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<p>The overall time and cost for a drug to go from the drug discovery to the consumer market is  significant,  showing  a  need  for  improved  drug  testing  and  discovery  methods.    Work  on nonlinear  optical  methods  for  both  small  active  pharmaceutical  ingredient  drug  formulation analysis and large biological therapeutic stability testing has been shown to improve testing times for formulation, stability and dissolution testing.  Herein, we review the existing and conventional approaches to address stability testing that the pharmaceutical industry uses, and how leveraging nonlinear optical (NLO) methods can improve the current challenges.  The specificity, sensitivity and low limit of detection of second harmonic generation is discussed in application to crystal formation in small-molecule active pharmaceutical ingredients.  The nonlinear optical methods second harmonic generation and two-photon excited ultraviolet fluorescence are directly compared to  ‘gold  standard’  powder  X-ray  diffraction,  which  is  commonly  used  for  measuring  crystal formation and growth of active pharmaceutical ingredients in amorphous solid dispersions.  In addition, the existing FRAP method (with multiple limitations) is improved upon with the ability to  perform  recovered  diffusion  coefficient  data  analysis  in  the  spatial  Fourier  domain.    The collective results discussed in this thesis are just a small subset of the total breadth of investigations marrying the new challenges in the pharmaceutical industry with the new NLO tools tailored to meet them</p>

Understanding molecular interactions at the surfaces of cellular membranes, including adsorption and transport, is of fundamental importance in both biological and pharmaceutical studies. At present, particularly with respect to small and medium size (drug-like) molecules, it is desirable to gain an understanding of the mechanisms that govern membrane adsorption and transport. To characterize drug-membrane interactions and mechanisms governing the process of molecular uptake at cellular membranes in living organisms, we need to develop effective experimental techniques to reach quantitative and time-resolved analysis of molecules at the membrane surfaces. Also, we preferably want to develop label-free optical techniques suited for single-cell and live cell analysis. Here, I discuss the nonlinear optical technique, second-harmonic light scattering (SHS), for studying molecule-membrane interactions and transport of molecules at the membrane of living cells with real-time resolution and membrane surface-specificity. Time-resolved SHS can quantify adsorption and transport of molecules, with specific nonlinear optical properties, at living organisms without imposing any mechanical stress onto the membrane. This label-free and surface-sensitive technique can even differentiate molecular transport at individual membranes within a multi-membrane cell (e.g., bacteria). In this dissertation, I present our current research and accomplishments in extending the capabilities of the SHS technique to study molecular uptake kinetics at the membranes of living cells, to monitor bacteria membrane integrity, to characterize the antibacterial mechanism-of-action of antibiotic compounds, to update the molecular mechanism of the Gram-stain protocol, to pixel-wise mapping of the membrane viscosity of the living cells, and to probe drug-induced activation of bacterial mechanosensitive channels in vitro. / Chemistry

Ionic self-assembled multilayers (ISAMs) can be formed by alternately dipping a substrate in anionic and cationic polyelectrolytes. Each immersion deposits a monolayer via electrostatic attraction, allowing for nanometer-scale control over film thickness. Additionally, ISAM films can be applied to arbitrary substrate geometries and can easily incorporate a variety of polymers and nanoscale organic or inorganic inclusions. The ISAM technique was used to tune and functionalize a rapid, sensitive fiber optic biosensor for textit{Brucella}, a family of bacteria that are detrimental to livestock and can also infect humans. The sensor was based on a turn-around point long period fiber grating (TAP-LPG). Unlike conventional LPGs, in which the attenuation peaks shift wavelength in response to environmental changes, TAP-LPGs have a highly sensitive single wavelength peak with variable attenuation. ISAMs were applied to a TAP-LPG to tune it to maximum sensitivity and to facilitate cross-linking of receptor molecules. Biotin and streptavidin were used to attach biotinylated hybridization probes specific to distinct species of textit{Brucella}. The sensor was then exposed to lysed cell cultures and tissue samples in order to evaluate its performance. The best results were obtained when using samples from textit{Brucella} infected mice, which produced a transmission change of 6.0 ± 1.4% for positive controls and 0.5 ± 2.0% for negative controls. While the sensor was able to distinguish between positive and negative samples, the relatively short dynamic range of the available fiber limited its performance. Attempts to fabricate new TAP-LPGs using a CO2 laser were unsuccessful due to poor laser stability. A second application of the ISAM technique was as a source of second-harmonic generation (SHG). SHG