Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2011. / Vita. Cataloged from PDF version of thesis. / Includes bibliographical references. / Chapter I. Introduction to the Ladder Polyethers. We introduce the bioactivity of the ladder polyether natural products and provide an overview of the puzzle that is their biogenesis. Cascades of endo-selective epoxide opening inspired by the biosynthetic proposal and promoted by simple neutral water can provide efficient access to these compounds. Chapter II. Water-Promoted Epoxide Opening Accommodates Methyl Substitution. ... Methyl (Me) substitution poses a challenge to the achievement of endo-selective epoxide-opening cascades, as these groups can direct the regioselectivity of epoxide opening. Water as reaction solvent and promoter overcomes such directing effects and enables the incorporation of proximally Me-substituted epoxides into endo-selective cascades. However, Me-substituted epoxides do reduce the overall efficiency of cascades. Chapter III. Kinetics of an Epoxide-Opening Cascade Promoted by Neutral Water. Evidence for a Stepwise Mechanism. ... Detailed investigation of the kinetics of an endo-selective epoxide-opening cascade in water reveals a stepwise mechanism, not a concerted one. While the first step proceeds with poor rate and selectivity, the second cyclization, which is templated by a fused THP diad, proceeds with excellent endo selectivity. Chapter IV. Preliminary Investigation of a Dioxane Template for Endo-Selective Epoxide-Opening Cyclization. ... Use of a 1,3-dioxane as template ring, a methylene acetal engenders endoselective epoxide opening under both acidic and basic conditions. Cyclization in neutral water proceeds with superb endo selectivity. Chapter V. Progress Toward the Synthesis of Gambierol via Endo-Selective Epoxide-Opening Cascades Promoted by Water. ... We report progress toward the biomimetic total synthesis of the ladder polyether gambierol. The FGH ring system has been synthesized in a 20 step longest linear sequence, via an endo-selective epoxide-opening cascade promoted by water. Chapter VI. Conclusion: Potential Implications of the Foregoing Work on the Biosynthesis of the Ladder Polyethers. We summarize lessons learned from in vitro emulation of the hypothesized biosynthesis of the ladder polyethers and speculate on the possibility of ring junction methylation subsequent to the epoxide-opening cascade step. / by Christopher J. Morten. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2008. / Vita. / Includes bibliographical references. / The muscle-type nicotinic acetylcholine receptor (AChR) is a ligand-gated ion channel required for fast synaptic transmission at the neuromuscular junction. It is the archetype of the Cys-Loop superfamily of receptors and a prototypic allosteric protein. The muscle-type AChR has two distinct transmitter binding sites found in the extracellular ligand-binding domain. When acetylcholine binds these sites, a series of still unresolved conformational changes occur, leading to opening of the transmembrane pore over 40 A distant from the binding sites. High resolution structures of the intact receptor and the acetylcholine binding protein have provided greater insight into the structural basis of the allosteric mechanism coupling agonist binding and pore opening. However, comprehensive models of the agonist-bound receptor in its closed and open states are still not available. In particular, the details describing the conformation of binding site residues and the dynamics of their interactions with agonists and competitive antagonists are still under investigation. These details are of particular importance to the design of AChR agonists, partial agonists, and competitive antagonists which may have therapeutic potential for treating neuromuscular and neurological pathologies. Using single-channel electrophysiology we investigated details of the agonist-bound open-state transmitter binding sites. Using a series of structurally related organic cations, we observed a structure-activity relationship that suggests cation-n binding interactions are important for open-state affinity. We also conducted a structure-function study to measure kinetic and thermodynamic differences in agonist binding to the two different transmitter binding sites in both the closed and open states. We observed that the two binding sites have unequal affinities for the agonist choline in the closed state and equal affinities in the open state. The state-dependent difference in affinities suggests that binding determinants from the a subunits predominantly determine open-state choline affinity at each site. / (cont.) In the last chapter, we exploit the state-dependent affinities of small molecules for the AChR to develop a probe for live-cell labeling. The ability of a noncompetitive antagonist incorporating state-dependent AChR binding, photoreactivity, and click chemistry moieties was characterized electrophysiologically, and state-dependent photolabeling of AChRs in live cells was demonstrated. A probe with these characteristics is suitable for investigating the activity-dependent changes in AChRs associated with the complex synaptic changes associated with neuromuscular and neurological disorders. / by Mathew C. Tantama. / Ph.D.

