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A variety of analytical techniques are showcased for their ability to provide insights into reaction mechanisms as well as active intermediate speciation. Pressurized Sample Infusion-Mass Spectrometry (PSI-ESI-MS), ion mobility-mass spectrometry (IMS-MS), and Nuclear Magnetic Resonance (NMR) spectroscopy are powerful analytical techniques capable of reaction monitoring. Contamination from vulcanized rubber was an issue with the PSI-ESI-MS technique as ions unrelated to the reaction were convoluting the mass spectrum. This was resolved by re-designing the PSI flask such that the septum was positioned above a condenser, preventing heat degradation of the septum and subsequent leaching of contam- inants into the reaction solution. The technique was then used to analyze the Buchwald-Hartwig amination reaction in real-time. The innovative use of Multiple Reaction Monitoring (MRM) scans facilitated observation of all catalytic intermediates, and elucidation of relative reaction rates for each step of the catalytic cycle. PSI-ESI-MS and NMR are complementary methods whereby catalytic intermediates are monitored via PSI-ESI-MS, and the rate of product formation is monitored via NMR spectroscopy. This combination of analytical methods was employed in the investigation of the Barluenga cross-coupling reaction between N-tosylhydrazones and aryl halides. A reaction screen revealed optimized homogeneous conditions, and the turnover limiting step was found to be off-cycle. IMS separates gaseous ions based on their size and shape immediately prior to MS analysis. Upon investigation of [PtCl3(C2H4)], and [PtCl3(CO)], it was found that residual [PtCl3] was forming [PtCl3(N2)] in the source of the instrument. Ion mobility was able to separate these isobaric ions, and DFT calculations and collision-induced dissociation experiments confirmed the existence of the gaseous [PtCl3(N2)] complex. NMR spectroscopy may also be employed as a strong reaction monitoring technique. The mechanism of C–H silylation by trimethyl(trifluoromethyl)silane and tetrabutylammonium difluorotriphenylsilicate was investigated using 19F-NMR. All intermediates and reaction byproducts were quantitatively observed, and the reaction conditions were optimized. A stopped-flow NMR system was used to gather data points in the first 0.2 seconds of the reaction. / Graduate

This dissertation focuses on the development of analytical methods based on Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) and their applications for separation and structural characterization of oligosaccharides. Porous graphitized carbon liquid chromatography (PGC-LC), gated-trapped ion mobility spectrometry (Gated-TIMS), and electronic excitation dissociation tandem mass spectrometry (EED MS/MS) are three essential techniques employed here. First, the EED method was optimized to generate more informative glycan tandem mass spectra for accurate structural analysis. Glycans were reduced and permethylated or labeled with a reducing-end fixed charge to increase sensitivity, avoid gas-phase structural rearrangement, and facilitate spectral interpretation. EED of glycans produced nearly complete series of Z-, Y- and 1,5X-ions, that appear in the spectra as triplets with characteristic spacing, thus facilitating accurate determination of the glycan topology. Additional radical-driven dissociation pathways were identified, from which different types of linkage-diagnostic ions (cross-ring, secondary, or internal fragments) were generated. The results demonstrated that linkage analysis can be accomplished by utilizing one or a combination of several linkage-diagnostic fragments. EED MS/MS was then implemented, in conjunction with PGC-LC or Gated-TIMS, for on-line separation and characterization of complex mixtures of glycans. These two methods were successfully applied for high-throughput and detailed structural analysis of N-glycans released from human serum, O-glycans released from bovine submaxillary mucin and free oligosaccharides. The performance of these methods was tested and improved through analysis of different types of glycans from a variety of biological sources. Finally, in collaboration with bioinformaticians, a spectral interpretation algorithm, GlycoDeNovo, has been developed for automated and de novo glycan topology reconstruction from their tandem mass spectra. A large number of EED tandem spectra of glycan standards generated in house were used as the training dataset to establish appropriate IonClassifiers for candidate ranking. GlycoDeNovo is capable of identifying correct topologies from MS/MS spectra of glycans in different derivatized forms. Several aspects of this collaborative project were covered in this thesis, including glycan derivatization, data acquisition and manual spectral interpretation to guide the development and evaluate the performance of the automated approach. In this thesis research, integrated approaches utilizing PGC-LC–EED-MS/MS and Gated-TIMS–EED-MS/MS, and the appropriate bioinformatics software, have been established for structural analysis of glycan mixtures. They hold great potential for comprehensive, automated, and de novo glycome characterization.

