Chemistry & Chemical Biology Department Theses and Dissertations

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Investigating the Photophysical Properties of Potential Organic Lead Sensors
(2023) Quinones, Carlos; Basu, Partha; Deng, Yongming; Pu , Jingzhi
LeadGlow (LG) was reported in 2009 for its ability to both sensitively and selectively detect Pb2+ in aqueous solutions. Utilizing the synthetic approach of LG, it is possible to generate a class of novel fluorophores. A derivative of first-generation LG was synthesized and reported here for the first time, intuitively named LG2. Both compounds contain interesting photophysical properties that have not been extensively researched prior to this work. Because of this, photophysical properties of both LG and LG2 are unveiled here for the first time. These properties were investigated by determinations of quantum yield (QY), average fluorescence lifetime, and DFT calculations. LG was found to have a higher QY (0.057) than LG2 (0.011); however, LG2 displays an average fluorescence lifetime (3.186 ns) 5x greater than that of LG. Both LG and LG2 are synthesized via Hg2+-facilitated desulfurization of their respective thiocarbonyls, resulting in a turn-on fluorescence feature. The thiocarbonyl-containing fluorophores (SLG and SLG2) display quenched fluorescence compared to their oxo-derivatives (LG and LG2), this work attempts to investigate the mechanism(s) responsible. A whole class of LeadGlow compounds can be synthesized and could be potentially used as fluorescence-based sensors.
Development of Mass Spectrometry-Based Analytical Assays for Environmental and Chemical Defense Applications
(2023-12) Dowling, Sarah Naciye; Manicke, Nicholas; Goodpaster, John; Laulhé, Sébastien; Sardar, Rajesh
Mass spectrometry (MS) is a powerful and versatile technique that is useful for addressing a wide range of complex analytical challenges. In this work, mass spectrometry-based assays were developed to address issues relating to environmental contamination and for detecting analytes of interest to the defense industry. Chapter one is an overview of the history of mass spectrometry, the fundamental operation of a mass spectrometer, as well as, advancements in chromatographic separation and ionization methods. Chapter two focuses on the development of an assay that uses blow flies as environmental sensors of chemical weapon release. In that work, a liquid chromatography – tandem mass spectrometry (LC-MS/MS) method was developed to detect chemical warfare agent simulants and chemical warfare agent hydrolysis products in flies exposed to the chemicals in controlled feeding experiments. The work in chapter three describes the development of a surface enhanced Raman spectroscopy assay coupled to paper spray mass spectrometry for a more fieldable and environmentally friendly approach to detect organophosphorus compounds. Chapter four describes the development of a paper spray mass spectrometry assay for the detection and semi-quantitation of per- and polyfluoroalkyl substances in whole blood without sample cleanup or chromatographic separations. This method would be useful in detecting high levels of these carcinogenic compounds in individuals highly exposed via their occupations. The final chapter (chapter five) returns to using blow flies as environmental sensors, but this time to detect insensitive munitions in the environment. The work focuses on the development of two different liquid chromatography mass spectrometry methods for the detection of insensitive munitions, which are less shock sensitive explosives, and their transformation products in the environment. Controlled feeding experiments were also performed where flies were exposed to contaminated soil and water sources to show the feasibility of this method in a more realistic scenario. The projects detailed herein show the extensive range with which mass spectrometry can be used for the detection of harmful chemistries of environmental concern.