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2009. / In title on title page, "[beta]" appear as lower case Greek letter. / Includes bibliographical references (leaves 35-36). / Cancer is a group of diseases characterized by uncontrolled cell growth and abnormal cell cycle and apoptosis regulation. Among the types of cancer, prostate cancer is the leading cause of death in men. Although many advances have been made in the last decade through anti-hormonal treatment, chemotherapy, and early screening, acquired chemotherapeutic resistance has presented a challenge to treating more advanced forms of prostate cancer. To meet this challenge a new compound, 11[beta]-dichloro, was designed that would integrate lessons learned from previous studies with other chemotherapuetics, specifically cisplatin. 11[beta]-dichloro is a novel aniline mustardestradienone that targets both DNA and the androgen receptor (AR), which is over expressed in many types of prostate cancer. The working hypothesis is that by causing substantial amount of un-repairable DNA damage and sequestering the transcription factor function of the androgen receptor it would result in a more effective treatment when compared to existing treatments. Hence, 11 [beta]-dichloro is expected to affect ARpositive prostate cancer cells more robustly than AR-negative cells, based on our repair shielding and transcription factor hijacking hypotheses. To assay differential toxicity, five different prostate cancer cell lines were used, namely, LNCaP (AR-positive, T887A), PC3 (AR-negative, p53 inactive), DU145 (AR-negative, p53 null), and the isogenic pair PC3-AR (AR-positive) and PC3-neo (AR-negative), which only differ in the AR status. Growth inhibition with LNCaP, PC3, and DU 145 cells showed that LNCaP cells are more sensitive to 11 [mu]-dichloro at concentrations higher than 5.0 tM. To better assay the effect of the AR in cell survival a clonogenic assay was developed using PC3-AR and PC3-neo cells. Preliminary growth inhibition studies with this isogenic pair showed differential toxicity towards AR-positive PC3-AR cells up to 10 [mu]M 11 [beta]-dichloro. / (cont.) However, the series of clonogenic assay experiments showed no differential toxicity between these two cell lines. Nevertheless, these experiments are not conclusive because they were not carried out using a clonal population of cells. 11 [beta]-dichloro has been shown in previous studies to cause up regulation of certain proteins involved in cell cycle arrest and apoptosis regulation. By looking more closely at the effect of 11 [mu]-dichloro treatment on these proteins, potential biomarkers for the effectiveness of cancer treatment can be developed. In this work special attention will be given to p21, a cyclin-dependent kinase inhibitor that was significantly down regulated at early time points after treatment with 11 [beta]-dichloro, but which showed increased levels at later time points. Levels of p21 were assayed through Western blotting using the five different prostate cancer cell lines specified above after treatment with 10 [mu]M 11[beta]-dichloro up to 15 hours. LNCaP cells showed decreased levels of p21 throughout the time course, but more significantly from the 3-9-hour time points. DU145 cells showed increased levels p21 after just 3 hours of exposure with a subsequent decrease to untreated levels at the 15-hour time point. PC3 cells showed increased levels of p21 after 6 hours, with larger increases (6- and 7-fold) at the 9- and 15-hour time points. The isogenic pair PC3-AR and PC3-neo also showed a different expression profile for p21 expression with PC3-neo cells showing increased levels of p21 all through out the time course ranging from 1.8- to 2.5-fold increase. However, PC3-AR cells did not exhibit any p21 at any of the time points except for the 15-hour time point where a faint band could be appreciated. Although qualitatively these observations maybe accurate the quantitative aspect of the analysis will have to be reproduced more thoroughly as p21 levels were not normalized to actin expression for each sample. / (cont.) Taken together these observations suggest that our candidate compound 11[beta]-dichloro exerts its effects on prostate cancer cells differently depending on the presence or absence of the androgen receptor and potentially p53 status. The model suggests that different mechanisms might be used in order to repair the DNA lesions caused by 11 [beta]-dichloro and that these mechanisms are dependent on the presence or absence of the AR since the AR can potentially block DNA repair proteins that are recruited to excise the lesion. / by Francis Héber González. / S.M.