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This study's focus is the association of end-of-therapy (EOT) PET results with progression-free (PFS) and overall survival (OS) in patients with diffuse large B-cell lymphoma receiving first-line chemoimmunotherapy. We develop a Bayesian hierarchical model for predicting PFS and OS from EOT PET-complete response (PET-CR) using a literature-based meta-analysis of 20 treatment arms and a substudy of 4 treatment arms in 3 clinical trials for which we have patient-level data. The PET-CR rate in our substudy was 72%. The modeled estimates for hazard ratio (PET-CR/non-PET-CR) were 0.13 for PFS (95% CI 0.10, 0.16) and 0.10 for OS (CI 0.07, 0.12). Hazard ratios varied little by patient subtype and were confirmed by the overall meta-analysis. We link these findings to designing future clinical trials and show how our model can be used in adapting the sample size of a trial to accumulating results regarding treatment benefits on PET-CR and a survival endpoint.

As new technologies permit the generation of hitherto unprecedented volumes of data (e.g. genome-wide association study data), researchers struggle to keep up with the added complexity and time commitment required for its analysis. For this reason, model selection commonly relies on machine learning and data-reduction techniques, which tend to afford models with obscure interpretations. Even in cases with straightforward explanatory variables, the so-called ‘best’ model produced by a given model-selection technique may fail to capture information of vital importance to the domain-specific questions at hand. Herein we propose a new concept for model selection, feasibility, for use in identifying multiple models that are in some sense optimal and may unite to provide a wider range of information relevant to the topic of interest, including (but not limited to) interaction terms. We further provide an R package and associated Shiny Applications for use in identifying or validating feasible models, the performance of which we demonstrate on both simulated and real-life data.

Synthetic chemists customarily tune the redox characteristics of π-conjugated molecules by introducing electron-donating or electron-withdrawing substituents onto the molecular core, or by modifying the length of the π-conjugated pathway. Any steric effects of such efforts on molecular geometry typically affect both the neutral and charged (oxidized or reduced) states indiscriminately. However, in electroactive systems that undergo significant conformational changes upon oxidation or reduction, we can leverage the steric and inductive effects of substitution to attain considerable control over individual redox potentials. Here, we make use of density functional theory to elucidate the interplay between electronic and geometric effects of peripheral substitution on the model system of phenothiazine. For instance, we introduce substituents at positions ortho to the nitrogen atom (positions 1 and 9) to induce steric strain in the radical-cation state without significant effect on the neutral molecule, thereby augmenting the overall ionization potential. Notably, this steric effect persists for electron-donating substituents; the resulting ionization potentials therefore deviate from outcomes foretold by Hammett constants. Moreover, the same procedure has limited effect on electron affinities because of differences in phenothiazines' relaxation process upon reduction compared to oxidation. Our results promote molecular design guidelines for manipulating redox potentials in classes of electroactive compounds that experience dramatic changes in geometry upon ionization.

TPS2684 Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel engineered cytokine that selectively binds the intermediate-affinity interleukin-2 (IL-2) receptor, preferentially activating and expanding antitumor CD8+ T cells and NK effector cells, with minimal effect on regulatory T cells. Nemvaleukin was designed to leverage antitumor effects of the IL-2 pathway while limiting typical IL-2‒associated toxicity. In ARTISTRY-1, the recommended phase 2 dose (RP2D) for nemvaleukin monotherapy of 6 µg/kg IV on days 1 to 5 of a 21-day cycle elicited durable and deep responses in pts with advanced melanoma and renal cell carcinoma (Boni et al. ASCO 2021:abstr 2513). Responses with nemvaleukin plus pembrolizumab were also observed in platinum-resistant ovarian, breast, cervical, gastrointestinal, and genitourinary cancers. ARTISTRY-3 will investigate the effects of nemvaleukin as monotherapy and in combination with pembrolizumab on the TME in pts with advanced solid tumors, and in an additional cohort (Cohort 2), to further assess a less frequent IV dosing schedule for nemvaleukin. Methods: The phase 1/2, open-label ARTISTRY-3 (NCT04592653) study will enroll adults (≥18 years) with select advanced solid tumors, ≥1 accessible lesion for biopsy, ≥1 target lesion (per RECIST v1.1), ECOG PS of 0 or 1, estimated life expectancy of ≥3 months, adequate hematologic reserve, and adequate hepatic and renal function. Primary objectives: to evaluate effects of nemvaleukin monotherapy on the TME (Cohort 1) and to determine RP2D for less frequent dosing schedule (Cohort 2). Additional objectives are to evaluate: efficacy, safety, immunogenicity, and pharmacokinetics of nemvaleukin monotherapy; effects of nemvaleukin plus pembrolizumab on the TME; and correlative biomarkers of nemvaleukin as monotherapy and combination. Following the protocol amendment, additional pts enrolled in Cohort 1 will receive lead-in monotherapy at a dose selected based on results from Cohort 2, and pre- and on-treatment biopsies will be collected for TME assessments. Subsequent cycles will be administered in combination with pembrolizumab, and a biopsy may be collected at cycle 4 or 5. Tumor types eligible for Cohort 2 are selected based on activity observed in the ARTISTRY-1 study. A quantitative system pharmacology model was applied to identify a less frequent schedule for nemvaleukin monotherapy and combination. Cohort 2 will initially assess safety and tolerability of nemvaleukin at 1 dose per 21-day cycle. Two doses per 21-day cycle may be implemented to achieve optimal PK/PD parameters. Bayesian optimal interval design methodology with open enrollment will be applied to facilitate dose escalation decisions. Clinical trial information: NCT04592653.

