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

TY - JOUR

T1 - 2,5-Diethyl-2,5-Dimethyloxolane (DEDMO) as a Nonpolar, Nonperoxide-Forming Ether Solvent for Organic Synthesis

AU - Noppawan, Pakin

AU - Sangon, Suwiwat

AU - Supanchaiyamat, Nontipa

AU - Sherwood, James

AU - Hunt, Andrew J.

N1 - Funding Information: This work was financially supported by Materials Chemistry Research Center, Department of Chemistry, Faculty of Science, Khon Kaen University. Andrew Hunt acknowledges the financial support of the Thailand Research Fund (Grant number RSA6280031) and Khon Kaen University. The Center of Excellence for Innovation in Chemistry (PERCH-CIC), Ministry of Higher Education, Science, Research and Innovation is also gratefully acknowledged. The authors acknowledge the use of the EPSRC funded Physical Sciences Data-science Service hosted by the University of Southampton and STFC under grant number EP/S020357/1. Funding Information: The authors thank the Materials Chemistry Research Center, Department of Chemistry, Faculty of Science, Khon Kaen University, for financial support. They gratefully acknowledge funding through the Thailand Research Fund under grant agreement number RSA6280031 and Khon Kaen University. The Center of Excellence for Innovation in Chemistry (PERCH-CIC), Ministry of Higher Education, Science, Research and Innovation is also gratefully acknowledged. COSMO-RS calculations are courtesy of, and authorized for the purposes of, Circa Group Pty Ltd. The authors acknowledge the use of the EPSRC funded Physical Sciences Data-science Service hosted by the University of Southampton and STFC under grant number EP/S020357/1. Publisher Copyright: © 2022 American Chemical Society.

PY - 2022/4/11

Y1 - 2022/4/11

N2 - 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-thyl-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 (II*) 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.

AB - 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-thyl-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 (II*) 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.

KW - bio-based solvent

KW - ether

KW - nonperoxide-forming

KW - nonpolar solvent

KW - organic synthesis

UR - http://www.scopus.com/inward/record.url?scp=85127379657&partnerID=8YFLogxK

U2 - 10.1021/acssuschemeng.1c07748

DO - 10.1021/acssuschemeng.1c07748

M3 - Article

AN - SCOPUS:85127379657

SN - 2168-0485

VL - 10

SP - 4486

EP - 4493

JO - ACS Sustainable Chemistry and Engineering

JF - ACS Sustainable Chemistry and Engineering

IS - 14

ER -