Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions

Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions Trevor A. Hamlin and Nicholas E. Leadbeater* Full Research Paper Address: Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, CT 06269, USA Open Access Beilstein J. Org. Chem. 2013, 9, 1843–1852. doi:10.3762/bjoc.9.215 Email: Nicholas E. Leadbeater* - Received: 24 May 2013 Accepted: 15 August 2013 Published: 11 September 2013 * Corresponding author This article is part of the Thematic Series "Chemistry in flow systems III". Keywords: flow processing; Raman spectroscopy; reaction monitoring; α,β-unsaturated carbonyl Guest Editor: A. Kirschning © 2013 Hamlin and Leadbeater; licensee Beilstein-Institut. License and terms: see end of document. Abstract An apparatus is reported for real-time Raman monitoring of reactions performed using continuous-flow processing. Its capability is assessed by studying four reactions, all involving formation of products bearing α,β-unsaturated carbonyl moieties; synthesis of 3-acetylcoumarin, Knoevenagel and Claisen–Schmidt condensations, and a Biginelli reaction. In each case it is possible to monitor the reactions and also in one case, by means of a calibration curve, determine product conversion from Raman spectral data as corroborated by data obtained using NMR spectroscopy. Introduction Continuous-flow processing is used in the chemical industry on production scales. In a research and development setting, there has been increasing interest in using flow chemistry on smaller scales. To this end, a wide range of companies now produce equipment for both micro- and mesofluidic flow chemistry [1,2]. Some of the advantages of these devices are increased experimental safety, easy scale-up and thorough mixing of reagents [3-7]. It is not surprising, therefore, that a wide range of synthetic chemistry transformations have been reported using this equipment [8,9]. When it comes to evaluating the outcome of reactions performed using flow chemistry and optimizing reaction conditions, one option is to use inline product analysis. This opens the avenue for fast, reliable assay in comparison with the traditional approach in which performance is evaluated based on offline product analysis. When interfaced with microreactors, inline analysis has taken significant strides in recent years [7,10]. Spectroscopic tools such as infrared [1115], UV–visible [16-18], NMR [19,20], Raman [21-25], and mass spectrometry [26,27] have all been interfaced with success. There have been less reports when it comes to 1843 Beilstein J. Org. Chem. 2013, 9, 1843–1852. mesoflow systems. Perhaps most developed is the area of infrared monitoring. The now ubiquitous ReactIR equipment has been interfaced with commercially available flow equipment to allow for real-time analysis of reactions and on-the-fly optimization of conditions [28-30]. In our laboratory we have had success interfacing a Raman spectrometer with a scientific microwave unit [31]. This has allowed us to monitor reactions from both a qualitative [32-35] and quantitative [36,37] perspective. A recent report of the use of Raman spectroscopy for monitoring a continuous-flow palladium-catalyzed cross-coupling reaction [38] sparked our interest in interfacing our Raman spectrometer with one of our continuous-flow units and employing it for inline reaction monitoring of a number of key medicinally-relevant organic transformations. Our results are presented here. Results and Discussion Interfacing the spectrometer to the flow unit In interfacing our Raman spectrometer with a continuous-flow reactor, our objective was to use a similar approach to that which proved successful when using microwave heating. Borosilicate glass is essentially “Raman transparent”. Therefore reactions could be monitored by placing a Raman probe near the reaction vessel, without requirement to place any parts of the spectrometer inside the reaction vessel. The exposure of metallic components to the microwave field was avoided using a quartz light-pipe extending both the excitation laser and the acquisition fiber optic components of the spectrometer almost without any loss of light. The optimum distance of the lightpipe to the outside wall of the reaction vessel was found to be approximately 0.5 mm. Moving to our continuous-flow reactor, we decided to place the spectroscopic interface just after the back-pressure regulator assembly. This meant that we did not need to engineer a flow cell capable of holding significant pressure. Instead we used an off-the-shelf flow cell traditionally used in conjunction with other spectroscopic monitoring tools. The cell had screw-threaded inlet and outlet tubes of the same diameter as the tubing of the flow unit (i.d. 1 mm). The sample chamber had a width of 6.5 mm, height of 20 mm and a path length of 5 mm giving the cell a nominal internal volume of 0.210 mL (Figure 1a). We built an assembly to allow us to hold the cell in a fixed location and vary the distance of the quartz light-pipe so as to optimize the Raman signal intensity. The apparatus is shown in Figure 1b. Figure 1: (a) Flow cell and (b) Raman interface used in the present study. experience of monitoring this reaction both qualitatively [32] and quantitatively [36] when using microwave heating so believed it would be a good starting point for our present study. The reaction works well when using ethyl acetate as the solvent. However, 1 is not completely soluble at room temperature. To overcome potential clogging of the back-pressure regulator as well as mitigating the risk of having solid particles in the flow cell (which would perturb signal acquisition), we leveraged a technique we developed for this and other reactions previously [39]. Once the reaction stream has exited the heated zone, it is intercepted with a flow of a suitable organic solvent. This solubilizes the product and allows it to pass through the back-pres- Testing the interface: The synthesis of 3-acetylcoumarin As our first reaction for study, we selected the piperidinecatalyzed synthesis of 3-acetylcoumarin (1) from salicylaldehyde with ethyl acetoacetate (Scheme 1). We had extensive Scheme 1: The reaction between salicylaldehyde and ethyl acetoacetate to form 3-acetyl coumarin (1). 1844 Beilstein J. Org. Chem. 2013, 9, 1843–1852. sure regulator unimpeded. In the case of 1, we intercept the product stream with a flow of acetone. Our first objective was to determine whether we could observe spectroscopically a slug of the coumarin passing through the flow cell. The Raman spectrum of 1 (Figure 2) exhibits strong Raman-active stretching modes at 1608 cm−1 and 1563 cm−1 while the salicylaldehyde and ethyl acetoacetate starting materials exhibit minimal Raman activity in this area. As a result, we chose to monitor the 1608 cm−1 signal. To mimic a product mixture, we (...truncated)