Solid-Phase Microextraction of Volatile Organic Compounds for Analytical and Forensic Applications
(2023-12) Davis, Kymeri Elizabeth; Goodpaster, John; Frédérique, Deiss; Nicholas , Manicke; Sébastien , Laulhé
Gas chromatography-mass spectrometry (GC-MS) is a frequently used technique in forensic chemistry for the identification of controlled substances and explosives. GC-MS can be coupled with solid-phase microextraction (SPME), in which a fiber with a sorptive coating is placed into the headspace above a sample or directly immersed in a liquid sample. Analytes are adsorbed onto the fiber which is then placed inside the heated GC inlet for desorption. Illicit drugs are often found in the form of impure solids, mixed with other drugs, adulterants, and diluents. A simple method for the quick identification of drugs including methamphetamine, cocaine, heroin, fentanyl, and pharmaceutical tablets was developed. Headspace SPME methods were utilized with an elevated extraction temperature for the detection of various drugs in powder and tablet form. An extraction temperature of 120oC was used to encourage analytes into the headspace of the vial. A sample of the solid drug was placed in a headspace vial with no prior sample preparation or clean-up. This vial was then heated inside of an agitator where the sample was extracted. It was found that drugs in solid and tablet form can be detected using this high temperature headspace SPME method at the temperature of 120oC with no prior sample preparation. This method is simple, efficient, and cost effective for the detection of legal and illicit drugs in solid form. Headspace SPME may also be used for the analysis of explosive materials. Canines trained at detecting hidden explosives should be trained using real explosive materials that have minimal contamination by other explosive odors to ensure accurate identification of potential threats. Therefore, the potential for cross-contamination between training aids is of importance. There are various storage methods in use by canine handlers such as plastic and cloth bags, but these can lead to cross-contamination between training aids during storage. Alternatively, odor-permeable membrane devices (OPMDs) may store training aides and be used as a delivery device. A membrane in the OPMD allows for volatile compounds from the training aids to be released during training while helping to prevent contaminants from entering the device. OPMDs were used in addition to traditional storage containers to monitor the contamination and degradation of 14 explosives used as canine training aids. Samples included explosives that contain highly volatile compounds like dynamite and explosives with less volatile compounds like RDX. Explosives were stored individually using traditional storage bags or inside of an OPMD at two locations, IUPUI and an Indianapolis Metropolitan Police Department. The police department actively used the training aids during canine trainings. Samples from each storage type at both locations were collected at 0, 3, 6, and 9 months and analyzed using Fourier transform infrared (FTIR) spectroscopy and GC-MS with SPME. FTIR analyses showed no signs of degradation of the training aids from any timepoint or location. GC-MS identified cross-contamination from ethylene glycol dinitrate and/or 2,3-dimethyl-2,3-dinitrobutane across almost all samples regardless of storage condition. The contamination was found to be higher among training aids that were stored in traditional ways and were in active use by canine teams. Additionally, Time 0 had the highest level of contamination, indicating that explosive training aids are received from the vendors with initial cross-contamination. To test the initial cross-contamination levels of training aids, 11 explosive materials were ordered from three different vendors. A 1-gram sample of each was collected and analyzed using SPME with GC-MS. In several cases, explosive materials that are commercially available already exhibit elevated levels of contamination. This indicates that training aids must be acquiring contamination during manufacturing and/or storage at the vendor facility. The cross-contamination of explosive canine training aids stored in OPMDs was further evaluated and compared to traditional storage methods. This was done by storing various combinations of storage containers such as cloth bags, velcro bags, and OPMDs along with explosives and using activated charcoal strips to collect the volatile compounds such as 2,3-dimethyl-2,3-dinitrobutane and ethylene glycol dinitrate. Only one type of storage container, a velcro bag, showed evidence of contamination, indicating that OPMDs may not further prevent cross-contamination of explosive training aids.
Design and Fabrication of Smart SERS Substrates for Forensic Science Applications
(2023-08) Simas, Maria Vitoria; Sardar, Rajesh; Goodpaster, John; Manicke, Nicholas; Christoph, Naumann
