Name: real-time monitoring of reactions performed using continuous-flow processing: the preparation of 3-acetylcoumarin as an example
Uploaded: 2015-11-18T13:00:00
Description: Watch this Scientific Journal Video about Real-time Monitoring of Reactions Performed Using Continuous-flow Processing: The Preparation of 3-Acetylcoumarin as an Example at JoVE.com

Financial support provided by National Science Foundation (CAREER award CHE-0847262. We thank Vapourtec Ltd and Enwave Optronics for equipment support, and Daniel Daleb of the University of Connecticut for his assistance in construction of the flow cell apparatus.

1. Find Suitable Signals for Reaction Monitoring
<ol>
	<li>Obtain Raman spectra for all starting materials and the product.</li>
	<li>Overlay spectra and identify an intense band that is unique to the product.</li>
	<li>Use this Raman band to monitor the progress of the reaction. A band at 1,608&#160;cm-1 was selected in this case.</li>
</ol>
2. Set up the Flow Cell
<ol>
	<li>Obtain a suitable flow cell. Here use one with the following dimensions: width of 6.5 mm, height of 20 mm, a...

<ol>
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The ease in which the Raman spectrometer can be interfaced with the flow unit makes this inline technique valuable for reaction monitoring. A number of reaction variables can be probed in an expedited manner, allowing the user to arrive at optimized reaction conditions faster than when using offline methods. Application of the techniques described herein also allows for monitoring of the formation of side products, assuming a suitable band can be found. Conditions can be screened and selected, which allow both for the hi...

By using continuous-flow processing, chemists are finding that they can perform a range of chemical reactions safely, effectively, and with ease1,2. As a result, flow chemistry equipment is becoming an integral tool for running reactions both in industrial settings as well as research labs in academic institutions. A wide variety of synthetic chemistry transformations have been carried out in flow reactors3,4. In select cases, reactions that do not work in batch have been shown to proceed smoothly under continuous-flow conditions5. For both reaction optimization and quality control, incorporation of in-line reaction monitoring with flow processing offers significant advantages. In-line monitoring provides continuous analysis with real-time response to actual sample conditions. This is faster and, in some cases, more reliable than comparable off-line techniques. A number of in-line analytical techniques have been interfaced with flow reactors7. Examples include infrared8,9, UV-visible10,11, NMR12,13, Raman spectroscopy14,15, and mass spectrometry16,17.
Our research group has interfaced a Raman spectrometer with a scientific microwave unit18. Using this, a range of reactions have been monitored from both a qualitative19 and quantitative20 standpoint. Building on this success, we have recently interfaced our Raman spectrometer with one of our continuous-flow units and employed it for in-line reaction monitoring of a number of key medicinally-relevant organic transformations.21 In each case it was possible to monitor the reactions and also in one example, by means of a calibration curve, we could determine product conversion from Raman spectral data. In Here we describe how to set up the apparatus and use it to monitor reactions. We use the piperidine-catalyzed synthesis of 3-acetylcoumarin (1) from salicylaldehyde with ethyl acetoacetate (Figure 1) as the model reaction here.
<img alt="Figure 1" src="/files/ftp_upload/52393/52393fig1.jpg" /> 
Figure 1. Base catalyzed condensation reaction between salicylaldehyde and ethyl acetoacetate to yield 3-acetylcoumarin (1). <a href="https://www.jove.com/files/ftp_upload/52393/52393fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

<table border="0">
	<tbody>
		<tr>
			<td>Salicylaldehyde</td>
			<td>Sigma-Aldrich</td>
			<td>S356</td>
			<td>Reagent Grade, 98%</td>
		</tr>
		<tr>
			<td>Ethyl acetoacetate</td>
			<td>Acros Organics</td>
			<td>117970010</td>
			<td>99%</td>
		</tr>
		<tr>
			<td>Piperidine</td>
			<td>Sigma-Aldrich</td>
			<td>104094</td>
			<td>Reagent Plus, 99%</td>
		</tr>
		<tr>
			<td>Hydrochloric acid</td>
			<td>Sigma-Aldrich</td>
			<td>320331</td>
			<td>ACS Reagent, 37%</td>
		</tr>
		<tr>
			<td>Ethyl acetate</td>
			<td>Sigma-Aldrich</td>
			<td>34858</td>
			<td>CHROMASOLV, for HPLC, &#62;99.7%</td>
		</tr>
		<tr>
			<td>Acetone</td>
			<td>Sigma-Aldrich</td>
			<td>650501</td>
			<td>CHROMASOLV, for HPLC, &#62;99.9%</td>
		</tr>
		<tr>
			<td>Flow cell</td>
			<td>Starna Cells</td>
			<td></td>
			<td>583.65.65-Q-5/Z20</td>
		</tr>
		<tr>
			<td>Flow unit</td>
			<td>Vapourtec</td>
			<td></td>
			<td>E-series system</td>
		</tr>
		<tr>
			<td>Raman spectrometer</td>
			<td>Enwave Optronics Inc</td>
			<td></td>
			<td>Model EZRaman-L</td>
		</tr>
	</tbody>
</table>

real-time monitoring of reactions performed using continuous-flow processing: the preparation of 3-acetylcoumarin as an example

By using inline monitoring, it is possible to optimize reactions performed using continuous-flow processing in a simple and rapid way. It is also possible to ensure consistent product quality over time using this technique. We here show how to interface a commercially available flow unit with a Raman spectrometer. The Raman flow cell is placed after the back-pressure regulator, meaning that it can be operated at atmospheric pressure. In addition, the fact that the product stream passes through a length of tubing before entering the flow cell means that the material is at RT. It is important that the spectra are acquired under isothermal conditions since Raman signal intensity is temperature dependent. Having assembled the apparatus, we then show how to monitor a chemical reaction, the piperidine-catalyzed synthesis of 3-acetylcoumarin from salicylaldehyde and ethyl acetoacetate being used as an example. The reaction can be performed over a range of flow rates and temperatures, the in-situ monitoring tool being used to optimize conditions simply and easily.

The continuous-flow preparation of 3-acetylcoumarin was chosen as a representative reaction for in-line monitoring. In batch, the reaction proceeds well when using ethyl acetate as the solvent. However, the product (1) is not completely soluble at RT. To prevent potential clogging of the back-pressure regulator, as well as mitigate the risk of having solid particles in the flow cell which would perturb signal acquisition, we used a technique we developed previously for this and other reactions22</su...

Watch this Scientific Journal Video about Real-time Monitoring of Reactions Performed Using Continuous-flow Processing: The Preparation of 3-Acetylcoumarin as an Example at JoVE.com

Real-time Monitoring of Reactions Performed Using Continuous-flow Processing: The Preparation of 3-Acetylcoumarin as an Example

Real-time monitoring allows for fast optimization of reactions performed using continuous-flow processing. Here the preparation of 3-acetylcoumarin is used as an example. The apparatus for performing in-situ Raman monitoring is described, as are the steps required to optimize the reaction.

By using inline monitoring, it is possible to optimize reactions performed using continuous-flow processing in a simple and rapid way. It is also possible ...

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