Chemistry Commons^™

Computer Aided Design: Targeting The Pac1r For Novel Therapeutics And Investigating Biologically Relevant Materials, Kyle Thomas Mckay

Graduate College Dissertations and Theses

Computer aided drug design, a collection of computational methodologies including structure and ligand based drug design, has emerged as an efficient and accurate way to expedite the drug discovery process. Structure based drug design — methods which rely on the 3-dimensional structural information of biological targets — are of particular interest to chemists. Unfortunately, structural information can be difficult to obtain, and this can limit the usefulness of these methodologies. New methodologies and workflows, which are less reliant on difficult to obtain structural information are needed to fill in the gaps and push the drug development process forward. The first …

Development Of [3,3]-Sigmatropic Rearrangements Of Zwitterionic And Cationic Intermediates Formed By Intramolecular Cyclization Of Tertiary Allylic Amines Tethered To Heterocumulenes, Joseph Pisano

Graduate College Dissertations and Theses

Guanidines are ubiquitous in nature and serve as useful building blocks in biologically active natural products as well as non-nucleophilic bases and organocatalysts. There is thus a need for methods for the synthesis of guanidine compounds as well as isoelectronic groups such as isothioureas. The 1,3-diaza-Claisen rearrangement represents a powerful reaction by which to synthesize highly substituted guanidines.

The scope of the zwitterionic 1,3-diaza-Claisen rearrangement has been further investigated through the introduction of a two-carbon tether. Electron-deficient carbodiimides can be synthesized through desulfurization of isothioureas, which undergo intramolecular cyclization through a tethered tertiary amine bearing an allylic group to afford …

Synthesis And Characterization Of Highly Contorted Aromatics And Semiconducting Thioacenes, Adam M. Dyer

Graduate College Dissertations and Theses

Polycyclic aromatic hydrocarbons (PAHs) have shown great promise to produce new organic electronic materials. The networks of delocalized π-electrons present in these conjugated molecules allow for the mobilization of charge carriers. Compared to traditional electronic devices, this new class represents a more sustainable, lower cost, and solution processable alternative. Instability and poor intermolecular interactions are two key challenges preventing widespread adoption of said organic devices. However, the synthetic nature of organic molecules allows for fine tuning of electronic properties, offering a solution to these issues. Introduction of contorted conformations and heteroaromatic rings to PAH systems are discussed within this document …

Vinyl Cations As Cyclopentenone Precursors Via C‒H Insertion Or Alkene Addition Reactions, Magenta Hensinger

Graduate College Dissertations and Theses

We report that Lewis acid mediated reactions of β-hydroxy-α-diazo carbonyls provide facile access to vinyl cation intermediates, which can form mono- and bicyclic cyclopentenone ring systems. Vinyl cations are sp hybridized cations that can be exploited as carbene surrogates or as electrophiles. The methodology reported in this dissertation is important because cyclopentenone rings are common motifs in natural products or can be used as synthetic intermediates.

The first portion of this dissertation will discuss vinyl cations we’ve used as carbene surrogates in metal free C‒H insertion reactions. Treating β-hydroxy-α-diazo carbonyls with a Lewis acid provided vinyl cation intermediates after loss …

Transient Effects In Solution-Processed Organic Thin Films, Jing Wan

Graduate College Dissertations and Theses

Due to the weak van der Waals forces between organic semiconductor molecules, the molecular packing depends sensitively on the processing methods and conditions. Thus, understanding the crystallization mechanisms during solution deposition are essential for fundamental studies and reproducible fabrication of electronic devices.The performance of Organic field effect transistors (OFETs) also depends heavily on extrinsic factors such as contact resistance and interfacial defects, which can produce a different kind of transient effect at the metal-semiconductor contact. We have observed structural transient effects during the crystallization process of two small molecule organic semiconductors made from solution. We report in situ X-ray scattering …

Using Chirality-Assisted Synthesis To Construct Light-Responsive, Freeform Helical Foldamers And Shape-Defined Polymers, Jessica Leigh Bocanegra

Graduate College Dissertations and Theses

Foldamers (i.e. polymers which fold into well-defined shapes) are able to imitate arrangements of proteins, nucleic acids, and polysaccharides. However, previously reported foldamers are limiting in their ability to bind a multitude of guests—mainly due to very rigid conformational skeletal structures. Additionally, these structures commonly rely on π-π stacking and hydrogen bonding to dictate their shapes. We now report a helical foldamer that has (i) the capacity to bind selectively around a myriad of molecules while (ii) still embodying a well-defined, synthetically-controlled shape. We were able to create such structures as single-handed helices with chirality-assisted synthesis (CAS, see: Angew. Chem. …