In the field of forensics and toxicology, it is crucial for analytical techniques to be practical, highly sensitive, and extremely accurate (specific and selective), especially when incorporating acquired data as evidence in a court case. To limit the breadth of this dissertation, the main forensic focuses are to assay (detection and quantification) drugs in patient biofluid specimens and to detect trace explosives. While currently there are a number of analytical tools such as LC/MS, GC/MS, ELISA immunoassays, and electrochemical and aptamer techniques utilized for these two applications, each one introduces its own unique drawback that hinders their accuracy, and therefore applicability, to be used in a legal environment. To overcome these disadvantages, surface enhanced Raman spectroscopy (SERS) has become increasingly popular in the forensic and toxicology field as it provides high sensitivity and specificity data while remaining flexible and efficient in critical situations such as an emergency department and/or an explosion site. In this dissertation, two different, novel SERS substrates are developed, each one designed to tackle a specific forensic application. While the fabrication method and materials of the substrates are significantly different from one another, both display ideal SERS properties due to their unique localized surface plasmon resonance (LSPR) properties at the nanoscale. LSPR is a phenomenon in which the free carriers (electrons or holes) on the surface of nanoparticles collectively oscillate upon light irradiation. In this current dissertation, we selectively focus on two different nanoparticle compositions where LSPR properties originate from the collective oscillation of free electrons. These oscillations of free carriers allow for an electromagnetic (EM) field enhancement of the incident laser which leads to an increase in the SERS enhancement. Particularly, the area in which the SERS signal is the most enhanced is the nanometer-sized gap between nanoparticles called “hot spots.” While primarily noble metal (e.g., Au and Ag) nanoparticles are heavily used for SERS substrate fabrication, this dissertation expands beyond that and focuses on both gold nanorods and oxygen deficient tungsten oxide (metal oxide semiconductor)-based SERS substrates. This dissertation is organized in three chapters, (1) Introduction, (2) Fabrication of a polymer microneedle-based, multimodal SERS and mass spectrometry substrate for the ultrasensitive detection of illicit drugs in human blood plasma, and (3) LSPR active WO3-x-based SERS substrate for the detection of explosives. In chapter 2, a multimodal substrate was strategically designed to serve as a SERS and electrospray ionization- mass spectrometry substrate by using a novel microneedle platform. The microneedles underwent a surface modification and gold nanorods were subsequently adsorbed onto the surface. Illicit drug analytes could then be drop-casted on the tip of the microneedles and left to dry for further SERS and mass spectrometry analysis. This novel platform detected two types of synthetic opioids, alprazolam and fentanyl, down to at least a picomolar limit of detection and successfully distinguished between the two when analyzing 10 patient blood plasma samples. Furthermore, the multimodal approach was confirmed through the detection of both drugs in patient plasma samples down to the ppb limit using mass spectrometry. Chapter 3 introduces an entirely new SERS substrate, which is fabricated using oxygen deficient tungsten oxide (WO3-x) nanoparticles for the detection of the target explosives, e.g., tetryl, TNT, and DNT. The oxygen deficiency in WO3-x nanoparticle lattice introduces free electrons in the conduction band that introduce LSPR properties into the nanoparticles giving rise to the EM field mechanism for SERS enhancement upon incident laser irradiation. Much like with noble metals, the oscillation of these free carriers at nanoparticle hot spots aid in the development of a functional and cheaper SERS substrate. The SERS enhancement factor (EF) of three different morphologies of WO3-x nanoparticles, i.e., nanorods, nanowires, and nanoplatelets are characterized and deemed comparable to noble metal nanoparticles. A Janowsky complex was formed using the explosive, tetryl, as the target analyte. Using our oxygen deficient WO3-x substrate, tetryl was successfully detected down to the nanomolar level. To our knowledge, this is the first time tetryl has been detected utilizing a non-noble metal-based SERS substrate. Taken together, this dissertation presents the unique aspect of nanotechnology for the development of (1) a multimodal MN-based ultrasensitive and (2) an inexpensive noble-metal comparable WO3-x-based SERS substrates, both of which that can be applied to forensic science research, specifically in forensic toxicology and explosive detection to better, and even save, the lives of individuals and improve their quality of life.
Electrochemical Tape-and-Paper-Based Sensor for the Quantification of Potassium
(2023-08) Zhang, Tommy; Deiss, Frédérique; Webb, Ian
Potassium levels in serum are used in the diagnosis of diseases involving cardiac arrhythmias, neuromuscular weakness, and chronic kidney diseases. These illnesses are becoming more prevalent, therefore, developing new potassium quantification methods would aid in advancing preventative care. Current methods of quantifying potassium mainly rely on the use of glass ion-selective electrodes which are costly, fragile, and requires frequent maintenance and recalibration. For faster and more accessible quantification of potassium, we are developing low cost, portable, and easy to fabricate electrochemical tape-and-paper-based devices. Our sensor bypasses the inconveniences of ion-selective electrodes and could ultimately serve as a point-of-care device to allow for regular monitoring or even home-use. Our sensing method relies on Prussian blue immobilized on the surface of electrodes as a potassium recognition element. Potassium ions intercalate into the Prussian blue lattice and subsequently changes the electrochemical characteristics of Prussian blue such as the redox peak potentials. These devices are highly robust, feature a limit of detection of 1.3 mM potassium and the response is linear to at least 100 mM, which contains the clinically relevant ranges required for diagnostics. Quantification was developed using cyclic voltammetry, demonstrated in Chapter 3. We observed changes in