Final Report Summary - MICRO(WAVE)-NMR (On-line monitoring of microwave-assisted chemical reactions by small-volume NMR techniques) The main objective of the project is the fabrication of a system which involves the coupling of two techniques, microwave irradiation as energy source to perform chemical reactions and nuclear magnetic resonance (NMR) spectroscopy to analyse the reaction progress. The system combines the potential and applications of both techniques, revealing its multidisciplinary / interdisciplinary aspect since a wide variety of chemical processes can be studied within the system. The main aim is the monitoring of the reaction progress in real time in order to optimise reaction conditions when microwaves are used, a rapid synthetic method, however usually requiring longer times to analyse the reaction. Novel techniques like miniaturised radiofrequency microcoils are being used as part of the detection system in order to increase the sensitivity of NMR. Thus, the project implies the optimisation of an NMR-probe with the use of such microcoils. There are several geometries for these microcoils, among them, planar spiral microcoils whose main advantage respect to the others (solenoidal, stripline) is its straightforward fabrication by miniaturised techniques and the possibility of being incorporated to lab-on-a-chip devices. Thus, the microcoils can be located on top of a glass substrate, defining the called NMR-chip. The NMR-chip is placed inside an NMR-magnet, when fixed on a small-volume NMR probe, for the detection of signals to determine the reaction progress. These microcoils enable the detection of low amount of material as well as the analysis of volume-limited samples. Three different NMR-chips have been fabricated, involving different detection volumes, number of rf-coils within the same substrate, and dimensions. In the MICRO(WAVE)-NMR project, a microwave reactor (Resonance Instruments Inc. Model 521) has been modified fabricating a flow-cell which could be connected to the mentioned NMR-chip by means of capillaries. The total system volume is very small in order to optimise reaction conditions with the lower cost and energy as possible, and the reaction volume is only 1.6 µl. The main advantage of the system is the possibility of observing many data points from a single on-flow experiment. Since the detection volume of the NMR-chip is smaller than the reaction volume, it is possible to analyse separately the different parts of the reaction volume which have been under microwave irradiation for different time, therefore, observing different product concentration for each of them within a single on-flow experiment. It enables a rapid optimisation of the reaction conditions, saving time, solvent, reagents and energy. The performance of the system was illustrated with the optimisation of a Diels-Alder cycloaddition, showing the expected gain in data points. On the other hand, and in order to obtain higher amounts of the compound of interest, a microwave flow cell with a bigger reaction volume, 350 µl, have been fabricated to be used in the same reactor. Thus, a good production rate (1.15 g/h) for a five member heterocyclic compound, 3,4,5-trimethylisoxazole, was obtained as part of a small library of pyrazole and isoxazole derivatives also prepared using the same experimental setup but with an off-line analysis of the reaction mixture.Focused on increasing the versatility of the setup, the microwave reactor has been substituted by a commercial flow microreactor (Labtrix start), and the analysis of the reaction progress has been monitored online by the called NMR-chip. It has enabled the synthesis of a small library of compounds, which exhibit significant biological activity, such as anti-obesity and anti-rheumatic, in short time and with very low cost. This new setup presents an additional advantage with respect to the former one. It gives even more information per single on-flow experiment when optimising all the experimental parameters. Information related to different temperatures, starting material concentration and residence times can be extracted from a single on-flow experiment (manuscript in preparation).Interested in a different activation mode of reactions, a different system has been fabricated involving the use of the NMR-chip for the analysis of the reaction progress and light emitted diodes (LEDs) as energy source. A printboard with 6 LEDs has been fabricated as well as a microreactor with different reaction volumes, 0.5 1.0 and 1.5 µl. The designed setup implies the placement of the LEDs in close proximity to the microreactor for an efficient irradiation of the reaction mixture. Different chemical actinometers are being used in order to characterise the efficiency of the system (manuscript in preparation).To conclude, different setups working in continuous flow mode and using NMR microcoils as detection system, for the online analysis of reaction progresses have been designed, fabricated and implemented for some reactions. Regarding the reaction zone, microwave irradiation (Resonance Instruments Inc.), conventional heating (Labtrix start) or ultraviolet-visible (UV-vis) light (LEDs) can be employed. It illustrates the versatility of the system and the wide variety of transformations that can be studied, considering the application of NMR spectroscopy in fields of physical, chemical, biological and medicinal sciences. The potential impact this system can have, is the possibility of being used as a standard reaction-analytical tool which could be employed by any member of our department for the rapid optimisation of the reaction conditions in different fields. 239346-figure1.png