is a nonlinear optical process in which light is instantaneously converted to half its wavelength in the presence of intense electric fields. Localized surface plasmons (LSPs) in metal nanoparticles produce strong electric field enhancements, especially at sharp tips and edges, that can be used to increase SHG. Colloidally grown silver nanoprisms were deposited onto nonlinear ISAM films and conversion of 1064 nm Nd:YAG radiation to its 532 nm second-harmonic was observed. Little enhancement was observed when using nanoprisms with LSP resonance near 1064 nm due to their large size and low concentration. When using shorter wavelength nanoprisms, enhancements of up to 35 times were observed when they were applied by immersion, and up to 1380 times when concentrated nanoprisms were applied via dropcasting at high enough densities to broaden their extinction peak towards the excitation wavelength. A maximum enhancement of 2368 times was obtained when concentrated silver nanoprisms with LSP resonance around 900 nm were spincast with an additional layer of PCBS. / Doctor of Philosophy / Polyelectrolytes are long molecules composed of chains of charged monomers. When a substrate with a net surface charge is dipped into an oppositely charged polyelectrolyte solution, a single layer of molecules will be electrostatically deposited onto the substrate. Because the surface charge now appears to match the charge of the solution, no further deposition occurs. However, the process can be repeated by rinsing the substrate and immersing in a solution with the opposite charge. This technique forms ionic self-assembled multilayers (ISAMs), which can be assembled with nanometer-level control over thickness. The flexibility of polymer chemistry allows ISAMs to be formed from polyelectrolytes with a wide variety of properties. Additionally, the technique can easily incorporate other nanoscale materials, such as nanoparticles, clay platelets, and biological molecules, and has been investigated for applications ranging from dye-sensitized organic solar cells to drug delivery and medical implant coatings. This dissertation presents two applications of ISAM films. In one, ISAM films were used to tune and functionalize an optical biosensor for Brucella. Brucellosis primarily infects livestock, in which it causes significant reproductive problems leading to economic losses, but can also cause flu-like symptoms and more serious complications in humans. A rapid, sensitive test for Brucella is required to monitor herds and adjacent wild carriers, such as elk and bison. Optical biosensors, which operate by detecting changes due to the interaction between light and the stimulus, could satisfy this need. Long period fiber gratings (LPGs) are periodic modulations induced in the core of an optical fiber that cause transmitted light to be scattered at a resonant wavelength, resulting in attenuation. Conventional LPGs respond to changes in strain, temperature, or external refractive index by shifting their resonant wavelength. When special conditions are met, an LPG may exhibit a turn-around point (TAP), where dual peaks coalesce into a single peak with a constant wavelength but variable attenuation depth. TAP-LPGs are more sensitive than ordinary LPGs, and could be developed into inexpensive sensors with single-wavelength light sources and detectors. In this work, ISAMs were deposited onto an LPG to tune it near its TAP. Segments of single-stranded DNA, called hybridization probes, that were specific to individual species of Brucella were attached to the ISAM film before the sensor was exposed to lysed bacterial cultures. It was found that the sensor could distinguish between Brucella and other types of bacteria, but was less successful at distinguishing between Brucella species. The project was limited by the available TAP-LPGs, which had less dynamic range than those used in prior work by this group. Attempts were made to establish a new supply of TAP-LPGs by fabrication with a CO2 laser, but these efforts were unsuccessful due to poor laser stability. The second project discussed in this dissertation investigated ISAM films as a source of second-harmonic generation (SHG), a nonlinear optical process in which light is converted to half its fundamental wavelength in the presence of intense electric fields. Nonlinear ISAMs were constructed by choosing a polyelectrolyte with a hyperpolarizable side group in which SHG can occur. The SHG efficiency was increased by factors of several hundred to several thousand by the addition of silver nanoprisms. Metal nanoparticles can produce strong electric field enhancements, especially at their tips and edges, when incident light causes resonant collective oscillations in their electrons called localized surface plasmons (LSPs). It was found that while silver nanoprisms whose LSP resonant wavelength matched the fundamental wavelength were too dilute to produce noticeable enhancement, better results could be obtained by depositing shorter wavelength nanoprisms at sufficient density to broaden their extinction peak via interparticle interactions. The best enhancement observed was for a sample where concentrated silver nanoprisms with LSP resonance around 900 nm were dropcast onto an ISAM film and coated with an additional polymer layer, resulting in 2368 times more SHG than the plain ISAM film.

