How to prepare LDA

Not Voodoo Home / How To / Comments?

1. To diisopropylamine (0.17 mL, 1.2 mmol) in 3 mL THF at -78°C was added 0.69 mL of a 1.6 M solution of n-BuLi in hexanes (1.1 mmol) and the mixture stirred 1 min at -78°C. [note: mixing n-BuLi with diisopropylamine instantaneously forms LDA since the pKas of butane and diisopropylamine differ by 15 units, i.e. 1015-fold difference in ionizability! Commercial redistilled diisopropylamine is dry enough for this or you can redistill it yourself. I like to distill questionable diisopropylamine from CaH₂, 100 mL/g.]
2. Then a solution of starting material (SM) (1 mmol) in 2 mL THF was added via cannula needle (using a slight positive pressure of N₂ into the SM flask to push this solution through the needle into the anion solution) and the mixture stirred 15 min at -78°C. [note: Adding SM to the LDA avoids undesired intermolecular reactions of lithiated SM with neutral SM. Rarely do deprotonations with LDA require more than 15 min. You can judge based on recovery of SM whether the anion requires more time to form or you need more LDA because adventitious water is present. If these two do not increase the yield then you may have an example where the electrophile has an acidic proton and it quenches the anion rather than forms a bond.]
3. Add the electrophile (1.2 mmol) as a solid or as a solution in 2 mL THF via cannula needle to the anion solution. Stir 15 min/-78°C and then 1 hour/0°C. [note: This is usually more than enough time for organolithium reactions.]
4. Dilute with 1 M aqueous NH₄Cl and EtOAc. Partition. Wash the organic layer with water, brine, dry (MgSO₄) and evaporate to provide the product residue ready for further purification.