A Protocol for Safe Lithiation Reactions Using Organolithium Reagents

The overall goal of this protocol is to perform a safe and effective lithiation reaction using organolithium reagents. This method can help answer key questions in chemistry by permitting molecular transformations at normally completely unreactive sites on molecules like hydrocarbons. These safety techniques are particularly relevant to the field of synthetic chemistry because individuals may need these powerful reagents for a synthesis, but be nervous about handling pyrophoric materials.

Highly reactive organolithium species must be handled and stored with special care. Always wear appropriate clothing and PPE for a pyrophoric reagent and never work in the laboratory alone. Before working with an organolithium reagent, identify the nearest safety shower, eyewash station, and fire extinguisher of the appropriate type.

Inspect the cap and seal of an organolithium reagent before each use. If salts or corrosive materials are visible on the cap or seal, slowly add the reagent to a beaker containing eight to 10 times its volume in dry ice within the fume hood. Always work in a clean, decluttered hood or glove box.

Prepare all quenching agents in your fume hood before starting work with an organolithium reagent. The actual protocol itself is simple to perform. The tricky part is safety.

By having your rinse and quench reagents and failsafes in place ahead of time, it's really no big deal if something goes wrong. If a reaction must be aborted, slowly transfer any unused organolithium reagent into the prepared beaker of dry ice. If the toluene or isopropanol ignites, cover the beaker with a watch glass to smother the flames.

In a clean, decluttered hood prepare the appropriate amounts of quenching materials and beakers. Then, place 1.8 milliliters of neat tert-butylamine and a stir bar in a 25 milliliter Schlenk flask stoppered with a rubber septum. Open the flask to the vacuum for one second to de-gas the tert-butylamine.

And then close the vacuum and back-fill the flask with inert gas. Repeat this process twice more, and then close the flask. To prepare an inert gas blanket, connect to a T adapter and inert gas source, an oil bubbler, and a luer-lock fitting adapter.

Connect a one inch 18 gauge needle to the luer-lock adapter. Secure the gas blanket above the flask and purge the line for five minutes. Decrease the flow rate to about one milliliter per second so that only a few bubbles appear per second in the oil bubbler.

Insert the inert gas blanket needle into the septum of the flask. Place the flask in a dry ice and acetone bath on a stir plate and stir gently until the tert-Butylamine has cooled. Securely clamp a bottle of tert-Butyllithium to a ring stand and remove the outer cap and any sealing materials present.

Then, transfer the inert gas blanket needle to the tert-Butyllithium bottle. Obtain a 20 milliliter or larger glass syringe with a securely fitting plunger. Attach a flexible 12 inch 16 gauge needle to the syringe.

Direct a gentle flow of inert gas through a separate Shlenk hose. Insert the tip of the syringe needle into the barrel of the hose. Draw the plunger in and out at least five times to purge the syringe.

Depress the plunger fully before withdrawing the syringe from the hose. Carefully pierce the tert-Butyllithium bottle septum and insert the needle into the liquid reagent. Gently withdraw the plunger to draw a slight excess of reagent.

Without removing the needle or disturbing the bottle, carefully point the syringe upwards by bending the needle. Gently expel the headspace gas and excess reagent into the reagent bottle. Right the syringe, and allow the needle to relax.

Then, transfer the inert gas blanket needle back to the reagent flask. Transfer the filled syringe and needle to the reaction flask so that the needle tip is securely above the stirring tert-Butylamine. Slowly add the tert-Butyllithium to the reaction flask.

Then, remove the long syringe needle form the reaction flask, leaving the inert gas blanket needle in place. Draw toluene from the beaker into the syringe to dilute the tert-Butyllithium residue. Submerge the needle tip in the isopropanol and expel the dilute mixture.

Rinse the syringe at least two more times with isopropanol to clean the syringe. Seal the septum of the tert-Butyllithium reagent bottle with grease and laboratory film and cap the bottle. Remove the dry ice bath and allow the reaction mixture to warm up to room temperature while stirring.

Once the flask has warmed to room temperature, remove the inert gas blanket needle. Store the reaction flask at negative 30 degrees Celsius overnight to obtain a white precipitate of lithium tert-Butylamide. Under an inert atmosphere, filter the suspension and wash the powder with cold pentane.

Dry the powder under vacuum. Prepare a beaker of isopropanol and a beaker of dry ice in a hood. Bring all needed reagents, equipment, glassware, and a sealed waste container into a clean, decluttered glove box.

Inside the glove box, prepare a vial of toluene. Inspect the cap and septum of the tert-Butyllithium bottle, and then secure the bottle with a ring stand. Remove the outer cap.

Securely fit a 1.5 inch 22 gauge needle into a glass syringe. Insert the syringe and needle into the bottle, and withdraw a slight excess of tert-Butyllithium. Invert the syringe and hold a paper wipe by the needle.

Slowly expel the headspace gas absorbing any liquid reagent on the paper wipe. Remove the stopper from a flask containing 1.8 milliliters of neat, de-gassed tert-Butylamine. Slowly add the tert-Butyllithium while stirring.

Stopper the flask and allow the mixture to cool to room temperature. While the reaction mixture cools to room temperature, draw toluene into the syringe to dilute the organolithium residue. Place the filled syringe with the needle and any paper waste into the designated airtight waste container and seal the container.

Purge the glove box for 10 minutes. Store the reagent bottle in the glove box freezer. Once the reaction mixture has cooled, store the flask at negative 30 degrees Celsius.

The product will further precipitate overnight. Remove the waste container from the glove box and immediately transfer it to a hood. Empty the syringe into a beaker of isopropanol and rinse several times.

Lithium tert-Butylamide was synthesized by lithiation of tert-Buylamine with the highly reactive tert-Butyllithium. The lithiation was performed both in small scale using Schlenk techniques, and in a glove box. Synthesis of the product was confirmed by proton NMR and X-ray crystallography.

Once mastered, this technique can be done in one or two hours if it's performed correctly. While attempting this procedure, it's important to remember to plan ahead, work in a clean space, and prepare failsafes before starting the reaction. There's an unfortunate amount of fear surrounding the use of organolithium reagents because misuse of these reagents has resulted in severe and very rarely fatal burns.

Don't forget that organolithium reagents can be extremely hazardous, and it's very important to follow all of the safety procedures that we've outlined and illustrated in this video when performing an organolithium reaction. Thanks for watching, and good luck with your experiments.

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Journal (Chemistry)

Journal (Chemistry)

A Protocol for Safe Lithiation Reactions Using Organolithium Reagents

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