Showing papers by "Donna G. Blackmond published in 2019"

Hindered dialkyl ether synthesis with electrogenerated carbocations

Abstract: Hindered ethers are of high value for various applications; however, they remain an underexplored area of chemical space because they are difficult to synthesize via conventional reactions1,2. Such motifs are highly coveted in medicinal chemistry, because extensive substitution about the ether bond prevents unwanted metabolic processes that can lead to rapid degradation in vivo. Here we report a simple route towards the synthesis of hindered ethers, in which electrochemical oxidation is used to liberate high-energy carbocations from simple carboxylic acids. These reactive carbocation intermediates, which are generated with low electrochemical potentials, capture an alcohol donor under non-acidic conditions; this enables the formation of a range of ethers (more than 80 have been prepared here) that would otherwise be difficult to access. The carbocations can also be intercepted by simple nucleophiles, leading to the formation of hindered alcohols and even alkyl fluorides. This method was evaluated for its ability to circumvent the synthetic bottlenecks encountered in the preparation of 12 chemical scaffolds, leading to higher yields of the required products, in addition to substantial reductions in the number of steps and the amount of labour required to prepare them. The use of molecular probes and the results of kinetic studies support the proposed mechanism and the role of additives under the conditions examined. The reaction manifold that we report here demonstrates the power of electrochemistry to access highly reactive intermediates under mild conditions and, in turn, the substantial improvements in efficiency that can be achieved with these otherwise-inaccessible intermediates.

Energy threshold for chiral symmetry breaking in molecular self-replication.

Abstract: The homochirality of biological molecules (right-handed sugars and left-handed amino acids) is a signature of life. Extensive research has been devoted to understanding how enrichment of one enantiomer over the other might have emerged from a prebiotic world. Here, we use experimental data from the model Soai autocatalytic reaction system to evaluate the energy required for symmetry breaking and chiral amplification in molecular self-replication. One postulate for the source of the original imbalance is the tiny difference in energy between enantiomers due to parity violation in the weak force. We discuss the plausibility of parity violation energy difference coupled with asymmetric autocatalysis as a rationalization for absolute asymmetric synthesis and the origin of the homochirality of biological molecules. Our results allow us to identify the magnitude of the energy imbalance that gives rise to directed symmetry breaking and asymmetric amplification in this autocatalytic system.

Highly Modular Synthesis of 1,2-Diketones via Multicomponent Coupling Reactions of Isocyanides as CO Equivalents

Abstract: A one-pot, four-component Pd-catalyzed coupling has been developed for the synthesis of unsymmetrical 1,2-diketones from aryl halides and alkyl zincs employing tert-butyl isocyanide as a CO source. The intermediate 1,2-diketones have been elaborated to quinoxalines. Mechanistic studies help to rationalize the high selectivity for the bis- vs monoinsertion product.

Kinetic Analysis of Catalytic Organic Reactions Using a Temperature Scanning Protocol

Abstract: Experimental and kinetic modelling studies are presented to describe the development of temperature scanning reaction progress protocol for batch reactions. Coupled with graphical manipulations, this approach enables the expansion of in‐situ kinetic studies from a focus on isothermal concentration profiles to include reaction temperature as a parameter for rapid kinetic and mechanistic analysis.

Autocatalytic Models for the Origin of Biological Homochirality

Abstract: Mechanistic studies of the Soai autocatalytic reaction in the context of biological homochirality.

Utilizing Native Directing Groups: Mechanistic Understanding of a Direct Arylation Leads to Formation of Tetracyclic Heterocycles via Tandem Intermolecular, Intramolecular C–H Activation

Abstract: A mechanistic study on a direct arylation using a native picolylamine directing group is reported. Kinetic studies determined the concentration dependence of substrates and catalysts, as well as catalyst degradation, which led to the development of a new set of reaction conditions capable of affording a robust kinetic profile. During reaction optimization, a small impurity was observed, which was determined to be a dual C-H activation product. A second set of conditions were found to flip the selectivity of the C-H activation to form this tetracycle in high yield. A catalytic cycle is proposed for the intermolecular/intramolecular C-H activation pathway.