Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2006. / Vita. / Includes bibliographical references. / Chapter 1. Metal-Based Turn-On Fluorescent Probes for Sensing Nitric Oxide. Nitric oxide, a reactive free radical, regulates a variety of biological processes. The absence of tools to detect NO directly, rapidly, specifically and selectively motivated us to develop metal-based fluorescent probes to visualize the presence of NO. We have prepared and investigated Co(II), Fe(II), Ru(II), Rh(II), and Cu(II) complexes as turn-on fluorescent NO sensors. Our exploration has provided insight into how the interaction of transition metal centers with nitric oxide can be utilized for NO sensing. Chapter 2. Fluorescence-Based Nitric Oxide Detection by Ruthenium Porphyrin Fluorophore Complexes. The ruthenium(II) porphyrin fluorophore complexes [Ru(TPP)(CO)(Ds-R)] (TPP = tetraphenylporphinato dianion; Ds = dansyl; R = imidazole (im), 1, or thiomorpholine (tm), 2) were synthesized and investigated for their ability to detect nitric oxide (NO) based on fluorescence. The X-ray crystal structures of 1 and 2 were determined. The Ds-im or Ds-tm ligand coordinates to an axial site of the ruthenium(II) center through a nitrogen or sulfur atom, respectively. Both exhibit quenched fluorescence when excited at 368 or 345 nm. / (cont.) Displacement of the metal-coordinated fluorophore by NO restores fluorescence within minutes. These observations demonstrate fluorescence-based NO detection using ruthenium porphyrin fluorophore conjugates. Chapter 3. Nitric Oxide-Induced Fluorescence Enhancement by Displacement of Dansylated Ligands from Cobalt. The cobalt complexes, [Co(Ds-AMP)2] (1) and [Co(Ds-AQ)2] (2), where Ds-AMP and Ds-AQ are the conjugate bases of dansyl aminomethylpyridine, Ds-HAMP, and dansyl aminoquinoline, Ds-HAQ, respectively, were synthesized in two steps as fluorescence-based nitric oxide (NO) sensors and characterized by X-ray crystallography. The fluorescence of both complexes was significantly quenched in CH3CN or CH3OH compared to that of the free Ds-HAMP or Ds-HAQ ligands. Addition of NO to a CH3CN solution of 1 or 2 enhanced the integrated fluorescence emission by factors of 2.1(_-+0.3) or 3.6(+0.4) within 35 or 20 min, respectively. Introduction of NO to methanolic solutions similarly increased the fluorescence by 1.4(±0.1) for 1 or 6.5(±1.4) for 2 within 1 h. / (cont.) These studies demonstrate that 1 and 2 can monitor the presence of NO with turn-on emission, and that their fluorescence responses are more rapid than those of previously reported cobalt systems in coordinating solvents such as CH3CN and CH3OH. H NMR and IR spectroscopic data revealed the formation of a {Co(NO)2'0 cobalt dinitrosyl adduct with concomitant dissociation of one ligand from the cobalt center as the metal-containing product of the NO reactions, indicating NO-induced ligand release to be the cause of the fluorescence Chapter 4. Fluorescent Nitric Oxide Detection by Copper Complexes Bearing Anthracenyl and Dansyl Fluorophore Ligands. Anthrancenyl and dansyl fluorophore ligands (AnCH2pipCS2K (1), Ds-Hen (2), Ds-HAMP (3), Ds-HAQ (4), and Ds-HAPP (5)) were prepared for copper(II). Five copper complexes, [Cu(AnCH2pipCS2)2] (6), [Cu(Ds-en)2] (7), [Cu(Ds-AMP)2] (8), [Cu(Ds-AQ)2] (9), and [Cu(Ds-APP)(OTf)] (10), were synthesized for fluorescent nitric oxide (NO) detection and were characterized by X-ray crystallography. A decrease in fluorescence of free ligands (1- 5) coordinated to the Cu(II) center was observed in all Cu(II) complexes (6-10). / (cont.) The fluorescence of fluorophore ligands in Cu(II) complexes was restored in the presence of NO in a CH3OH/CH2C12 solvent. Furthermore, compounds 7, 8, and 10, exhibited fluorescence response to NO in aqueous pH 7.0 or 9.0 buffered solutions. Fluorescence enhancement of these Cu(II) complexes occurs by NO-induced reduction from Cu(II) to Cu(I), as demonstrated spectroscopically. The present work suggest that a copper(II) complex would be effective as a fluorescent probe for sensing NO in both organic and aqueous settings. Chapter 5. Direct Nitric Oxide Detection In Aqueous Solution by Copper(II) Fluorescein