Exploitation of Biomass for Applications in Sustainable Materials Science

Biorefinery may be defined as the process of accessing chemical commodities from living systems; consequently, biomass becomes the antecedent for renewable resources through biorefinery. Advantages to this process over petroleum refinery include: (1) increased potential for sustainable products, (2) increased diversity in chemical structure including heterocycles, and (3) potential for regional resource independence. Despite these clear advantages, adoption of biorefined commodities can be limited by the risk associated with small initial application portfolios and concomitant uncertainties. The strategies adopted by our dynamic and collaborative research team entail continuous engagement of those issues by: (1) preparing renewable polymers, (2) chemical diversification of biomass-derived platform chemicals, (3) direct modification of biopolymers, and (4) development of petroleum replacements. Battling the inveterate proclivity towards portents of gloom need not solely justify investigations into biorenewable feedstock chemicals; the ramifications of bioinspired molecular inquiry create opportunities to go beyond mere sustainability through innovation. This dissertation includes specific examples which illustrate utilization of three types of biomass: (1) oil seeds, (2) lignin, and (3) carbohydrates. Each class of biomass-derived materials offered unique advantages as well as challenges associated with their varied structures. The presentation has been divided into five sections: (1) biomass, sustainable chemistry and design thinking; (2) styrene replacements and their application in renewable vinyl ester thermosets; (3) catalyst-free lignin valorization by acetoacetylation; (4) chemical diversification of 5-(hydroxymethyl)furfural; (5) valorization of cellulose-derivable platform chemicals by cycloaddition with a potentially bioderivable reactive intermediate: benzyne.National Science Foundation (NSF) (Grants IIA-1330840 and IIA-1355466)ND-EPSCoR (Doctoral Dissertation Award

Unravelling [3+2] Cycloaddition Reactions through the Molecular Electron Density Theory

Después de la primera clasificación de las reacciones 32CA en reacciones de tipo zw y pr, establecidas en el año 2014, la estructura y reactividad de los TACs más importantes utilizados en las reacciones 32CA ha sido completamente caracterizado en base a la MEDT propuesta recientemente. Entre la gran cantidad de trabajo desarrollado a lo largo de la presente tesis doctoral, se han seleccionado y discutido ocho publicaciones representativas, que permitieron caracterizar dos nuevos tipos de reactividad y consolidar la reactividad original de tipo zw. Así, dependiendo de las cuatro estructuras electrónicas diferentes de los TACs, es decir, pseudodiradical, pseudoradical, carbenoide y zwitteriónica, las reacciones 32CA se han clasificado en reacciones de tipo pdr, pmr, cb y zw. Mientras que las reacciones 32CA de tipo pdr son las más rápidas, las reacciones de tipo zw son las más lentas. Las diferentes estructuras electrónicas en el estado fundamental de los reactivos explican esta tendencia de reactividad y revelan que la reactividad de los TACs carbenoides es diferente. Además, ningún TAC puede considerarse una estructura 1,2-zwitteriónica, tal y como se propone para los “1,3-dipolos”. El carácter polar de la reacción, medido por el valor de la GEDT calculado en la estructura del TS, afecta a los cuatro tipos de reactividad, de tal forma que cuanto más fuertes sean las interacciones nucleofílicas / electrofílicas que tienen lugar en el TS, más rápida es la reacción, e incluso puede cambiar el mecanismo molecular de acuerdo con las funciones de Parr definidas dentro de la CDFT. Esta racionalización basada en la MEDT de las reacciones 32CA esclarece las propuestas mecanísticas de Huisgen y Firestone establecidas en los años 60. Independientemente del tipo de reactividad y el carácter polar de la reacción, el análisis topológico de la ELF a lo largo de las reacciones 32CA que tienen lugar en un solo paso sugiere que los cambios de enlace no son “concertados” sino secuenciales, descartando así la clasificación de estas reacciones como “pericíclicas”. En la presente tesis doctoral, la teoría clásica de las reacciones 32CA, establecida en los años 60 del siglo pasado y que aún prevalece en la actualidad, es revisitada y reinterpretada en base a la MEDT. Se establece un nuevo y sólido modelo de reactividad para las reacciones 32CA, enfatizando que la visión actual de la química orgánica necesita replantearse en base al análisis de la densidad electrónica.After the first classification of [3+2] cycloaddition (32CA) reactions into zw-type and pr-type reactions, established in 2014, the structure and reactivity of the most important three-atom-components (TACs) used in 32CA reactions has been completely characterised within the recently proposed Molecular Electron Density Theory (MEDT). Among the huge amount of work developed along the present Ph.D thesis, eight representative publications have been selected and discussed herein, which allowed characterising two new reactivity types as well as consolidating the original zw-type reactivity. Thus, depending on the four different electronic structures of TACs, i.e. pseudodiradical, pseudoradical, carbenoid and zwitterionic, 32CA reactions have been classified into pdr-, pmr-, cb- and zw-type reactions. While pdr-type 32CA reactions are the fastest, zw-type reactions are the slowest. The different electronic structures at the ground state of the reagents account for this reactivity trend and reveal that the reactivity of carbenoid TACs is different. In addition, no TAC can be considered a 1,2-zwitterionic structure as proposed for “1,3-dipoles”. The polar character of the reaction, measured by the global electron density transfer value computed at the transition state structure (TS), affects the four reactivity types in such a manner that the stronger the nucleophilic/electrophilic interactions taking place at the TS, the faster the reaction, and may even change the molecular mechanism according to the Parr functions defined within Conceptual DFT. This MEDT rationalisation of 32CA reactions unravels classical Huisgen’s and Firestone’s mechanistic proposals established in the 60’s. Regardless of the reactivity type and polar character of the reaction, topological analysis of the electron localisation function along one-step 32CA reactions suggests that the bonding changes are not “concerted”, but sequential, thus ruling out the classification of these reactions as “pericyclic”. In the present thesis, the classical theory of 32CA reactions, established in the 60’s of the past century and still prevailing today, is revisited and reinterpreted based on MEDT. A solid new reactivity model for 32CA reactions is established, emphasising that the way that organic chemists conceive organic chemistry demands a contemporary revision aimed towards the analysis of electron density

