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

The development of safer and more sustainablesolvents is an important discipline in the context of stricterregulations and environmental protection. This work demonstratesthe sustainable synthesis of a potentially bio-based, inherentlynonperoxide-forming ether solvent, namely, 2,5-diethyl-2,5-dime-thyloxolane (DEDMO), in quantitative yields with high atomeconomy (97%) and reaction mass efficiency (94%) fromrenewable sources. Quantum mechanical calculations of theoreticalNMR chemical shifts and DP4+ probability modeling indicatedthat thecisisomer of DEDMO was most plausible (with aprobability value of 99.98%); however, the actual NMR datasuggested a 1:1 mixture ofcisandtransisomers for DEDMO. Thesolvation properties of DEDMO have also been evaluated using Kamlet-Abboud-Taft (KAT) parameters, Hansen solubilityparameters (HSPs), andin silicomodeling COSMO-RS. The KAT parameter relating to a combined effect of solvent polarity andpolarizability (pi*) 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 silicoCOSMO-RS modeling suggested that DEDMO has similar characteristics to hydrocarbonsolvents such asn-hexane or toluene. The substitution of all hydrogen atoms at the alpha-position to the ethereal oxygen with an alkylgroup, such as the methyl and ethyl groups of DEDMO, inhibits its ability to form explosive peroxides. Moreover, the stericconcealment of the ethereal oxygen of DEDMO leads to similar properties to hydrocarbon solvents rather than traditional ethersolvents. The performance of DEDMO as a solvent is demonstrated in an enzymatic esterification, as well as heterocyclic synthesisby means of a Biginelli reaction, and annulation reactions. Application testing of DEDMO revealed that its behavior was similar insolvent properties to hydrocarbon solvents; in fact, results were typically between those of toluene andn-hexane. The presence ofethyl groups enhances its nonpolar character, and as such, DEDMO was demonstrated to perform better than the green quaternaryethers TMO in some reactions. Preliminaryin silicotoxicity predictions indicate that DEDMO is nonmutagenic, and thus DEDMOis a potentially green hindered ether solvent for the substitution of conventional nonpolar solvents