Synthesis of a Trivalent P-Chloro-Dithienophosphole and its Reactivity with Organometallic Reagents

P-chloro-dithieno[3,2-b:2’,3’-d]phosphole was synthesized and isolated from the reaction of an aminophosphole and HCl. Developed to act as a common starting material for P-functionalized phospholes, the compound exhibits a surprising reactivitiy by generating dimeric biphospholes. Despite this apparent sensitivity, when reacting with organolithium and Grignard reagents, a series of differently P-functionalized dithieno[3,2-b:2’,3’-d]phospholes was accessible. Unexpectedly, organolithium reagents showed reduced reactivity with the chlorophosphole, limiting yields of the desired products due to the competing dimerization. Nonetheless, P- functionalized phospholes were isolated from reactions of the title compound with both Grignard and organolithium reagents in yields equivalent to, or higher, than by previous methods. A bithiophene- bridged bisphosphole system was also successfully synthesized without the necessity of generating a bis(dichlorophosphino) reagent. Finally, the isolated P-functionalized phospholes were analyzed for their photophysical properties. In general, these compounds are strong absorbers in the UV/visible range of the optical spectrum. The phospholes’ emissions were consistent with several previously reported, however, typically with low quantum yields.NSERC, CFI, CRC, Alberta Innovates - Technology Future

Structure-reactivity studies on hypervalent square-pyramidal dithieno[3,2-b:2’,3’-d]phospholes

A series of neutral pentacoordinate dithieno[3,2-b:2’,3’-d]phosphole compounds were synthesized by [4+1] cycloaddition with o-quinones. Counter to the expected trigonal bipyramidal geometry, the luminescent hypervalent dithienophospholes exhibit square pyramidal geometry with inherently Lewis acidic phosphorus center that is stabilized via supramolecular π-stacking interactions in the solid state and in solution. Due to their Lewis-acid character, the compounds react with nucleophiles, suggesting their potential as mediator in organic transformations. The new species thus present an intriguing structural plaform for the design of neutral P(V) Lewis acids with useful reactivities.NSERC, CFI, Canada Research Chair

T Cell Receptor-Independent, CD31/IL-17A-Driven Inflammatory Axis Shapes Synovitis in Juvenile Idiopathic Arthritis

T cells are considered autoimmune effectors in juvenile idiopathic arthritis (JIA), but the antigenic cause of arthritis remains elusive. Since T cells comprise a significant proportion of joint-infiltrating cells, we examined whether the environment in the joint could be shaped through the inflammatory activation by T cells that is independent of conventional TCR signaling. We focused on the analysis of synovial fluid (SF) collected from children with oligoarticular and rheumatoid factor-negative polyarticular JIA. Cytokine profiling of SF showed dominance of five molecules including IL-17A. Cytometric analysis of the same SF samples showed enrichment of αβT cells that lacked both CD4 and CD8 co-receptors [herein called double negative (DN) T cells] and also lacked the CD28 costimulatory receptor. However, these synovial αβT cells expressed high levels of CD31, an adhesion molecule that is normally employed by granulocytes when they transit to sites of injury. In receptor crosslinking assays, ligation of CD31 alone on synovial CD28nullCD31+ DN αβT cells effectively and sufficiently induced phosphorylation of signaling substrates and increased intracytoplasmic stores of cytokines including IL-17A. CD31 ligation was also sufficient to induce RORγT expression and trans-activation of the IL-17A promoter. In addition to T cells, SF contained fibrocyte-like cells (FLC) expressing IL-17 receptor A (IL-17RA) and CD38, a known ligand for CD31. Stimulation of FLC with IL-17A led to CD38 upregulation, and to production of cytokines and tissue-destructive molecules. Addition of an oxidoreductase analog to the bioassays suppressed the CD31-driven IL-17A production by T cells. It also suppressed the downstream IL-17A-mediated production of effectors by FLC. The levels of suppression of FLC effector activities by the oxidoreductase analog were comparable to those seen with corticosteroid and/or biologic inhibitors to IL-6 and TNFα. Collectively, our data suggest that activation of a CD31-driven, αβTCR-independent, IL-17A-mediated T cell-FLC inflammatory circuit drives and/or perpetuates synovitis. With the notable finding that the oxidoreductase mimic suppresses the effector activities of synovial CD31+CD28null αβT cells and IL-17RA+CD38+ FLC, this small molecule could be used to probe further the intricacies of this inflammatory circuit. Such bioactivities of this small molecule also provide rationale for new translational avenue(s) to potentially modulate JIA synovitis

