Graduate Thesis Or Dissertation
 

Towards the Routine Computational Investigation of Complex Organocatalysis and Reaction Processes

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  • In this Dissertation, the mechanism and stereomechanics of complex organocatalysis and reaction processes are disclosed. The technologies and protocols currently being developed and utilized to efficiently investigate these systems using theory are highlighted. A detailed computational study of peptide-catalyzed acylations is disclosed. In particular, the magnitude of all possible non-bonding interactions in this reaction have been computed. ⁺CH•••O⁻ interactions are greater in magnitude than other non- bonding interactions in this reaction (~41-48 vs ~3-15 kcal/mol). This suggests that counterion effects manifested through ⁺CH•••O⁻ are critical in the transition state. The base counterion is anchored between the reactive alcohol undergoing base-catalysis and acylated N-methylimidazolium through ⁺CH•••O⁻. Considering the relative magnitudes of interactions, realization of ⁺CH•••O⁻s is of the highest priority among all other non-bonding interactions. Stereocontrol arises from the ability of the peptide to conform around a conserved, rigid substrate transition state geometry. A study of the mechanism and stereomechanics of the organocatalytic site- selective silylation of meso-1,2-diols is disclosed. Previous hypotheses of the mechanics of this reaction stemmed from the reversible and rapid formation of the substrate-catalyst complex in which the substrate is preferentially bound syn to the catalyst oxazolidine i-Pr. Computed silylation barriers show that this syn-complex is part of a parasitic equilibrium and does not lead to product formation. This revises existing hypotheses about the mechanism and factors that control site-selectivity. Steric congestion involving the catalyst i-Pr groups in the transition state hinders silylation of the syn-bound substrate. Site-selectivity is mainly controlled by two factors: 1) match/mis-match between the substrate diol conformational chirality and the chiral organic catalyst, and 2) steric interactions between the silylating reagent and the catalyst-substrate complex. MIDA boronates, a coupling reagent, has been used as an increasingly general platform for building-block based small molecule construction, largely due to the dramatic and general rate differences with which they are hydrolysed under various basic conditions. Yet the mechanistic underpinnings of these rate differences have remained unclear, hindering efforts to address current limitations of this chemistry. In this Dissertation, the hydrolysis mechanism mediated by aqueous sodium hydroxide is disclosed. All computational predictions and experimental evidence lead to the conclusion that NaOH-mediated hydrolysis begins with the rate-limiting, but facile attack at a MIDA carbonyl carbon by hydroxide (∆G‡comp = 2.2 kcal/mol). The second hydrolysis involves the attack at the boron by either hydroxide or water. Computations predicted a ¹²C/¹³C KIE of 1.03 at the MIDA carbonyl carbon in the rate-limiting step, consistent with the experimental observed ¹²C/¹³C KIE of 1.047. Moreover, the NaOH-mediated mechanism discovered through computations corroborate experimental observations of single ¹⁸O incorporation into MIDA after hydrolysis.
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  • 2017-08-04 to 2018-05-29
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