Dissertations / Theses on the topic '030699 Physical Chemistry not elsewhere classified'

For decades there has been interest in understanding early prebiotic Earth, including its atmospheric chemistry. Saturn’s moon Titan is the only other body in our Solar System with an atmosphere thought to resemble that of early Earth’s, and for this reason it has garnered a lot of attention over the years. Much is now known about the smaller molecules present in that atmosphere, starting with the most abundant, N₂ and CH₄, and going up to slightly larger molecules such as cyanoacetylene and benzene. As the molecules get larger, however, so does the gap in knowledge, especially as it pertains to nitriles. This dissertation aims to add to the story of Titan’s nitriles by first characterizing a molecule thought to be the photochemical product of the reaction between cyanoacetylene and benzene, 3-phenyl-2-propyne-nitrile (PPN). The UV spectra of PPN proved immensely interesting due to the strong presence of in-plane and out-of-plane vibrations of b₂ and b₁ symmetry, respectively. This is possibly a result of strong vibronic coupling between several excited electronic states or Coriolis coupling between complementary b₁ and b₂ vibrational levels. The multi-layer extension of the multi-configuration time dependent Hartree (ML-MCTDH) algorithm was used to understand how the excited states and the vibrational levels might interact, and emission and absorption spectra were modeled and compared to the experimental spectra. The second group of molecules studied included the ortho-, meta-, and para-methyl PPN. Strong methyl rotor activity is seen in the m-methyl PPN, with some activity in the p-methyl PPN. The methyl rotor activity in the m-methyl PPN is similar to other meta-substituted toluenes, and allows us to describe the methyl rotor barrier height in both ground and excited electronic state. Additionally, in all three methylated PPNs we see evidence for strong vibronic coupling in the abundance of out-of-plane vibrations, as had been seen in PPN.

The work presented here employs cryogenic ion spectroscopy for the study of protein structure, kinetics, and dynamics. The main technique used is IR-UV double resonance spectroscopy. Here peptide ions are generated through nano electrospray ionization, guided into a mass spectrometer, mass selected, and then guided into a cryogenically held octupole ion trap. Ions are subsequently cooled to their vibrational ground state through collisions with 5 K helium allowing for high resolution IR and UV spectra to be recorded. The IR spectra are highly sensitive to an ion’s conformation, and the well resolved UV spectra provides a means generate conformer specific IR spectra. With the use quantum mechanical calculations, it is possible to calculate the vibrational spectra of candidate structures for comparison with experimental spectra. Strong correlations between theory and experiment allow for unambiguous structural assignments to be made.

Structural studies are performed on β-turn motifs and well as salt-bridge geometries. Beta-turns are a commonly occurring secondary structure in peptides and proteins. It is possible to artificially encourage the formation of this secondary structural element through the incorporation of the D-proline (^DP) stereoisomer followed by a gly or ala residue. Interestingly, the L-proline (^LP) stereoisomer is seen to discourage the formation of beta turn structure. Here were probe the inherent conformational preferences of the diastereomeric peptide sequences YA^LPAA and YA^DPAA. The findings agree with solution phase studies, the ^DP sequence is observed to adopt a beta turn however, the ^LP sequence is found to undergo a sterically driven trans à cis isomerization about the proline amide bond. We find the energetics associated with this unfavorable interaction and show the ability to reverse it by proper substitution of Ala₂ for a Gly.

The studies directed towards gas phase salt bridges have been limited to single amino acids or dipeptides. Generally, these species are ionized using a metal ion or adducted with water or excess electrons in order to stabilize a zwitterionic motif. Here we take the first look at a salt bridge motif incorporated into polypeptide in order to understand how the solvation from the secondary structure can aid in stabilizing these motifs in non-polar environments. We find a unique salt bridge motif in the YGRAR sequence in which the tyrosine OH acts as a neutral bridge to form a network between the C-terminal arginine and the ion pair formed between the central arginine and C-terminal carboxylate group. This binding motif has not been discussed in literature and appears as an important structural element in non-polar environments as all salt bridge character is lost upon substituting Tyr for Phe. We are the process of mining the PDB for these types of interactions.

To better understand how cryo-cooling impacts the resulting population distribution at 10 K we measured the distribution among the two major conformation of the YGPAA ion. This was carried out using population transfer spectroscopy. In this method conformational isomerization is induced vis single conformer infrared excitation. The change in population can be related to the final population distribution at 10 K. With this number, we were able to develop a cooling model to simulate the change in the distribution as a function of cooling. The cooling rates, were experimental established, and the isomerization rates and starting population were theoretically derived through RRKM and thermodynamic calculations. With these parameters and cooling model, we found that the room temperature population distribution is largely preserved. When isomerization events involve breaking a hydrogen bond, they become too slow to complete with the cooling time scale of the experiment, effectively freezing in the room temperature structures. These are important physical parameters to characterize when performing structural studies at 10 K.

Finally, we demonstrate a 2-Color IRMPD technique that is able to generate linear spectra at varied temperatures. This is in sharp contrast to traditional IRMPD which results in non-linear and skewed spectra. The importance of generating linear spectra when making structural assignments is highlight by comparing the performance between both techniques. Furthermore, with this technique we show the ability to record the spectra of ion prepared with high internal energies. This provides spectroscopic snapshots of the unfolding events leading to dissociation. Overall, the versatility of this technique to record ground state spectra comparable to IR-UV DR, to record linear spectra at room temperature, and to probe dynamics proves this technique to be useful in the field of ion spectroscopy.

Open questions remain on the influence of various conditions and ion behavior on the hydration-shell of oily molecules. My research uses Raman spectroscopy and Raman multivariate curve resolution to study the hydration-shell of oily molecules as tools to help answer some of these open questions.

More specifically, I present results on the effect of molecular crowding on the structure of water around various oily molecules, and report the effect of molecular crowding on hydrophobic crossover. These results are important, as crowding has the potential to influence several fields, such as biology and environmental sciences. This work shows that increasing molecular concentration results in oil-oil crowding, decreases the tetrahedrality of the water structure around the oily molecules, and subsequently, the crossover temperature.

In addition to studying the hydration-shell under crowded conditions, I also present work on ion affiliation for the hydration-shell of an oily molecule. Ion affiliation for oil/water interfaces has been an ongoing topic of research since the Hoffmeister experiments because of their effect on biological processes. This study focuses on hydroxide and its affiliation for tert-butyl alcohol in comparison to other electrolytes. These results show iodide is less repelled by the oil/water interface in comparison to hydroxide.

Finally, I present findings on the influence of hydrogen peroxide in comparison to other small molecules on the water structure of an oily molecule. Hydrogen peroxide has been shown to reach supercooled temperatures, which may be useful in future studies of liquid phase transitions or studies on solute behavior at supercooled conditions. It is found that hydrogen peroxide does not significantly influence the water structure around tert-butyl alcohol, while other small molecules display significant water structure changes.

All these projects aim to contribute results to heated debates, as well as share information for future experiments.

The hydrogen bond is one of nature’s ubiquitous molecular interactions. Its role ranges from that of a static provider of structural integrity in proteins to that of a dynamic coordinate, along which excited state deactivation in sunscreen molecules is achieved. The work in this dissertation employs a supersonic expansion to collisionally cool peptide oligomers and a sunscreen chromophore to the zero-point vibrational level of their low lying conformational minima. These species are interrogated using high-resolution, conformer-specific ultraviolet and infrared laser spectroscopic techniques with the aim of elucidating their intrinsic conformational preferences, hydrogen bonding networks, and excited state deactivation mechanisms.

Synthetic foldamers are oligomers composed of non-natural building blocks, such as b- and g-amino acids. Incorporation of such residues into a peptide backbone results in secondary and tertiary structures that are distinct from those found in nature. Herein, the folding propensity of a series of mixed a/b and pure b-peptides is presented. In each case, both the left- and right-handed emergence of mixed-helical secondary structures, the 11/9- and the 12/10-helix, are observed. Next, the intrinsic conformational preferences of a series of increasingly complex asparagine-containing peptides are characterized. Asparagine, with its flexible carboxamide sidechain, is omnipresent within the prion forming domain of the misfolded proteins associated with several neurodegenerative diseases. Asparagine’s propensity for b-turn structures is discussed and compared with that of analogous peptide sequences found in nature.

Methyl anthranilate is a natural product that contains an identical electronic chromophore to the sunscreen agent, meradimate. The excited state deactivation mechanism of methyl anthranilate and its water complex is determined with extensive ultraviolet spectroscopic characterization, and is discussed within the broader context of its role as a sunscreen agent. Vibronic analysis coupled with computational results indicate extensive heavy-atom rearrangement leading to hydrogen atom dislocation, rather than full transfer, on the S₁ surface. This phenomenon is further characterized with infrared spectroscopy and theoretical modeling, in which the NH stretch is adiabatically separated from other internal coordinates. Extensive dilution of the dislocated NH stretch oscillator strength over many transitions and ~1,300 cm^-1 is predicted. These results may have implications for similar molecules, such as salicylic acid and its derivatives.

Supersaturating drug delivery systems are an attractive solubility enabling formulation strategy for poorly soluble drugs due to their potential to significantly enhance solubility and hence, bioavailability. Compendial dissolution testing is commonly used a surrogate for assessing the bioavailability of enabling formulations. However, it increasingly fails to accurately predict in vivo performance due its closed-compartment characteristics and the lack of absorptive sink conditions. In vivo, drug is continually removed due to absorption across the gastrointestinal membrane, which impacts the luminal concentration profile, which in turn affects the dissolution kinetics of any undissolved material, as well as crystallization kinetics from supersaturated solutions. Thus, it is critical to develop an improved methodology that better mimics in vivo conditions. An enhanced approach integrates dissolution and absorption measurements. However, currently-used two-compartment absorptive apparatuses, employing a flat-sheet membrane are limited, in particular by the small membrane surface area that restricts the mass transfer, resulting in unrealistic experimental timeframes. This greatly impacts the suitability of such systems as a formulation development tool. The goal of this research is two-fold. First, to develop and test a high surface area, flow-through, absorptive dissolution testing apparatus, designed to provide in vivo relevant information about formulation performance in biologically relevant time frames. Second, to use this apparatus to obtain mechanistic insight into physical phenomenon occurring during formulation dissolution. Herein, the design and construction of a coupled dissolution-absorption apparatus using a hollow fiber membrane module to simulate the absorption process is described. The hollow fiber membrane offers a large membrane surface area, improving the mass transfer rates significantly. Following the development of a robust apparatus, its application as a formulation development tool was evaluated in subsequent studies. The dissolution-absorption studies were carried out for supersaturated solutions generated via anti-solvent addition, pH-shift and by dissolution of amorphous formulations. The research demonstrates the potential of the apparatus to capture subtle differences between formulations, providing insight into the role of physical processes such as supersaturation, crystallization kinetics and liquid-liquid phase separation on the absorption kinetics. The study also explores dissolution-absorption performance of amorphous solid dispersions (ASDs) and the influence of resultant solution phase behavior on the absorption profile. Residual crystalline content in ASDs is a great concern from a physical stability and dissolution performance perspective as it can promote secondary nucleation or seed crystal growth. Therefore, the risk of drug crystallization during dissolution of ASDs containing some residual crystals was assessed using absorptive dissolution measurements and compared to outcomes observed using closed-compartment dissolution testing. Mesoporous silica-based formulations are another type of amorphous formulations that are gaining increased interest due to higher physical stability and rapid release of the amorphous drug. However, their application may be limited by incomplete drug release resulting from the adsorption tendency of the drug onto the silica surface. Thus, the performance of mesoporous silica-based formulations was also evaluated in the absorptive dissolution testing apparatus to determine the impact of physiological conditions such as gastrointestinal pH and simultaneous membrane absorption on the adsorption kinetics during formulation dissolution. Overall, the aim of this research was to demonstrate the potential of the novel in vitro methodology and highlight the significance of a dynamic absorptive dissolution environment to enable better assessment of complex enabling formulations. In vivo, there are multiple physical processes occurring in the gastrointestinal lumen and the kinetics of these processes strongly depend on the absorption kinetics and vice-a-versa. Thus, using this novel tool, the interplay between solution phase behavior and the likely impacts on bioavailability of supersaturating drug delivery systems can be better elucidated. This approach and apparatus is anticipated to be of great utility to the pharmaceutical industry to make informed decisions with respect to formulation optimization.

High resolution tandem mass spectrometry (MSⁿ) coupled with various separation techniques, such as high-performance liquid chromatography (HPLC) and gas chromatography (GC), is widely used to analyze mixtures of unknown organic compounds. In a mass spectrometric analysis, analytes of interest are at first transferred into the gas phase, ionized (protonated or deprotonated) and introduced into the instrument. Tandem mass spectrometric experiments may then be used to gain insights into structure and reactivity of the analyte ions in the gas phase. The tandem mass spectral data are often compared to those reported in external databases. However, the tandem mass spectra obtained for protonated analytes may be markedly different from those in external databases because protonation site manifested during a mass spectrometric experiment can be affected by the ionization technique, ionization solvents and condition of the ion source. This thesis focuses on investigating the effects of instrumental conditions and analyte concentrations on the protonation sites of 4-aminobenzoic acid. Reactivities of radical species were also investigated. A modified bracketing method was developed and proton affinities of a series of mono- and biradicals of pyridine were measured. In another study, a para-benzyne analog was generated in both solution and the gas phase and its reactivities towards various neutral reagents in the gas phase were compared to those in solution.

Chapter 2 discusses the fundamental aspects of the instruments used in this research. In chapter 3, the effects of residual moisture in linear quadrupole ion trap on the protonation sites of 4-aminobenzoic acid are considered. Chapter 4 focuses on the use of gas-phase ion-molecule reactions with trimethoxymethylsilane (TMMS) for the identification of the protonation sites of 4-aminobenzoic acid. Further, the effects of analyte concentration on the protonation sites of 4-aminobenzoic acid are considered. Chapter 5 introduces a modified bracketing method for the experimental determination of proton affinities of a series of pyridine-based mono- and biradicals. In chapter 6, successful generation of para-benzynes in solution is discussed. The reactivity of a para-benzyne analog, 1,4-didehydrophenazine, is compared to its reactivity in the gas phase.