Terahertz (THz) spectroscopy is a powerful tool that uses ultrashort pulses of light to study the properties of materials on picosecond time scales. THz light can be generated through a variety of methods. In our lab, we generate THz through the process of optical rectification in nonlinear optical (NLO) organic crystals. THz light can be used to study several phenomena in materials, such as spin precession, electron acceleration, vibrational and rotational motion. The work presented in this dissertation is divided into two parts: (1) the generation of THz light and (2) applications of THz light. The first portion of this work shows how THz light is generated, with an emphasis on the generation through optical rectification. We also show how to improve the generation of THz light by creating heterogenous multi-layer structures with yellow organic THz generation crystals. Additionally, we show that crystals used for THz generation can also be used to generate second-harmonic light. In the second half of this work, we show that THz light can be used to study the vibrational motion of molecular systems. We model how resonant vibrational modes in a fluorobenzene molecule can be excited with a multi-THz pump to transfer energy anharmonically to non-resonant modes. We also show that we can use two-dimensional (2D) THz spectroscopy to excite infrared-active vibrational modes and probe Raman-active modes in a CdWO4 crystal to obtain a nonlinear response. We show that the nonlinear response is due to anharmonic coupling between vibrational modes and we can quantify the relative strengths of these anharmonic couplings, which previously was only accessible through first-principles calculations.

Recent analyses by polarization resolved second-harmonic (SH) microscopy have demonstrated that ferroelectric (FE) domain walls (DWs) can possess non-Ising wall characteristics and topological nature. These analyses rely on locally analyzing the properties, directionality, and magnitude of the second-order nonlinear tensor. However, when inspecting FE DWs with SH microscopy, a manifold of different effects may contribute to the observed signal difference between domains and DWs, i.e., far-field interference, Čerenkov-type phase-matching (CSHG), and changes in the aforementioned local nonlinear optical properties. They all might be present at the same time and, therefore, require careful interpretation and separation. In this work, we demonstrate how the particularly strong Čerenkov-type contrast can selectively be blocked using dark- and bright-field SH microscopy. Based on this approach, we show that other contrast mechanisms emerge that were previously overlayed by CSHG but can now be readily selected through the appropriate experimental geometry. Using the methods presented, we show that the strength of the CSHG contrast compared to the other mechanisms is approximately 22 times higher. This work lays the foundation for the in-depth analysis of FE DW topologies by SH microscopy.

The Nonlinear optical (NLO) microscopy is a very powerful and noninvasive tool to analyze the material properties, such as the local symmetry, as well as to visualize ferroelectric domains and domain walls. As a result, NLO microscopy becomes a very powerful tool in characterization and quality control which are key tasks in material development and device fabrication. One such area where NLO microscopy is widely used, is thin film materials. Thin film and nanosized materials with dimensions ranging from a few micrometers thickness down to atomically thin 2D materials, offer many innovative and intriguing features for applications in electronics, optics, and many other fields. In order to provide physical stability, these thin film and 2D materials are usually supported on substrates and handles, leading to multiple effects, such as thin film resonance and reflections at the thin film-substrate interface, that influence the genuine NLO signal from the sample. These effects are not present in bulk samples; therefore, it is natural to erroneously consider that these effects are also not present in thin film materials. This work tries to identify, quantify, and disentangle the parameters that influence nonlinear microscopy in thin film materials. To achieve this, Second Harmonic Generation (SHG) microscopy and Third Harmonic Generation (THG) microscopy were applied as two archetypal NLO processes. In particular the influence of thin film interference and phase matching on the signal strength is analyzed. Furthermore, key differences between three and four photon processes, such as the role of the Gouy-phase shift and the focal position is studied. This understanding can be extended to other three and four-photon processes, such as Coherent Anti-Stokes Raman Scattering (CARS). Wedge-shaped samples were used for the experiments here, whose