UC Berkeley

Chapter 1. A literature review of supramolecular reaction control and the efforts made towards developing supramolecular catalysts is presented. Representative examples of the fundamental ways in which supramolecular encapsulation can promote reactivity are given, with emphasis placed on catalytic reactions involving self-assembled hosts. The [Ga4L6]12- supramolecular assembly developed by the Raymond group is introduced, and previous work on its ability to enhance the reactivity of its encapsulated guests is reviewed.

Chapter 2. The tetrahedral [Ga4L6]12- assembly encapsulates propargyl enammonium cations capable of undergoing the aza Cope rearrangement. For propargyl enammonium substrates that are encapsulated in the [Ga4L6]12- assembly, rate accelerations of up to 184 are observed when compared to the background reaction. After rearrangement, the product iminium ion is released into solution and hydrolyzed allowing for catalytic turnover. The activation parameters for the catalyzed and uncatalyzed reaction were determined, revealing that a lowered entropy of activation is responsible for the observed rate enhancements. The catalyzed reaction exhibits saturation kinetics; the rate data obey the Michaelis-Menten model of enzyme kinetics, and competitive inhibition using a non-reactive guest has been demonstrated.

Chapter 3. The tetrahedral [Ga4L6]12- assembly catalyzes the Nazarov Cyclization of 1,3-pentadienols with extremely high levels of efficiency. The catalyzed reaction proceeds at a rate over a million times faster than that of the background reaction, an increase comparable to those observed in some enzymatic systems. This catalysis operates under aqueous conditions at mild temperature and pH ranges, and the reaction is halted by the addition of an appropriate inhibitor. The product of this reaction, pentamethylcyclopentadiene, is a competitive guest in the host assembly, and the catalysis suffers from product inhibition. This was alleviated by the addition of maleimide, which readily undergoes a Diels-Alder reaction with the product to form a more weakly-encapsulated adduct.

Chapter 4. The kinetically-controlled, regioselective deprotonation of cyclopentenyl cations mediated by encapsulation within the [Ga4L6]12- assembly is presented. The regiochemistry of the deprotonation step determines which one of two possible products is formed. Although this deprotonation step occurs at both possible positions outside the host interior, encapsulation renders the process >95% regioselective. Moreover, subtle differences in the stereochemistry of the encapsulated cyclopentenyl cation switch the product selectivity of this process. This reactivity shares several features with the regioselective, enzyme-controlled deprotonation of the geranyl cation involved in the biosynthesis of myrcene and β-ocimene.

Chapter 5. Mechanistic studies of the processes described in the two preceding chapters are presented. A combined experimental and computational approach is used to elucidate the reaction mechanism of both the catalyzed and the uncatalyzed Nazarov cyclization of pentadienols. Kinetic analysis, 18O exchange experiments, and computational studies implicate a mechanism in which encapsulation, protonation and water loss from substrate are reversible, followed by irreversible electrocyclization. While electrocyclization is rate-determining in the uncatalyzed reaction, the barrier for water loss and for electrocyclization are nearly equal in the assembly-catalyzed reaction. Analysis of the proposed energetics of the catalyzed and uncatalyzed reaction revealed that transition state stabilization contributes significantly to the catalytic rate acceleration.