Motivation Metagenomic read classification is a critical step in the identification and quantification of microbial species sampled by high-throughput sequencing. Although many algorithms have been developed to date, they suffer significant memory and/or computational costs. Due to the growing popularity of metagenomic data in both basic science and clinical applications, as well as the increasing volume of data being generated, efficient and accurate algorithms are in high demand. Results We introduce MetaOthello, a probabilistic hashing classifier for metagenomic sequencing reads. The algorithm employs a novel data structure, called l-Othello, to support efficient querying of a taxon using its k-mer signatures. MetaOthello is an order-of-magnitude faster than the current state-of-the-art algorithms Kraken and Clark, and requires only one-third of the RAM. In comparison to Kaiju, a metagenomic classification tool using protein sequences instead of genomic sequences, MetaOthello is three times faster and exhibits 20–30% higher classification sensitivity. We report comparative analyses of both scalability and accuracy using a number of simulated and empirical datasets. Availability and implementation MetaOthello is a stand-alone program implemented in C ++. The current version (1.0) is accessible via https://doi.org/10.5281/zenodo.808941. Supplementary information Supplementary data are available at Bioinformatics online.

Stable electron-donating organic compounds are of interest for numerous applications that require reversible electron-transfer reactions. Although many organic compounds are stable one-electron donors, removing a second electron from a small molecule to form its dication usually leads to rapid decomposition. For cost-effective electrochemical energy storage utilizing organic charge-storage species, the creation of high-capacity materials requires stabilizing more charge whilst keeping molecular weights low. Here we report the simple modification of N-ethylphenothiazine, which is only stable as a radical cation (not as a dication), and demonstrate that introducing electron-donating methoxy groups para to nitrogen leads to dramatically improved stability of the doubly oxidized (dication) state. Our results reveal that this derivative is more stable than an analogous compound with substituents that do not allow for further charge delocalization, rendering it a promising scaffold for developing atom-efficient, two-electron donors.