Searching for Neutralisers of Energetic Organic Compounds: A Theoretical Approach from the Perspective of Quantum Chemistry

Neutralising energetic molecules is a valuable approach to minimize the risks of unpredictable explosions and associated tragic events. Quantum chemical methods offer highly efficient and effective tools for studying these compounds. The main objective of this dissertation is to quantify the impact of intermolecular interactions on the sensitivity of energetic compounds. Concerning the cyclic compounds RDX (1,3,5- trinitro-1,3,5-triazinane) and HMX (1,3,5,7-tetranitro-1,3,5,7-tetrazocane), a quantitative analysis with MEP evidenced anomalies arising from the marked depletion of negative charge distribution. The EDA-NOCV results reveal that the electrostatic and orbital contributions are the dominant factors driving the assembly of the M = {Ti, Zr, Hf}-based complexes. The chemical nature of the O· · ·M = {Ti, Zr, Hf} bonding has been investigated by using the QTAIM theory. Additionally, the topological properties of the N–NO2 trigger bonds were quantified before and after the O· · ·M interaction. These intermolecular interactions strengthens the trigger bonds, revealing an increased stability to decomposition. The IRI-based analysis was carried out to further investigate the electronic properties of group 4 transition metals in coordination environments. With regard to the aliphatic compound FOX-7 (1,1-diamino-2,2-nitroethylene), we examined three types of interactions: oxygen and nitrogen from a nitro group interacting with the metal atom, as well as nitrogen from an amino group interacting with the same metal atom. The local chemical reactivity of FOX-7 was elucidated through a quantitative study of MEP. Results derived from QTAIM showed that the C–NO2 bonds are influenced by the O· · ·M = {Ti, Zr, Hf} bonding. Furthermore, this interaction rules the complex formation when a nitro group interacts with MMCs. The interaction energies calculated by EDA-NOCV revealed that the (H2N)2C=C(NO2)- (O)NO· · · Cp2MCH+3 complexes are significantly more structurally stable (by about 21.8 kcal/mol) than the (O2N)2C=C(NH2)-H2N· · · Cp2MCH+3 complexes. This work is crucial to validate the proposal of using MMCs (metallocene methyl cations) as a neutraliser of energetic molecules