Prussian blue redox peak potentials at different concentrations of potassium and followed the expected Nernstian response. We investigated multiple methods of immobilizing Prussian blue onto the electrode surfaces to investigate stability and reproducibility in Chapter 4. Adsorption, in-situ synthesis, and carbon paste incorporation of Prussian blue was tested. Prussian blue-carbon paste devices had reproducibility issues and featured broad reduction peaks. In-situ synthesis of Prussian blue directly onto the surface of the electrodes also featured broad reduction peaks but the Prussian blue response was reproducible. The issue with in-situ synthesis was the stability of the Prussian blue layer, which was susceptible to degradation after repeated use of the device, which is required for evaluating the performance of the device. Although adsorption using Prussian blue in water had some reproducibility issues as well, this method led to the most stable Prussian blue layer, had distinct reduction peaks, and was simple to perform. Various solvents were used to dissolve Prussian blue in Chapter 5 to investigate methods of increasing device reproducibility when using adsorption. A few organic solvents were able to dissolve Prussian blue to form a stable solution with the goal of forming a more uniform Prussian blue layer and potentially improving consistency of the layer immobilization. While these alternative solvents were able to dissolve Prussian blue, they also damaged the graphite electrodes on the devices, which altered the electrochemical responses of the devices to the point where potassium quantification was no longer possible. Due to incompatibility between these alternative solvents and the devices, adsorption of Prussian blue in water continued to be used. Different modes of adsorption were explored and was optimized in Chapter 6. By altering the adsorption setup and allowing the Prussian blue particles to settle evenly onto a level electrode surface, device reproductivity increased substantially. To understand the applicability of the devices in real samples, interferent studies were performed in Chapter 7. Other cations such as Na+, Li+, Ca2+, Mg2+, and Ba2+ were not observed to enter the Prussian blue lattice in the cyclic voltammograms. Monovalent cations that share the same charge as K+ but have smaller ionic radius, Na+ and Li+, were able to decrease K+ sensitivity. Divalent cations that had a smaller ionic radius than K+ did not alter sensitivity. The exception was Ba2+, which also decreased K+ sensitivity. These results suggested that both ionic radius and charge of a species were important factors in impacting K+ intercalation into the Prussian blue lattice. Other interferents such as sulfates, phosphates, carbonates, urea, and lactic found in serum and sweat samples were tested. The presence of these interferents decreased the current intensity of the reduction peak of Prussian blue, which resulted in less definition in the peaks. For the future of this project, the effects of interferents found in serum and sweat must be investigated further. Additionally, reproducibility of the devices could be improved further if less harsh organic solvents are tested for adsorption, square wave voltammetry could be used for quantification to evaluate the viability of alternative voltametric techniques, and Prussian blue analogues could be implemented into the devices for quantification of other cations.
Machine Learning Facilitated Quantum Mechanic/Molecular Mechanic Free Energy Simulations
(2023-08) Snyder, Ryan; Pu, Jingzhi; Naumann, Christoph; Webb, Ian; Deng, Yongming
Bridging the accuracy of ab initio (AI) QM/MM with the efficiency of semi-empirical (SE) QM/MM methods has long been a goal in computational chemistry. This dissertation presents four ∆-Machine learning schemes aimed at achieving this objective. Firstly, the incorporation of negative force observations into the Gaussian process regression (GPR) model, resulting in GPR with derivative observations, demonstrates the remarkable capability to attain high-quality potential energy surfaces, accurate Cartesian force descriptions, and reliable free energy profiles using a training set of just 80 points. Secondly, the adaptation of the sparse streaming GPR algorithm showcases the potential of memory retention from previous phasespace, enabling energy-only models to converge using simple descriptors while faithfully reproducing high-quality potential energy surfaces and accurate free energy profiles. Thirdly, the utilization of GPR with atomic environmental vectors as input features proves effective in enhancing both potential energy surface and free energy description. Furthermore, incorporating derivative information on solute atoms further improves the accuracy of force predictions on molecular mechanical (MM) atoms, addressing discrepancies arising from QM/MM interaction energies between the target and base levels of theory. Finally, a comprehensive comparison of three distinct GPR schemes, namely GAP, GPR with an average kernel, and GPR with a system-specific sum kernel, is conducted to evaluate the impact of permutational invariance and atomistic learning on the model’s quality. Additionally, this dissertation introduces the adaptation of the GAP method to be compatible with the sparse variational Gaussian processes scheme and the streaming sparse GPR scheme, enhancing their efficiency and applicability. Through these four ∆-Machine learning schemes, this dissertation makes significant contributions to the field of computational chemistry, advancing the quest for accurate potential energy surfaces, reliable force descriptions, and informative free energy profiles in QM/MM simulations.
