Making the Brightest Ones Dim: Maximizing the Photothermal Conversion Efficiency of BODIPY-Based Photothermal Agents.

The successful implementation of photothermal therapy (PTT) in cancer treatment hinges on the development of highly effective photothermal agents (PTAs). Boron dipyrromethene (BODIPY) dyes, being well known for their high brightness and quantum efficiencies, are the antithesis of PTAs. Nonetheless, a systematic exploration of the photophysics and photothermal characteristics of a series of π-extended BODIPY dyes with high absorptivity in the near-infrared (NIR) region has achieved superior photothermal conversion efficiencies (>90%), in both monomeric state and nanoparticles after encapsulation in a biocompatible polyethyleneglycol 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy-(polyethylene glycol)-2000]. Optimal PTA candidates combine strong NIR absorption provided by extended donor-acceptor conjugation and an optimization of the electronic and steric effects of meso-substituents to maximize photothermal conversion performance. The PTT-optimized meso-CF3-BODIPY, TCF3PEn exhibits exceptional efficacy in inducing cancer cell apoptosis and in vivo tumor ablation using low-power NIR laser irradiation (0.3 W cm-2, 808 nm) as well as excellent biological safety, underscoring its potential for advancing light-induced cancer therapies.

A Facile Preparation of N-Heterocyclic Olefins: Ring-Opening Polymerization of ß-Butyrolactone and Frustrated Lewis Pair Reactivity.

A direct synthesis of N-heterocyclic olefins (NHOs) and their mesoionic congeners (mNHOs) from N-heterocyclic carbenes and N-aziridinylimines is reported. The reaction provided diverse functionalized (m)NHOs and π-extended analogues. The prepared NHOs initiated the ring-opening polymerization of ß-butyrolactone, and insertion of aldehyde and nitrile into an NHO-B(C6 F5 )3 adduct was demonstrated.

Skeletal Transformation of Unactivated Arenes Enabled by a Low-Temperature Dearomative (3 + 2) Cycloaddition.

Simple aromatic compounds like benzene are abundant feedstocks, for which the preparation of derivatives chiefly begins with electrophilic substitution reactions or, less frequently, reductions. Their high stability makes them particularly reluctant to participate in cycloadditions under ordinary reaction conditions. Here, we demonstrate the exceptional ability of 1,3-diaza-2-azoniaallene cations to undergo formal (3 + 2) cycloadditions with unactivated benzene derivatives below room temperature, providing thermally stable dearomatized adducts on a multi-gram scale. The cycloaddition, which tolerates polar functional groups, activates the ring toward further elaboration. On treatment with dienophiles, the cycloadducts undergo a (4 + 2) cycloaddition-cycloreversion cascade to yield substituted or fused arenes, including naphthalene derivatives. The overall sequence results in the transmutation of arenes through an exchange of the ring carbons: a two-carbon fragment from the original aromatic ring is replaced with another from the incoming dienophile, introducing an unconventional disconnection for the synthesis of ubiquitous aromatic building blocks. Applications of this two-step sequence to the preparation of substituted acenes, isotopically labeled molecules, and medicinally relevant compounds are demonstrated.

Enantioselective extraction of unprotected amino acids coupled with racemization.

Scalable and economical methods for the production of optically pure amino acids, both natural and unnatural, are essential for their use as synthetic building blocks. Currently, enzymatic dynamic kinetic resolution (DKR) underpins some of the most effective processes. Here we report the development of enantioselective extraction coupled with racemization (EECR) for the chirality conversion of underivatized amino acids. In this process, the catalytic racemization of amino acids in a basic aqueous solution is coupled with the selective extraction of one enantiomer into an organic layer. Back-extraction from the organic layer to an acidic aqueous solution then completes the deracemization of the amino acid. The automation of the EECR process in a recycling flow reactor is also demonstrated. Continuous EECR is made possible by the sterically hindered chiral ketone extractant 5, which prevents the coextraction of the copper racemization catalyst because of its nonplanar geometry. Furthermore, the extractant 5 unexpectedly forms imines with amino acids faster and with greater enantioselectivity than less bulky derivatives, even though 5 cannot participate in intramolecular resonance-assisted hydrogen bonding. These features may allow EECR to challenge the preponderance of enzymatic DKR in the production of enantiomerically enriched amino acids.

Amine-Reactive Activated Esters of meso-CarboxyBODIPY: Fluorogenic Assays and Labeling of Amines, Amino Acids, and Proteins.