Design and synthesis of small molecule probes for metabolic processes

Synthesis of a photoactivated uncoupler I was completed and subsequently used by collaborators to demonstrate mitochondria uptake. The synthesis of a ratiometric, targetable calcium sensor was completed up to intermediate II (9 steps), alongside a thiohydantoin heterocycle III synthesised in 5 steps. A co-worker has subsequently completed the probe synthesis based on this route, with the resulting probe showing good binding and optical responses in testing. Numerous routes to 5,6-disubstituted phenanthridinium salts were investigated towards the synthesis of a mitochondrially targeted superoxide probe and hydroxylated standards. In the course of this work a novel cyclisation was developed based on intramolecular SNAr giving access to 9-benzyloxyphenanthridinium salt V. Rapid and high-yielding access to 5,6-disubstituted phenanthridinium salts IX was then achieved through forming benzophenones VIII via Suzuki coupling and converting these to imines with the alkylamine. The nitrogen atom of the imine then undergoes cyclisation onto the aryl fluoride in an intramolecular SNAr upon heating. This transformation was shown to have good steric and electronic tolerance in the synthesis of 13 phenanthridinium analogues with 6 structural diversification points. Subsequent DFT calculations by a colleague showed this reaction proceeds in a concerted fashion and as such represents a considerable mechanistic novelty. Efforts towards a new probe for mitochondrial superoxide led to the synthesis of 3-tertbutyl-dihydrophenanthridine X, which does not intercalate into DNA upon oxidation. This concept was refined and lead to the development of neopentyl ethidium XI and the targeted analogue MitoBNH XII and its deuterated analogue XIII

Diels-Alder Reactions in Multi-Ring Forming Processes

The Diels-Alder reaction is one of the most powerful reactions available to the synthetic organic chemist. Its greatest strength is its ability to generate the most prevalent cyclic system, namely the six-membered ring, in one synthetic operation from a versatile array of substrates. This thesis explores the application of the Diels-Alder reaction to multi-ring forming processes. Chapter 1 - By way of introduction, the first chapter provides a brief commentary on the pursuit of efficiency in synthetic organic chemistry and, as a matter of course, the power of the Diels-Alder reaction as a multi-bond forming process. As a preamble, it signposts these important themes, which have driven the investigations conducted in this thesis. Chapter 2 - The second chapter encapsulates two separate pieces of synthetic work. Firstly, the diene-transmissive twofold Diels-Alder reaction sequence of [3]dendralene with relatively un-activated cyclic dienophiles is developed. This methodology permits access to a diverse array of polycyclic structures, with twenty structurally distinct tetracyclic frameworks prepared. Secondly, Chapter 2 reports the application of this methodology to the concise enantioselective synthesis of the popular synthetic target and biologically-important marine natural product, (+)-xestoquinone. Notably, this work a) constitutes the first application of the parent [3]dendralene in total synthesis; and b) constructs three out of the four carbocyclic rings of the natural product via a Diels-Alder reaction, resulting in the shortest preparation of the molecule to date. This work is presented as a journal article draft for submission to Science. Chapter 3 - In the third chapter, the pentacyclic marine natural products, (+)-xestoquinone and (+)-halenaquinone are introduced in detail. Previous syntheses of these natural products as well as structurally similar compounds are comprehensively and systematically reviewed to place the preceding synthetic work (Chapter 2) in context. Chapter 4 - In Chapter Four, the diene-transmissive Diels-Alder reaction sequence of parent and substituted [3]dendralenes is developed to use enantiomerically pure, readily available, cyclic dienophiles for the first time. This methodology builds upon the key Diels-Alder reaction sequence reported in the synthesis of (+)-xestoquinone (Chapter 2) and enables the rapid synthesis of a range of chiral polycyclic frameworks in enantiopure form. Chapter 5 - Chapter Five reviews the development and application of the intramolecular Diels-Alder reaction to total synthesis and takes the form of an invited journal article drafted for publication in Angewandte Chemie. The application of the Diels-Alder reaction to multi- ring forming events is explored from a different perspective to that examined throughout the rest of this thesis