Investigation Of The Intramolecular 1,3-Diaza-Claisen Rearrangement In The Ring Expansion Reactions Of Vinyl Pyrrolidines And Vinyl Piperidines, Teruki Watanabe

Graduate College Dissertations and Theses

The 1,3-diaza-Claisen rearrangement was discovered and developed in the Madalengoitia group since 2004. The rearrangement is initiated by the desulfurization of the electron deficient thiourea and isothiourea to obtain the highly electrophilic carbodiimide which can be reacted with an allylic tertiary amine to form the zwitterionic intermediate which then undergoes [3,3]-sigmatropic rearrangement. Previous investigation includes multiple examples of successful formation of complex guanidines through intermolecular and intramolecular variants. Providing an easy access to guanidine which is one of the most prevalent functional groups in the biologically relevant system, the rearrangement can be a valuable tool in the organic synthesis.

The …

Chirality-Assisted Synthesis Of Single-Handed Freeform Helical Ladder Polymers, Kyle Everett Murphy

Graduate College Dissertations and Theses

In nature, shape defines function, and as such scientists have long since attempted to mimic nature in a pursuit to reach a similar level of fidelity. Complex macromolecular structures and shapes have been developed with interesting and unique functionalities—such as the design and synthesis of molecular machines. However, macromolecular structures such as these are difficult to synthesize. My work in the Schneebeli group builds upon this challenge, where I have developed a strategy to precisely control the shape of macromolecules to generate well-defined structures. This was accomplished with stereoisomerically pure triptycene-like derivatives as the building block pieces which have an …

The Development And Expansion Of A Cationic 1,3-Diaza Claisen Rearrangement That Affords Guanidines, Jordan Tocher

Graduate College Dissertations and Theses

Guanidines are found readily in many natural product scaffolds and biological systems. However, the chemical makeup of the guanidines is such that synthesis of guanidine-containing molecules remains challenging. In 2004, the Madalengoitia group first reported a zwitterionic 1,3-diaza Claisen rearrangement that affords complex guanidines. This was later expanded from the initial strained-bridged bicyclic systems to systems that encompassed more linear precursors, positively charged intermediates, and compounds with ring-expansion applications.

Due to the historical precedent that introduction of a positive charge into a rearranging system can benefit the kinetics and thermodynamics of a reaction, experiments were designed in order to probe …

An Exploration Of Β -Hydroxy- Α -Diazo Carbonyls In Synthesis: Fragmentation, Vinyl Cation Formation And Conjugate Addition Reactions, Jian Fang

Graduate College Dissertations and Theses

β-hydroxy-α-diazo carbonyl compounds have been shown to display diverse reactivity profiles that can lead to a variety of useful products. This specific combination of functional groups can react in several mechanistically distinct ways depending on the presence or absences of other groups within the molecule. For example, -silyloxy-β-hydroxy-α-diazo carbonyls react with Lewis acids via fragmentation reactions to generate tethered aldehyde ynoate or ynone products. A portion of this thesis describes how this methodology was applied toward the synthesis of an important bioactive natural product: aspidospermidine. β-Hydroxy-α-diazo carbonyls are also convenient precursors to vinyl cations. The vinyl cation is generated by …

Sulfur And Selenium In Peptides And Proteins: Part I – Chemoselective Methods For Disulfide Bond Formation, Part Ii – Function Of Selenium In Enzymes., Emma Jean Ste.Marie

Graduate College Dissertations and Theses

Selenocysteine (Sec), the 21st proteogenic amino acid, was first identified in 1976 by Thressa Stadtman. In proteins, Sec replaces the far more common sulfur-containing amino acid cysteine (Cys). A key question since Stadtman’s discovery is: Why does Sec replace Cys? This question is especially relevant since Cys-orthologs of Sec-enzymes catalyze the identical reaction with only slightly reduced efficiency, and incorporation of Sec into a protein is much more complicated and bioenergetically costly compared to Cys. The study of selenoproteins is very difficult because Sec is incorporated into proteins by recoding a UGA stop codon as a sense codon. Production of …

I. Contorted Polycyclic Aromatic Hydrocarbons: Attempted Synthesis Of [12]Circulene Derivatives Ii. Synthesis And Characterization Of Novel [1]Benzothieno[3,2-B][1]Benzothiophene Derivatives, Jonathan Hollin

Graduate College Dissertations and Theses

There has been increasing interest in the development of organic materials due to their unique structural and electronic properties. Organic compounds have the advantage of being able to be deposited from solution, leading to low-cost, high-area electronics production. Contorted polycyclic aromatic hydrocarbons have been shown to have potential for use in organic field-effect transistors (OFETs) and organic photovoltaic devices (OPVs) due to their supramolecular properties and charge carrier mobilities. Thiophene-based materials have also shown great promise in OFETs due to their high charge carrier mobilities, stability during device operation, solubility in organic solvents, and structural versatility.