Fluorescence-based amine-reactive dyes are highly valuable for the sensing of amines and the labeling of biomolecules. Although it would be highly desirable, large changes in emission spectra and intensity seldom accompany the conjugation of known amine-reactive dyes to their target molecules. On the contrary, amide bond formation between amines and the pentafluorophenyl (2-PFP) and succinimidyl (2-NHS) esters of meso-carboxyBODIPY results in significant changes in emission maxima (Δλ: 70-100 nm) and intensity (up to 3000-fold), enabling the fast (down to 5 min) and selective fluorogenic detection and labeling of amines, amino acids, and proteins. This approach further benefits from the demonstrated versatility and high reliability of activated ester chemistry, and background hydrolysis is negligible. The large "turn-on" response is a testament of the extreme sensitivity of meso-carboxyBODIPYs to the minimal changes in electronic properties that distinguish esters from amides. Applications to the detection of food spoilage, staining of proteins on electrophoretic gels or in living cells, and the expedited synthesis of organelle-specific fluorescence microscope imaging agents are further demonstrated.

Long-Range Order Self-Assembly of Conjugated Block Copolymers at Inclined Air-Liquid Interfaces.

Here, we report that long-range order, direction-controlled, ultrathin conjugated polymer films can be formed by the self-assembly of conjugated block copolymers (i.e., poly(3-hexylthiophene)-block-poly(ethylene glycol)) at inclined air-water interfaces. Structure analyses revealed well-aligned nanowire arrays of poly(3-hexylthiophene) with a dramatically increased ordered domain size compared to the polymer films formed on a flat water surface. The improved degree of order was attributed to the flow field created by the enhanced solvent evaporation at the top of the water contact line. Note that it is challenging to prepare such well-ordered and molecularly thin films of conjugated polymers by conventional fabrication methods. The long-range order polymer film showed hole mobility an order of magnitude higher than polymer films formed on a flat interface when implemented as an active layer of field-effect transistor devices. This study demonstrates that a simple interface modification can significantly impact the self-assembly process, structure, and function of polymer films formed at the air-liquid interface.

Binary Self-Assembly of Conjugated Block Copolymers and Quantum Dots at the Air-Liquid Interface into Ordered Functional Nanoarrays.

Controlling the nanoscale morphology of conducting polymer/nanoparticle hybrid films is a highly desired but challenging task. Here, we report that such functional hybrid films with unprecedented structural order can be formed through the self-assembly of conjugated block copolymers and CdSe quantum dots at the air-water interface. The one-step assembly of quantum dots and block copolymers composed of polythiophene and polyethylene glycol (P3HT-b-PEG) at the fluidic interface generated a highly ordered assembly structure of P3HT nanowires and one-dimensional quantum dot arrays. Structure analyses revealed a unique self-assembly behavior and size dependency, which are distinct from the conventional self-assembly of coil-type polymers on solid substrates. Interestingly, hydrophobic quantum dots reside at the interface between P3HT and PEG domains without disrupting the P3HT packing structure, which is advantageous for the optoelectronic properties. Furthermore, large particles bridge the P3HT nanowires at both ends, while small particles decorate each P3HT/PEG interfaces, thus forming tight p-n junctions for a broad size range of nanoparticles. The nanoparticle-incorporated hybrid films showed more than an order of magnitude higher photocurrent and light sensitivity compared to polymer-only films, consistent with the assembly structure with close contact between the organic and inorganic semiconductors.

Endoplasmic Reticulum-Targeted Ratiometric N-Heterocyclic Carbene Borane Probe for Two-Photon Microscopic Imaging of Hypochlorous Acid.

The naphthoimidazolium borane 4 is shown to be a selective probe for HOCl over other reactive oxygen species. Unlike other boronate-reactive oxygen species (ROS) fluorogenic probes that are oxidized by HOCl through a nucleophilic borono-Dakin oxidation mechanism, probe 4 is distinguished by its electrophilic oxidation mechanism involving B-H bond cleavage. Two-photon microscopy experiments in living cells and tissues with the probe 4 demonstrate the monitoring of endogenous HOCl generation and changes in HOCl concentrations generated in the endoplasmic reticulum during oxidative stress situations.

Addition, Substitution, and Ring-Contraction Reactions of Quinones with N-Heterocyclic Carbenes.

