Invoking Halogen Bonding: An Investigation of Halogenation Reactions Promoted By the Halogen Bonding Phenomenon Between Commercially Available Halogenating Reagents And Lewis Basic Additives
- Baker, Sarah Irene
- Advisor(s): Baxter, Ryan D;
- Hratchian, Hrant P
Abstract
Halogenation has become of great interest. Recent studies show the biological advantages when pharmaceuticals contain various halogen-carbon bonds. Halogenated compounds are used in metal-catalyzed cross-coupling reactions, pesticides, and natural products. Previously, our lab has reported radical benzylic C-H fluorination using Selectfluor, as a mild oxidant and fluorine source, in the presence of unprotected amino acids and Ag(I). In doing control reactions, we found that N-protected amino acids did not yield any product, suggesting free nitrogen was required. In contrast to the amino acid/Ag(I) method, we found that a carboxylate group was not required as long as a free nitrogen additive, such as pyridine. Herein, we report an effective method for C-H fluorination via halogen-bonding between Selectfluor and monosubstituted pyridine additives. Computational and NMR studies showed that the Lewis basicity of the pyridine additive must be optimum for halogen-bonding but not strong enough to promote unwanted side reactions.
Using this knowledge, we expanded this strategy to include C-H bromination using N-bromosuccinimide. During the initial investigation, we discovered aromatic bromination was favored over benzylic. While optimizing the reaction conditions, we determined lactic acid was an efficient catalyst for aromatic bromination. Several lactic acid derivatives were investigated and found to affect the efficiency of aromatic bromination via halogen-bonding interactions. This method gives access to a relatively less toxic procedure using catalytic mandelic acid under aqueous conditions at room temperature.
The last chapter of this dissertation depicts the development of an alternative method for halohydrin formation of alkenes. Several brominating reagents were assessed, and the best for this reaction was N-bromosaccharin. Through experimental investigations, it was determined that the carbonyl in the substrate was essential for the halohydrin formation to occur. Future work will further explore the reactivity of the carbonyl oxygen.
Chapter 2 is work adapted from J. Org. Chem. 2022, 87, 8492-8502.