Molecular dynamics simulations of spore photoproduct containing DNA systems
(2023-05) Hege, Mellisa; Pu, Jingzhi; Blacklock, Brenda; Georgiadis, Millie; Deng, Yongming
Bacterial endospores have been a topic of research interest over the last several decades given their high resistance to ultraviolet (UV) damage. Unlike vegetative bacterial cells, which form cyclobutane pyrimidine dimers (CPD) and pyrimidine 6-4 pyrimidone photoproducts (6-4PPs) as the major product upon UV irradiation, endospore bacteria form a spore photoproduct (5-(R-thyminyl)-5,6-dihydrothymine or SP) as the major product. Vegetative bacteria cells are subject to regular cell activities and processes such as division and deoxyribonucleic acid (DNA) replication, which are prone to damage from UV exposure. However, in endospores, which have a largely anhydrous inner environment, the DNA remains dormant when bound to spore-specific small acid-soluble proteins (SASP) and dipicolinic acid, making spores highly resistant to radiation, heat, desiccation, and chemical harm. During spore germination, SP lesions in DNA are repaired by a distinctive repair enzyme, spore photoproduct lyase (SPL). In this thesis, molecular dynamics (MD) simulations were carried out to (i) examine how the formation of the SP lesion in DNA affects the global and local structural properties of duplex DNA and (ii) study how this lesion is recognized and repaired in endospore. The first part of this work was focused on designing and developing a structurally and dynamically stable model for dinucleotide SP molecule (TpT), which was subsequently used as an SP patch incorporated into duplex DNA. Computationally, this requires modifications of the bond and nonbonded force field parameters. The stability of the patch and developed parameters was tested via solution-phase MD simulations for the SP lesion incorporated within the B-DNA dodecamer duplex (PDB 463B). The second part involved applying the new SP patch to simulate the crystallographic structure of the DNA oligomer containing SP lesions. Solution-phase MD simulations were performed for the SP-containing DNA oligomers (modeled based on PDB 4M94) and compared to the simulations of the native structure (PDB 4M95). Our analysis of the MD trajectories revealed a range of SP-induced structural and dynamical changes, including the weakened hydrogen bonds at the SP sites, increased DNA bending, and distinct conformational stability and distribution. In the third part of this thesis project, we carried out MD simulations of SP-containing DNA bound with SASPs to examine how the DNA interacts differently with SASP in the presence and absence of the SP lesion. The simulation results suggested decreased electrostatic and hydrogen bonding interactions between SASP and the damaged DNA at the SP site compared to the undamaged DNA-protein complex. In addition, decreased helicity percentage was observed in the SASPs that directly interact with the SP lesion. The last part of this this thesis work focused on the SP-dimer flipping mechanism, as the lesion is likely flipped out to its extrahelical state to be recognized and repaired by SPL. Using steered molecular dynamic (SMD) simulations and a pseudo-dihedral angle reaction coordinate, we obtained possible SP flipping pathways both in the presence and absence of SASP. Collectively, these simulation results lend new perspectives toward understanding the unique behavior of the SP lesion within the DNA duplex and the nucleoprotein complex. They also provide new insights into how the SP lesion is efficiently recognized and repaired during spore germination.
QM/MM Applications and Corrections for Chemical Reactions
(2023-05) Kim, Bryant; Pu, Jingzhi; Naumann, Christoph; Vilseck, Jonah; Webb, Ian
In this thesis, we present novel computational methods and frameworks to address the challenges associated with the determination of free energy profiles for condensed-phase chemical reactions using combined quantum mechanical and molecular mechanical (QM/MM) approaches. We focus on overcoming issues related to force matching, molecular polarizability, and convergence of free energy profiles. First, we introduce a method called Reaction Path-Force Matching in Collective Variables (RP-FM-CV) that efficiently carries out ab initio QM/MM free energy simulations through mean force fitting. This method provides accurate and robust simulations of solution-phase chemical reactions by significantly reducing deviations on the collective variables forces, thereby bringing simulated free energy profiles closer to experimental and benchmark AI/MM results. Second, we explore the role of pairwise repulsive correcting potentials in generating converged free energy profiles for chemical reactions using QM/MM simulations. We develop a free energy correcting model that sheds light on the behavior of repulsive pairwise potentials with large force deviations in collective variables. Our findings contribute to a deeper understanding of force matching models, paving the way for more accurate predictions of free energy profiles in chemical reactions. Next, we address the underpolarization problem in semiempirical (SE) molecular orbital methods by introducing a hybrid framework called doubly polarized QM/MM (dp-QM/MM). This framework improves the response property of SE/MM methods through high-level molecular polarizability fitting using machine learning (ML)-derived corrective polarizabilities, referred to as chaperone polarizabilities. We demonstrate the effectiveness of the dp-QM/MM method in simulating the Menshutkin reaction in water, showing that ML chaperones significantly reduce the error in solute molecular polarizability, bringing simulated free energy profiles closer to experimental results. In summary, this thesis presents a series of novel methods and frameworks that improve the accuracy and reliability of free energy profile estimations in condensed-phase chemical reactions using QM/MM simulations. By addressing the challenges of force matching, molecular polarizability, and convergence, these advancements have the potential to impact various fields, including computational chemistry, materials science, and drug design.
