The objective of the current study was to investigate the feasibility of the inline optical fiber
Raman spectroscopy as a tool for the process monitoring of the continuous flow organic
syntheses. The synthesis of 2-bromo-3,4,5-trimethoxytoluene (product) was studied as a model
reaction under a set of different conditions. The reaction was carried out under the batch as well
as in the multi jet oscillating disc (MJOD) milli reactor. The reaction was varied by doubling the
concentration of the substrate; 3,4,5-trimethoxytoluene (0.15M, 0.3M and 0.6M) whereas the
concentration of the solvent (acetic anhydride) was kept constant. The Raman instrument was
adjusted to record five spectra per minute. The recorded spectral data was then preprocessed
employing the second order differentiation to minimize the band overlapping in the spectra.
Multivariate data analysis namely, Principal Component Analysis (PCA), was used to evaluate
the spectra due to the presence of overlapping bands for the purpose of process monitoring. The
measurement system was tested against the possible process disturbances, the oscillator and the
feeding pumps. PCA showed that these disturbances had no impact on the measurement system.
The Raman instrument successfully monitored the different organic reactions and discriminated
them on the basis of the type of variation occurred. The Raman frequencies; 675, 1050 and 550
cm-1 were assigned to the solvent, substrate and the product. The various reactions undergoing
any disagreement were differentiated from the normal reactions mainly due to the temperature
effect, malfunctioning of the pump, lower conversion of the substrate, lower yield of the product,
formation of the intermediates etc. The offline results obtained from the NMR spectroscopy
verified the outcomes of Raman measurements. Thus, it was concluded that the optical fiber
Raman spectroscopy proved to be a reliable, rapid and sensitive inline analytical method for the
monitoring of the organic processes. Raman spectroscopy along with an appropriate
chemometric tool could be employed as a Process Analytical Technology (PAT) in the
pharmaceutical and fine chemical industry
