Performing Highly Exothermic Reactions Safely in Minutes with the IceCubeTM Flow Reactor

IceCubeTM Flow Reactor Application Note

INTRODUCTION

Exothermic reactions, by their very nature, often progress rapidly through unstable intermediates. Maintaining a firm control over parameters such as temperature and pressure is problematic, so their utilization is limited in synthetic practice. However, flow techniques have the potential of keeping such reactions under control via their improved heat and mass transfer capabilities, allowing one to exploit untapped or avoided chemistries such as organomettalic chemistry, nitration, and ozonolysis. In this application note, we share details of the Grignard reaction, using EtMrBr and lithiation, which demonstrate the versatility of the IceCube™ flow reactor, dedicated to the safe running of exothermic reactions. The Grignard reaction was performed using various aldehydes and ketones as starting materials, applying only one reaction zone, while the bromo-lithium exchange and the subsequent nucleophilic addition reaction required the use of both reaction zones in the IceCube™ flow reactor.

INSTRUMENTATION

The IceCube™ is a revolutionary continuous flow low-temperature reactor specifically for high energy reactions to be performed in a highly controlled and safe manner. The IceCube™ reactor is made up of 4 modules: the Ozone Module, Pump Module, Reactor Module, and the Control Unit. The modules can be configured separately to match the application you wish to perform.

The Reactor Module is a highly versatile reactor capable of controlling extremely exothermic reactions safely and simply. It is composed of two reactor zones with Peltier heating/cooling and a reaction line made of Teflon for a wide chemical compatibility. Difficult or dangerous reactions such as nitration, lithiation, azide generation or ozonolysis may now be performed and quenched immediately without having to isolate dangerous intermediates. Main reactor zone temperature range: -70-+80°C, secondary reactor zone temperature range: -30-+80°C.

The Pump Module is made up of two rotary piston pumps which have good chemical compatibility. The pumps are connected to two pressure sensors and 3-way valves, which control the path of the reactant or solvent through the reactor. Flow rate: 0.2-4 mL/min. Max pressure: 6 bar.

The Ozone Module™ provides you with a safe and efficient way of generating ozone from oxygen. The ozone/oxygen amount is precisely controlled through the built-in mass flow controller. The system can also be used as a powerful and compact stand-alone ozonizer. Oxygen flow rate: 10-100 mL/min. O3/O2 v/v%: 14% at 20 mL/min oxygen flow rate. This module was not applied when performing the Grignard and lithiation reactions.

The Control Module is a small touch screen, which provides full control over all the attached modules. The reaction parameters can be easily set and monitored over time. The provided software has predefined processes for different applications, such as ozonolysis, but it is also possible to design a customized configuration with it.

Reaction
EntryStarting MaterialProductYield (%)
1Starting Material 1Product 197
2Starting Material 2Product 262
3Starting Material 3Product 393
4Starting Material 4Product 499
5Starting Material 5Product 590
6Starting Material 6Product 683
7Starting Material 7Product 799

Table 1. Examples of Grignard reactions in the IceCube™ flow reactor

GRIGNARD REACTIONS IN FLOW

Alkylation of Aldehydes and Ketones

During each reaction run (Table 1 Entry 1-7), a 0.5 M starting material solution (in THF) was introduced into the IceCube™ flow reactor by one of the pumps in the Pump Module, while the other pump supplied the 2 equivalent Grignard reagent (EtMgBr in THF) solution, each with a 0.5 mL/min flow rate. The reagent lines were combined with a PTFE T-piece before it was introduced into a 1/8” 8 mL PTFE reactor loop. The reactions were conducted at room temperature, and the combined flow rates were set to allow a residence time of 8 minutes in each case. The intermediate products were collected on cc. NH4Cl solution.

RESULT

Table 1. indicates moderate to excellent yields using different substrates with throughput from 1.162 kg/h-1L-1 to 1.856 kg/h-1L-1.

This synthetic approach enables you to utilize the spectrum of the Grignard reactions in a quick, safe, and easy way in the IceCube™ flow reactor.

Scheme 1. User interface on the Control Unit while performing Grignard reactions

LITHIATION IN FLOW

General Experimental Protocol

A 0.3 M dibromobenzene solution was combined with the 1.25 M n-BuLi solution by a PTFE T-piece. The two solutions were supplied by rotary piston pumps in the Pump Module. The combined reagent and reactant solutions were then introduced into a 1/8” PTFE reactor loop, which gave rise to the monolithiated intermediate compound at room temperature. A 0.7 Mbenzaldehyde solution was introduced into another PTFE T-piece by a third pump, which was combined with the stream of solution of the intermediate compound from the first reactor. The nucleophilic addition reaction was conducted in another 1/8” PTFE loop at room temperature in the secondary reactor zone, then finally the secondary intermediate compound was hydrolyzed by aqueous cc. NH4Cl solution.

RESULT

As it can be seen in Table 2, keeping the reaction time extremely low (4 and 6 sec respectively) was crucial to achieving the high conversion and selectivity of the desired product (see Schemes4 and 5 for comparison). The design of the IceCube™ flow reactor plates allowed the utilization of a low reaction volume to avoid using a high amount of solvent and enabled the quick testing of the various flow conditions.

Scheme 2. Selective Br/Li exchange and subsequent nucleophilic addition reaction in the IceCube™ flow reactor

Scheme 3. Reaction setup of the IceCube™ flow reactor for selective Br/Li exchange and subsequent nucleophilic addition reactions.

EntryFlow rates (mL/min)Reactor ZoneConversion (%)Selectivity (%)
Pump #1Pump #2Pump #3FirstSecond
Volume (mL)Residence time (sec)Temperature (°C)Volume (mL)Residence time (sec)Temperature (°C)
161.5343225423258910
230.751.54642544625935
361.531825423259059
461.530.542516258878

Table 2. Experimental reaction conditions and results

Scheme 4. GC-MS spectra of Table 2, Entry 1 (89% conversion, 10% selectivity)

Scheme 5. GC-MS spectra of Table 2, Entry 4 (88% conversion, 78% selectivity)

CONCLUSION

We have demonstrated a generalized Grignard reaction performed in the IceCube™ flow reactor. The optimized conditions were successfully implemented during the substrate scope resulting in various products. The second example described a selective bromo-lithium exchange reaction followed by the subsequent nucleophilic addition step. These reactions clearly prove the flexibility and the user-friendly design of the IceCube™ flow reactor allowing the easy change of reaction time in a wide range

GENERAL GUIDELINE

This step-by-step guide will help you plan your reaction especially when precipitation might occur. Please, note that ThalesNano makes no warranties or indemnities, expressed or implied, and assumes no liability in connection with the use of any information from this guide.

1.) use the 1/8” OD tubing instead of 1/16” OD(against precipitation).

2.) use a T–mixer (against precipitation).

3.) perform the experiments without involving the pressure sensor and pressure regulator into the reaction line (against precipitation).

4.) use a low concentration, such as 0.2 M as a start.

5.) Depending on the nature of the reaction, either start with setting an 8-minute or a 30-second reaction time for the reaction, e.g. for slower reactions (Grignard): 0.5mL/min flow rate for the two starting materials respectively and assemble an 8 mL loop; for fast reactions (lithiation): 0.2 mLmin flow rate for the 2 starting materials and 0.8 mL loop.

6.) First, determine the reaction time by either increasing or decreasing the flow rate and loop volume compared to point 5.

7.)Increase the concentration, if higher throughput is required, taking into consideration that it might require a change in the length of the reaction time