The Need to have Flow Methods Operate at Low Temperature

It may have been placed at an earlier date but it was just simply an issue with getting to the topic: Cold Flow — perhaps the strongest in flow developments since a high percentage of reactions are performed from RT to -70C (maybe even -78C). Nice thing is that many of these low temperature reactions will need techniques discussed early on in-line removal of a reactive or species which might clog a flow line or need an in-line work up. For today, I will highlight 2 examples to illustrate the importance of these developments and you can venture into this arena with periodic updates on my side from time to time…..I will stick to Cold Flow since the term Cryo leaves me with the feeling that I am an Asimov book (besides it means icy cold anyway).

The first example (OL 2011) should stick out a particularly valuable: the preparation of aromatic and hetroaromatic boronic acids (and boronates) following a lithium halogen exchange. Two things should jump out prior to performing these sorts of reactions: solubility (concentration of reactants and products) and how to cool effectively without in-line quenching or cooling reactor operation. In each of these cases, a team from the University of Cambridge and Cambridge Reactor Design (Ley, Browne, Baxendale, Baumann and Harji) walk us through an effective reactor design and implementation. For starters, picking the formation of an aryl and heteroaryl boronate with low-temperature lithium-halogen exchange is particularly pleasing with the abundance of starting materials available.

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In the figures below, a low-temperature reactor with a flow coil and a pre-cooled coil for the introduction of reagents into the entire block of temperature controlled region is used — along with that is an in situ IR to monitor the flow of reagents and product formation (have to say that this is key when checking for a buildup of a material at any phase of the flow of materials.

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Polar Bear Low Temp Reactor
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Low temp coil – Chip Temp Controlled

Concentration studies show the effective operable area for the the formation of the final boronic acids.

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Following the formation of the boronic acids, the system was set-up for the formation of a variety of boronates.

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Although an number of questions come to mind doing this sort of chemistry, this group detailed the ability to operate the cooling reactor for long periods of operation to ensure durability, taking nBuLi straight from a reagent bottle avoids the need to generate reactants prior to flow, and in these cases optimal flow of solvent ratios were studied to ensure successful processing.

The second example stayed true to the control of low temperature reaction zones as well as an in-line FlowIR to monitor and correlate batch to flow method design. In this report out of ThalesNano, the group illustrates the value of the IceCube reactor (uses a two-zone cooling and heating zone areas to either cool or heat when needed to complete a multi-step process). In the report, they performed a Swern Oxidation under flow conditions and studied the temps needed for the conversation without the formation of reactive by-products often associated with the reaction from a batch process.

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For the sequence of reactant flow, they have 3 areas of input for the flow: a solution of the alcohol in DMSO, Oxalyl choride in DCM and TEA at the end of the reaction. Optimized for concentration and flow, the group monitored the reaction for the formation of the desired aldehyde as well as potential side-reactions during the course of the reaction — in that, they were able to show the temperature ranges that were effective and when undesired formations were taking place.

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Although the IceCube has an extended range of of -70C to 80C and -30 to 80C, they were able to show a full conversion from -30 to -10C without any deleterious effects in the reaction — a choice of temperature range control in the reaction zones coupled with with FlowIR monitoring makes this an easy operation in reaction feasibility.

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Hope you enjoyed the 2 examples — there will be several upcoming posts with this theme in mind since it is a reasonably new area of capability in the last few years — so we will want to see a variety of applied synthetic transformations and combined cooling/heating multi-step methods in a full flow manner as a way to encompass flow chemisty’s full potential as a research and development technology. Happy Reading!


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