Complexes. Fluorescein-based ligands (FL., n = 1 - 5) for Cu(II) were synthesized and their photophysical properties were determined. Introduction of nitric oxide (NO) to a pH 7.0 buffered solution of Cu(FLn) (1 M CuCl2 and 1 uM F Ln) induces an increase in fluorescence at 37 °C. The fluorescence response of Cu(FL.) is direct and specific, which is a significant improvement of commercially available small molecule-based probes that are capable only of indirect NO detection. NO-triggered fluorescence increase of Cu(FLn) occurs by reduction of Cu(II) to Cu(I) with concomitant dissociation of the N-nitrosated fluorophore ligand from copper. / (cont.) Spectroscopic and product analyses of the reaction of the copper fluorescein complex with NO suggest that the N-nitrosated fluorescein ligand (FLn-NO) is the species for fluorescence turn-on. Density functional theory (DFT) calculations of FL5 versus FL-NO reveal how N-nitrosation of the fluorophore ligand causes the fluorescence increase. The investigation of copper-based probes described in the present work is the basis for developing a metal complex for fluorescent NO detection. Chapter 6. Visualization of Nitric Oxide in Living Cells by a Copper-Based Fluorescent Probe. Nitric oxide (NO) is a highly reactive gaseous free radical that serves as a messenger for cellular signaling. To visualize NO in living cells, a turn-on fluorescent probe was designed and synthesized for use in combination with microscopy. Unlike existing fluorescent sensors, the construct, a Cu(II) complex of a fluorescein modified with an appended metal-chelating ligand (FL), directly and immediately images NO rather than a derivative reactive nitrogen species (RNS). Nitric oxide produced by both constitutive (cNOS) and inducible (iNOS) NO synthases in live neurons and macrophages is detected by the Cu(II)-based imaging agent in a concentration- and time-dependent manner. / (cont.) The sensitivity to nM levels of NO and the spatiotemporal information provided by this complex demonstrate its value for numerous biological applications. Appendix. Fluorescent Detection of Nitric Oxide by a Rhodium Fluorophore Embedded in a Silastic Polymer Using Two-Photon Microscopy. A Silastic membrane embedded with a dirhodium fluorophore conjugate, [Rh2(M-O2CPr)4(Ds-pip)] (Ds-pip = dansyl-piperzine), was prepared. Nitric oxide (NO) in aqueous media replaces the Ds-pip bound to the dirhodium core in the solid state, inducing the fluorescence increase observed by two-photon spectroscopy. This observation is the first effort for NO detection using two-photon microscopy and represents an initial step toward fiber-optic-based NO sensing in aqueous media using this dirhodium-containing polymer. / by Mi Hee Lim. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2011. / Vita. Cataloged from PDF version of thesis. / Includes bibliographical references. / Cyclization Cascades Leading to the Tricyclic Fragment of Armatol A The synthesis of the fused 6,7,7-tricycle of armatol A was investigated. Fragments containing both a ketone and an aldehyde for subsequent fragment coupling were generated via a triepoxide cascade. Elimination of the secondary alcohol in the oxepane ring proved challenging; however, employing the Shapiro reaction successfully provided the desired oxepene. Ketone and aldehyde tricycles were synthesized in 11 and 7 steps, respectively, and both enantiomers of aldehyde fragment were synthesized. These short routes enable the preparation of sufficient quantities of these tricycles for fragment coupling studies. Fragment Coupling, Synthesis, and Determination of the Absolute Configuration of Armatol A A stereoselective synthesis of a bromooxepane ring via a bromonium-initiated epoxide-opening cyclization was explored. Functionalization of the primary alcohol formed from this cascade allowed for a variety of coupling strategies to be explored to form the carbon framework of armatol A. Difficulties reducing a cis alkene adjacent to a tertiary alcohol forced a strategic revision; an analogous trans alkene was easily reduced to form the acyclic alkyl chain connecting the ring-containing fragments of armatol A. Stereoselective