QDIS Blog

Lesser known solvents

by Ed Vawter @ 12:06 pm. Filed under Drug Development

I want to talk about a couple of alternative solvents that get overlooked quite a bit in organic synthesis. The first is diethoxymethane (DEM; CAS [462-95-3]).

It has several uses based on it’s properties. First, it is a very good solvent fr Grignards and other organometallic reactions due to its low water levels typically less than 150 ppm (water solubility in DEM is 1.3% w/w). It llso has limited solubility in water; 4.2% w/w. It also has a low boiling ponit (88 °C) and Another attractive property is that DEM azetropes with ethanol (bp 74 °C, 58% DEM) and with water (bp 75 °C, 90% DEM).

It does tend to form peroxides after being opened and it is flammable (flashpoint of -5 °C). It is stable to base but does decompose under strong acid conditions.

While the solvent has been known for some time, it has only in the past ~6 years been commercially available in large quantities (55 gal drum to railroad tankcars from Eastman). It is in general a good replacement for dichloromethane, tetrahydrofuran, glyme (1,2-dimethoxyethane), and methylal (1,1-dimethoxymethane).

Here’s some information from Eastman Chemical and a publication from a few years ago in Org. Process Res. and Dev. 2001, 5, 127.

Eastman Chemical Information

Applications of Diethoxymethane as a Versatile Process Solvent and Unique Reagent in Organic Synthesis

Another solvent that gets overlooked is 1,3-dimethyl-2-imidazolidone (DMEU or DMI; CAS [80-73-9]). This can be used as a replacement for the highly toxic HMPA as a dipolar aprotic solvent.

It is very similar to 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone [7226-23-5] but has a lower boiling point.

It is similar to dimthylformamide but tends to be more stable. It is stable to alkali metals and strong bases and has a boiling point of 225 °C. Mitsui Chemicals America has a nice site with information on 1,3-dimethyl-2-imidazolidone including physical properties, chemical properties and some applications.

I have used both of these in my past and have been happy with the results and hope others will consider them for future projects.

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