Beyond Strain Release: Delocalization-Enabled Organic Reactivity

The release of strain energy is a fundamental driving force for organic reactions. However, absolute strain energy alone is an insufficient predictor of reactivity, evidenced by the similar ring strain but disparate reactivity of cyclopropanes and cyclobutanes. In this work, we demonstrate that electronic delocalization is a key factor that operates alongside strain release to boost, or even dominate, reactivity. This delocalization principle extends across a wide range of molecules containing three-membered rings such as epoxides, aziridines, and propellanes and also applies to strain-driven cycloaddition reactions. Our findings lead to a “rule of thumb” for the accurate prediction of activation barriers in such systems, which can be easily applied to reactions involving many of the strained building blocks commonly encountered in organic synthesis, medicinal chemistry, polymer science, and bioconjugation. Given the significance of electronic delocalization in organic chemistry, for example in aromatic π-systems and hyperconjugation, we anticipate that this concept will serve as a versatile tool to understand and predict organic reactivity

Atropisomerism in Diarylamines:Structural Requirements and Mechanisms of Conformational Interconversion

In common with other hindered structures containing two aromatic rings linked by a short tether, diarylamines may exhibit atropisomerism (chirality due to restricted rotation). Previous examples have principally been tertiary amines, especially those with cyclic scaffolds. Little is known of the structural requirement for atropisomerism in structurally simpler secondary and acyclic diarylamines. In this paper we describe a systematic study of a series of acyclic secondary diarylamines, and we quantify the degree of steric hindrance in the ortho positions that is required for atropisomerism to result. Through a detailed experimental and computational analysis, the role of each ortho‐substituent on the mechanism and rate of conformational interconversion is rationalised. We also present a simple predictive model for the design of configurationally stable secondary diarylamines

A Systematic Evaluation of Chip-Based Nanoelectrospray Parameters for Rapid Identification of Proteins from a Complex Mixture

HPLC-MS/MS is widely used for protein identification from gel spots and shotgun fractions. Although HPLC has well recognized benefits, this type of sample infusion also has some undesirable attributes: relatively low sample throughput, potential sample-to-sample carryover, time-varying sample composition, and no option for longer sample infusion for longer MS analyses. An automated chip-based ESI device (CB-ESI) has the potential to overcome these limitations. This report describes a systematic evaluation of the information-dependant acquisition (IDA) and sample preparation protocols for rapid protein identification from a complex mixture using a CB-ESI source compared with HPLC-ESI (gradient and isocratic elutions). Cytochrome c and a six-protein mixture (11–117 kDa) were used to develop an IDA protocol for rapid protein identification and to evaluate the effects of sample preparation protocols. MS (1–10 s) and MS/MS (1–60 s) scan times, sample concentration (50–500 fmol/μL), and ZipTipC18 cleanup were evaluated. Based on MOWSE scores, protein coverage, experimental run time, number of identified proteins, and reproducibility, a 12.5 min experiment (22 cycles, each with one 3 s MS and eight 10 s MS/MS scans) was determined to be the optimal IDA protocol for CB-ESI. This work flow yielded up to 220% greater peptide coverage compared with gradient HPLC-ESI and provided protein identifications with up to a 2-fold higher throughput rate than either HPLC-ESI approach, whilst employing half the amount of sample over the same time frame. The results from this study support the use of CB-ESI as a rapid alternative to the identification of protein mixtures

α-Amino bicycloalkylation through organophotoredox catalysis †

Bridged bicycloalkanes such as bicyclo[1.1.1]pentanes (BCPs) and bicyclo[3.1.1]heptanes (BCHeps) are important motifs in contemporary drug design due to their potential to act as bioisosteres of disubstituted benzene rings, often resulting in compounds with improved physicochemical and pharmacokinetic properties. Access to such motifs with proximal nitrogen atoms (i.e. α-amino/amido bicycloalkanes) is highly desirable for drug discovery applications, but their synthesis is challenging. Here we report an approach to α-amino BCPs and BCHeps through the visible-light enabled addition of α-amino radicals to the interbridgehead C–C bonds of [1.1.1] and [3.1.1]propellane respectively. The reaction proceeds under exceptionally mild conditions and displays broad substrate scope, providing access to an array of medicinally-relevant BCP and BCHep products. Experimental and computational mechanistic studies provide evidence for a radical chain pathway which depends critically on the stability of the α-amino radical, as well as effective catalyst turnover