installation of the tertiary alcohol allowed for a detailed investigation of the absolute structure of armatol A. At the outset, four diastereomers were consistent with the published data for the natural product. After determining that this tertiary alcohol must be syn to the adjacent THP ring stereocenter, the syntheses of the two remaining possible diastereomers of armatol A were completed. Of the four diastereomers shown in the figure, diastereomer B was confirmed by synthesis to be the correct structure of armatol A. Using this information, structural revisions of the entire family of armatols were proposed, as was a new biogenesis of these natural products. Four possible diastereomers of armatol A based on reported data... / by Brian Saxton Underwood. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, February 2011. / "February 2011." Vita. Cataloged from PDF version of thesis. / Includes bibliographical references. / The chemical diversity found in plants has served as a major source of inspiration to many synthetic and biological chemists. Nature has evolved enzyme active sites to catalyze the synthesis of structurally complex compounds that serve as pharmaceuticals, insecticides, dyes, perfumes, and biofuels. In Catharanthus roseus, approximately 130 structurally complex monoterpene indole alkaloids are produced, including the clinically used anti-mitotic drugs, vinblastine and vincristine. The common intermediate to all monoterpene indole alkaloids is strictosidine, the product of an asymmetric Pictet- Spengler condensation of tryptamine and the iridoid monoterpene secologanin. This reaction is catalyzed by the enzyme strictosidine synthase. This thesis describes the use of kinetic isotope effects, the rate dependence on pH, as well as structural and computational data to propose a mechanism by which strictosidine synthase catalyzes the Pictet-Spengler reaction. Notably, the data also shed light on the mechanism of the widely used nonenzymatic reaction. Interestingly, the Pictet-Spenglerase strictosidine synthase belongs to a superfamily of enzymes that have mainly been observed to catalyze ester hydrolysis. Using the [beta]-propeller fold conserved in both strictosidine synthase and the related hydrolase, paraoxonase, rational mutagenesis was used to convert strictosidine synthase into a hydrolase. Intriguingly, during the rational design process, the function of a closely related strictosidine synthase homolog was also functionally characterized as a hydrolase. In addition to reengineering proteins with new catalytic activity, the chemical diversity in plants can also modified using metabolic engineering. However, this approach requires knowledge of the genetic blueprints of the plant to be known. Using the recently released C. roseus transcriptome sequencing data along with co-expression analysis, this thesis describes the functional characterization of a new P450 gene involved in metabolizing a key intermediate in the biosynthesis of bioactive bisindole alkaloids. With the functional characterization of this new gene, a combination of gene silencing and synthetic biology techniques will provide a greater understanding on how to "tune" alkaloid biosynthesis in C. roseus in order to generate more functionally diverse molecules. / by Lesley-Ann Giddings. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2011. / Vita. Cataloged from PDF version of thesis. / Includes bibliographical references. / Iminoacetonitriles participate as reactive dienophiles in intramolecular Diels-Alder cycloadditions affording quinolizidines and indolizidines. The resulting a-amino nitrile cycloadducts are versatile intermediates that can be further elaborated in a stereoselective manner. This thesis describes the development of intramolecular, enantioselective aza Diels- Alder cycloadditions promoted by chiral Brønsted acids as well as the discovery that iminoacetonitriles can also participate in acid catalyzed cycloadditions. The second part of this thesis reports the total synthesis of (-)-quinolizidine 2071 using an intramolecular, enantioselective cycloaddition of an iminoacetonitrile as the key step. / by Shaun D. Fontaine. / Ph.D.

