William J. Brittain

Tetra‐ortho‐fluoroazobenzenes (TFAs) exhibit several unique properties, including a large separation in the n→π^* absorption bands, which allows for efficient photoisomerization using green light, and exceptional thermal stability of their metastable Z‐isomer. These features make them attractive for light‐responsive applications, but controlling the thermal Z‐to‐E isomerization has remained a challenge. In this work, we present a hybrid molecular system that couples a TFA subunit with a spiropyran photoswitch. The TFA subunit retains its ability to undergo selective photoisomerization with green light. Z‐to‐E isomerization in the hybrid occurs approximately 1000 times faster than in a TFA model compound. This acceleration arises from a rate‐determining step involving the formation of merocyanine—the ring‐opened form of spiropyran. The transient phenolate form of merocyanine promotes rapid Z‐to‐E isomerization of the TFA, consistent with the known behavior of azobenzene phenolates. The thermodynamics of TFA isomerization are coupled with those of the spiropyran ring‐opening, allowing the isomerization process to be regulated by external stimuli that influence the spiropyran–merocyanine equilibrium. In addition to observing a 100–1000‐fold solvent‐dependent rate increase, we demonstrate a 10⁶‐fold acceleration in TFA isomerization via either photochromism or adsorptiochromism.

Tetra‐ortho‐fluoroazobenzenes (TFAs) exhibit several unique properties, including a large separation in the n→π^* absorption bands, which allows for efficient photoisomerization using green light, and exceptional thermal stability of their metastable Z‐isomer. These features make them attractive for light‐responsive applications, but controlling the thermal Z‐to‐E isomerization has remained a challenge. In this work, we present a hybrid molecular system that couples a TFA subunit with a spiropyran photoswitch. The TFA subunit retains its ability to undergo selective photoisomerization with green light. Z‐to‐E isomerization in the hybrid occurs approximately 1000 times faster than in a TFA model compound. This acceleration arises from a rate‐determining step involving the formation of merocyanine—the ring‐opened form of spiropyran. The transient phenolate form of merocyanine promotes rapid Z‐to‐E isomerization of the TFA, consistent with the known behavior of azobenzene phenolates. The thermodynamics of TFA isomerization are coupled with those of the spiropyran ring‐opening, allowing the isomerization process to be regulated by external stimuli that influence the spiropyran–merocyanine equilibrium. In addition to observing a 100–1000‐fold solvent‐dependent rate increase, we demonstrate a 10⁶‐fold acceleration in TFA isomerization via either photochromism or adsorptiochromism.

Azobenzene compounds are putative solar thermal fuels (STF) due to the excellent photostability and structural control of isomerization rates. Azobenzenes, in which both Z‐ and E‐isomers are liquid at room temperature, are promising candidates for STF flow technology. A literature survey of melting points led to the synthesis and isomer separation of ortho‐ and meta‐monosubstituted azobenzenes with fluoro, methyl, ethyl, trifluoromethyl and methoxy substituents and several dimethyl substituted azobenzenes. Four of the compounds are liquid azobenzenes with higher specific energy than literature work with higher molar mass, liquid compounds. Eight of the compounds unexpectedly displayed a higher melting point for the Z‐isomer which is rarely observed. Intermolecular close contacts in the crystal lattice of the Z‐isomer are the main factor responsible for the higher melting temperatures.

Tubulin polymerization inhibitors (TPIs) are promising ligands utilized in chemotherapy for modern cancer treatment. However, the current TPIs exhibit many serious side effects that may pose limitations in chemotherapy. Combretastatin A-4 (CA-4) is a natural TPI that binds at the colchicine binding site located on microtubules. The only cis isomer of CA-4 is bio-active; however, due to its short half-life, it isomerizes quickly to its bio-inactive trans geometric isomer. Preventing shortcomings of CA-4, azobenzene based CA-4, called azo-CA-4 (azo-CA-4), identified as a novel TPI. The geometric isomerization of azo-CA-4 can be controlled upon exposure of ultraviolet (UV) light to remotely control its bioactivity. Cis-azo-CA-4 is 200-500 times more active (IC50 = 0.2-10 µM) than trans-azo-CA-4 (IC50 = 50-110 µM) against various cancer cell lines. Photo-pharmacology uses light to control drug activity, introduce a unique mechanism to develop novel photo-responsive TPIs. Further, the green chemistry approach using ethanol and water as a green solvent in the synthesis of azo-CA-4 delivers advanced methodology in novel TPI development .

Microarrays are powerful tools in biomedical research and have become indispensable for high-throughput multiplex analysis, especially for DNA and protein analysis. The basis for all microarray processing and fabrication is surface modification of a chip substrate and many different strategies to couple probe molecules to such substrates have been developed. We present here a critical assessment of typical biochip generation processes from a surface science point of view. While great progress has been made from a molecular biology point of view on the development of qualitative assays and impressive results have been obtained on the detection of rather low concentrations of DNA or proteins, quantitative chip-based assays are still comparably rare. We argue that lack of stable and reliable deposition chemistries has led in many cases to suboptimal quantitative reproducibility, impeded further progress in microarray development and prevented a more significant penetration of microarray technology into the diagnostic market. We suggest that surface-attached hydrogel networks might be a promising strategy to achieve highly sensitive and quantitatively reproducible microarrays.

We report the effect of substituents on the force-induced reactivity of a spiropyran mechanophore. Using single molecule force spectroscopy, force-rate behavior was determined for a series of spiropyran derivatives substituted with H, Br, or NO₂ para to the breaking spirocyclic C–O bond. The force required to achieve the rate constants of ∼10 s^–1 necessary to observe transitions in the force spectroscopy experiments depends on the substituent, with the more electron withdrawing substituent requiring less force. Rate constants at 375 pN were determined for all three derivatives, and the force-coupled rate dependence on substituent identity is well explained by a Hammett linear free energy relationship with a value of ρ = 2.9, consistent with a highly polar transition state with heterolytic, dissociative character. The methodology paves the way for further application of linear free energy relationships and physical organic methodologies to mechanochemical reactions, and the characterization of new force probes should enable additional, quantitative studies of force-coupled molecular behavior in polymeric materials.

TheZisomer of azobenzene exhibits nonbonded interactions between ortho substituents on adjacent phenyl groups. Foro,o′‐difluoroazobenzene derivatives, through‐space¹⁹F‐¹⁹F spin‐spin coupling is observed. The coupling constant decreases as the nuclear magnetic resonance probe temperature is decreased culminating in collapse to a single peak. We have used density functional theory and X‐ray crystallography to argue that phenyl group rotation is responsible for this loss of through‐space coupling. We experimentally measured phenyl rotation barriers in the range of 37 to 44 kJ/mol foro,o′‐difluoroazobenzene derivatives. These rotation barriers are qualitatively similar to literature experimental values for fluxional systems but higher than calculated values forZ‐azobenzene.This is the only project in 35 years that I discussed with J.D.R. This mechanistic interpretation of an unusual nuclear magnetic resonance phenomenon is a classic physical organic investigation inspired by my training with Roberts. I tell this scientific story interwoven with a few observations about working with Roberts.