thickness was varied from bulk thickness down to approximately 50 nm. In both cases, it was found that the signal in the back reflection is the phase-matched co-propagating signal and not the counter-propagating signal which may naively be expected. It was also found that the signal from the surrounding material, and support does not affect the SH signal from the sample because the second-order nonlinear tensor is only available in non-centrosymmetric material. However, the signals from the surrounding do affect the TH signal from the sample because a third-order nonlinear tensor is available in every material. Furthermore, the THG signal from the thin film starts to vanish as the thickness increases, opposite to what happens in SHG. To back up the experimental findings, two numerical models were used. The first model is the numerical simulation, while the second is a semi-analytical paraxial model. This thesis lays the groundwork for performing quantitative NLO 𝜇-spectroscopy on thin films and 2D materials, as it identifies and quantifies the impact of the corresponding sample and setup parameters on the NLO signal, in order to distinguish them from genuine material properties.:1. Introduction 1 2. Theoretical background 7 2.1. Non-linear optical polarization . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 2.2. The non-linear susceptibility tensor . . . . . . . . . . . . . . . . . . . . . . . . 10 2.3. Phase-matching and emission efficiency . . . . . . . . . . . . . . . . . . . . . . 12 2.4. Nonlinear effects in focused Gaussian beams . . . . . . . . . . . . . . . . . . . 17 3. Methodology and principle 25 3.1. Lithium niobate (LN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 3.2. Wedge preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 3.3. Data generation & processing . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 3.4. Simulation models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 4. SHG in thin films 37 4.1. Coherence interaction length . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 4.1.1. Experimental data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 4.1.2. Comparison of numerical and experimental data . . . . . . . . . . . . . 44 4.2. Thin film interference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 4.3. Influence of NA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 4.4. Reproducibility of experiments . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 4.5. Detection depth of coherent interaction length oscillations . . . . . . . . . . . 54 4.6. Sensitivity to focus positioning . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 5. THG in thin films 57 5.1. Coherence interaction length . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 5.1.1. Quantifying the coherence interaction length . . . . . . . . . . . . . . . 61 5.2. Comparison of simulated and experimental data . . . . . . . . . . . . . . . . . 63 5.3. Thin film interference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 6. Conclusion and outlook 67 Appendices 69 A. Additional reflective layer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 B. Focus fields . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 List of Figures 78 List of Tables 79 Acronyms 82 Own Publications 93 / Die nichtlineare optische Mikroskopie (NLO) ist ein sehr leistungsfähiges und nichtinvasives Instrument zur Analyse der Materialeigenschaften, z. B. der lokalen Symmetrie, sowie zur Visualisierung ferroelektrischer Domänen und Domänenwände. Dadurch wird die NLO-Mikroskopie zu den wichtigsten Aufgaben bei der Materialentwicklung und der Herstellung von Bauelementen gehören. Ein solcher Bereich, in dem die NLO-Mikroskopie weit verbreitet ist, sind Dünnschichtmaterialien. Dünnschicht- und Nanomaterialien mit Abmessungen von wenigen Mikrometern Dicke bis hin zu atomar dünnen 2D-Materialien bieten viele innovative und faszinierende Eigenschaften für Anwendungen in der Elektronik, Optik und vielen anderen Bereichen. Um die physikalische Stabilität zu gewährleisten, werden diese Dünnschicht- und 2D-Materialien in der Regel auf Substraten und Handlegriffen getragen, was zu zahlreichen Effekten führt, wie z. B. Dünnschichtresonanz und Reflexionen an der Grenzfläche zwischen Dünnschicht und Substrat, die das echte Signal der Probe beeinflussen. Diese Effekte sind bei Bulk-Proben nicht vorhanden; daher ist es naheliegend, fälschlicherweise anzunehmen, dass diese Effekte auch bei Dünnschichtmaterialien nicht vorhanden sind. In dieser Arbeit wird versucht, die Parameter, die die nichtlineare Mikroskopie in Dünnschichtmaterialien beeinflussen, zu identifizieren, zu quantifizieren und zu entflechten. Zu diesem Zweck wurden die Mikroskopie der zweiten Harmonischen (SHG) und die Mikroskopie der dritten Harmonischen (THG) als zwei archetypische NLO-Prozesse untersucht. Insbesondere wird