On-line monitoring of microwave-assisted chemical reactions by small-volume NMR techniques
Marie Curie Reintegration Grants (ERG)
The main project objective is the design, fabrication, and implementation of a hyphenated system formed by a continuous-flow microwave reactor and a microfluidic NMR-chip with the main goal of on-line monitoring microwave-assisted chemical processes. To reach the main aim, different tasks had to be developed, starting with the design and optimization of every component of the system, continuing with the interfacing of the different parts and to end with the testing for some reactions. On the other hand, the versatility of the setup allows the exchange of the microwaves by another mode of heating in order to broaden the scope of the system.
-Design, development and optimization of new NMR-chips suitable for the microwave set-up.
Different NMR-microchip designs have been designed and fabricated in collaboration with the University of Twente, varying the detection volume (6 nL, 50 nL, 100nL), the rf-microcoil and substrate dimensions, the number of microcoils within a substrate and the shape of the microfluidic channel. These modifications result in different sensitivity and resolution in the NMR spectrum. The NMR-chip has to be placed in an optimum and fixed position inside the bore of a superconducting magnet, therefore a slider and a chip holder has also been designed and fabricated. The use of the chip-holder and the NMR-chip allowed the detection of low amount of materials, with a limit of detection of 5 nanomol of sample for 1H-NMR (9.4 T). It illustrates the enhancement of the NMR sensitivity, main aim when working with microcoils. Figure 1 shows the different NMR chip designs.
Figure 1. Left: NMR-chip (rf-microcoil on top of a glass substrate where a microfluidic channel is defined) with a detection volume of 6 nL and a single coil.
-Design and fabrication of the continuous flow microwave cell.
A microwave reactor (Resonance Instruments, Inc. Model 521) fabricated for batch synthesis purposes was customizing replacing the sample vial by a designed flow cell. This microwave reactor has a cylindrical cavity applicator separated from the microwave solid state generator via an output coaxial cable, allowing the positioning of the reaction vessel in close proximity, i.e. within the strayfield of the NMR magnet. The flow cell is formed by a capillary (fused silica) wound in and out of the cavity and wrapped around a WeflonTM bar. The reaction volume is around 1.5 µl, although it can be changed within a wide range. On the other hand, another flow cell with a reaction volume of 350 µl and made of glass was designed for scaling-up purposes. Regarding the interfacing of the two systems, the continuous flow microwave reactor and the NMR chip, fused silica capillaries defining a total system volume of only 5µl were used to connect both parts.
-Optimization of the set-up and study of several reactions.
A model reaction, the Diels-Alder cycloaddition of 2,5-dimethylfuran and dimethylacetylene dicarboxylate was chosen to proof the concept and to illustrate the performance of the setup. Due to the fact that the microfluidic chip has a lower detection volume (6 nL) than the microwave reaction volume (1.6 µL), the latter can be divided in different zones for analysis. Considering the fact that the onset of the microwave, i.e. the time needed to attain the maximum heating power, is only a few seconds, switching on the irradiation power when working under flow conditions, every small portion of the reaction volume is exposed to microwave irradiation for different times. Consequently, multiple data points can be sampled subdividing the microwave reaction volume in volumes between 6 nL and 1.6 µL. Therefore, many data points can be obtained within a single on-flow experiment, enabling a rapid optimization of the reaction conditions, and with very low cost.
In order to broaden the scope of the system to a wide variety of chemical transformations, the preparation of a library of five-membered heterocyclic compounds which exhibit significant biological activity has been investigated. When using the microwave flow-cell fabricated for scale-up purposes, a good production rate (1.15 g/h) of 3,4,5-trimethylisoxazole is obtained. A more versatile continuous flow microreactor has been hyphenated to the NMR-chip to reach the synthesis of such library. The results indicates that even a higher number of data points than the obtained with the former setup can be extracted from a single on-flow experiment (manuscript in preparation).
-Design of a photoactivated continuous flow microreactor hyphenated to an NMR-chip.
The goal is the fabrication of a setup for the on-line monitoring of photoactivated chemical processes by the NMR-chip. Three main parts can be distinguished in the setup. 1) A microreactor with different reaction volumes, 0.5, 1, and 1.5 µl, to hold the reaction mixture. 2) A print-board in which 6 environmentally friendly light-emitted diodes (LEDs) have been connected in series, together with the corresponding electronic circuit. The LEDs can be found at different wavelengths, what increases the versatility of the setup. 3) A holder to fix the LEDs very close to the microreactor in order to reduce the distance between the light source and the sample for higher reaction efficiency. The setup has been designed and fabricated and some reactions are being tested (manuscript in preparation).