25 mm I.D., availablefrom Magritek) is mounted in the bore of the Spinsolve to reduce the heat exchange between the flowing sample andthe magnet which enables the monitoring of reactions at a range of temperatures. The reaction mixture was pumped
through the bore of the magnet using 2 mm O.D. (1 mm I.D) PTFE tubing. To reduce the tubing length, L1, from thereactor to the sensitive volume of the Spinsolve the pump is placed after the magnet. The pump can be set to workin continuous mode or in stop flow mode to acquire points with a time resolution of about 15 seconds.

• Tubing type:• Maximum OD:• Typical ID:•••••

Typical Length:
Volume L1:
Total volume:
Tmax reactor:
Tmax magnet:

PTFE
2 mm
1.0-1.5 mm

3 m (L1+L2+L3)
1.5 ml
5 ml
100°C
30°C

Figure 5: Flow Setup. The reaction mixture is pumped
from the reactor to the magnet via L1, from the magnet
to the pump via L2 and from the pump back to thereactor via L3.

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