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2001. / Includes bibliographical references. / Although several theoretical models for the behavior of magnetic crystals smaller than a single domain size were developed in the 1950's and 60's, they have hardly been verified experimentally because of the lack of appropriate material systems. This thesis is an attempt to develop such a system using metallic cobalt as a magnetic material and to verify its magnetic behavior in the context of a Stoner-Wohlfarth model of coherent rotation. The problem of preparing crystals of a desired shape and the effect of the crystal shape on its magnetic properties is also addressed. Cobalt nanocrystals are prepared by thermal decomposition of dicobalt octacarbonyl in solution and in the presence of suitable surfactants and coordinating ligands, which influence the shape of the resulting crystals as well as their internal structure. The presence of trialkylphosphines in the growth solution leads to the formation of spherical nanocrystals with mixed fcc-hcp structure, where as trioctylphosphine oxide leads to a newly discovered structure of [epsilon]-cobalt. The final size of the crystals is controlled by the precursor-to-ligand ratio, and low polydispersity is achieved by the separation of nucleation and growth stages. Size-selective precipitation is used to further reduce the size variation of the samples. As a result, cobalt nanocrystals in the size range of 4-12 nm in diameter can be routinely produced with size distributions as small as 6%. The study of magnetic properties reveals the superparamagnetic nature of cobalt nanocrystals of this size range at room temperature. At low temperatures, a good qualitative agreement with the theoretical (Stoner-Wohlfarth) model is found, / (cont.) although quantitative results are strongly influenced by the presence of an oxide shell around each nanocrystal. The presence of two surfactants (trialkylphosphines and sodium carboxylates) during the growth leads to the formation of a significant number of triangular and rod-shaped nanocrystals. Unlike disordered spherical particles, these nanocrystals have pure fcc structure without visible defects. The length of the rods is roughly controlled by the concentration of carboxylates in the growth solution and can be changed within a 40-400 nm range. Unlike spherical crystals of comparable volume, the rods are ferromagnetic even at room temperature due to an added effect of shape anisotropy. A growth mechanism for the formation of nanorods with cubic structure is also proposed. / by Dmitry P. Dinega. / Ph.D.

Thesis: Ph. D. in Organic Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2016. / Cataloged from PDF version of thesis. Vita. / Includes bibliographical references. / Chapter 1. Introduction to Carbene Ligands in Surface Chemistry: From Stabilization of Discrete Elemental Allotropes to Modification of Nanoscale and Bulk Substrates In this chapter, we review the development of carbene surface chemistry from its inception through 2015, covering elemental allotrope substrates, nanomaterials, and bulk surfaces, as well as persistent and non-persistent carbenes. We synthesize from the reviewed reports a mechanistic understanding of this chemistry and outline the road ahead in this field. Chapter 2. Addressable Carbene Anchors for Gold Surfaces New strategies to access functional monolayers could augment current surface modification methods. Here we present addressable N-heterocyclic carbene (ANHC) anchors for gold surfaces and provide experimental and theoretical characterization of ANHC monolayers. Additionally, we demonstrate grafting of highly fluorinated polymers from surface-bound ANHCs. Chapter 3. Reactions of Persistent Carbenes with Hydrogen-Terminated Silicon Surfaces We report here the use of persistent aminocarbenes to functionalize via Si-H insertion reactions a range of hydrogen-terminated silicon surfaces: from model compounds, to nanoparticles, and planar Si(l 11) wafers. In particular, a cyclic(alkyl)(amino)carbene and an acyclic diaminocarbene underwent Si-H insertion, forming persistent C-Si linkages and thereby installing amine or aminal functionality in proximity to the surface. Our results pave the way for the further development of persistent carbenes as universal ligands for silicon and potentially other non-metallic substrates. Chapter 4. Cycloelimination of Imidazolidin-2-Ylidene N-Heterocyclic Carbenes: Mechanism and Insights into the Synthesis of Stable "NHC-CDI" Amidinates We report the discovery that 1,3-bis(aryl)imidazolidin-2-ylidenes, one of the most widely studied classes of N-heterocyclic carbenes (NHCs), undergo quantitative conversion to zwitterionic "NHC-CDI" amidinates upon heating to 100 °C in solution. The mechanism of this novel NHC decomposition process was studied in detail and enabled the rational synthesis of a new class of bench stable amidinates. Chapter 5. Toward Dynamic and Hierarchically Structured Polymer Gels: An Introduction to Polymer Metal-Organic Cage Gels Key challenges in polymer network/gel chemistry are overviewed. Polymer metal-organic cage gels capable of addressing some of these key challenges are introduced. Chapter 6. Highly Branched and Loop-Rich Gels Via Formation of Metal-Organic Cages Linked by Polymers We report here a new class of gels (called 'polyMOC' gels) assembled from polymeric ligands and metal-organic cages (MOCs) as junctions with M₂L₄ or M₁₂L₂₄ stoichiometries. The latter features increased branch functionality and large shear moduli, but also an abundance of elastically inactive loop defects that allow via ligand exchange the introduction of function at no cost to the gel's mechanical properties. / by Aleksandr V. Zhukhovitskiy. / Ph. D. in Organic Chemistry

Thesis: Ph. D. in Biological Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2018. / Cataloged from PDF version of thesis. / Includes bibliographical references. / Biological reactivity is typically carried out by large enzymes. There are few examples of reactive, amino-acid-based polymers shorter than 100 residues in length. Of those that do exist, the majority are very short tags (<15 amino acids). Here, we attempted to first discover peptides roughly 30 amino acids in length that promote a nucleophilic aromatic substitution reaction and then understand the features and properties that emerge. Using the 20 canonical amino acids, there are 20³⁰ different peptide sequences possible in this size realm. To isolate a portion of the space capable of reacting with a perfluoroaromatic small molecule, we performed an mRNA display selection. This uncovered a host of putative reactive peptides with little similarity at the sequence level. The primary isolate (MP01) displayed reactivity confirming the success of the selection and was sensitive to truncation and denaturants. We next set out to study the reactivity of an expanded portion of the isolated peptides and look for shared structural or mechanistic themes. Analyzing an additional 26 peptides with almost no sequence similarity, we discovered diverse levels of reactivity along with sequences capable of undergoing multiple reactions. Using computational structure prediction and circular dichroism spectroscopy we discovered that both mixed alpha-helical and random coil as well as beta-sheet-based reactive peptides existed. Studying their structural properties revealed that many of the peptides undergo significant structural alterations upon reaction with the perfluoroaromatic. Returning to MP01 we studied its mutational tolerance as well as its structural and mechanistic properties. Alanine scanning mutagenesis revealed mutations that diminished reactivity in addition to others that improved its function. Computational structure prediction suggested a mixed helical and random coil structure. Combining the beneficial mutations with insights from modeling initiated an iterative process that ultimately led to a 100-fold improved reaction rate. This sequence (MP01-Gen4) was six mutations different from MPG 1 and was more reactive than any other peptide discovered. MP01-Gen4 displayed flexibility and lacked a defined three-dimensional structure, however, it was significantly more helical than its progenitor. This sequence also displayed structural alterations, becoming more helical in the presence of its small molecule reaction partner, when either covalently reacted or noncovalently interacting. / by Ethan Daniel Evans. / Ph. D. in Biological Chemistry

Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1995. / Vita. / Includes bibliographical references. / by Anna W. Poon. / M.S.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2008. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Vita. / Includes bibliographical references. / The experimental measurement technique of ultrafast dynamic ellipsometry (UDE) was developed for measuring material motion and changes in optical properties of samples under laser driven shock loading. Ultrafast dynamic ellipsometry, a technique based on space-shifted spectral interferometry, uses the time-dependent frequency of a chirped laser pulse to provide time encoding, allowing the picosecond probing of material dynamics in a single shot. With this technique, the sample is probed at two different incident angles with both s- and p-polarized light, which measures the motion of the material and any change in its complex refractive index. Ultrafast dynamic ellipsometry was first used to ascertain the Hugoniot and the shocked refractive indices of thin polymer films of polycarbonate, poly(methyl methacrylate) (PMMA), poly(chlorotrifluoroethylene-co-vinylidene fluoride) (Kel-F 800), and polydimethylsiloxane (Sylgard 184). Next, UDE was used to measure the Hugoniots of liquid samples over a range of nearly one-dimensional stresses in a single laser shot by capitalizing on the spatial energy distribution of the shock generating laser beam. Using the spatially resolved UDE data, the Hugoniots and shocked refractive indices of cyclohexane, toluene, methanol, and water were measured, each in a single laser shot. Two additional liquids, nitromethane and carbon disulfide, were also investigated with UDE, and both liquids showed evidence of chemical reaction in the first 200 ps after the arrival of the shock wave. Ultrafast dynamic ellipsometry was used in conjunction with high-speed schlieren imaging to determine the nature of the insult provided by ablation of a thin titanium film in optical detonators. / (cont.) We found that the titanium ablates in fragmented sections, which impact the explosive material to initiate the optical detonators. Finally, UDE was applied to the study of metallic phase transitions. The change in the complex refractive index of crystalline silicon was measured during ultrafast laser induced melting. The fabrication of thin metal films of iron and cerium is described, and preliminary UDE data were recorded in an attempt to probe the ??-?? phase transformation in iron and the ??-?? transformation in cerium. / by Cynthia Anne Bolme. / Ph.D.

Massachusetts Institute of Technology. Dept. of Chemistry. Thesis. 1971. Ph.D. / Vita. / Includes bibliographical notes. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 2015. / Cataloged from PDF version of thesis. Vita. / Includes bibliographical references. / Liquid water possesses an extended network of hydrogen bonds that is responsible for many of its interesting properties. Mobility of hydroxide ions in aqueous solutions is much higher compared to the ions of similar size and charge density. A proton can efficiently move from a neighboring water molecule to the hydroxide ion due to the presence of hydrogen bonds, resulting fast structural diffusion of the ion. On the other hand, this hydrogen bonding network of water undergoes fluctuations on femtoseconds to picoseconds timescale, influencing the intertwined hydroxide transport process. Studying the influence of water's hydrogen bonding network on the proton transport process in aqueous hydroxide solutions is experimentally challenging, largely due to the lack of a suitable technique that is sensitive to the changes in the system on few tens of femtoseconds timescale. Vibrations in aqueous hydroxide solutions are sensitive to the strength of hydrogen bonding and hence vibrational frequencies, intensities and line shapes are closely associated with the structure and dynamics of the hydroxide ions. In this thesis, we have employed ultrafast infrared spectroscopy in conjunction with theoretical modeling to understand the nature of the vibrations and their dynamics in aqueous hydroxide solutions. The infrared spectra of aqueous solutions of NaOH and other strong bases exhibit a broad continuum absorption for frequencies between 800 and 3500 cm-¹, which is attributed to the strong interactions of the hydroxide ion with its solvating water molecules. This continuum absorption has limited distinguishable features whose molecular origin holds the key in explaining the vibrational dynamics. We have performed ultrafast transient absorption and 2DIR experiments on aqueous NaOH solutions, by exciting the O-H stretch vibrations and probing the response from 1350-3800 cm-¹, using a newly developed sub-70 fs broadband infrared source. By probing the entire mid-infrared continuum absorption of aqueous hydroxide solutions with ultrafast pulses, the broadband infrared source allows us to monitor time-dependent changes in this broad spectral window. These experiments, in conjunction with harmonic vibrational analysis of OH-(H₂O)₁₇ clusters, reveal that O-H stretch vibrations of aqueous hydroxides arise from coupled vibrations of multiple water molecules solvating the ion. These delocalized vibrations cannot be distinguished based on the local structure of the hydroxide ion. However, they can be classified according to the symmetry defined by the relative phase of vibrations of the O-H bonds hydrogen bonded to the ion. In general, we find the asymmetric O-H stretch vibrations to be more intense and shifted to lower frequencies compared to the symmetric ones. Analysis of transient absorption and waiting time dependent 2DIR spectroscopy shows that the vibrations in aqueous hydroxide solutions relax on 100-300 fs timescale. Alongside, the O-H stretch vibrations originating from the bulk-like water molecules as well as the asymmetric O-H stretch vibrations of the water molecules solvating the hydroxide ion lose their frequency memory within 160-180 fs. Such loss in frequency memory on similar timescales is likely to happen through migration of vibrational excitation between two types of O-H stretch vibrations. Spectral features in strongly hydrogen bonded systems like water and aqueous hydroxide solutions are very broad, particularly the induced absorption features in the transient absorption and 2DIR spectra. With the development of broadband mid-infrared pulses, we are able to detect nonlinear response of these systems in the frequency window of 1350-3800 cm-¹, observing >1700 cm-¹ broad induced absorption features. Qualitatively, strong coupling between intra- and intermolecular vibrations lead to such broadening. In order to explain the experimental results, we have developed a self-consistent phenomenological model that consists of an intramolecular and an intermolecular vibration, with strong nonlinear coupling between them. We find that the experimental results are reproduced when the coupling between the vibrations is strong enough to yield eigenstates with mixed intra- and intermolecular vibrational character. In such scenarios, the identities of individual intra- and intermolecular vibrational modes are lost. / by Aritra Mandal. / Ph. D.