A recent study by Piers et al. observed that deconstruction of the BODIPY core reveals the well–known β–diketiminato ligand where asymmetric derivatives that undergo BF2 chelation may lead to a fluorophore scaffold with more energetically discrete states. This concept was successfully demonstrated with anilido–pyridine boron difluoride which exhibited a ten–fold increase in Stokes shift compared to BODIPY. This finding represents a fundamental leap in fluorophore design as any molecule, asymmetric or not, with the appropriate O,O, N,N, or N,O architecture can feasibly undergo BF2 chelation and become luminescent. A modular approach has a distinct advantage over BODIPYs as such a scaffold can ideally be broken down into two halves and combined prior to metalation. This convergent strategy also allows for derivatization at the early stages of synthesis, which lays the groundwork for refined structure–property relationship studies.

With the goal of developing a variety of novel BF2 chelates, this research plan aims to acquire a better understanding of how to control luminescence as a function of asymmetry through the strategic conversion of already known precursors containing O,O, N,N, or N,O architectures into efficient and tunable fluorescent molecules with broad Stokes shifts. Furthermore, this research plan endeavors to utilize these scaffolds in useful and practical applications such as mechanochromically luminescent materials as well as water soluble dyes used for protein markers and molecular sensors.

Asymmetric Boron Difluorides: A Search for Highly Tunable Fluorescent Dyes

Aleksey V. Kozlov, Elijah J. Glascock, Tara M. Cristallo, and Daniel T. Chase*

References

AcknowledgementsThis research was supported in part by a grant to Gonzaga University from the Howard Hughes Medical Institute, the Gonzaga Science Research Program, and the Department of Chemistry and Biochemistry.

Asymmetric Boron Difluorides: A Potential Solution

Project Goal

With an understanding of how to effectively utilize scaffold asymmetry to influence Stokes shifts, an important goal is to determine what upper limits of optical band gap reduction are possible while maintaining sufficiently broad Stokes shifts. This can be reasonably achieved through increased conjugation and ring fusion where frontier orbitals may experience an even greater enhancement of spatial separation. The strategic incorporation of heavy atoms into these scaffolds may also serve as an efficient method to bathochromically shift absorption and emission profiles through phosphorescence pathways. Furthermore, heavy atoms are also known to contribute to singlet oxygen generation, a critical component in photodynamic therapy.

Department of Chemistry and Biochemistry, Gonzaga University, Spokane Washington 99258-0089; chased@gonzaga.edu

The continual development of novel fluorescent dyes is fueled by their broad multidisciplinary use in the physical and biological sciences. Examples of their versatile application include organic light–emitting diodes, laser dyes, photo–switchable circuitry, molecular and ionic sensors, biological stains and markers, and photosensitizers. While numerous dye families have found success in these fields, perhaps the most recognized fluorophores are the boron dipyrromethenes, better known as BODIPYs. First reported in 1968 and later commercialized in the 1990’s, BODIPYs are valued for their sharp and intense UV–absorbing and emitting capabilities, high quantum yields, good solubility, and high stability to a variety of chemical environments. A considerable disadvantage of BODIPYs is their narrow Stokes shifts where its symmetrical core structure affords energetically similar ground and excited states. This often results in undesirable auto–excitation pathways, limiting dye performance. A strategy in current use to circumvent this issue relies on the installation of secondary and tertiary fluorophore units with overlapping absorption and emission wavelengths via intramolecular energy transfer pathways. While this technique has merit, molecules that utilize this design are synthetically tedious and suffer low quantum yields due to non–unity energy transfers. Considering these problematic issues, a fundamentally important question arises: is it possible to create a dye family that has all of the positive aspects of BODIPYs but without the negative ones?

An Introduction to Fluorescent Dyes β-Ketoiminate and β-Diketiminato BF2 Synthesis

One of the current tasks involves the examination of how asymmetric chelation changes can affect emission wavelengths. An intriguing and simple example are distyryl BF2 complexes which have been reported to exhibit full–color emission and be utilized as near–infrared probes for in vivo detection of amyloid–β deposits. As the starting material prior to chelation is 2,4-pentadione, a ubiquitous ligand in classic transition metal chemistry, we were especially surprised to see limited reporting of similar BF2 chelates using N,O and N,N scaffolds.