Despite the common use of quinones as oxidizing agents in N-heterocyclic carbene (NHC)-based organocatalysis and transition-metal catalysis, the direct reactivity of quinones with NHCs remains underexplored. In this paper, we report the reactivity of NHCs with common p- and o-quinones, uncovering three unreported reactions involving contractions of the quinone ring that lead to push-pull furanolactone chromophores, NHC fulvalenes, and α-acylimidazolium cyclopentenone derivatives. These experiments also provide a rationale for the superior compatibility of tetra- tert-alkylated diphenoquinones in NHC-based oxidative transformations.

N-Heterocyclic Carbene Boranes as Reactive Oxygen Species-Responsive Materials: Application to the Two-Photon Imaging of Hypochlorous Acid in Living Cells and Tissues.

N-Heterocyclic carbene (NHC) boranes undergo oxidative hydrolysis to give imidazolium salts with excellent kinetic selectivity for HOCl over other reactive oxygen species (ROS), including peroxides and peroxynitrite. Selectivity for HOCl results from the electrophilic oxidation mechanism of NHC boranes, which stands in contrast to the nucleophilic oxidation mechanism of arylboronic acids with ROS. The change in polarity that accompanies the conversion of NHC boranes to imidazolium salts can control the formation of emissive excimers, forming the basis for the design of the first fluorescence probe for ROS based on the oxidation of B-H bonds. Two-photon microscope (TPM) ratiometric imaging of HOCl in living cells and tissues is demonstrated.

Instantaneous Colorimetric and Fluorogenic Detection of Phosgene with a meso-Oxime-BODIPY.

The meso-oxime-substituted-1,3,5,7-tetramethyl BODIPY (1-oxime) was developed into a colorimetric and fluorogenic probe to selectively detect and quantify phosgene. The fast (<10 s) and sensitive (LOD = 0.09 ppb) phosgene detection is achieved by the conversion of the meso-oxime to the meso-nitrile, resulting in a large fluorescence turn-on response. The utility of 1-oxime was established for the visual detection of phosgene in solution and in a practical solid-state platform, making it a suitable candidate for on-site monitoring of phosgene gas exposure in the workplace.

Transition metal-catalyzed site- and regio-divergent C-H bond functionalization.

Recent advances in transition metal-catalyzed C-H bond functionalization have profoundly impacted synthetic strategy. Since organic substrates typically contain several chemically distinct C-H bonds, controlling the regioselectivity of C-H bond functionalization is imperative to harness its full potential. Moreover, the ability to alter reaction pathways to selectively functionalize different C-H bonds in a substrate represents a greater opportunity and challenge. The choice of catalysts, ligands, solvents, and even more subtle variations of the reaction conditions have been shown to allow the formation of regioisomeric C-H functionalization products starting from the same precursors. This review describes recent advances in transition metal-catalyzed divergent C-H bond functionalization that highlight its potential in organic synthesis.

Air-Liquid Interfacial Self-Assembly of Non-Amphiphilic Poly(3-hexylthiophene) Homopolymers.

Here, we demonstrate that the self-assembly of poly(3-hexylthiophene) (P3HT) at the air-water interface can lead to free-standing films of densely packed P3HT nanowires. Interfacial self-assembly on various liquid subphases, such as water, diethylene glycol, and glycerol, indicates that the viscosity of the subphase is an important factor for the formation of well-ordered nanostructures. The thin-film morphology is also sensitive to the concentration of P3HT, its molecular weight (MW), and the presence of oxidative defects. The densely packed nanowire films can be easily transferred to solid substrates for device applications. The ultrathin films of P3HT prepared by the interfacial assembly showed significantly higher hole mobility (∼3.6 × 10-2 cm2/V s) in a field-effect transistor than comparably thin spin-cast films. This work demonstrates that the air-liquid interfacial assembly is not limited to amphiphilic polymers and can, under optimized conditions, be applied to fabricate ultrathin films of widely used conjugated polymers with controlled morphologies.

Synthesis of α-methylene-δ-oxo-γ-amino esters via Rh(ii)-catalyzed coupling of 1-sulfonyl-1,2,3-triazoles with Morita-Baylis-Hillman adducts.