IMPORTANCE: Sepsis is a heterogeneous syndrome. Identification of distinct clinical phenotypes may allow more precise therapy and improve care. OBJECTIVE: To derive sepsis phenotypes from clinical data, determine their reproducibility and correlation with host-response biomarkers and clinical outcomes, and assess the potential causal relationship with results from randomized clinical trials (RCTs). DESIGN, SETTINGS, AND PARTICIPANTS: Retrospective analysis of data sets using statistical, machine learning, and simulation tools. Phenotypes were derived among 20 189 total patients (16 552 unique patients) who met Sepsis-3 criteria within 6 hours of hospital presentation at 12 Pennsylvania hospitals (2010-2012) using consensus k means clustering applied to 29 variables. Reproducibility and correlation with biological parameters and clinical outcomes were assessed in a second database (2013-2014; n = 43 086 total patients and n = 31 160 unique patients), in a prospective cohort study of sepsis due to pneumonia (n = 583), and in 3 sepsis RCTs (n = 4737). EXPOSURES: All clinical and laboratory variables in the electronic health record. MAIN OUTCOMES AND MEASURES: Derived phenotype (α, β, γ, and δ) frequency, host-response biomarkers, 28-day and 365-day mortality, and RCT simulation outputs. RESULTS: The derivation cohort included 20 189 patients with sepsis (mean age, 64 [SD, 17] years; 10 022 [50%] male; mean maximum 24-hour Sequential Organ Failure Assessment [SOFA] score, 3.9 [SD, 2.4]). The validation cohort included 43 086 patients (mean age, 67 [SD, 17] years; 21 993 [51%] male; mean maximum 24-hour SOFA score, 3.6 [SD, 2.0]). Of the 4 derived phenotypes, the α phenotype was the most common (n = 6625; 33%) and included patients with the lowest administration of a vasopressor; in the β phenotype (n = 5512; 27%), patients were older and had more chronic illness and renal dysfunction; in the γ phenotype (n = 5385; 27%), patients had more inflammation and pulmonary dysfunction; and in the δ phenotype (n = 2667; 13%), patients had more liver dysfunction and septic shock. Phenotype distributions were similar in the validation cohort. There were consistent differences in biomarker patterns by phenotype. In the derivation cohort, cumulative 28-day mortality was 287 deaths of 5691 unique patients (5%) for the α phenotype; 561 of 4420 (13%) for the β phenotype; 1031 of 4318 (24%) for the γ phenotype; and 897 of 2223 (40%) for the δ phenotype. Across all cohorts and trials, 28-day and 365-day mortality were highest among the δ phenotype vs the other 3 phenotypes (P 33% chance of benefit to >60% chance of harm). CONCLUSIONS AND RELEVANCE: In this retrospective analysis of data sets from patients with sepsis, 4 clinical phenotypes were identified that correlated with host-response patterns and clinical outcomes, and simulations suggested these phenotypes may help in understanding heterogeneity of treatment effects. Further research is needed to determine the utility of these phenotypes in clinical care and for informing trial design and interpretation.

Non-aqueous redox flow batteries (NAqRFBs) employing redox-active organic molecules show promise to meet requirements for grid energy storage. Here, we combine the rational design of organic molecules with flow cell engineering to boost NAqRFB performance. We synthesize two highly soluble phenothiazine derivatives, N-(2-methoxyethyl)phenothiazine (MEPT) and N-[2-(2-methoxyethoxy)ethyl]phenothiazine (MEEPT), via a one-step synthesis from inexpensive precursors. Synthesis and isolation of the radical-cation salts permit UV-vis decay studies that illustrate the high stability of these open-shell species. Cyclic voltammetry and bulk electrolysis experiments reveal the promising electrochemical properties of MEPT and MEEPT under dilute conditions. A high performance non-aqueous flow cell, employing interdigitated flow fields and carbon paper electrodes, is engineered and demonstrated; polarization and impedance studies quantify the cell's low area-specific resistance (3.2–3.3 Ω cm2). We combine the most soluble derivative, MEEPT, and its tetrafluoroborate radical-cation salt in the flow cell for symmetric cycling, evincing a current density of 100 mA cm−2 with undetectable capacity fade over 100 cycles. This coincident high current density and capacity retention is unprecedented in NAqRFB literature.

Electron-withdrawing substituents are introduced onto the phenothiazine core to raise its oxidation potential for use as a redox shuttle in high-voltage lithium-ion batteries. A perfluorinated derivative oxidizes at 4.3 V vs. Li+/0, and functions for ca. 500 h of 100% overcharge in LiNi0.8Co0.15Al0.05O2/graphite coin cells at a charging rate of C/10.

Biological researchers have proposed the existence of protein domains specific to individual taxonomic kingdoms of organism that do not participate directly in catalytic activity and yet are essential to genetic complementation of loss-of-function mutations [1]. Under the scope of this project, we design and implement a computational algorithm for unsupervised identification of new kingdom-specific sequence motifs to distinguish protein domains warranting empirical investigation. We execute this algorithm on sequences for a protein with empirically documented kingdom-specific domain, and validate the results with respect to biological realism by mapping to a 3-D protein structure and comparing against existing protein annotations.