Development of Carbon‒Carbon, Carbon‒Nitrogen, and Carbon‒Hydrogen Bond Functionalization Methodologies and Efforts Toward the Total Synthesis of Dragmacidin E

University of Minnesota Ph.D. dissertation.August 2017. Major: Chemistry. Advisor: Christopher Douglas. 1 computer file (PDF); xviii, 330 pages.Chapter 1: this chapter introduces the area of carbon‒carbon sigma bond activation, as well as the contributions made to the field by the Douglas group. Efforts to develop a diastereoselective intramolecular alkene cyanoamidation methodology involving C‒CN bond activation are described. The development of an intramolecular alkene aminocyanation methodology utilizing N‒CN bond activation is also described. Chapter 2: this chapter provides a brief summary of the development of metal-organic cooperative catalysis approaches to bond activation and functionalization methodologies, including prior work reported by the Douglas group on the intramolecular hydroacylation of alkenes. Efforts to develop chiral organic co-catalysts for these intramolecular alkene hydroacylation reactions are also described. Chapter 3: this chapter introduces the dragmacidin family of natural products. A particular emphasis is placed on previously reported syntheses of dragmacidins D, E, and F, and how these synthetic efforts have contributed to the structural assignment of this family of natural products. Chapter 4: this chapter depicts our efforts toward the total synthesis of dragmacidin E. A retrosynthetic analysis focused on utilizing the intramolecular alkene hydroacylation methodology developed by the Douglas group is described, as well as efforts to synthesize a suitable substrate for this key synthetic step

The Hexadehydro-Diels–Alder (HDDA) Reaction-Enabled Bottom-up Synthesis of Elaborated Polycyclic Aromatics

University of Minnesota Ph.D. dissertation. May 2019. Major: Chemistry. Advisor: Thomas Hoye. 1 computer file (PDF); xvi, 482 pages.Polycyclic arenes are an important class of organic molecules with promising semiconducting properties. Their relatively low cost, band-gap tunability, and ease of fabrication render them suitable for a host of applications for the next-generation optoelectronics devices. The biggest challenge to realize the full potential of organic semiconductors is the chemical synthesis of atomically precise polycyclic aromatics. The current strategies to assemble these materials heavily rely on transition-metal catalyzed cross-coupling reactions of prefunctionalized arenes, which in a way limit the vision of material scientists when search for potential compounds. This thesis describes a complementary synthetic approach to polycyclic aromatic products from polyynes via the hexadehydro-Diels–Alder (HDDA) reaction. The HDDA reaction is a variant of the classic Diels–Alder reaction, which generates pristine benzyne intermediates purely thermally. This mechanistically intriguing transformation also has served as a great platform for many discoveries of fundamentally new reactivities. Here multiple aspects of the HDDA reaction are discussed: (1) reaction of perylenes with HDDA-benzynes and photochemical HDDA reactions, (2) accessing other reactive intermediates via HDDA-generated benzynes, (3) copper(I)- and BF3- catalyzed trapping reactions of benzynes, (4) rapid construction of polyacenes via the domino HDDA reaction, and (5) a cascade strategy for using classically generated benzynes as in situ diynophiles for accessing HDDA-naphthynes