Electroanalytical Paper-Based Sensors for In-Field Detection of Chlorate-Based Explosives and Quantification of Oxyanions
(2023-05) Guimarães Vega, Carolina; Deiss, Frédérique; Manicke, Nicholas; Goodpaster, John; Long, Eric
Improvised explosive devices (IEDs) are a global threat due to their destructive potential, the easy access to raw materials, and online instructions to manufacture them. These circumstances have led to an increase in the number of IEDs using potassium chlorate as an oxidizer. The standard methods to detect chlorate are mainly designed for laboratory-only testing. Thus, field instrumentation capable of detecting oxidizers from explosives fuel-oxidizers is critical for crime scene investigation and counterterrorism efforts (described in Chapter 1). We developed a paper-based sensor for the in-field detection of chlorate (described in Chapter 2). The sensor is low-cost, disposable, portable, and inexpensive to fabricate, and its flexibility features allow for surface sampling without sample destruction. The sensor has an electrodeposited molybdate sensing layer, as chlorate was reported to have a catalytic effect on the molybdate reduction. The chlorate detection relies on monitoring the change in redox activity of the molybdate sensing layer using different electroanalytical techniques. We effectively demonstrated the analytical performance of the sensor (Chapter 3), obtaining a limit of detection of 1.2 mM and a limit of quantification of 4.10 mM. We evaluated the selectivity of the sensor by testing other oxidizers, such as perchlorate and nitrate, which did not present any electrochemical activity with the molybdate sensing layer. Additionally, we performed an interferent study with sugar, commonly used as fuel in IEDs, and other common white household powders such as baking soda, flour, and corn starch and neither a false positive nor a false negative result was observed (Chapter 3). As bromate has been reported to have a stronger catalytic effect than chlorate on the redox activity of molybdate, the quantification of bromate was also explored, and a bromate sensor was developed using the findings of the chlorate sensor (Chapter 4). The reaction mechanism involved in the molybdate reduction was explored and discussed in Chapter 5. The capability of the sensor in detecting chlorate from combusted samples and post-blast samples was successfully demonstrated in Chapter 6, as well as the design of encased prototypes to allow for an in-field presumptive test, storage, and transport for in-laboratory confirmatory tests and compared the performance of the sensor to the available commercial tests.
Phosphonium-Salt Mediated Activation of C-O Bonds: Applications and Mechanistic Studies
(2023-05) Irving, Charles D.; Laulhé, Sébastien; Manicke, Nicholas; Minto, Robert; Deng, Yongming
The C-O single bond is found in numerous functional motifs including carboxylic acids, alcohols, and ethers. These compounds represent ideal precursors towards C-X (X = C, H, or heteroatom) bond formation due to their inherent stability and abundance in nature. As such, synthetic chemists continue to develop new technologies for the transformation of these precursors into biologically useful targets such as amides and amines. However, due to the stability of the C-O single bond, accessing such targets remains a consistent challenge. The activation of the carboxylic acids towards peptide synthesis has been facilitated through various coupling agents, including organoboron and transition metal catalysts. However, coupling agents can generate stochiometric, difficult-to-remove, toxic waste by-products. Organoboron/transition metal catalyzed condensations offer a more atom economical approach but suffer from varying degrees of optical erosion and poor sustainability. Phosphonium-based deoxyaminative technologies provide access to amines from alcohols via a phosphorus oxygen double bond formation driving force, but possesses a narrow nucleophilic nitrogen source scope, and poor atom economy. Transition metal/enzyme catalyzed “hydrogen borrowings” represent atom economical deoxyaminative alternatives. Still, their respective use of costly metals, and multiple enzymatic cascade steps severely limit the sustainability and scope of such protocols. An ambient deoxyamidation of carboxylic acids and deoxyamination of alcohols was developed through the use of N-haloimides activated by triphenylphosphine. Such technologies were found to possess broad functional tolerance and formed C-N bonds via a coupling to free amines, and the direct installment of the imide motif. Mechanistic experiments suggest that such transformations take place via the in situ generation of two separate phosphonium reactive species.

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