It is known that both THF and 2-MeTHF are popular solvents in organic synthesis. In the same way, so many studies described that 2-MeTHF is a good replacement for THF in specialized applications such as Grignard reagent reacts with carbonyl compounds. Then is 2-MeTHF actually a better synthesis solvent than THF? Believe most chemistry researchers will ask this.

From the perspective of green chemistry, the answer is YES. 2-MeTHF can be derived from renewable resources and is more stable to acids and alkalis that is not easy to form peroxides. Additional, 2-MeTHF can be separated into phases for post-treatment more easily as the feature of water-immiscible.

Next, I will continue to explain why 2-MeTHF has greater advantages from the following three aspects.

1. Introduction for 2-MeTHF and THF

2-MeTHF, also known as 2-methyltetrahydrofuran, a biomass‐derived solvent with broad application in organic chemistry, is a colorless clear liquid with an ether-like smell. It is easily soluble in organic solvents such as ethanol, ether, acetone, benzene and chloroform. It can be also soluble in water and the solubility in water increases with decreasing temperature. Generally speaking, commercial products often add 0.1% hydroquinone stabilizer and the maximum allowable concentration in the air is 0.04%. This is because it is prone to deterioration when exposed to air and bright flames or strong oxidizers may cause burning hazards.

THF, also known as Tetrahydrofuran, is also a colorless clear, water-miscible liquid with low viscosity. At early stages, it is widely used in the reactions involving metal reagents, such as LDA, n-BuLi, etc. It can also be used in reduction reactions such as LiAlH4 and DIBAL-H or in addition reactions such as Grignard reagent addition reaction and so on.

2. Properties comparing between 2-MeTHF and THF

Below table 1 shows that Its boiling point is 80.2 degrees, which is higher than the boiling point of THF at 66 degrees. In addition, the difference from the solubility is that THF is miscible with water and 2-MeTHF in water is relatively poor. Therefore, there is no additional solvent layering required when using the solvent of 2-MeTHF.

Properties2-MeTHF THF
Molecular weight86.1 72.1
Boiling point(℃)80.266
Melting point(℃)-136-108.5
Vapor pressure at 20℃(mm)102143
Density at 20℃(g/ml)0.8540.887
Viscosity at 25℃(cp)0.600.55
Refractive index at 20℃1.4081.465
Heat of vaporization(cal/g)at boiling point87.129.6
Solubility in water at 20℃(g/100g)14
Water solubility 20℃(g/100g)4.4
Azeotrope boiling point(℃)71(11wt%)64(6.0wt%)
SP value8.99.5
Repeated Does Toxicity26111.3
Table 1

The data in table 2 shows that the solvent polarity and Lewis basicity of 2-MeTHF is lower than THF. That’s to say, 2-MeTHF can replace many reactions that are carried out in THF, and the effect may be better. What’s more, 2-MeTHF is much better than THF considering the toxicity issues.

Dielectric const6.977.5
Dipole moment, Debye1.381.69
Water Solubility, g/100g4.4
Hildebrand, MPa½16.918.7
Solvation energy, kcal/mol0.60
Donor number1820.5
Table 2

3. Reactions comparing

As mentioned earlier, the Grignard reaction, Reformatsky reaction, Lithiation reaction, Hydride reduction reaction, and coupling reaction carried out in THF can also be carried out using 2-MeTHF. Take the Grignard reaction as an example. See table 3, basically, 2-MeTHF can be equal to THF, and for some reactions, it is even better than THF.

Halide ReagentElectrophile2-MeTHF, %THF, %
2-Chlorobenzyl chlorideMEK5812
Table3: Nonisolated yields

DCM is also a popular solvent in organic synthesis work which is sensitive to nucleophiles such as amines. For the two-phase reaction, 2-MeTHF has more advantages than DCM and often shows superior high activity. However, 2-MeTHF is not as sensitive as DCM even though its boiling point is higher than DCM.

In addition, the advantage of 2-MeTHF for extracting highly polar compounds is also more obvious than other solvents such as toluene. Of course, as an ether solvent, 2-MeTHF shows a similar oxidation rate to THF. Relatively speaking, 2-MeTHF is more acid-resistant than THF. The following figure shows the stability test of the two under the action of 5N HCl at 60 degrees.

Time(h)2-MeTHF(%) degradedTHF(%)degraded
Table 4: Stability test result under the action of 5N HCl at 60 degrees

4. Applications comparing

In large-scale production, the initiation step of the Grignard reaction is usually difficult to control, and the subsequent reaction process will be strongly exothermic. Solvents usually account for most of the production process, so safety, cost and selection of appropriate post-processing methods are essential. Among the commonly used solvents, there is a lower boiling point for ether (Et2O) and THF and can form peroxides easily, which are unfavorable for the reaction with dangerous. So these two solvents are not ideal solvents for industrial production.

2-MeTHF is currently being widely used in industrial production as a new type of solvent. In addition, it can be used as an automotive fuel additive to replace part of gasoline. Its advantage is that it can be miscible with gasoline in any ratio and has excellent oxidation and vapor pressure properties. Studies have shown that the proportion of 2-MeTHF in gasoline exceeds 60%, which will not have any impact on engine performance and the fuel consumption of automobiles will not increase.


2-MeTHF is a promising alternative solvent in the search for environmentally benign synthesis strategies.

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