Carbon-nitrogen bond-forming reactions in supercritical and expanded-liquid carbon dioxide media : green synthetic chemistry with multiscale reaction and phase behavior modeling
Author(s)Ciccolini, Rocco P
Green synthetic chemistry with multiscale reaction and phase behavior modeling
Massachusetts Institute of Technology. Dept. of Chemical Engineering.
Jefferson W. Tester.
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The goal of this work was to develop a detailed understanding of carbon-nitrogen (C-N) bond-forming reactions of amines carried out in supercritical and expanded-liquid carbon dioxide (CO2) media. Key motivations behind this study were the importance of nitrogen-containing compounds in the pharmaceutical and fine chemical industries and a growing commercial interest in utilizing environmentally-friendly syntheses and processing with cost-efficient, green solvents. The thermodynamics and reaction engineering characteristics associated with the synthesis of several model C-N bond-forming reactions were examined both experimentally and theoretically. Operating conditions and engineering correlations were identified that will facilitate process scale-up and potential commercialization of these and other fundamentally-important CO2-based processes. Amine chemistry in CO2-based media was complicated by the facility of nucleophilic amines to react with carbon dioxide to form carbamic acids, which sometimes interfered with desired reaction pathways. Experimental observations and a complimentary ab initio quantum chemical calculation study revealed that carbamic acid formation was suppressed when adding bulky N-substituents to primary amines and when operating at low pressures and/or high temperatures. With a firm understanding of amine-CO2 chemistry, we developed a synthetic protocol that produced classes of pharmacologically-significant nitrogen heterocycles known as tetrahydroisoquinolines and tetrahyrdo-carbolines. Our method involved (1) the in situ carbamation of amines from their reaction with carbon dioxide and a dialkyl carbonate and (2) the Pictet-Spengler cyclization of these carbamates by their reaction with an aldehyde in the presence of acid. The conversion of amines to their carbamate derivatives offered suitable N-protection against carbamic acid formation.(cont.) For nearly all reactions studied, the Pictet-Spengler step proceeded nearly quantitatively. The efficiency of amine carbamation via the CO2/dimethyl (cont) carbonate (DMC) reaction system was highly sensitive to process operating conditions. Phase behavior, amine conversion, and carbamate yield and selectivity all varied appreciably with temperature, pressure, and amine feed concentration. For example at 130 oC, carbamate selectivity increased from 50 to 75% with increasing pressure up to the mixture critical pressure of the CO2/DMC binary system (P, mixco2/DMC ). Selectivity decreased to 55% for ... mix of the entire reaction system (P,mixsystem). Above Pmixsytem,, selectivity increased to 80%. At 105 bar, decreasing temperature from 150 to 100 oC led to an increase in carbamate selectivity by 25%. Finally, decreasing the amine feed concentration from 4 to 1 M resulted in an increase in carbamate selectivity by 30%. Mixture critical pressures (Pc,mix) and liquid-phase densities, species concentrations, and volume expansion were measured for the CO2/DMC system over a wide range of operating conditions. Importantly, we developed an equation-of-state (EOS) model and several empirical engineering correlations that were used to predict vapor-liquid equilibrium properties in P-T-xi regimes for which data were not available. Deviations from experimental data and empirical correlations were typically less than 9%. Pmix CO2/DMC data were measured for 37 < T < 150 oC and were correlated well by a third-order polynomial. Liquid-phase carbon dioxide concentration ([CO2]I) varied linearly with pressure for 37 to 100 oC. Liquid-phase volume expansion (AV/) measured for the same temperature range increased exponentially with increasing pressure. Maximum-possible values of [C02]1 and AVI decreased with increasing temperature. [CO211 was 2 to 4 times larger than that of pure CO2 when compared at the same Tand P.(cont.) We also developed and optimized a practical and high atom-economy C02-based synthetic protocol that afforded amides via the amination of ketenes generated in situ from the thermolysis of 1-alkynyl ethers. A variety of amines, 1-alkynyl ethers, and ketenes participated efficiently in the reaction and produced amides in yields comparable to those of conventional solvents. Experimental phase partitioning observations agreed well with EOS-based predictions and aided in the determination of process operating conditions. Amide yield varied in the order secondary > branched-primary > primary amines, which suggested that carbamic acid formation may have diminished reaction efficiency. t-butoxy-substituted 1-alkynyl ethers produced ketenes at rates faster than ethoxy-substituted ethers and allowed for a considerable reduction in operating temperature. Extension of the amide synthesis protocol to an intramolecular variant that afforded lactams resulted in a significant decrease in selectivity when compared to conventional solvents. We suspected that multi-phasic behavior led to this discrepancy and were able to increase selectivity by 25% using CO2/co-solvent mixtures. Finally, an ab initio quantum chemical kinetic model was developed and was capable of qualitatively predicting observed amide formation dynamics. Product selectivity and amine consumption rate predictions, for example, agreed well with experimental data.
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2008.Includes bibliographical references.
DepartmentMassachusetts Institute of Technology. Dept. of Chemical Engineering.
Massachusetts Institute of Technology