The development of high-performance benchtop NMR spectrometers provides a practical and information-rich way to monitor on-line/in-line the progress of chemical reaction. NMR provides not only the structural information about the different chemical species involved in the reaction but also quantitative information about the concentration of reactants and products. By following the conversion in real time, chemists get the required insight to understand the kinetics of the reaction. Another advantage of using NMR for reaction monitoring is the ability to observe reaction intermediates. These can often be missed with endpoint reaction analysis, since intermediate, by definition, gets produced in the early stage and consumed during later stage of the reaction.
In recent years, the availability and affordability of benchtop NMR systems have offered the opportunity for schools to incorporate NMR spectroscopic techniques into organic chemistry curricula. With simple button-clicking, instructors and students can perform different NMR experiments to confirm the reaction products, or to monitor a reaction with NMR. This application note describes an example of using the Spinsolve 60 MHz Carbon ULTRA to monitor a frequently used reaction in the organic chemistry laboratory – the Claisen-Schmidt (or cross-aldol, Scheme 1) condensation reaction to synthesize dibenzalacetone. Students can visualize the kinetic profile of different chemical components in real-time. They can also observe the reaction intermediate, which is a concept that is seldomly demonstrated in laboratory experiment since intermediate species are not easily isolated from the reaction mixture for characterization. With the hands-on experience in the lab, students will develop a deeper understanding of chemistry concepts that they learn in lectures and familiarize themselves with the modern NMR techniques being adopted in industry.
Scheme 1. Claisen-Schmidt condensation reaction for the synthesis of dibenzalacetone analog
For the reaction described in this application note and depicted in Scheme 1, 4-fluorobenzaldehyde (1) and acetone (2) were chosen as starting material to generate 4-(4-fluorophenyl)-3-buten-2-one (3) as an intermediate as well as the major product known as DBA analog [1,5-bis(4-fluorophenyl)-1,4-pentadien-3-one, (4)]. Compound 1 was used in excess (2.2 equivalents) to ensure the completion of the reaction. The reaction was monitored for about 80 minutes with a total of 60 1D proton spectra acquired. These spectra are displayed in the stack plot (Figure 1), with the increasing reaction time going up the vertical axis. Four integral regions were defined to monitor different chemical components. Their integral values are plotted over time in Figure 2 (right). The integral value of 2 (red integral region) decreased rapidly during the first 20 minutes of the reaction. The rate of conversion of 2 then slowed down, until 2 was completely consumed towards the end of the experiment.
Figure 1. Left: Stack plot of 1H NMR spectra of the reaction progress; Right: integral over time plot of the defined integral regions
The diagnostic signal of aldehyde 1 can be observed as a singlet at 9.1 ppm (brown integral region). The plot of this integral shows at the beginning a similar pattern as the one of acetone 2. It decreased rapidly during the first 20 minutes, but then the consumption rate slowed down and remained almost constant for the rest of the reaction. Since aldehyde 1 was added to the reaction in excess, its signal was still observed at the end of the experiment.
During the progress of the Claisen-Schmidt reaction, a singlet was observed at 1.85 ppm (green integral region). The chemical shift and multiplicity of this signal match the expected signal of the methyl group in intermediate 3. The plot for this singlet showed characteristic of an intermediate species, where its concentration increased during the first five minutes of the reaction, then slowly decreased until it was undetectable in the reaction mixture. Therefore, this signal was assigned to the methyl group in the intermediate 3 (Scheme 1 and 2) where the acetone 2 had reacted with only one molecule of 4-fluorobenzaldehyde 1. The presence of intermediate 3 in the reaction mixture can provide an explanation for the slower consumption rate of acetone 2 after 20 minutes. Since intermediate 3 undergoes a similar chemical transformation as acetone 2 (Scheme 2), it can compete with acetone, therefore decreases acetone’s consumption rate towards the end of the experiment.
The blue integral region covered a new signal that appeared in the complex aromatic region due to the coupling between proton and fluorine on the benzene rings in both reactants and product. This signal was assigned to the allylic protons on the α-carbon of the ketone group in the final product 4. The concentration of the final product (blue curve in Figure 2) increased at a high rate at the beginning of the reaction, then slowed down to almost reach a plateau towards the end of the experiment.