der Einfluss von Dünnschichtinterferenzen und Phasenanpassung auf die Signalstärke analysiert. Darüber hinaus werden die wichtigsten Unterschiede zwischen Drei- und Vier-Photonen-Prozessen, wie die Rolle der Gouy-Phasenverschiebung und der Fokusposition, untersucht. Dieses Verständnis kann auf andere Drei- und Vier-Photonen-Prozesse, wie z. B. die kohärente Anti-Stokes-Raman-Streuung (CARS), ausgeweitet werden. Für die Experimente wurden keilförmige Proben verwendet, deren Dicke von der Bulk-Dicke bis hinunter zu etwa 50 nm variiert werden. In beiden Fällen wurde festgestellt, dass es sich bei dem Signal in der Rückreflexion um das phasenangepasste Mitausbreitungssignal handelt und nicht um das Gegenausbreitungssignal, das man naiverweise erwarten könnte. Es wurde auch festgestellt, dass das Signal aus der Umgebung das SH-Signal der Probe nicht beeinflusst, da der nichtlineare Tensor zweiter Ordnung nur in nicht-zentrosymmetrischem Material vorhanden ist. Die Signale aus der Umgebung beeinflussen jedoch das TH-Signal der Probe, da ein nichtlinearer Tensor dritter Ordnung in jedem Material vorhanden ist. Außerdem verschwindet das THG-Signal des dünnen Films mit zunehmender Dicke, anstatt wie bei SHG zuzunehmen. Um die experimentellen Ergebnisse zu untermauern, wurden zwei numerische Modelle verwendet. Bei dem ersten Modell handelt es sich um eine numerische Simulation, bei dem zweiten um ein halbanalytisches paraxiales Modell. Diese Arbeit legt den Grundstein für die Durchführung quantitativer NLO 𝜇-Spektroskopie an dünnen Schichten und 2D-Materialien, da sie die Auswirkungen der entsprechenden Proben und Einrichtungsparameter auf das NLO-Signal identifiziert und quantifiziert, um sie von den echten Materialeigenschaften zu unterscheiden.:1. Introduction 1 2. Theoretical background 7 2.1. Non-linear optical polarization . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 2.2. The non-linear susceptibility tensor . . . . . . . . . . . . . . . . . . . . . . . . 10 2.3. Phase-matching and emission efficiency . . . . . . . . . . . . . . . . . . . . . . 12 2.4. Nonlinear effects in focused Gaussian beams . . . . . . . . . . . . . . . . . . . 17 3. Methodology and principle 25 3.1. Lithium niobate (LN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 3.2. Wedge preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 3.3. Data generation & processing . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 3.4. Simulation models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 4. SHG in thin films 37 4.1. Coherence interaction length . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 4.1.1. Experimental data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 4.1.2. Comparison of numerical and experimental data . . . . . . . . . . . . . 44 4.2. Thin film interference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 4.3. Influence of NA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 4.4. Reproducibility of experiments . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 4.5. Detection depth of coherent interaction length oscillations . . . . . . . . . . . 54 4.6. Sensitivity to focus positioning . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 5. THG in thin films 57 5.1. Coherence interaction length . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 5.1.1. Quantifying the coherence interaction length . . . . . . . . . . . . . . . 61 5.2. Comparison of simulated and experimental data . . . . . . . . . . . . . . . . . 63 5.3. Thin film interference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 6. Conclusion and outlook 67 Appendices 69 A. Additional reflective layer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 B. Focus fields . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 List of Figures 78 List of Tables 79 Acronyms 82 Own Publications 93

This thesis focuses on preparation of novel compounds suitable for nonlinear optics (NLO). In particular, the target property is the second harmonic generation (SHG) and the group of interest are salts of the cations with delocalized electrons which can serve as carriers of the NLO properties. In particular, four derivatives of the highly interesting molecule of guanidine were selected and their NLO potential was proven by quantum chemical computations. In total, twenty new structures were described and those with the noncentrosymmetric structure assembly were examined for the SHG efficiency. Four of the prepared compounds exhibited a noticeable SHG efficiency, two of them even comparable to urea. The most promising compound, the guanylurea hydrogen phosphite (GUHP), was examined in more detail while many interesting NLO properties were revealed. The results of this work are presented also in 10 attached publications which are an integral part of the thesis. Keywords: nonlinear optics, second harmonic generation, guanidine derivatives, guanylurea, N-phenylbiguanide, N,N-dimethylbiguanide, N,N,N˝-triphenylguanidine

