(624b) Intensification of Cryogenic Lithiation-Borylation Though Use of a High Heat Transfer Loop Reactor

Lithium-hydrogen exchange is a common chemical transformation used to functionalize molecules, specifically to add boron to phenyl rings. One challenging class of these lithiations is the case where fluorine directs the lithium to the ortho position. These ortho-fluorine lithiated phenyl species can undergo highly exothermic decomposition through benzyne intermediates and are therefore run at deep cryogenic conditions. Not only does the intermediate need to be kept cold, but the subsequent borylation step also generates a substantial amount of heat that can promote the decomposition reaction. The challenge of handling the heat generation means operating this process requires good control of the temperature and rate of heat generation. In a batch process, this means slow addition of reagents at low temperatures. Changing operation from a batch to a continuous process presents the opportunity to increase the heat transfer rate and potentially support higher temperatures and faster mixing.

A small scale cryogenic flow chemistry platform was used to initially screen this reaction in a series of two tubular reactors.(1) At this milliliter scale, the lithiation was operated at -50 °C with the lithiated intermediate directly mixed with the boron source without degradation in a simple y-mixer. The reaction was further scaled up by approximately a factor of 3 to generate gram quantities of material and faced several challenges in the mixing section with respect to heat removal.(2) These were overcome by reconfiguring the mixing zones and better controlling heat removal from the reactor. These early results indicate that further scaling up of the process using the same configuration would present insurmountable problems.

We will discuss an additional 10x scale up capable of producing kilogram quantities of material over the course of a day. This required redesigning the borylation reactor to use a loop reactor with a heat exchanger inline to remove the heat of reaction rapidly. We will also show how careful design of the lithiation reactor would produce plug-flow performance even under laminar flow at the larger scale. The envisioned production scale continuous plant would have a 100x smaller footprint and reduction in potential chemical energy contained in the unstable intermediate. This would be safer and more economical than the equivalent batch process.

References:
1. Newby, J. et al. Design and Application of a Low-Temperature Continuous Flow Chemistry Platform. Org. Process Res. Dev. 2014, 18, 1211-1220.

2. Newby, J. et al. Reconfiguration of a Continuous Flow Platform for Extended Operation: Application to a Cryogenic Fluorine-Directed ortho-Lithiation Reaction. Org. Process Res. Dev. 2014, 18, 1221-1228.