Bumpy Roads Lead to Beautiful Places: The Twists and Turns in Developing a New Class of PN-Heterocycles

Abstract

The Haley and Johnson labs at the University of Oregon have been collaborating since 2006, combining skillsets in synthetic organic, physical organic, and supramolecular chemistries. This joint project has produced many examples of host molecules that bind anionic guests and give chemical, photophysical, and/or electrical responses. Many of these receptors utilize two-armed arylethynyl backbones that have a variety of hydrogen- or halogen-bonding functional groups appended. However, in attempts to produce a bisamide-containing host using a peptide-coupling protocol with P(OPh)3 present, we isolated something unexpected – a heterocycle containing neighboring P and N atoms. This ‘failed’ reaction turned into a surprisingly robust synthesis of phosphaquinolinones, an unusual class of PN-heterocycles. This Account article tells the rollercoaster story of these heterocycles in our lab. It will highlight our key works to this field, including a suite of fundamental studies of both the original PN-naphthalene moiety, as well as a variety of structural modifications to the arene backbone. It will also discuss the major step forward the project took when we developed a phosphaquinolinone-containing receptor molecule capable of binding HSO4 – selectively, reversibly, and with recyclability. With these findings, the project has gone from hospice care to making a full, robust recovery.1 Introduction2 Initial Discovery3 Setbacks Breathe New Life4 A New Dynamic Duo Develops Dozens of Derivatives5 Physicochemical Characterization5.1 Fluorescence5.2 Molecular Structures5.3 Solution Dimerization Studies6 Applying What We Have Learned6.1 Development of Supramolecular Host6.2 Use of PN Moiety as an Impressive Fluorophore7 Conclusions and Outlook

2-λ5-Phosphaquinolin-2-ones as Non-cytotoxic, Targetable, and pH-Stable Fluorophores

“…Slow diffusion of pentane into a concentrated solution of 8 in CHCl 3 gave single crystals suitable for X-ray diffraction. In the resultant structure (Figure S1), the P–N, PO, P–C, and C–C bond distances are 1.674(3), 1.478(3), 1.784(3), and 1.341(5) Å, respectively, all of which are in line with previously reported parameters . Without the traditional phosphonamide N–H group, however, the molecule forms a 1D hydrogen-bonded “polymer” between the phosphonamide PO of one molecule and the amide group of its nearest neighbor (Figure S2), with a N···O intermolecular distance of 2.832(4) Å.…”

“…Recently, we reported that the phosphorus- and nitrogen-containing (PN) scaffold built from a 2-λ 5 -phosphaquinolin-2-one framework (Figure ) possesses interesting photophysical properties, which include coumarin-like fluorescence emission of 450–650 nm, quantum yields up to 93%, structural modularity, and Stokes shifts ranging from 3800–10 000 cm –1 . , In addition to a variety of studies examining the effects of arene core modification and integration of heteroatoms into the scaffold, , several structure–property relationships have been drawn for substituent group placement on the PN-heterocycle scaffold, which include both the phenyl group on the phosphorus as well as the substituents at the 3- and 6-positions, , thus guiding the development of the fluorophores in this study ( vide infra ). Moreover, most of the PN-systems are compatible with Lipinski’s “Rule of Five”, as they have <5 hydrogen bond donors, <10 hydrogen bond acceptors, a mass <500 amu, and a low octanol–water partition coeffient, suggesting that this class of compounds may be cell permeable.…”