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No description available.

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Over the last forty years the steady use of radical reactions as the key steps in syntheses has increased. The most commonly used radical reagent is tributyl tinhydride. However such tin based radical reagents are toxic and often contaminate the product as they are difficult to remove. As an alternative to these tin reagents, a novel NaBH4/U.V. system was developed. This system was successfully used to effect the radical reduction of various aromatic halides. In light of these results it was thought that other useful transformations such as C-C bond formation could be achieved. Radical cyclisation onto unsaturated bonds, halogen atom transfers radical cyclisation (HATRC) and 1-5 hydrogen atom translocations were explored. This, 1-5 hydrogen atom translocations, methodology has been successfully applied to the synthesis of the spirocyclic natural products (±) horsfiline and coerulescine. With this success the use of the NaBH4/U.V. system on pyridine substrates was explored. Unfortunately this was not achieved with our current understanding of this reaction. However the use of tributylgernamium hydride, which is considered a ‘green’ radical reagent when compared to tin based reagents, proved successful. The novel application of this reagent in the 1-5 hydrogen atom transfer reaction on pyridine substrates was successfully demonstrated. Its use was successfully employed in the synthesis of a pyridine based bioisostere derivative of horsfiline.

Much recent discussion has highlighted the challenges posed by what have variously been called “disruptive”, “discontinuous”, “breakthrough” and “radical” innovations. Although the labelling may vary, the underlying themes appear to be consistent. In particular it is clear that under conditions in which the dominant “rules of the game” change as a result of emergent or shifting markets, major movements at the technological frontier, dislocations in the regulatory environment etc, even organizations with well-developed innovation capabilities get into difficulties. This is less a matter of particular technological, market or political stimuli than of the limitations of the repertoire of organizational responses available to the firm. This resurfaces a long-running concern with managing innovation in two different modes, namely “exploitation” and “exploration”. This thesis reports the results of exploratory research into specific aspects of the organizational culture within the Research and Development (R&D) setting of a small mature UK based company, Cerulean. In doing so it also identifies and discusses key management interventions for developing an innovation culture that facilitates radical product innovation. Cerulean designs and manufactures quality control instrumentation and has in the past been very successful with radically new products. In recent years this propensity for “radicalness” has declined and the company now wishes to regain this capability. A grounded research methodology and a participative action research approach was utilised to surface issues that clearly illustrated both the presence and intensity of aspects of organisation culture that enabled and inhibited radical product innovation. Participative analysis of the data identified nine emerging themes and key constructs of an innovation culture that was found to influence “radicalness” in new product development ventures. The interrelationships between the themes were discussed in the context of current theoretical perspectives in the field of innovation management. This led to the development of a conceptual model that incorporates two “ideal” archetypal forms of innovation culture. A composite instrument was developed based on existing evaluation tools and used to assess the innovation culture. First use of the instrument indicated areas of opportunity in developing a radical innovation culture. Further participative analysis of the emergent themes and the assessment and evaluations of the extant innovation culture, resulted in a series of management interventions to stimulate the development of a culture to facilitate radical product innovation. The design of the interventions was also informed by the literature and other organizations, part of a national Discontinuous Innovation Forum (DIF) undergoing similar ambitions. The proposed interventions comprise a series of linked management actions in the form of a plan to shift the innovation culture of the company closer to a desired radical innovation culture.

Wyosine derivatives are highly complex modified ribonucleic acid (RNA) bases found in archaea and eukarya. They are a modification of a genetically encoded guanosine found at position 37 of phenylalanine encoding transfer ribonucleic acid (tRNA). The second step in the biosynthesis of all wyosine derivatives, in both archaea and eukarya, is the transformation of N-methylguanosine to 4-demethylwyosine by the radical S-adenosyl-l-methionine enzyme TYW1. When these studies were initiated, the substrate of TYW1 was unknown. Four possible substrates; acetyl CoA, acetyl phosphate, phosphoenolpyruvate, and pyruvate; were tested for activity. Only incubation with pyruvate led to production of 4-demethylwyosine. As only two new carbons are incorporated into the RNA base at this step, ¹³C isotopologues were used to identify the carbons that are transferred into 4-demethylwyosine. These experiments revealed that C2 and C3 of pyruvate are incorporated into 4-demethylwyosine, with C1 lost as an unknown byproduct. Utilizing pyruvate containing deuteriums in place of protons on the C3 carbon, the regiochemistry of the addition was determined. It was found that C3 forms the methyl group of 4-demethylwyosine and C2 becomes the bridging carbon in the imidazoline ring. The site of hydrogen atom abstraction by 5'-deoxyadenosyl radical was identified as the N-methylguanosine methyl group through the use of tRNA containing a deuterated methyl group. The putative mechanism for this transformation involved the formation of an enzyme substrate Schiff base through a conserved lysine residue. Utilizing sodium cyanoborohydride a Schiff base was trapped between TYW1 and pyruvate. The mass of the trapped adduct responded as expected when different isotopologues of pyruvate were used, demonstrating that it is due to pyruvate. Moreover, the fragment of TYW1 that contained the trapped adduct contained two lysine residues, one of which was shown to be required for activity both in vivo and in vitro. It was initially proposed that TYW1 contained two iron-sulfur clusters, and then subsequently shown to have two 4Fe-4S clusters. Site directed mutagenesis, along with iron and sulfide analysis identified the cysteines; as C26, C39, and C52; coordinating the second 4Fe-4S cluster. This study identified pyruvate as the substrate of TYW1, and provided evidence for key steps in the transformation of N-methylguanosine to 4-demethylwyosine.

Molecular and cluster anions have been investigated using photoelectron velocity-map imaging spectroscopy to study the nature of electrons in radical species. We report a negative-ion photoelectron imaging study of benzonitrile and several of its hydrated, oxygenated, and homo-molecularly solvated cluster anions. The photodetachment transition from the unsolvated benzonitrile anion to the X̃¹A₁ state of the neutral peaks at 58 ± 5 meV. The electron affinity (EA) of the lowest excited electronic state of benzonitrile, ã³A₁, is determined as 3.41 ± 0.01 eV. The next excited state, the open-shell singlet ùA₁, is found about an electron-volt above the triplet, corresponding to a vertical detachment energy of 4.45 ± 0.01 eV. The step-wise and cumulative solvation energies of benzonitrile anions by several types of species were determined, including homo-molecular solvation by benzonitrile, hydration by 1–3 waters, oxygenation by 1–3 oxygen molecules, and mixed solvation by various combinations of O₂, H₂O, and benzonitrile. Ethylene has been shown to be a degradation product following the 1-e⁻ attachment to ethylene carbonate. As a solvent molecule for (O₂)^(□), our photoelectron imaging study shows a relatively small solvation energy of ≤0.24 eV for the expected 𝜋-𝜋 interaction in the ((O₂)^(□))(C₂H₄) cluster anion. The EA of the O₂(C₂H₄) cluster was measured at 0.69 ± 0.01 eV, while the 𝑋³A″ ← 𝑋²A″ photodetachment transition shows a 1400 ± 100 cm⁻¹ vibrational progression in the 1064 nm spectrum. Negative-ion photoelectron imaging was used to investigate the substituted carbene derivative of fluoroacetonitrile. We report a closed-shell singlet ground state for the cyanofluorocarbene, FCCN, with an adiabatic electron affinity EA = 2.081 ± 0.002 eV and a singlet-triplet gap of ΔEₛ₋ₜ = 0.42 ± 0.04 eV. The open-shell singlet ¹A″ state was also observed experimentally. We find that the experimentally measured ΔEₛ₋ₜ of FCCN agrees well with the general trend of similar carbenes. We report preliminary results on the photoelectron imaging of phenylcarbene, cyanophenylcarbene, and chlorophenylcarbene anions. Triplet phenylcarbene is observed to have an EA of ≤0.83 eV, considerably lower than the previously indirectly-determined value. Transitions to the singlet and triplet ground state of both cyanophenylcarbene and chlorophenylcarbene are observable, though unidentified bands make full assignment difficult. Cyanophenylcarbene is found to have a triplet ground-state, with a tentative EA of 2.04 eV. Chlorophenylcarbene is found to have a singlet ground-state. The phenyl-group is found to favor the singlet state slightly. The cyanofluoromethyl radical, FC(H)CN, was estimated to have an EA of 1.53 ± 0.08 eV, by a combination of experimental and theoretical results.. With similar methodology, we report the adiabatic electron affinity of the cyanobenzyl radical, EA(PhCHCN) = 1.90 ± 0.01 eV, and assign an upper limit of the EA for the chlorobenzyl radical, EA(PhCHCl) ≤ 1.12 eV. These values were used to estimate the C-H bond dissociation energy (BDE)s for these substituted methanes. Fluoroacetonitrile was found to have a BDE of D𝐻₁₉₈ = 90.7 ± 2.8 kcal mol^(□1). The C-H bond dissociation energies at the benzyl-α sites of the phenylmethanes are determined as 80.9 ± 2.3 kcal mol⁻¹ for benzyl nitrile and an upper limit of 84.2 kcal mol⁻¹ for benzyl chloride. These results are discussed in terms of substituent interactions in a simple MO framework and in relation to other similar molecules, including recently reported results for chloroacetonitrile. The 532 nm photoelectron spectrum of glyoxal provides the first direct spectroscopic determination of the adiabatic electron affinity, EA = 1.10(2) eV. This assignment is supported by a Franck-Condon simulation of the experimental spectrum that successfully reproduces the observed spectral features. The vertical detachment energy (VDE) of the glyoxal radical anion is determined as VDE = 1.30(4) eV. The EA of methylglyoxal is determined as ≤0.8 eV based on the signal-to-noise ratio of the 𝑋¹A′←𝑋²A″ transition, with a VDE = 1.28(4) eV. The EA of the a³A″ ← X²A″ and 𝐴¹A″ ← 𝑋²A″ transitions are determined as 3.28(3) eV and 3.614(5) eV respectively. The intrinsically short-lived ethylenedione molecule (OCCO) was observed and investigated using anion photoelectron spectroscopy. The adiabatic electron affinity of its ³Σg^(□) ground state is 1.936(8) eV. The vibrational progression with a 417(15) cm⁻¹ frequency observed within the triplet band corresponds to a trans-bending mode. Several dissociative singlet states are also observed, corresponding to two components of the ¹Δg state and the ¹Σg⁺ state. The experimental results are in agreement with the theory predictions and constitute the first spectroscopic observation and characterization of the elusive ethylenedione molecule. Two glyoxal derivatives related to the ethylenedione anion (OCCO⁻), ethynediolide (HOCCO⁻) and glyoxalide (OHCCO⁻), were studied. These anions provide access to the corresponding neutral reactive intermediates: the HOCCO and OHCCO radicals. In the HOCCO/OHCCO anion photoelectron spectrum, we identify several electronic states of this radical system and determine the adiabatic electron affinity of HOCCO as 1.763(6) eV. This result is compared to the corresponding 1.936(8) eV value for ethylenedione (OCCO). Initial attempts were made to detect and observe the dicyanoacetylene anion, NCCCCN⁻, by photoelectron imaging. While it is believed the experimental design path of H₂⁺ abstraction from fumaronitrile is sound, no spectral signature can be assigned to NCCCCN⁻. Calculations targeting the low-lying transitions from the anion indicate that the molecule should have a significantly positive electron affinity and at least the ground state should be accessible with the currently available laser sources. The cluster ion O₂(N₂O)⁻ of the same nominal mass as NCCCCN⁻ is identified as an interfering ion and ideas have been proposed for resolving this difficulty.