This thesis concerns quadratic response properties and their application to properties in Jablonski diagrams such as resonant two-photon absorption and excited state absorption. Our main interest lies in optical power limiting applications, and in this context, molecules containing heavy metal atoms prove superior. Therefore, we are interested in how relativity affects these properties, and in order to assess this, a four-component relativistic framework is adopted. To properly address the molecular properties of interest, both relativistic effects and electron correlation need to be accounted for. These two properties are not additive, and, therefore, correlation needs to be incorporated into the four-component framework. We present the implementation of quadratic response properties at the four-component density functional level of theory. For second-harmonic generation, we have, with numerical examples, demonstrated that correlation and relativity are indeed not additive and that the inclusion of noncollinear magnetization is of little importance. We report that both electron correlation as well as relativity strongly affect results for second-harmonic generation. For example, relativity alone reduces the µβ-response signal by 62% and 75% for meta- and ortho-bromobenzene, respectively, and enhances the same response by 17% and 21% for meta- and ortho-iodobenzene, respectively. In the four-component framework, we present the implementations of single and double residues of the quadratic response function, which allows for the evaluation of resonant two-photon absorption cross sections and excited state properties. Using these tools, we discuss different levels of approximation to the relativistic Hamiltonian and we demonstrate that for two-photon absorption, a proper treatment of relativistic effects qualitatively alters the spectrum. For example, already for an element as light as neon, significant differences are seen between the relativistic and nonrelativistic spectra as triplet transitions acquire substantial absorption cross sections in the former case. Finally, quantum mechanics in conjunction with electrodynamics is applied to determine clamping levels in macroscopic samples. The microscopic properties of the optically active chromophores are determined by response theory, and then, electrodynamics is used to describe the interactions between the chromophores and incident laser pulses. Using this approach a series of molecules have been investigated and their performances have been compared and ranked in order to find novel materials for optical power limiting applications.

We demonstrate four experimentally simple methods for measuring very complex ultrashort light pulses. Although each method is comprised of only a few optical elements, they permit the measurement of extremely complex pulses with time-bandwidth products greater than 65,000. First, we demonstrate an extremely simple frequency-resolved-optical gating (GRENOUILLE) device for measuring the intensity and phase of pulses up to ~20ps in length. In order to achieve the required high spectral resolution and large temporal range, it uses a few-cm-thick second harmonic-generation crystal in the shape of a pentagon. This has the additional advantage of reducing the device's total number of components to three. Secondly, we introduce a variation of spectral interferometry (SI) using a virtually imaged phased array and grating spectrometer for measuring long complex ultrashort pulses up to 80 ps in length. Next, we introduce a SI technique for measuring the complete intensity and phase of relatively long and very complex ultrashort pulses. It involves making multiple measurements using SI (in its SEA TADPOLE variation) at numerous delays, measuring many temporal pulselets within the pulse, and concatenating the resulting pulselets. Its spectral resolution is the inverse delay range--many times higher than that of the spectrometer used. The waveforms were measured with ~ fs temporal resolution over a temporal range of ~ns and had time-bandwidth products exceeding 65,000, which to our knowledge is the largest time-bandwidth product ever measured with ~fs temporal resolution. Finally, we demonstrate a single-shot measurement technique that temporally interleaves hundreds of measurements with ~fs temporal resolution. It is another variation of SI for measuring the complete intensity and phase of relatively long and complex ultrashort pulses in a single shot. It uses a grating to introduce a transverse time delay into a reference pulse which gates the unknown pulse by interfering it at the image plane of an imaging spectrometer. It provided ~125 fs temporal resolution and a temporal range of 70 ps using a low-resolution spectrometer.