Herein we present the R package rFSA, which implements an algorithm for improved variable selection. The algorithm searches a data space for models of a user-specified form that are statistically optimal under a measure of model quality. Many iterations afford a set of feasible solutions (or candidate models) that the researcher can evaluate for relevance to his or her questions of interest. The algorithm can be used to formulate new or to improve upon existing models in bioinformatics, health care, and myriad other fields in which the volume of available data has outstripped researchers’ practical and computational ability to explore larger subsets or higher-order interaction terms. The package accommodates linear and generalized linear models, as well as a variety of criterion functions such as Allen’s PRESS and AIC. New modeling strategies and criterion functions can be adapted easily to work with rFSA.

A phenothiazine derivative with high solubility in carbonate solvents containing lithium salts showed extensive overcharge protection and, as a result, has been evaluated as a catholyte for non-aqueous redox flow batteries. We report the testing of 3,7-bis(trifluoromethyl)-N-ethylphenothiazine as a catholyte and 2,3,6-trimethylquinoxaline as the anolyte in redox flow batteries containing 0.05, 0.15, and 0.35 M active material and found the longest capacity retention over about 60 cycles at 0.15 M. To our knowledge, this is the most soluble catholyte candidate with a robust radical cation.

The substitution of sterically bulky groups at precise locations along the periphery of fused-ring aromatic systems is demonstrated to increase electrochemical oxidation potentials by preventing relaxation events in the oxidized state. Phenothiazines, which undergo significant geometric relaxation upon oxidation, are used as fused-ring models to showcase that electron-donating methyl groups, which would generally be expected to lower oxidation potential, can lead to increased oxidation potentials when used as the steric drivers. Reduction events remain inaccessible through this molecular design route, a critical characteristic for electrochemical systems where high oxidation potentials are required and in which reductive decomposition must be prevented, as in high-voltage lithium-ion batteries. This study reveals a new avenue to alter the redox characteristics of fused-ring systems that find wide use as electroactive elements across a number of developing technologies.

Overcharge, a condition in which cell voltage rises to undesirably high potentials, can be prevented in lithium-ion batteries by incorporating redox shuttles into the battery electrolyte. Although extensive overcharge protection has been demonstrated in batteries with LiFePO4 cathodes, the redox shuttles that work in these batteries are incompatible with higher voltage cathodes. Designing stable additives with higher oxidation potentials is necessary to protect high voltage batteries from overcharge. Toward that goal, we synthesized diarylamines with varied structures, including fused heteroaromatic ring systems and electron-withdrawing substituents. We found that trends in oxidation potentials correlated with those in calculated adiabatic ionization potentials. Some diarylamine derivatives protected batteries from overcharge with varying degrees of success.

3,7-Bis(trifluoromethyl)-N-ethylphenothiazine (BCF3EPT) was evaluated as a redox shuttle for overcharge protection in lithium-ion batteries. Constant-charging experiments were performed to compare the compound to 1,4-di-tert-butyl-2,5-dimethoxybenzene and N-ethylphenothiazine. BCF3EPT showed significantly longer overcharge protection when compared to either benchmark at the same concentrations in LiFePO4/graphite batteries.

Redox flow batteries (RFBs) are promising candidates for grid storage, but current systems have not met the stringent cost and/or safety requirements needed for widespread implementation. Replacing vanadium with organic compounds may lower materials cost, and utilizing non-aqueous (aprotic) electrolyte solvents, in place of water, could enable a 2- to 3-fold increase in operating voltage. Both features make non-aqueous RFBs candidates for large-scale stationary storage. A limited number of organic compounds have been reported as stable electron donors and acceptors, with even fewer materials being studied as small molecule two-electron donors and/or two-electron acceptors. Our recent efforts have focused on the development of highly soluble electron donors and acceptors with stable oxidized and reduced states. This presentation will focus on design strategies utilized to increase molecular stability in all relevant states of charge as well as solubility. In particular, we highlight the design, synthesis, and electrochemical analysis of organic redox couples. Results will be presented on the cycling of phenothiazine and naphthoquinone derivatives in flowing full cell battery prototypes.

