hexamethylphosphoramide

Hexamethylphosphoramide, commonly abbreviated as HMPA, is an organophosphorus compound with the formula C6H18N3OP. It is a colorless, viscous liquid at room temperature and is notable for its high polarity and very strong coordinating ability. As a polar aprotic solvent, HMPA can stabilize cations in solution, making it useful in various organic transformations that involve strong bases or highly reactive anions.

Structure and properties: The molecule consists of a phosphoryl group (P=O) bound to three dimethylamide groups (NMe2), giving six methyl groups in total. The three NMe2 substituents contribute to its high dielectric constant and strong solvating power, particularly for metal cations such as lithium or magnesium in organometallic chemistry. Its solubility profile and coordinating behavior enable it to facilitate reactions that are sluggish in other solvents.

Preparation: HMPA is typically prepared by reacting phosphorus oxychloride (or related phosphorus chlorides) with dimethylamine to form the corresponding amide, followed by hydrolysis or subsequent processing to yield hexamethylphosphoramide.

Uses and limitations: Historically, HMPA has been employed as a solvent and as a coordinating additive in organic synthesis, especially to stabilize enolates and organometallic reagents and to promote selective lithiation or metalation. However, concerns about toxicity have led to restricted use in some settings and a shift toward safer alternatives such as dimethylpropyleneurea (DMPU) or dimethylimidazolidinone (DMI), which offer similar solvating properties with lower health risks.

Safety and handling: HMPA is regarded as a hazardous chemical with potential health risks upon exposure. Proper engineering and personal protective equipment, including fume hood containment and gloves, are advised. Waste should be disposed of according to applicable regulations, with efforts to substitute safer solvents where feasible.