A rhodium(ii)-catalyzed coupling of 1-sulfonyl-1,2,3-triazoles, prepared from 1-alkynes and sulfonyl azides, with Morita-Baylis-Hillman (MBH) adducts afforded highly functionalized α-methylene-δ-oxo-γ-amino esters in excellent yields with broad functional group tolerance. This transformation can also be successfully accomplished as a multicomponent all-in-one-pot reaction of 1-alkynes, sulfonyl azides and MBH adducts in the presence of Cu(i) and Rh(ii) catalysts.

Molecular Rotors for the Detection of Chemical Warfare Agent Simulants.

The fluorogenic probe o-OH is able to detect and quantify organophosphorus nerve agent mimics in solution and in the vapor phase following immobilization on a solid substrate, making the system a suitable candidate for the field detection of chemical warfare agents. Detection is achieved by the suppression of internal rotation upon phosphorylation of a reactive phenolate, resulting in a large fluorescence "turn-on" response.

Tailoring the Solid-State Fluorescence Emission of BODIPY Dyes by meso Substitution.

4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) derivatives bearing varied substituents at the meso position (i.e., CF3 , CH3 , COOR, CHO, CN, Cl, iPr) were synthesized to elucidate the structure-property relationships that give rise to emissive J-aggregates. Several new BODIPY derivatives can be added to the previously reported 1,3,5,7-tetramethyl-8-trifluoromethyl derivative to the list of those forming J-aggregates, in addition to other dyes that are emissive in the solid state without forming J-aggregates.

Excimers beyond pyrene: a far-red optical proximity reporter and its application to the label-free detection of DNA.

A family of organic chromophores that, like pyrene, forms emissive excimers is reported. Their chemical and photophysical properties are superior to pyrene for the design of chemo- and biosensors. Unlike hydrophobic pyrene, which requires excitation by cell-damaging UV irradiation, these polar dyes absorb strongly in the visible range, and their excimers emit brightly in the red to far-red region of the electromagnetic spectrum. The intensity of the emission signal is greatly increased upon formation of a preassociated dimer that is triggered upon aggregation or crystallization. In demonstration of the potential of this new family of excimer-forming dyes, a probe that is capable of detecting label-free DNA in water down to 10 pM and also doubles as a visualization agent for DNA in gel electrophoresis is reported.

Advances in tandem reactions with organozinc reagents.

The design and implementation of tandem reactions provides organic chemists with numerous challenges, in particular that of undesired cross-reactivity between substrates. Among organometallics, the use of organozinc reagents in tandem reactions provides several advantages as a result of their broad functional group tolerance and compatibility with transition metals. This review highlights prominent examples of recent advances in tandem reactions with organozinc reagents that illustrate their potential in organic synthesis.

Tandem one-pot synthesis of polysubstituted NH-pyrroles involving the palladium-catalyzed intramolecular oxidative amination of the zinc bromide complex of ß-enamino esters.

The Pd-catalyzed oxidative olefin amination of the zinc bromide complex intermediate, formed by the sequential reaction of nitriles with a Reformatsky reagent and 1-alkynes, affords pyrrole derivatives in good to excellent yields. This tandem protocol provides a simple, efficient, and atom- and pot-economical way to quickly build polysubstituted NH-pyrroles starting from readily available reagents in a regiocontrolled manner with a broad substrate scope and high functional group tolerance. In contrast, the Pd-catalyzed oxidative olefin amination of an isolated α-vinyl-ß-enamino ester did not proceed effectively, but the reaction efficiency can be restored by addition of n-BuZnBr or Zn(OAc)2, indicating the crucial role of the zinc complex in this transformation. The synthetic utility of this protocol is exemplified by the rapid synthesis of pyrrolophenanthrenes and pyranopyrrolones through selective Pd- and Cu-catalyzed C-C and C-O bond-forming reactions.

From triazoles to imidazolines through the sequential N-H insertion of α-imino rhodium-carbenes into ß-enamino esters/enamine-imine tautomerization/conjugate addition cascade.

A rhodium(II)-catalyzed denitrogenative coupling of N-sulfonyl-1,2,3-triazoles with ambiphilic ß-enamino esters affords 2,5-dihydro-1H-imidazoles (3-imidazolines) with broad functional group tolerance. Mechanistic studies using a deuterium-labeled triazole suggest that the reaction proceeds in a cascade through the N-H insertion of an α-imino rhodium-carbene, followed by enamine-imine tautomerization and conjugate addition. Moreover, the reaction proceeds with high diastereoselectivity for α-substituted ß-enamino esters (R(3) = Me, Ph) to give a single diastereomer.