The demand for a stable and compatible redox shuttles for use in lithium-ion batteries has prompted us to explore strategies to tune and improve the properties of redox shuttles. We have studied over 50 new diarylamine derivatives synthesized in our laboratory including one compound in which we introduced trifluoromethyl groups (–CF3) at the positions para to the nitrogen atom in N-ethylphenothiazine (EPT). The high electronegativity of the CF3 group raises the oxidation potential, and its incorporation also significantly increases solubility in battery electrolyte. Here we report 3,7-bis(trifluoromethyl)-N-ethylphenothiazine (BCF3EPT) as a new redox shuttle, which we have observed to have the highest reported solubility in battery electrolyte of all redox shuttles that maintain extended overcharge performance. We have compared its performance with 1,3-di-tert-butyl-2,5-dimethoxybenzene (DBB), EPT, and other robust redox shuttles. In our hands, overcharge cycling of BCF3EPT far surpasses any reported redox shuttle, and – because it can be dissolved at higher concentrations – it tolerates faster charging rates than both DBB and EPT.

Commercial redox flow batteries (RFBs) contain highly acidic and corrosive electrolytes, a cause for concern with widespread use to due concerns about safety and environmental contamination. Replacing these electrolytes with non-aqueous equivalents allows for a safer storage medium. Additionally, utilization of organic electroactive materials may lead to more scalable technologies that do not rely on mined materials such as vanadium and lithium. Furthermore, non-aqueous electrolytes could enable a 2- to 3-fold increase in operating voltage due to the wider operating voltage of non-aqueous systems. Despite the promise for a safer, scalable, higher energy system, the number of organic compounds reported in non-aqueous flow battery systems has been limited to a few classes of compounds, many of which suffer from instability and/or insolubility, especially in charged states. Our recent efforts have focused on the development of organic electron donors and acceptors with stable oxidized and reduced states. This presentation will focus on design strategies utilized to increase molecular stability and solubility in all relevant states of oxidation while keeping syntheses short, high yielding, and scalable. In particular, we highlight the design, synthesis, and electrochemical analysis of new phenothiazine and napthoquinone derivatives designed to serve as one- or two-electron donors. We show that tactical placement of substituents leads to improved stability and increased solubility. Additionally, a new approach to modification of redox potentials using strategic substituent placement will be presented.

The development of low-cost, large-scale energy storage technologies is required for increased reliance on non-polluting, intermittent renewable energy sources connected to our electrical grid. Our research focuses on the development of organic materials for charge storage in non-aqueous redox flow batteries (RFBs). At present, most commercial RFBs contain aqueous, vanadium-based electrolytes, which have been demonstrated on scales as large as 1.5 MW. With non-aqueous electrolytes, a wider electrochemical window allows for 2-3 times higher operating voltages, while avoiding the use of corrosive electrolytes. Most of the organic species reported as electron donors are only stable in the neutral and singly oxidized states; removal of a second electron results in an unstable dication. Here we sought to increase the stability of dication species without significantly raising molecular weight, thus preserving atom economy. Considering phenothiazine donors, we found that the addition of certain substituents led to improved stability of the dication form; specifically, electron-donating methoxy groups (Figure 1) are more effective in stabilization than non-conjugated substituents. This presentation will include the synthesis of these materials, as well as electrochemical and spectroelectrochemical analysis. Furthermore, the results of density functional theory calculations will be presented to evaluate the design of a stable two-electron donor. Figure 1. Structural representation of 3,7-dimethoxyphenothiazine derivatives (a) and cyclic voltammograms of N-ethyl-3,7-dimethoxyphenothiazine (DMeOEPT) showing reversible first and second oxidations (b). Figure 1

Redox flow batteries (RFBs) are promising candidates for grid storage, with a few large-scale systems currently in operation. However, current systems have not met the stringent cost and/or safety requirements needed for widespread implementation. Replacing vanadium with organic compounds may lower materials cost, and utilizing non-aqueous (aprotic) electrolyte solvents, in place of water, could enable a 2- to 3-fold increase in operating voltage. Both features make non-aqueous RFBs candidates for large-scale stationary storage. Currently a limited number of organic compounds have been reported as stable electron donors and acceptors, with even fewer materials being studied as small molecule two-electron donors and/or two-electron acceptors. Yet if the amount of charged stored within an individual molecule were raised without significantly increasing the molecular weight, then electrolyte capacity could be increased proportionally, assuming solubility of neutral and charged species is retained. Our recent efforts have focused on the development of highly soluble electron donors and acceptors with stable oxidized and reduced states. This presentation will focus on design strategies utilized to increase molecular stability in all relevant states of charge as well as solubility. In particular, we highlight the design, synthesis, and electrochemical analysis of phenothiazine and napthoquinone derivatives designed to serve as two-electron donors and two-electron acceptors, respectively. We show that tactical placement of substituents leads to improved stability of doubly oxidized and doubly reduced species, whilst retaining atom economy and that high solubility.

