Reaction monitoring and process optimization utilizing 1H NMR spectroscopy with the 60 MHZ benchtop NMR Spectrometers

As technologies for improving chemical processes continue to evolve, traditional chemistry has started moving towards more automated approaches, with the goal of synthesizing, analyzing, and purifying chemicals in a continuous manner. This transition towards automation would allow chemists to focus on planning, interpreting data, developing more projects and an additional focus on technical work. One approach used to move towards automation is the implementation of flow chemistry. Compared to traditional batch mode chemistry, flow chemistry continuously introduces reagents into the flow reactor, while the products are continuously eluted from the flow reactor. However, a prerequisite of flow chemistry is to have a good analytical method that can conduct rapid, reproducible, and efficient analysis so that one can modify and optimize the reaction conditions. In this blog post, I’ll feature work done by Vilela et al. with the NMReady-60 and illustrate how it can be used for on-line reaction monitoring and to optimize reaction conditions for the generation of singlet oxygen using BODIPY photosensitisers.

In this experiment the capabilities of a range of photosensitizing BODIPY derivatives to form singlet oxygen for the oxidation of a-terpinene to ascaridole (Figure 1) was compared between flow and traditional batch mode chemistry. The key step for the formation of ascaridole is the formation of a triplet electronic excited state (T₁) of the BODIPY derivative photosensitizers. This is done through an intersystem conversion (ISC) from the singlet excited state (S₁) upon absorption of a photon. The system then undergoes a triplet-triplet annihilation (TTA) energy transfer process which results in an excited state singlet oxygen and ground state BODIPY photosensitizers. However, this TTA process is in competition with phosphorescent radiant decay (hv_p) to revert the photosensitizer to its ground state, but the former is observed to occur more rapidly.

Figure 1. Reaction pathway for the oxidation of α-terpinene to yield ascaridole following a [4 + 2] Alder-ene cycloaddition with singlet oxygen formed by homogenous and heterogeneous BODIPY derivative photosensitizers.

When monitoring the conversion rate of the various photosensitizers with nuclear magnetic resonance (NMR) spectroscopy, the transition from batch mode to flow mode resulted in an almost 3-fold increase without any optimisation of experimental conditions. A magnified stack plot of ¹H NMR spectra showing the conversion of α-terpinene to ascaridole using a BODIPY derived photosensitizer is shown in Figure 2 (left). As the reaction progresses, the signal at 5.6 ppm disappears, and a concomitant increase in the intensity of the signal at 6.4 ppm is observed. As shown in Figure 2 (right), the data obtained by NMR spectroscopy also demonstrates that the experiment is light dependent, as evidenced by the conversion rate over time for the oxidation reaction where light is present (white columns) and where light is absent (grey columns). The grey spaces show a plateau while the white spaces depict conversion occurring.

Figure 2. Left) Conversion of α-terpinene to ascaridole under standard flow conditions, monitored by on-line ¹H NMR spectroscopy using the NMReady-60. Right) Graph depicting the conversion rate over time. The LED light source was cycled off and on in 20-minute intervals throughout the reaction. Grey columns reflect periods where the LED is off. An asterisk is used to represent a signal from the photosensitizer.

In addition to monitoring the reaction, on-line NMR spectroscopy was also used for the optimization of reaction conditions for singlet oxygen production, as depicted in Figure 3. This figure displays the conversion rate of the material at varying pressures and flow rates, and based on the data obtained with the NMready-60, the most optimal combination was determined and used to increase the conversion rate by 5-10 times. Using on-line NMR spectroscopy, The Vilela Lab was able to determine the conversion rate of their BODPIY derivatives relative to one another with and without optimization. After all optimizations for the system were implemented, an overall 24-fold enhancement of singlet oxygen photosensitization was achieved, as compared to the initial starting conditions.

Figure 3. Rates of conversion of α-terpinene to ascaridole with varying flow rates and pressures, monitored using on-line NMR spectroscopy.

As shown by the Vilela lab, the NMReady-60 can be easily and readily used to monitor the conversion of α-terpinene to ascaridole by utilizing BODIPY derived photosensitizers. It was also demonstrated that the NMReady-60 could also be used to optimize experimental parameters, making it easy for comparisons to be made between the various photosensitizers. The paper is Open Access and you can download it here. If you would like to know more about on-line NMR spectroscopy or are interested in how NMR spectroscopy could help you, please do not hesitate to contact us.

Reference

(1)      Gomez, M. V.; De La Hoz, A. Beilstein J. Org. Chem. 2017, 13, 285–300.
(2)      Thomson, C. G.; Jones, C. M. S.; Rosair, G.; Ellis, D.; Marques-Hueso, J.; Lee, A. L.; Vilela, F. J. Flow Chem. 2020, 10, 327–345.