2,5-Diethyl-2,5-Dimethyloxolane (DEDMO) as a Nonpolar, Nonperoxide-Forming Ether Solvent for Organic Synthesis

The development of safer and more sustainable solvents is an important discipline in the context of stricter regulations and environmental protection. This work demonstrates the sustainable synthesis of a potentially bio-based, inherently nonperoxide-forming ether solvent, namely, 2,5-diethyl-2,5-dimethyloxolane (DEDMO), in quantitative yields with high atom economy (97%) and reaction mass efficiency (94%) from renewable sources. Quantum mechanical calculations of theoretical NMR chemical shifts and DP4+ probability modeling indicated that the cis isomer of DEDMO was most plausible (with a probability value of 99.98%); however, the actual NMR data suggested a 1:1 mixture of cis and trans isomers for DEDMO. The solvation properties of DEDMO have also been evaluated using Kamlet–Abboud–Taft (KAT) parameters, Hansen solubility parameters (HSPs), and in silico modeling COSMO-RS. The KAT parameter relating to a combined effect of solvent polarity and polarizability (π*) was 0.32 for DEDMO, which was lower than other quaternary ethers such as 2,2,5,5-tetramethyloxolane (TMO) (0.35) and cineole (0.41). In silico COSMO-RS modeling suggested that DEDMO has similar characteristics to hydrocarbon solvents such as n-hexane or toluene. The substitution of all hydrogen atoms at the α-position to the ethereal oxygen with an alkyl group, such as the methyl and ethyl groups of DEDMO, inhibits its ability to form explosive peroxides. Moreover, the steric concealment of the ethereal oxygen of DEDMO leads to similar properties to hydrocarbon solvents rather than traditional ether solvents. The performance of DEDMO as a solvent is demonstrated in an enzymatic esterification, as well as heterocyclic synthesis by means of a Biginelli reaction, and annulation reactions. Application testing of DEDMO revealed that its behavior was similar in solvent properties to hydrocarbon solvents; in fact, results were typically between those of toluene and n-hexane. The presence of ethyl groups enhances its nonpolar character, and as such, DEDMO was demonstrated to perform better than the green quaternary ethers TMO in some reactions. Preliminary in silico toxicity predictions indicate that DEDMO is nonmutagenic, and thus DEDMO is a potentially green hindered ether solvent for the substitution of conventional nonpolar solvents.