The Utility of Ether Solvents and Special Auxiliaries with Organometallic Reagents

Organometallic reagents, such as organolithium compounds and Grignard reagents, are not monomeric in solvents that cannot donate Lewis electron pairs; therefore, because they are self-associated they often are not as reactive with an organic substrate as the monomer would be.  Ether solvents, with or without other chemical auxiliaries, can often dissociate organometallic reagents into monomers without degrading them. Each useful ether has its own limited temperature range. At too low a temperature the solvent either solidifies or becomes too viscous to be worked with and at too high a temperature reaction between the organometallic and the ether destroys the reagent. These de-oligomerizing solvents vary in such important aspects as price per unit volume, ease of purification, and the simplicity with which they can be made effectively anhydrous. The extent to which each of the solvents is miscible with water and recoverable from water also plays a role in the practical usefulness of each.

Special Auxiliary Chemicals

Besides ethers and polyethers there are various other complexing additives that can be useful when added in some low multiple of the organometallic’s molarity. These also modify the reactivity and stability of an organometallic reagent already in one of these ethers.  Sometimes, one of these additives makes it possible to use an ether solvent that otherwise would fail when used alone. Sometimes,  one of these additives activates a reagent so effectively that a solvent that is even less complexing than an ether or not complexing at all (like toluene) can be employed successfully. Some of the additives used successfully are: N,N’-tetramethylethylenediamine; HMPA; N,N’-dimethyl- ethylenephosphoramide; triethylenediamine; or lithium bromide.

Because ethers have such useful properties in organometallic reactions and can be supplemented or replaced, associated special advantages and disadvantages are important to know. Solvent choice is in general the most important discrete, discontinuous element among reaction conditions ( time and temperature are continuous variables). Let us look at the various ether solvents.

Diethyl Ether

Diethyl ether is the most frequent solvent for making Grignard reagents in the laboratory. Butyllithium can also be prepared in diethyl ether in the laboratory. At scale diethyl ether’s dangerous flammability and its exceptional tendency to form peroxides makes it unsuitable for making organometallics of any kind without extraordinary costly precautions. It is simply not done. 

Tetrahydrofuran (THF)

THF is the most common replacement at scale when making both Grignard and organolithium reagents. When the combination of too high a temperature with too long a time organolithiums decompose THF.  For example, a molecule of butyllithium splits THF into one equivalent of ethylene and one equivalent of the anion of acetaldehyde. 

THF has the disadvantages that it is miscible with water and consequently is a problem to recover and it forms no azeotropes to help in solvent switches to remove water and to dry it.

2-Methyltetrahydrofuran

2-Methyl THF has become popular because it has the advantage of being largely immiscible with water, thus enabling its simpler recovery while retaining the ability to complex organometallic reagents. Its boiling point of 80.2ºC is still acceptable but of course, it is more expensive than THF.