Organic Process Research & Development 2009, 13, 1022–1025
Communications to the Editor
Online Analysis of Flowing Streams Using Microflow HPLC
Christopher J. Welch,* Xiaoyi Gong,* James Cuff, Sarah Dolman, Jason Nyrop, Fiona Lin, and Hallena Rogers
Separation and Purification Center of Excellence, Department of Process Research, Merck & Co., Inc., Rahway,
New Jersey, U.S.A.
Abstract:
However, a number of online analytical technologies including
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FTIR, NMR, UV, Raman, visible, mass spectrometry,
The application of a recently developed online HPLC reaction
sampling instrument for monitoring flow chemistry reactions is
described. The system was found to work well for online analysis
of flowing streams at or near atmospheric pressure, allowing for
convenient time-based withdrawal, dilution, and HPLC analysis
of the output of flow reactors. A general study of the capability of
the instrument to sample from flowing streams is presented, along
with a detailed study in which the instrument is used to character-
ize a thermal isomerization reaction carried out using a hot-zone
flow reactor.
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and HPLC
have been used or have shown promise for
monitoring of flow chemistry reactions.
We recently reported the development of a mobile online
microflow HPLC system and its use for kinetic profiling of a
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variety of batch reactions. In this study we investigate the
utility and limitations of this now commercially available
instrument for online monitoring of continuous flow reactors.
Results and Discussion
At the outset of this study we already knew that the Express
RT instrument (Figure 1) performed well for withdrawing
samples from a reaction flask, diluting and analyzing the
resulting aliquots by HPLC. We anticipated that the system
would also work for sampling from a flowing stream. The
Express RT instrument is composed of a compact sampling
unit capable of performing automated sampling and dilution, a
microbore HPLC system capable of executing rapid gradients
and quick turnaround times, and a computer system and
software for data acquisition and analysis.
The Express RT system does not have the ability to
accurately sample from a pressurized reaction vessel. We had
originally considered this capability during the initial design
discussions with Eksigent, reasoning that a high-pressure
sampling feature would be useful for monitoring reaction
progress for hydrogenations or other reactions taking place
within a pressurized vessel. We ultimately opted for a simple
Introduction
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In recent years, there has been a growing interest in the use
of flow chemistry for carrying out chemical reactions and
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processes. Flow chemistry reactions present some unique and
special analytical challenges that differ from those encountered
in typical batch reactions. This difference stems from the fact
that, with flow systems, the chemical reaction is continually
being initiated over the entire period of the run as new starting
materials are pumped into the reactor. In an ideal flow reaction
system operating at constant flow rates and temperature, product
exiting the flow reactor early in a run will be identical in
composition to product produced at a later time. However,
relatively minor changes in flow rates or reactor temperature,
or the presence of air bubbles or clogging will alter the residence
time and reaction conditions of the system, and therefore may
lead to significant changes in the quality of product being
produced. Consequently, flow chemistry is particularly in need
of analytical technologies that can afford continuous assessment
of product purity over time. At this time, analysis of most
laboratory-scale flow chemistry reactions is typically handled
by manual collection of effluent and offline HPLC analysis.
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*
Author for correspondence. E-mail: christopher_welch@merck.com.
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Vol. 13, No. 5, 2009 / Organic Process Research & Development
10.1021/op9001017 CCC: $40.75 2009 American Chemical Society
Published on Web 05/21/2009