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2013. / Cataloged from PDF version of thesis. / Includes bibliographical references. / Increases in global energy demand and rising levels of atmospheric carbon dioxide demand renewable alternatives to fossil fuels as the primary energy sources of the 21st century. Solar energy is by far the most abundant renewable energy resource, yet its widespread use has been hampered by a lack of suitable methods to store energy from sunlight in a cheap and efficient manner. Solar driven water splitting is a promising method of storing solar energy, but a critical bottleneck in developing efficient photoelectrochemical (PEC) water splitting systems lies in the kinetic sluggishness of the water splitting reactions, particularly the oxygen evolution reaction (OER). In this thesis the structural and mechanistic underpinnings for the activity of a promising nickel-based oxygen evolving catalyst (OEC) are discussed. The catalyst is particularly attractive as a result of the simplicity of its preparation as a thin film from aqueous borate-buffered solutions of Ni₂ . Electrochemical and in situ X-ray absorption near-edge structure (XANES) studies of this nickel-borate (Ni-Bi) catalyst indicate that upon initial electrodeposition, Ni centers in the film exist predominantly in the +3 oxidation state and the as-deposited material is largely inactive towards the OER. Catalytic activation is achieved by anodization of the as-deposited material in concentrated borate buffer, pH 9.2, a process which serves to oxidize the nickel centers to a mixed-valence Ni(II/IV) state. Extended X-ray absorption fine structure (EXAFS) spectroscopy studies indicate that Ni-Bi is comprised of nanometer-sized clusters of edge sharing NiO₆ octahedra. A structural transformation is observed during anodization that is akin to that observed in the [beta]-NiOOH-[gamma]-NiOOH transformation, challenging the long-held view that the phase that is the most catalytically active towards the OER is the all-Ni(III) [rho]-NiOOH. Electrokinetic studies indicate that the as-deposited Ni-Bi exhibits a Tafel slope close to 2.3 x 2RT/F, consistent with a turnover-limiting electron transfer (ET) from the geometrically distorted low-spin d⁷ Ni(III) state. Upon anodization to the mixed valence Ni(III/IV) state and elimination of geometric distortion, ET from the resting state becomes more facile resulting in a low Tafel slope of 2.3 x RT/2F, indicative of a rapid two-electron pre-equilibrium followed by a rate limiting chemical step, likely O₂ formation. Anodized Ni-Bi also exhibits an inverse third order dependence in proton activity and inverse first order dependence in borate anion. This kinetically-relevant two-electron, three-proton proton-coupled electron transfer (PCET) equilibrium prior to rate limiting O₂ formation forms the mechanistic basis for the pHdependent difference in activity between Ni-Bi and its cobalt-based analog, which contrarily mediates oxygen evolution via a kinetically-relevant one-electron, one-proton PCET transformation. The difference in catalytic O₂ evolution mechanism is a principal factor in the determination of the overall solar-to-fuels efficiency of PEC water splitting systems. / by Daniel Kwabena Bediako. / S.M.

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1983. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND SCIENCE. / Includes bibliographical references. / by Mark Nelson Spencer. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1996. / Includes bibliographical references. / by Paul H. Weinreb. / Ph.D.

Thesis (S.M. in Organic Chemistry)--Massachusetts Institute of Technology, Dept. of Chemistry, 2012. / Vita. Cataloged from PDF version of thesis. / Includes bibliographical references (p. 36). / The development of a methodology to access C7 pinacolatoboron substituted indole derivatives is described. It has been applied to indole, tryptophan, and tryptamine derivatives. Further functionalization to a C7 phenolic tryptamine derivative is also described. / by Owen S. Fenton. / S.M.in Organic Chemistry

Massachusetts Institute of Technology. Dept. of Chemistry. Thesis. 1972. Ph.D. / MICROFICHE COPY ALSO AVAILABLE IN SCIENCE LIBRARY. / One blank unnumbered leaf inserted. Vita. / Includes bibliographical references. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2007. / Vita. / Includes bibliographical references. / Two distinct structural scaffolds elaborated from Schiff-base macrocycles were designed to study the proton-coupled electron transfer chemistry of 0-0 bond forming and activation chemistry. The "Hangman" architecture is composed of hydrogen-bonding functionalities poised over a redox active manganese salophen or salen platform. The complexes proved to be proficient catalase mimics (disproportionation of hydrogen peroxide to water and oxygen). Detailed spectroscopic, computational, and structure-function relationship studies elucidated the key redox, steric, and secondary coordination sphere effects for optimal catalytic ability. The incorporation a chiral backbone into the macrocycle led to catalysts that perform enantioselective epoxidation of unfunctionalized olefins. A macrocycle with an amide, imine, and bisphenolic functionalities was also incorporated as the redox platform in the Hangman framework; the manganese complex also performed catalytic oxygen atom transfer to olefins. The second framework, dubbed "Pacman", is composed of two salen platforms linked cofacially by rigid pillars xanthene or dibenzofuran. A series of bimetallic complexes, including chromium, iron, manganese, cobalt, copper, and zinc were generated. Mossbauer spectroscopy was used in the characterization of the iron salen complexes, which were also examined for photolytic oxidation chemistry. / by Jenny Yue-fon Yang. / Ph.D.