Investigation of novel thermal cyclisation reactions

[For full abstract, with illustrations, see pdf file]. Part 1. Concise Synthesis of Highly Substituted Isoquinolin-1(2H)-ones via IMDA The primary goal of this DPhil research project was to further investigate the mechanism of a novel thermally activated cyclisation reaction discovered within the Parsons’ research group. Through the synthesis and cyclisation of the substituted pyrrole rings 2.38a-c we have investigated the mechanism and increased the scope of the cyclisation reaction. We have also developed a robust route to advanced intermediate 2.10 in the synthesis of hymenialdisine 2.1. Part 2. Investigation and Development of a Novel Cascade Reaction The aim of this DPhil research project was to devise and execute a series of experiments to gain a better mechanistic understanding of the novel thermal cyclisation, discovered within the Parsons’ research group. To further investigate the mechanism and scope of the cyclisation, the model system 2.1 was initially selected. Through extensive modification and manipulation of the cyclisation precursor 2.1, we have increased the scope of the cyclisation and postulated a reaction pathway. During these studies remarkable transformation of ketone 2.81 to alkyne 2.82 was also observed. The repeatability of the above reactions was also investigated by synthesising various analogues

Computational and experimental investigation of elemental sulfur and polysulfide

Petroleum processing results in the generation of significant quantities of elemental sulfur (S8), leading to a surplus of sulfur worldwide. Despite its abundance and low cost, the use of sulfur in value-added organic compound synthesis is limited due to its unpredictable and misunderstood reactivity. This dissertation aims to address this issue by tackling it from two angles. Firstly, by utilizing Density Functional Theory (DFT) calculations, the reactivity of sulfur in the presence of nucleophiles is studied. This facilitates the identification of organic polysulfide intermediates that can be generated under different conditions, as well as the corresponding reactivity for each type of nucleophile. This computational study begins with a benchmarking of numerous DFT functionals against experimental data and high-accuracy ab initio computations to determine the best functional(s) for studying elemental sulfur and polysulfides in organic reactions. Using the best DFT method, the mechanism of monosulfide formation from cyanide and phosphines is explained. At the end of this computational study, the mechanism of 2-aminothiophene formation via the Gewald reaction is elucidated. Secondly, attempts are made to synthesize sulfur-based organic compounds using elemental sulfur or compounds with a sulfur source through the utilization of boron, imine, and aryne chemistry. In summary, this dissertation aims to expand the use of sulfur in organic chemistry by providing an understanding to predict its reactivity with nucleophiles, as well as demonstrating its potential for the low-cost synthesis of valuable sulfur-based organic compounds

Tethering surface tension to organic synthesis: a quest for chemoselectivity

The development of chemoselective processes is of utmost importance for the future of synthetic organic chemistry and has been described as ‘one of the greatest obstacles to complex molecule synthesis.’ This dissertation was written with this main objective in mind, which was pursued from two perspectives. Development of surface-tension driven droplet devices towards parallel and chemoselective synthesis of substituted 2H-chromen-2-ones was at first investigated on a sub-millimolar scale (Chapters 1-3). Multi-droplet sorting devices were manufactured and key parameters such as droplet composition, substrate temperature and orientation were optimised. Test reactions in aqueous propylene glycol (PG) were conducted in batch conditions, affording 3,6-disubstituted coumarins references via Knoevenagel condensation of 5-substituted salicyladehydes with activated methylene compounds and acid-promoted intramolecular cyclisation. Reactivity transposition onto droplets was thoroughly investigated, leading to a three-pair reagent (3x3) chemical sorter. Product quantification method by 1H-NMR spectroscopy was successfully implemented in micro-liter sized droplets, proving how chemoselectivity can be achieved following such unconventional, synthetic methodology. The second project studied chemoselective formation of 2-alkenyl tertiary anilines and 1,1,2-trimethylindolinium hexafluorophosphates via charged aza-Claisen rearrangement and thermal cyclisation of quaternary N-allylated ammonium salts (Chapter 4-6). In the latter case, early attempts of the reaction were unsuccessful due to decomposition catalysed by the bromide anion, but a switch to a non-nucleophilic anion (PF6-) allowed the ring closure to occur. Compound library synthesis was carried out to assess the synthetic methodology robustness. Key strengths and limitations were identified and ammonium substrate regiochemical effects were examined and discussed. Finally, interesting research avenues were suggested to broaden substrate scope studies and, most importantly, to link structural connectivity analysis of ammonium salts with modulation of their surface properties