[n]Circulenes are a class …

Expansion Of The Intramolecular Zwitterionic-1,3-Diaza-Claisen Rearrangement Beyond Bridged-Bicyclic Electron-Deficient Isothioureas To Generate Substituted Cyclic Guanidines, Matthew William Luedtke

Graduate College Dissertations and Theses

Guanidines are ubiquitous in nature and have important applications in biological chemistry and industry, presenting themselves in biomacromolecules and organic materials respectively. The zwitterionic-1,3-diaza-Claisen rearrangement has allowed facile access to a variety of highly-substituted, complex guanidines, which would otherwise require a significant amount of time or resources to synthesize.

Previously, the intramolecular version of the 1,3-diaza-Claisen rearrangement has been used to generate tricyclic guanidines from bridged, bicyclic electron-deficient isothioureas. Extension of this methodology to simpler electron-deficient isothioureas has afforded stable zwitterionic intermediates, which have been isolated via silica gel column chromatography with common organic solvents. Heating the zwitterionic intermediates in …

The Synthesis Of Highly Substituted Aromatics And The Reaction Of Alkene Pi Systems With Vinyl Cations, Nicholas Jarrod Dodge

Graduate College Dissertations and Theses

Aldol cyclotrimerizations have been used to achieve the rational chemical synthesis of both fullerenes and fullerene fragments in the past. Under certain conditions this reaction produces the corresponding cyclotetramer which has sometimes been regarded as an undesired byproduct. This work details efforts to synthesize and use these cyclotetramers toward a synthesis of a C240 fullerene fragment. One principal focus in this work is tridecacyclene, a cyclic tetramer of acenaphthylene given its name by our group for its thirteen rings. Relatively low yields for the synthesis of tridecacyclene and its derivatives drove us to investigate the mechanism of its formation and …

Fragmentation, Rearrangement, And C-H Insertion: Reactions Of Vinyl Cations Derived From Diazo Carbonyls, Sarah Elizabeth Cleary

Graduate College Dissertations and Theses

Many commercialized medicinal compounds are analogs of chemicals isolated from sources found in nature (also called natural products). However, the natural sources of these chemicals, such as plants, fungi, or insects, only offer small quantities of these bioactive agents. Thus, it is typically desirable to find ways to synthesize these products and their analogs in large quantities using cost-effective methods that also minimize the impact on the environment. It is also important to develop strategies that expedite the process of modifying the natural products, which allows medicinal chemists to determine which functional groups are enhancing or deleterious to the bioactivity. …

Unprecedented Reactivity And Applications Of 1-Aza-2-Azoniaallene Salts, Ramya Srinivasan

Graduate College Dissertations and Theses

1-Aza-2-azoniaallene salts, derived by oxidation of substituted hydrazones, are highly reactive cationic heteroallenes. These species participate in several mechanistically distinct reactions including: (1) intramolecular [3+2] cycloadditions, (2) polar [4 +2] cycloadditions, (3) stereospecific C-H aminations, (4) electrophilic aromatic substitutions, and (5) chloroamination reactions. We have shown that this versatile reactivity is governed by the length of the tether and nature of the π-system.

A novel intramolecular electrophilic aromatic substitution reaction is observed when the tether length separating the 1-aza-2-azoniaallene salt and a pendant aryl ring is three methylene units to generate alkylaryl azo products. Variations in the electronics and sterics …

Tetrabenzo[8]Circulene: Synthesis And Structural Properties Of Polycyclic Aromatic Hydrocarbons With Negative Curvature, Robert William Miller

Graduate College Dissertations and Theses

Contorted polycyclic aromatic hydrocarbons have found increasing utility in the application of molecular electronics due to the surpamolecular properties that result from these non-planar structures. The [n]circulene series of molecules are particularly attractive members of the contorted aromatic family due to the unique structural implications that result from their changing value of n. For example, when n ≤ 5, the structures adopt a bowl-like shape; when n = 6, a planar structure is observed; and when 7 ≤ n ≤ 16, the compounds assume a saddle-like shape. Very few molecules exhibit the structural contortions that these contorted aromatics do – …

Generation Of Electron Deficient Carbodiimides And Their Application In The Guanidine Forming, Zwitterionic 1,3-Diaza-Claisen Rearrangement, Joel Walker

Graduate College Dissertations and Theses

The 1,3-diaza Claisen rearrangement was initially discovered by the Madalengoitia group in the early 2000s. Tertiary, allylic, amines nucleophilically add to the carbon of a heterocumulene (isocyanate, isothiocyanate, or carbodiimide) to generate a zwitterion which then undergoes [3,3]-sigmatropic rearrangement. The rearrangements conducted with a carbodiimide generate guanidine-containing skeletons. The guanidine functional group is found in many biologically active products, making it a worthwhile chemical target.