The redox potentials of pi-conjugated organic molecules and polymers are essential factors that determine in part their performance in energy collection and storage applications. In these systems, the control of redox potentials usually involves substitution with electron-donating and/or electron-withdrawing groups, making use of the well-known Hammett constants as predictors of the extent of the change of redox potentials. An additional, less utilized route exploits strain-induced disruptions of π-conjugated frameworks by either (1) introducing bulky substituents to manipulate the dihedral torsions among the π-conjugated moieties or (2) to instill curvature into pi-conjugated networks. In each of these strained examples, the π-conjugated networks are strained in both the ground (neutral) and ionized (oxidized or reduced) electronic states. Taking these studies as inspiration, we sought to develop molecular design principles that impart strain in π-conjugated molecules in only one electronic state, enabling a new method to synthetically control redox potentials. This presentation will include on our approaches to raising oxidation potentials, including calculations, synthesis, electrochemical analysis, and – in some cases – cycling in overcharging lithium-ion batteries. A key highlight is the use of electron-donating alkyl groups to raise oxidation potentials – the opposite effect to what Hammett constants predict.

Many of the electrochemical energy-storage systems under consideration for large-scale power storage and allocation rely on stable electroactive materials to shuttle and/or store charge. Here we seek to design a new class of organic compounds, based on the electroactive molecule phenothiazine, for use as (a) redox-shuttle additives to mitigate excess charge in overcharging lithium-ion batteries, and (b) catholyte materials for use in redox flow batteries. This presentation will include the results of density functional theory calculations that are used to model the physicochemical effects of substituent identity and placement on phenothiazine by introducing electron-donating and/or -withdrawing substituents at strategic positions around the heterocyclic core. Substituent crowding is shown to effect changes in oxidation potential at odds with those anticipated from Hammett constants, as well as changes in energetically optimal conformations, consistent with more-restricted relaxation pathways afforded by the additional steric strain. A subset of the compounds under consideration were subsequently selected for synthesis and electrochemical analysis. The results of this testing suggest that, unlike prior methods of increasing oxidation potentials using electron-withdrawing groups, strategic placement of substituents can be exploited to raise oxidation potentials without raising reduction potentials, thereby preventing access to reduction decomposition pathways. The results of this analysis reveal strategies for designing and tuning the properties of new electroactive compounds for energy-storage applications and beyond.

Phenothiazine and five N-substituted derivatives were evaluated as electrolyte additives for overcharge protection in LiFePO4 /synthetic graphite lithium-ion batteries. We report on the stability and reactivity of both the neutral and radical-cation forms of these six compounds. While three of the compounds show extensive overcharge protection, the remaining three last for only one to a few cycles. UV/Vis studies of redox shuttle stability in the radical cation form are consistent with the overcharge performance: redox shuttles with spectra that show little change over time exhibit extensive overcharge performance, whereas those with changing spectra have limited overcharge protection. In one case, we determined that a C-N bond cleaves upon oxidation, forming the phenothiazine radical cation and leading to premature overcharge protection failure; in another case, poor solubility appears to limit protection.

3,7-Disubstituted N-ethylphenothiazine derivatives were synthesized as redox shuttle candidates for lithium-ion batteries. Battery cycling results show that three derivatives prevent overcharge.