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Neste trabalho é apresentada uma nova geometria e os critérios de projeto para dispositivos de espectrometria de mobilidade iônica, com objetivo de aumentar a relação entre sinal e ruído detectados pelos eletrômetros que compõem a região de detecção, quando associado à ionização baseada em descargas elétricas que tipicamente emitem maior interferência eletromagnética em relação a outros tipos de ionização. A geometria e os critérios de projeto foram estabelecidos com o auxílio do simulador de trajetórias iônicas SIMION versão 8.1 e comparada com espectrômetros de mobilidade iônica do estado-da-arte. Os resultados das simulações dos dispositivos foram avaliados por meio dos testes estatísticos não-paramétricos de Iman-Davenport e Holm. O resultado indicou que a geometria proposta apresentou compatibilidade com as melhores características dos espectrômetros atuais com confiança estatística a 95 %. Na sequência a geometria proposta foi simulada, fabricada e testada para detecção dos íons de: tolueno - C7H8 (C5H5+, C6H5+, C7H7+), propanol - C3H8O (CH3+, CH3O+, C2H3+, C2H4O+, C2H5O+, C3H6+, C3H7+, C3H7O+) e água - H2O (H+, HO+, H2+, O+). Os picos de corrente iônica detectada nos eletrômetros indicaram coerência com as trajetórias simuladas para estes conjuntos de íons. Além disso, os resultados experimentais apresentaram um aumento na relação entre sinal e ruído para a nova geometria proposta que foi validada pelo teste de comparação pareada não-paramétrico de Wilcoxon a 95 % de confiança estatística. / In this work, a new geometry and a design criteria for ion mobility spectrometry devices was presented, aiming to increase the signal-to-noise ratio detected by electrodes of the detection region, when associated with ionization based on electrical discharges. The new geometry and the design criteria were established in the SIMION version 8.1 (an ionic trajectory simulator) and compared with the state-of-art ion mobility spectrometers. The results from device simulations were evaluated using the non-parametric statistical test of Iman-Davenport and Holm. The result indicated that the proposed design criteria presented compatibility with the best characteristics of current spectrometers with statistical evidence at 95%. The proposed geometry was simulated, fabricated and tested for the following solvents: toluene - C7H8 (C5H5+, C6H5+, C7H7+), propanol - C3H8O (CH3+, CH3O+, C2H3+, C2H4O+, C2H5O+, C3H6+, C3H7+, C3H7O+) and water - H2O (H+, HO+, H2+, O+). The peaks of ion current detected in the electrometers occurred at approximate positions of the simulated trajectories for these sets of ions. In addition, the experimental data showed an increase in the signal-to-noise ratio for the proposed new geometry that was validated by the test statistic of Wilcoxon signed rank at 95% statistical confidence.

Neste trabalho é apresentada uma nova geometria e os critérios de projeto para dispositivos de espectrometria de mobilidade iônica, com objetivo de aumentar a relação entre sinal e ruído detectados pelos eletrômetros que compõem a região de detecção, quando associado à ionização baseada em descargas elétricas que tipicamente emitem maior interferência eletromagnética em relação a outros tipos de ionização. A geometria e os critérios de projeto foram estabelecidos com o auxílio do simulador de trajetórias iônicas SIMION versão 8.1 e comparada com espectrômetros de mobilidade iônica do estado-da-arte. Os resultados das simulações dos dispositivos foram avaliados por meio dos testes estatísticos não-paramétricos de Iman-Davenport e Holm. O resultado indicou que a geometria proposta apresentou compatibilidade com as melhores características dos espectrômetros atuais com confiança estatística a 95 %. Na sequência a geometria proposta foi simulada, fabricada e testada para detecção dos íons de: tolueno - C7H8 (C5H5+, C6H5+, C7H7+), propanol - C3H8O (CH3+, CH3O+, C2H3+, C2H4O+, C2H5O+, C3H6+, C3H7+, C3H7O+) e água - H2O (H+, HO+, H2+, O+). Os picos de corrente iônica detectada nos eletrômetros indicaram coerência com as trajetórias simuladas para estes conjuntos de íons. Além disso, os resultados experimentais apresentaram um aumento na relação entre sinal e ruído para a nova geometria proposta que foi validada pelo teste de comparação pareada não-paramétrico de Wilcoxon a 95 % de confiança estatística. / In this work, a new geometry and a design criteria for ion mobility spectrometry devices was presented, aiming to increase the signal-to-noise ratio detected by electrodes of the detection region, when associated with ionization based on electrical discharges. The new geometry and the design criteria were established in the SIMION version 8.1 (an ionic trajectory simulator) and compared with the state-of-art ion mobility spectrometers. The results from device simulations were evaluated using the non-parametric statistical test of Iman-Davenport and Holm. The result indicated that the proposed design criteria presented compatibility with the best characteristics of current spectrometers with statistical evidence at 95%. The proposed geometry was simulated, fabricated and tested for the following solvents: toluene - C7H8 (C5H5+, C6H5+, C7H7+), propanol - C3H8O (CH3+, CH3O+, C2H3+, C2H4O+, C2H5O+, C3H6+, C3H7+, C3H7O+) and water - H2O (H+, HO+, H2+, O+). The peaks of ion current detected in the electrometers occurred at approximate positions of the simulated trajectories for these sets of ions. In addition, the experimental data showed an increase in the signal-to-noise ratio for the proposed new geometry that was validated by the test statistic of Wilcoxon signed rank at 95% statistical confidence.