To this end, strained, tertiary, allylic, amine 2-benzyl-2-azabicyclo[2.2.1]hept-5-ene reacts with in-situ generated carbodiimides in the 1,3-diaza-Claisen rearrangement to afford structurally interesting bicyclic guanidines. Use of more electron deficient carbodiimides makes these rearrangements more facile; however, …

Tridecacyclene: Synthesis And Structural Properties Of Non-Planar Polycyclic Aromatic Hydrocarbons And Studies Towards A Fragment Of The Fullerene C240, Daniel Sumy

Graduate College Dissertations and Theses

While investigating strategies to prepare precursors to highly strained buckybowls, we focused our attention on the Lewis acid aldol cyclization of 1-acenaphthenone derivatives which has been shown to produce a cyclic tetramer as a byproduct. Surprisingly, despite the interesting structural and electronic properties that have recently been observed as a result of the incorporation of eight-membered rings into polycyclic aromatic hydrocarbons, this cyclic tetramer has largely been ignored. As a result of this, we set our sights on the isolation and characterization of this cyclic tetramer.

The initial approach employed subjecting 1-acenaphthenone to the most common conditions used in trimerization—TiCl4 …

Investigations Into Carbon Nanotube And Natural Product Synthesis., Geoffrey Giampa

Graduate College Dissertations and Theses

This dissertation describes research into the synthesis of carbon nanotubes using traditional organic synthetic methods, as well as work on the fragmentation of β-hydroxy-α-diazoesters with a γ-hetero group and applications of their reactivity towards natural product synthesis.

Carbon nanotubes are unique structures that can exhibit different electronic properties based on their chiral vector, and are a potential future source of semiconductors. Current methods of synthesis are unable to be adapted to commercial synthesis, providing the opportunity for the application of organic synthetic methods to generate them more uniformly and on a larger scale.

The generation of tethered aldehyde ynoates and …

I. A New Route To Azomethine Ylides: Shifting The Reliance On Amino Ester Precursors Ii. Applications In Total Synthesis, Natalie Kay Machamer

Graduate College Dissertations and Theses

Nitrogen-containing heterocycles have great utility in the biomedical and medicinal fields and one such heterocycle is the 5-membered pyrrolidine ring. The synthesis of pyrrolidine rings has been studied extensively with the routes relying on anodic oxidation, transition metals and dipolar cycloadditions with azomethine ylides. Previous work in the Waters group has been focused on new routes to azomethine ylides through a domino sequence. Through a thermal aza-Cope rearrangement followed by [3+2] dipolar cycloaddition the synthesis of a library of 2-allyl pyrrolidines was accomplished. It was discovered that by using allylic amines and glyoxals at room temperature a cycloadduct was isolated …

Investigation Of A Ring Fragmentation Reaction For The Synthesis Of Tethered Aldehyde Ynones And Medium Sized Cyclic Ynones And Ynolides, Ali Bayir

Graduate College Dissertations and Theses

The fragmentation of γ-silyloxy-β-hydroxy-α-diazoesters to provide tethered aldehyde ynoates was discovered and developed in Prof. Brewer's laboratory. This reaction is a Lewis acid mediated heterolytic cleavage of the Cβ-γ bond of a γ-silyloxy-β-hydroxy-α-diazocarbonyl functional group array contained in a ring compound.

This dissertation describes a further study of this ring fragmentation reaction and application of this fragmentation to the preparation of synthetically useful organic molecules. The purpose of this dissertation work was three fold. The first objective was to extend this ring fragmentation reaction to the synthesis of tethered aldehyde ynones by fragmenting various γ-silyloxy-β-hydroxy-α-diazo ketone compounds. The second objective …

Application Of A Ring Fragmentation/Azomethine Ylide 1,3-Dipolar Cycloaddition Sequence In The Synthesis Of Demissidine, Zhe Zhang

Graduate College Dissertations and Theses

Edible potatoes originated in the Andes and were brought to Europe in the 16th century. Their introduction spurred both the European population growth and economic development. Being the world's fourth-largest food crop, potatoes continue to shape the global economy and world history. Glycoalkaloids are natural insect deterrents generated by potatoes, and are known for their toxic effects as well as potential medicinal utilities. Demissidine, the aglycone of the primary glycoalkaloids, represents one major Solanum alkaloid. Its unique indolizidine framework presents a challenging synthetic target in organic chemistry. Our synthesis of demissidine starts from readily available epiandrosterone and takes advantage of …