Only about 3% of the electrical energy consumed today is supplied by intermittent energy sources such as solar and wind power. To decrease our reliance on CO2-producing fossil fuels, which currently supply almost 70% of electricity, it is necessary to smooth out the intermittency of renewable energy production. The development of low-cost electrical energy storage (EES) systems could lead to significant integration with the electrical grid. Redox flow batteries (RFBs) are of great interest as a low-cost solution, and systems as large as 20 MWh (check value) have been employed for commercial applications. The commercialization of vanadium-based RFBs has been enabled by the combination of low cost, long lifetime, and high efficiency, and stands out due to the unique ability to scale storage capacity independently of the reactor area. Despite their advantages, current RFBs are limited in charging voltage to ca. 1.5 V due to the electrochemical instability of water above this potential. The replacement of the acidic, aqueous electrolytes with aprotic organic equivalents could allow for higher charging voltages – up to 4-5 V, depending on the identity of the electrolyte solvent.1 Compared to aqueous RFBs, non-aqueous RFBs are still in their infancy due to limited stability and/or solubility of electro-active materials, membrane crossover, and the cost of materials. Recently the performance of organic compounds has been tested in flow systems or stationary mimics. More recently, reports of non-aqueous RFBs containing organic electro-active materials have surfaced. N-oxidanyl amines (e.g. TEMPO), dialkoxybenzenes, and phenothiazines serve as electron-donating electro-active materials, while phthalimide, anthroquinones, quinoxilanes, fluorenone, and viologen act as electron-accepting counterparts. Many of the electron donors have been used as electron-transfer catalysts in other energy storage and collection applications, including redox shuttles for overcharge protection of lithium-ion batteries (LIBs), electron-transfer agents in lithium-air batteries, and redox mediators in dye-sensitized solar cells, among others. Our recent work in protecting LIBs from overcharge has led to the development of several phenothiazine derivatives that exhibit high stability in the neutral and singly oxidized (radical cation) forms,2-6 and some examples exhibit high solubility in organic electrolytes – the combination of which inspired us to evaluate these materials as electron-donating electro-active materials for non-aqueous RFBs.7 Here we will share our recent results in the evaluation of highly soluble phenothiazine derivatives using a variety of electrochemical techniques and – in some cases – in flow batteries. Two highly soluble (miscible) derivatives – one of which is a liquid at room temperature – can be prepared in large scales in one step from commercially available phenothiazine. The persistency of the singly oxidized state has enabled us to synthesize and isolate radical cation salts, which can be used in symmetric flow tests. Additionally, we have found that appropriate identity and positioning of substituents around the periphery of the phenothiazine ring has led to a reversible second oxidation event as measured by cyclic voltammetry. Cycling tests reveal that the dication of these molecules is more stable than versions that do not contain substituents and give an atom economy as low as 150 g/mol e-. References: Darling, R. M. et al., Energy. Environ. Sci., 2014, 7, 3459-3477. Kaur, A. P. et al., J. Mater. Chem. A, 2016 , 4, 5410-5414. Kaur, A. P. et al., J. Electrochem. Soc., 2016, 163, A1-A7. Kaur, A. P. et al. , J. Mater. Chem. A, 2014, 2, 18190–18193. Ergun, S. et al., J. Phys. Chem. C, 2014, 118, 14824–14832. Ergun, S. et al., Chem. Commun., 2014, 50, 5339–5341. Kaur, A. P. et al., Energy Tech., 2015, 3, 476–480.

The development of robust electro-active materials is critical for a variety of electrochemical energy storage applications. Phenothiazines, phenoxazines, carbazoles, and triphenylamines are among some of the numerous electron-donating aromatic compounds that have been studied for numerous applications in organic electronics, photovoltaics, and electrochemically-mediated synthesis. Their use as electrolyte components and electrode materials has only been studied by a few groups, yet these materials are easy to functionalize, enabling tuning their electronic properties, solubility, and stability. My research group initially explored derivatives of these compounds as redox shuttles for overcharge protection of lithium-ion batteries. With systematic variations in structure, our efforts combining analytical techniques with density functional theory calculations have enabled us to identify decomposition products and to predict reasonable mechanisms that lead to failure in neutral and oxidized states. Our development of robust derivatives that survived for thousands of hours of overcharge was a result of the design rules that came from these studies. Recently we have expanded our use of these compounds as catholyte components for non-aqueous redox flow batteries. In one to three steps from commercially available materials, we have prepared highly soluble phenothiazine derivatives (solubility of 1-2 M in organic electrolytes) that can serve as one- and/or two-electron donors with long lifetimes in the charged states. This presentation will focus on the synthesis, spectroscopic, and electrochemical analysis of these materials as electron donors for redox flow batteries.