Fluorescence-based Measurement of the Lewis Acidities of Lanthanide Triflates in Solution

Despite the prominence of rare earth complexes to act as Lewis-acid catalysts in organic synthesis, the comprehensive measure of the Lewis-acid strength of such compounds has yet to be performed due to incompatibilities with existing methods. We report our results in measurement of a sequence of lanthanide triflates via our recently established Fluorescent Lewis adduct (FLA) method. The persistence in solution of these Lewis acids as solvated coordination complexes is accurately measurable by the FLA method. However, several of the RE species exhibit fluorescence quenching, which may potentially inhibit the measurement. Nevertheless, meaningful FLA measurements were still able and the results correspond to both periodic trends and were even consistent with previous correlated reported dat

Probing the Impact of Solvent on Lewis Acid Catalysis via Fluorescent Lewis Adducts

Over the years, various multiparameter methods have been developed to measure the strength of a Lewis acid. However, a major challenge for these measurements lies in the complexity that arises from variables such as solvent and other fundamental interactions, as well as perturbations of Lewis acids as their reaction environment changes. Herein, we evaluate the impact of solvent effects on the Fluorescent Lewis Adduct (FLA) method using a series of representative Lewis acids. The solution-state nature of the FLA method in particular, offers the ability to correlate Lewis Acid Units (LAUs) obtained from the FLA measurement with chemical reactivity. The binding of a Lewis acid in various solvents reveals a measurable dichotomy between both polarity and donor ability of the solvent. While not strictly separable, we observe that, as solvent polarity increases observed LAUs increase; however, as solvent donor ability increases, the observed LAUs decrease. This dichotomy was confirmed by titration data and catalytic Diels-Alder cycloaddition and hydrosilylation reactions, illustrating that solvation effects can be appropriately gauged by LAU values determined from the FLA method

Phosphoryl- and Phosphonium-Bridged Viologens as Stable Two- and Three-Electron Acceptors for Organic Electrodes

Low molecular weight organic molecules that can accept multiple electrons at highreduction potentials are sought after as electrode materials for high-energy sustainable batteries. To date their synthesis has been difficult, and organic scaffolds for electron donors significantly outnumber electron acceptors. Herein, we report two highly electron deficient phosphaviologen derivatives from a phosphorus-bridged 4,4-bipyridine and characterize their electrochemical properties. Phosphaviologen sulfide (PVS) and P-methyl phosphaviologen (PVM) accept two and three electrons at high reduction potentials, respectively. PVM can reversibly accept 3 electrons between 3-3.6 V vs. Li/Li+ with an equivalent molecular weight of 102 g/(mol e-) (262 mAh/g), making it a promising scaffold for sustainable organic electrode materials having high specific energy densities

Fluorescent Lewis Adducts: A Refined Guide for Lewis Acidity

The evaluation of the chromaticity of a series of fluorescent Lewis adducts with highly luminescent dithienophospholes enables the unequivocal determination of the strength of Lewis acids. Our method provides a simple, robust, and efficient avenue to discern an exhaustive list of species from across the period table

CCDC 930515: Experimental Crystal Structure Determination

Related Article: Brynna J. Laughlin,Tyler L. Duniho,Samantha J. El Homsi,Benjamin E. Levy,Nihal Deligonul,Joshua R. Gaffen,John D. Protasiewicz,Andrew G. Tennyson,Rhett C. Smith|2013|Org.Biomol.Chem.|11|5425|doi:10.1039/C3OB40580J,An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

CCDC 930514: Experimental Crystal Structure Determination

Related Article: Brynna J. Laughlin,Tyler L. Duniho,Samantha J. El Homsi,Benjamin E. Levy,Nihal Deligonul,Joshua R. Gaffen,John D. Protasiewicz,Andrew G. Tennyson,Rhett C. Smith|2013|Org.Biomol.Chem.|11|5425|doi:10.1039/C3OB40580J,An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures