A Combined Synthetic, In situ IR Spectroscopic and Computational Investigation of the Lithiation-Trapping Reactions of N-Boc Heterocycles

This thesis describes some novel aspects of the α-lithiation-trapping of N-Boc heterocycles, including computational DFT modelling of the lithiation and kinetic studies of both the lithiation and trapping reactions of N-Boc heterocycles. Chapter 2 details the use of in situ IR spectroscopy to monitor the progress of the α-lithiation reactions of a wide variety of N-Boc heterocycle substrates with vastly different reactivities. Different s-BuLi/ligand combinations were also found to have a dramatic effect on the rate of lithiation. Kinetic analysis of the in situ IR spectroscopic data enabled the rates of lithiation to be quantified which allowed the construction of a reactivity order for N-Boc heterocycles that were investigated. In Chapter 3, the α-lithiation reactions of the N-Boc heterocycles studied in Chapter 2 were modelled with DFT. Many of the reactivity differences of the N-Boc heterocycles that were uncovered by the experimental investigation were accounted for by the DFT modelling. Correlation of the experimental and computational results allowed the reactivities of unknown N-Boc heterocycles to be predicted using only DFT modelling. Chapter 4 describes the investigation of the rates of trapping of lithiated N-Boc heterocycles using in situ IR spectroscopy. Kinetic analysis of the in situ IR spectroscopic data revealed some remarkable differences in the rates of trapping for a small selection of different N-Boc heterocycles and electrophiles. Chapter 5 reports the use of synthesis, in situ IR spectroscopic analysis and DFT modelling to investigate how the electrophile and ligand employed can affect the diastereoselectivity of the lithiation-trapping of a 3,4-disubstituted N-Boc pyrrolidine.