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Future Work – Diamide BF2Synthesis

Of similar interest to β-ketoiminate and β-diketiminato BF2 complexes are N,O and N,N diamide derivatives. Their successful synthesis would further elucidate the role of heteroatomic meso substitution and provide more opportunities to compare solution and solid state emission and quenching.

Loudet, A.; Burgess, K. Chem. Rev. 2007, 107, 4891.Ziessel, R.; Ulrich, G.; Harriman, A. New. J. Chem. 2007, 31, 496.Treibs, A.; Kreuzer, F.-H. Justus Liebigs Ann. Chem.1968, 718, 208.Harriman, A.; Mallon, L. J.; Elliot, K. J.; Haefele, A.; Ulrich, G.; Ziessel, R. J. Am. Chem. Soc. 2009, 131, 13375. Ziessel, R.; Ulrich, G.; Haefele, A.; Harriman, A. J. Am. Chem. Soc. 2013, 135, 11330.Chen, Y.; Zhao, J.; Guo, H.; Xie, L. J. Org. Chem. 2012, 77, 2192.Araneda, J. F.; Piers, W. E.; Heyne, B.; Parvez, M.; McDonald, R. Angew. Chem. Int. Ed. 2011, 50, 12214.Bradshaw, T. D.; Westwell, A. D. Curr. Med. Chem. 2004, 11, 1009.Woodroofe, C. C.; Meisenheimer, P. L.; Klubert, D. H.; Kovic, Y.; Rosenberg, J. C.; Behney, C. E.; Southworth, T. L.; Branchini, B. R. Biochemistry, 2012, 51, 9807.De Silva, H. I.; Henry, W. P.; Pittman, C. U., Jr. Synthesis, 2012, 44, 3337.Gorman, A.; Killoran, J.; O’Shea, C.; Kenna, T.; Gallagher, W. M.; O’Shea, D. F. J. Am. Chem. Soc. 2004, 126, 10619. Murtagh, J.; Frimannsson, D. O.; O’Shea, D. F. Org. Lett.2009, 11, 5386.Wu, D. O’Shea, D. F. Org. Lett. 2013, 15, 3392.Dolmans, D.; Fukumura, D.; Jain, R. K. Nat. Rev. Cancer 2003, 3, 380.Marsden, J. A.; Miller, J. J.; Shirtcliff, L. D. Haley, M. M. J. Am. Chem. Soc. 2005, 127, 2464. Zuchhero, A. J.; Wilson, J. N.; Bunz, U. H. F. J. Am. Chem. Soc. 2006, 128, 11872.Carrër, A.; Florent, J.-C.; Auvrouin, E.; Rousselle, P.; Bertounesque, E. J. Org. Chem. 2011, 76, 2502.

The 2014 Nobel Prizes in Chemistry and Physics were awarded for the development of super–resolved fluorescence microscopy and the blue light–emitting diode, respectively.

Interestingly, these compounds weakly fluoresce in solution but samples in the solid state exhibit comparatively intense and bathochromically shifted luminescence. This is presumably due restriction of intramolecular rotation, resulting in aggregate–induced emission. In addition to obtaining HRMS, UV–Vis, fluorescence lifetimes, X–ray crystallography, cyclic voltammetry, solvatochromic studies, and HOMO–LUMO computations, efforts to produce distyryl BF2 complexes are underway.

Aryl benzamide BF2 Synthesis

Numerous reports have found that heteroatomic meso substitution on the BODIPY core serves as an effective method to bathochromically shift absorption and emission profiles by as much as 150 nm with respect to BODIPY where examples have been successfully utilized as near–infrared probes for cellular imaging. However, these compounds still exhibit narrow Stokes shifts. We therefore wish to investigate a series of asymmetric arylbenzamide BF2 scaffolds with the hope that analogous meso substitution can provide similar bathochromic profiles while maintaining broad Stokes shifts. Preliminary observations indicate that these compounds readily fluoresce a blue–green hue but exhibit quenching in the solid state.

Conjugation Extension, Ring Fusion, and Dimerization