Solid phase microextraction (SPME), needle trap device (NTD), and membrane extraction with a sorbent interface (MESI) are solvent-free sample preparation techniques that were developed to perform the rapid routine analysis of organic compounds (VOCs) in various environmental matrices by integrating sampling, extraction, preconcentration and sample introduction procedures into one step. A portable ion mobility spectrometry (IMS) analyzer has some advantages, such as small size, light weight, operability under ambient pressure, air as carrier gas, and sensitivity, all of which make IMS suitable for on-site monitoring for low concentration of analytes. The aforementioned sampling and preconcentration techniques were coupled with a portable IMS analyzer, as well as a thermal desorption unit that can accommodate SPME, NTD and MESI, which was modified and combined with IMS for on-site monitoring of volatile organic compounds (VOCs) from human breath and plant emissions. Experimental results demonstrated that low detection limits were achievable for gaseous analytes, (25 ng/L for acetone (SPME-IMS), 43 ng/mL (NTD-IMS) and 2.3 ng/mL (MESI-IMS) for α-pinene). These three analytical systems were applied for on-site rapid determination of acetone in human breath and α-pinene from plant emissions respectively. The salient features of these systems that make them suitable for on-site monitoring of volatile organic compounds in different sources are: small size, simple operation, fast and/or on-line sampling, rapid analysis.

Solid phase microextraction (SPME), needle trap device (NTD), and membrane extraction with a sorbent interface (MESI) are solvent-free sample preparation techniques that were developed to perform the rapid routine analysis of organic compounds (VOCs) in various environmental matrices by integrating sampling, extraction, preconcentration and sample introduction procedures into one step. A portable ion mobility spectrometry (IMS) analyzer has some advantages, such as small size, light weight, operability under ambient pressure, air as carrier gas, and sensitivity, all of which make IMS suitable for on-site monitoring for low concentration of analytes. The aforementioned sampling and preconcentration techniques were coupled with a portable IMS analyzer, as well as a thermal desorption unit that can accommodate SPME, NTD and MESI, which was modified and combined with IMS for on-site monitoring of volatile organic compounds (VOCs) from human breath and plant emissions. Experimental results demonstrated that low detection limits were achievable for gaseous analytes, (25 ng/L for acetone (SPME-IMS), 43 ng/mL (NTD-IMS) and 2.3 ng/mL (MESI-IMS) for α-pinene). These three analytical systems were applied for on-site rapid determination of acetone in human breath and α-pinene from plant emissions respectively. The salient features of these systems that make them suitable for on-site monitoring of volatile organic compounds in different sources are: small size, simple operation, fast and/or on-line sampling, rapid analysis.

Molecular ionization is owed much of its development from the early implementation of electron ionization (EI). Although dramatically increasing the library of compounds discovered, an inherent problem with EI was the low abundance of molecular ions detected due to high fragmentation leading to the difficult task of the correct chemical identification after mass spectrometry (MS). These problems stimulated the research into new ionization methods which sought to "soften" the ionization process. In the late 1980s the advancements of ionization techniques was thought to have reached its pinnacle with both electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI). Both ionization techniques allowed for "soft" ionization of large molecular weight and/or labile compounds for intact characterization by MS. Albeit pervasive, neither ESI nor MALDI can be viewed as "magic bullet" ionization techniques. Both techniques require sample preparation which often included native sample destruction, and operation of these techniques took place in sealed enclosures and often, reduced pressure conditions. New open-air ionization techniques termed "ambient MS" enable direct analysis of samples of various physical states, sizes and shapes. One particular technique named Direct Analysis In Real Time (DART) has been steadily growing as one of the ambient tools of choice to ionize small molecular weight (< 1000 Da) molecules with a wide range of polarities. Although there is a large list of reported applications using DART as an ionization source, there have not been many studies investigating the fundamental properties of DART desorption and ionization mechanisms. The work presented in this thesis is aimed to provide in depth findings on the physicochemical phenomena during open-air DART desorption and ionization MS and current application developments. A review of recent ambient plasma-based desorption/ionization techniques for analytical MS is presented in Chapter 1. Chapter 2 presents the first investigations into the atmospheric pressure ion transport phenomena during DART analysis. Chapter 3 provides a comparison on the internal energy deposition processes during DART and pneumatically assisted-ESI. Chapter 4 investigates the complex spatially-dependent sampling sensitivity, dynamic range and ion suppression effects present in most DART experiments. New implementations and applications with DART are shown in Chapters 5 and 6. In Chapter 5, DART is coupled to multiplexed drift tube ion mobility spectrometry as a potential fieldable platform for the detection of toxic industrial chemicals and chemical warfare agents simulants. In Chapter 6, transmission-mode DART is shown to be an effective method for reproducible sampling from materials which allow for gas to flow through it. Also, Chapter 6 provides a description of a MS imaging platform coupling infrared laser ablation and DART-like phenomena. Finally, in Chapter 7 I will provide perspective on the work completed with DART and the tasks and goals that future studies should focus on.

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