Phenothiazines have seen widespread use as stable electron-donating organic compounds with generally stable oxidized states, making them an amenable core for functionalization toward electrochemical energy storage applications. With phenothiazine itself as a starting material, functionalization of the 3, 7, and 10 positions is facile, providing options to modify redox potentials and improve stability in both the neutral and singly oxidized (radical cation) states. In one to three steps, we can create highly soluble, stable derivatives that are suitable for applications requiring the donation of one or two electrons. We have observed thousands of hours of overcharge protection in lithium-ion batteries and more recently have moved into testing these species as the electro-active materials for non-aqueous redox flow batteries. This presentation will focus on the synthesis and characterization of new derivatives, highlighting new results in which we found that a liquid phenothiazine that can be prepared in one step from commercially-available starting materials can serve as an electron donor and solvent, dissolving some lithium salts to concentrations of at least 1 M.

The performance of aromatic compounds as redox shuttles for overcharge protection in lithium-ion batteries is variable and difficult to predict. Redox shuttles can decompose in battery electrolyte in their neutral and oxidized forms, both of which are present during overcharge protection. The reasons for differing stability in compounds with only slight structural differences is often unclear, and the exploration of decomposition of redox shuttles has been severely limited, restricting our ability to design improved versions of redox shuttles. To better understand the stability and reactivity of redox shuttles (also relevant to the improvement of positive electrode materials in non-aqueous redox flow batteries) our research has focused on measuring the stability of neutral and oxidized forms of redox shuttle candidates as well as using a variety of spectroscopic methods to analyze the byproducts of decomposition, both from radical cations generated in model solvents and electrolytes from postmortem analysis of failed batteries. Figure 1

In designing robust, effective redox shuttles for overcharge protection in lithium-ion batteries, a variety of factors are necessary to consider and evaluate. The stability and reactivity of the radical cation form of a redox shuttle candidate are critical to extensive overcharge performance. Radical cations are subject to a variety of reactions because of their unpaired electron and positive charge, making them subject to nucleophilic attack and dimerization, among other reactions including disproportionation or premature reduction. Equally as important is the stability of the neutral form of the redox shuttle, which may decompose through reaction with electrolyte, SEI, and/or be reduced at the anode/electrolyte interface. Neither stability nor reactivity is easy to predict, although an understanding of organic chemistry can lead to some general guidelines for the design of less reactive species. Density functional theory (DFT) calculations can be used to predict energies of reaction and have been employed by Curtiss, Dahn, and our group. DFT calculations can also be used to compute oxidation and reduction potentials, helping to identify promising candidates before synthesizing materials. This presentation focuses on our work using DFT calculations to help us identify promising redox shuttles and to gain a better understanding of their reactivity and includes experimental data in support of some of the proposed mechanisms of decomposition.

3,7-Bis(trifluoromethyl)-N-ethylphenothiazine (BCF3EPT) is one of several derivatives of phenothiazine prepared in our laboratory for evaluation as redox shuttles for overcharge protection in lithium-ion batteries. We varied alkyl substituents at the N position and incorporated electron-withdrawing substituents at the 3 and 7 positions. Derivatives with ethyl and iso-propyl groups at the N position were the most stable, and those with chloro and trifluoromethyl substituents were the most robust in overcharging lithium-ion batteries. BCF3EPT showed the highest rate performance when dissolved at 0.5 to 1.5 M in 1.2 M LiPF6 in EC/EMC in graphite/LFP coin cells. At 0.08 M BCF3EPT, batteries lasted over one year in overcharge at a charging rate of C/10. When compared to dimoethoxybenzene-based redox shuttles, the radical cation of BCF3EPT – generated by chemical oxidation with tris(2,4-dibromophenyl)aminium hexachloroantimonate – was more stable in battery electrolyte. The stability of the radical cation form of redox shuttles is critical to overcharge protection and limited effects of the redox shuttle on SEI formation, so the stability of the radical cation of BCF3EPT may explain its extended performance in side-by-side overcharging experiments. In addition to overcharge protection studies, we also studied BCF3EPT as an electron-donating electro-active material in non-aqueous redox flow batteries including one example in which BCF3EPT and trimethylquinoxilane (TMeQ) were incorporated into 1 M LiBF4 in PC and tested in a stationary coin cell following a setup used by Brushett’s group, testing concentrations up to 0.4 M of both species, the anolyte being the limiting factor in high concentration batteries. Lastly, we have focused on the scale-up of BCF3EPT, which we prepare in three steps from commercially available phenothiazine. So far the first and second transformations have yields of more than 95%, and the last step - the trifluoromethylation – can be conducted in over 90% yield. Figure 1