Visible light photoredox-catalyzed decarboxylative alkylation of 3-aryl-oxetanes and azetidines via benzylic tertiary radicals and implications of benzylic radical stability

4-Membered heterocycles offer exciting potential as small polar motifs in medicinal chemistry but require further methods for incorporation. Photoredox catalysis is a powerful method for the mild generation of alkyl radicals for C–C bond for-mation. The effect of ring strain on radical reactivity is not well understood, with no studies that address this question sys-tematically. Examples of reactions that involve benzylic radicals are rare, and their reactivity is challenging to harness. This work develops a radical functionalization of benzylic oxetanes and azetidines using visible light photoredox catalysis to prepare 3-aryl-3-alkyl substituted derivatives and assesses the influence of ring strain and heterosubstitution on the reactivity of small-ring radicals. 3-Aryl-3-carboxylic acid oxetanes and azetidines are suitable precursors to tertiary benzylic ox-etane/azetidine radicals which undergo conjugate addition into activated alkenes. We compare the reactivity of oxetane radi-cals to other benzylic systems. Computational studies indicate that Giese additions of unstrained benzylic radicals into acry-lates are reversible and result in low yields and radical dimerization. Benzylic radicals as part of a strained ring, however, are less stable and more -delocalized, decreasing dimer and increasing Giese product formation. Oxetanes show high product yields due to ring strain and Bent’s rule rendering the Giese addition irreversible

Electrophilic Activation of [1.1.1]Propellane for the Synthesis of Nitrogen-Substituted Bicyclo[1.1.1]pentanes

Strategies commonly used for the synthesis of functionalised bicyclo[1.1.1]pentanes (BCP) rely on the reaction of [1.1.1]propellane with anionic or radical intermediates. In contrast, electrophilic activation has remained a considerable challenge due to the facile decomposition of BCP cations, which has severely limited the applications of this strategy. Herein, we report the electrophilic activation of [1.1.1]propellane in a halogen bond complex, which enables its reaction with electron-neutral nucleophiles such as anilines and azoles to give nitrogen-substituted BCPs that are prominent motifs in drug discovery. A detailed computational analysis indicates that the key halogen bonding interaction promotes nucleophilic attack without sacrificing cage stabilisation. Overall, our work rehabilitates electrophilic activation of [1.1.1]propellane as a valuable strategy for accessing functionalised BCPs

The reactivity of strained carbocycles

The idea that increasing a reaction driving force will increase its rate is a central principle of chemistry. This principle has been used to great effect for the design of ‘strain-release’ reactions, in which a driving force is provided by building strain energy into the reactant. However, strain release alone is unable to account for the contrasting reactivity of even the simplest of systems, such as cyclopropane and cyclobutane which release near-identical amounts of strain energies but display stark differences in their rates of ring-opening. In this Thesis, the dominance of strain release is challenged by introducing the concept of electronic delocalisation to enhance reactivity: a more delocalised bond will be easier to break, and therefore incur a lower activation barrier to its cleavage resulting in a faster reaction rate. This idea is first explored through a computational study of the electronic structure and reactivity of [1.1.1]propellane (Chapter 2), before the importance of delocalisation is explored in the development of a new synthesis of alpha-chiral bicyclo[1.1.1]pentanes – important motifs in drug discovery (Chapter 3). The relationship between reaction rate, strain release and delocalisation is then quantified through the development of a predictive model for the reactivity of small rings in general (Chapter 4), where three-membered rings are found to be unique in their ability to cause delocalisation-enabled reactivity. In summary, this Thesis introduces a framework to better understand the relationship between ring strain and reactivity, and in doing so guide synthetic efforts towards new reaction design

A System for Plan Recognition in Discrete and Continuous Domains

For my thesis I seek to implement a programming framework which can be used to model and solve plan recognition problems. My primary goal for this system is for it to be able to easily handle continuous probability spaces as well as discrete ones. My framework is based primarily on the probabilistic situation calculus developed by Belle and Levesque, and is an extension of a programming language developed by Levesque called Ergo. The system I have built allows one to specify complex domains and dynamic models at a high-level and is written in a language which is user-friendly and easy to understand. It has strong formal foundations, can be used to compare multiple different plan recognition methods, and makes it easier to perform plan recognition in tandem with other forms of reasoning, such as threat assessment, reasoning about action, and planning to respond to the actions performed by the observed agent