Defense Date
9-21-2025
Graduation Date
Fall 12-19-2025
Availability
Immediate Access
Submission Type
dissertation
Degree Name
PhD
Department
Chemistry and Biochemistry
School
School of Science and Engineering
Committee Chair
Thomas Montgomery
Committee Member
Jeffrey Evanseck
Committee Member
Michael Cascio
Committee Member
Osvaldo Gutierrez
Keywords
Organic Chemistry, Organic Synthesis, Density Functional Theory, Chemistry, Theoretical Chemistry
Abstract
Density functional theory (DFT) provides a method for calculating the ground-state energies of complex molecular systems through evaluating the electron density instead of the full wave function. When results match either experimental outcomes, calculations with DFT offer a computationally efficient method to help explain chemical phenomena. The transformation of tertiary amine N-oxides to azomethine ylides, a simple route to the precursor for 1,3-dipolar cycloadditions that result in the pyrrolidine scaffolds found in natural products, has received only minimal attention due to concerns that its mechanism includes a highly electrophilic intermediate. Utilizing DFT to model the mechanism of the conversion of tert-butyl pyrrolidine N-oxide demonstrated that a more energetically favorable pathway moves through a novel intermediate, the multi-ion bridge, instead of the highly electrophilic iminium. These findings remain consistent with experiment and higher orders of computational theory, and since the multi-ion bridge is neither electro- nor nucleophilic, it offers a better explanation for the major products resulting from N-oxides containing nucleophilic unprotected alcohols. Continued exploration with more complex approaches for computationally modeling explicit solvents further improved the mechanistic understanding without deviating from the multi-ion bridge pathway. Beyond deepening mechanistic understandings, DFT provides the potential for quicker predictive screening, saving both experimental time and costs. Applying the time-dependent offset of DFT (TD-DFT), a method was developed to predict the lambda max of aza-DIPY dyes, which is accurate within 5% of the experimental value. Additionally, progress was made on developing a predictive model for the stereoselectivity of 1,3-dipolar cycloaddition from N-oxide-derived azomethine ylides.
Language
English
Recommended Citation
Neal, M. J. (2025). Discovery of the Multi-Ion Bridge Intermediate: A Computational Exploration of the Mechanism for Azomethine Ylide Formation from N-Oxides (Doctoral dissertation, Duquesne University). Retrieved from https://dsc.duq.edu/etd/2388
Additional Citations
Neal, M. J.; Hejnosz, S. L.; Rohde, J. J.; Evanseck, J. D.; Montgomery, T. D. Multi-Ion Bridged Pathway of N-Oxides to 1,3-Dipole Dilithium Oxide Complexes. J. Org. Chem. 2021, 86 (17), 11502-11518.
Neal, M. J.; Chartier, E. J.; Lane, A. M.; Hejnosz, S. L.; Jesikiewicz, L. T.; Liu, P.; Rohde, J. J.; Lummis, P.; Fox, D. J.; Evanseck, J. D.; et al. N-Oxide Insertion into LDA Dimeric Aggregates for Azomethine Ylide Formation: Explicit Solvation in Quantum Mechanical Treatment of Polarized Intermediates. J. Org. Chem. 2025. DOI: 10.1021/acs.joc.4c03090.