A flow chemistry system in combination with solid-supported reagents and scavengers was used to perform fluorination reactions in a continuous mode. Using an inline analysis method, the effect of the solid supported reagents and scavengers on the product stream can be investigated. Two fluorination reactions (shown in this white paper) were performed and the product stream analyzed using inline infrared (IR) spectroscopy.
The intensity of IR energy absorbed at a particular wavelength is defined by Beer’s law to be proportional to concentration. Therefore, it is possible, using an inline IR instrument, to track the relative concentration of individual components. This really becomes a useful measurement to make if it is possible to analyze data and report the result in real time, one of the main challenges of the optimization of these types of systems.
Figure 2 (in this white paper) shows the relative concentration profiles of the reactants and products during the reaction. The graph clearly shows the formation of the product and confirms that the silica gel column is effective as a scavenger for the unreacted aldehyde (as none is detected with the reaction products). Interestingly, the expected time for the product to pass through the cell is 20min (A), which is calculated from the volume of material injected and the flow rate at which it is being pumped (4mL of material pumped at 0.2mL/min would take 20 minutes to pass through completely). Therefore, it would not be expected to detect any product after these 20 minutes. However, as a result of dispersion, diffusion, and chromatographic effects caused by the reaction setup, it can clearly be seen that it takes an additional 16 minutes (B) for all of the product to appear.
In another reaction, the formation of the product can clearly be seen. In this case however it is observed that there is a time delay between the appearance of the product and the remaining unreacted ester (the ester in this case was not expected to be scavenged by the cleanup column). This time delay of five minutes represents the chromatographic effect of having the silica gel column inline. This type of example demonstrates how an inline reaction monitoring strategy using inline IR spectroscopy can help scientists gain understanding of the formation of reaction products and the presence of unreacted materials in the product stream in real time. This information can clearly be used to determine the presence of starting materials in the product stream, when the product has formed, and could also be used to determine when steady state reaction conditions have been reached, so could be used as a real time trigger for fraction collection for example. This technology also provides immediate understanding of the effectiveness of the scavenging column, as well as demonstrating the dispersion effect that inline columns have on the shape and length of the reaction plug which can be quite significant. Using this information it should be possible, for example, to extend the length of the silica gel column inline to achieve a separation of the product from the starting material by means of chromatography; i.e. performing flash column chromatography inline.
The white paper – Enhanced Development and Control of Continuous Processes – discusses in further detail how to monitor product streams and dispersion effects in a continuous flow reactor, and then use that information to successfully perform a multi-step synthesis, where a third reagent stream is stoichiometrically controlled based on the output of the first part of the reaction.