Wednesday, April 11, 2012

Process Wednesday: organolithiums and flow chemistry

Credit: Grongsaard et al., Org. Process. Res. Dev.
One of the concerns that I have about implementing flow chemistry in the lab is plugging or other issues of moving slurries through narrow tubes. But this work from Merck [1] tends to indicate that might be less of an issue than I thought -- and that it may serve to help with those issues:
For the bulk production, this formylation step was first run in 2 × 5 kg batches in a 100 L vessel at −60 °C. During the second batch, the reaction solution turned into a thick gel at the dianion (14) stage, a phenomenon which had not been observed in gram scale experiments. The batch temperature had to be raised to −45 °C and the agitator manually manipulated until the mixture was sufficiently mobile to allow stirring to continue automatically. Fortuitously, these additional operations did not impact the reaction yield, as each 5 kg batch gave a 76% assay yield of aldehyde 5. However, from a practical perspective, the gelling problem encountered with the longer hold times needed for temperature control in these kilogram scale runs presented a concern for further scale-up in fixed vessel equipment. This spurred a preliminary evaluation of the feasibility of performing the formylation under flow conditions, which have been applied to a number of other organolithium processes, since the more efficient mixing and heat transfer in a continuous operation could result in shorter hold times...
The reactor was constructed of 0.25-in. internal diameter stainless steel tubing and immersed in a dry ice/acetone bath to maintain a low temperature. Reagent streams were fed by peristaltic pumps with pressure gauges (PI) through polytetrafluoroethylene (PTFE) tubing.  
[snip] To demonstrate proof-of-principle for this process, a preparative scale run was perfomed using the setup shown at the bottom of Figure 1. The anion 13 derived from 1 kg of bromide 11 was processed through the flow reactor in 1 h, at a flow rate of 114 mL/min. Efficient cooling of the system in the rudimentary cold bath was maintained even at this high flow rate (the temperatures recorded at steady-state were −70, −65, and −55 °C at T1, T2, and T3, respectively). The solution assay yield of aldehyde 5 at the end of the run (85%) was higher than on the 5 kg scale in batch mode (76%), and the level of debrominated side-product was lower (4% vs 7−8%). Furthermore, even with a slightly higher concentration of dianion 14 in flow mode (in 7 volumes of solvent compared to 10 in batch mode), no gelling or plugging of the reactor was observed. 
(I think the high-tech flow reactor cooling vessel is a big plastic box, if I'm not mistaken.) A pretty neat experiment -- and a challenge to all of us to try flow chemistry.

1. Grongsaard, P. et al. "Convergent, Kilogram Scale Synthesis of an Akt Kinase Inhibitor." Org. Process. Res. Dev. ASAP,


  1. Interesting example. If the dianion "gel" behaves like a Bingham plastic fluid (solidifies until shear stress is high enough to induce flow) then pushing the suspension through a narrow tube can prevent low shear zones. In low shear stress zones crystals aggregate and the suspension appears solid.

    In a reactor the high shear stress zone is near the agitator (mixing cavern with fast moving fluid). The resulting low viscosity at the impeller causes poor power draw and gives a "reactor candle" effect (agitator shaft = wick).

    Bingham plastic fluids are fascinating. The effect limits scale-up in in some crystallizations where it is sometimes caused by edge-to-face aggregation of plate crystals.

    1. You're clearly more knowledgeable than I -- thanks for your input!