Two-step anti-cooperative self-assembly process into defined π-stacked dye oligomers: insights into aggregation-induced enhanced emission

Aggregation-induced emission enhancement (AIEE) phenomena received great popularity during the last decade but in most cases insights into the packing structure – fluorescence properties remained scarce. Here, an almost non-fluorescent merocyanine dye was equipped with large solubilizing substituents, which allowed the investigation of it''s aggregation behaviour in unpolar solvents over a large concentration range (10⁻² to 10⁻⁷ M). In depth analysis of the self-assembly process by concentration-dependent UV/Vis spectroscopy at different temperatures revealed a two-step anti-cooperative aggregation mechanism. In the first step a co-facially stacked dimer is formed driven by dipole–dipole interactions. In a second step these dimers self-assemble to give an oligomer stack consisting of about ten dyes. Concentration- and temperature-dependent UV/Vis spectroscopy provided insight into the thermodynamic parameters and allowed to identify conditions where either the monomer, the dimer or the decamer prevails. The centrosymmetric dimer structure could be proven by 2D NMR spectroscopy. For the larger decamer atomic force microscopy (AFM), diffusion ordered spectroscopy (DOSY) and vapour pressure osmometric (VPO) measurements consistently indicated that it is of small and defined size. Fluorescence, circular dichroism (CD) and circularly polarized luminescence (CPL) spectroscopy provided insights into the photofunctional properties of the dye aggregates. Starting from an essentially non-fluorescent monomer (Φ_Fl = 0.23%) a strong AIEE effect with excimer-type fluorescence (large Stokes shift, increased fluorescence lifetime) is observed upon formation of the dimer (Φ_Fl = 2.3%) and decamer (Φ_Fl = 4.5%) stack. This increase in fluorescence is accompanied for both aggregates by an aggregation-induced CPL enhancement with a strong increase of the g_lum from ∼0.001 for the dimer up to ∼0.011 for the higher aggregate. Analysis of the radiative and non-radiative decay rates corroborates the interpretation that the AIEE effect originates from a pronounced decrease of the non-radiative rate due to π–π-stacking induced rigidification that outmatches the effect of the reduced radiative rate that originates from the H-type exciton coupling in the co-facially stacked dyes.

The self-assembly of a dipolar merocyanine into preferred dimers and small-sized chiral aggregates leads to enhanced emission due to a reduced non-radiative rate as well as amplified circular polarized luminescence.     

Ring-opening and ring-expansion reactions of carborane-fused borirane

Though the reaction chemistry of three-membered ring molecules such as cyclopropanes and their heteroatom-containing analogues has been extensively studied, the chemical properties of their boron analogues, boriranes, are little known thus far. This work describes the diverse reactivity patterns of carborane-fused borirane 2. This borirane engages in ring-opening reactions with different types of Lewis acids, such as BBr₃, GeCl₂, GaCl₃, BH₃(SMe₂) and HBpin, affording a series of ring-opening products, in which M–X or B–H bonds add across the B–C(cage) bond of the three-membered ring in 2. On the other hand, borirane 2 can undergo ring-expansion reactions with unsaturated molecules such as PhCHO, CO₂ and PhCN to give ring-expansion products, five-membered boracycles, via a concerted reaction mechanism as supported by DFT calculations. The results of this work not only enrich the reaction chemistry of boriranes, but also offer new routes to boron-containing compounds and heterocycles.

Carborane-fused borirane can not only engage in ring-opening reactions with different types of Lewis acids, but also undergo ring-expansion reactions with unsaturated molecules such as PhCHO, CO₂ and PhCN to give five-membered boracycles.     

Depolymerization of supramolecular polymers by a covalent reaction; transforming an intercalator into a sequestrator

Controlling the reciprocity between chemical reactivity and supramolecular structure is a topic of great interest in the emergence of molecular complexity. In this work, we investigate the effect of a covalent reaction as a trigger to depolymerize a supramolecular assembly. We focus on the impact of an in situ thiol–ene reaction on the (co)polymerization of three derivatives of benzene-1,3,5-tricarboxamide (BTA) monomers functionalized with cysteine, hexylcysteine, and alkyl side chains: Cys-BTA, HexCys-BTA, and a-BTA. Long supramolecular polymers of Cys-BTA can be depolymerized into short dimeric aggregates of HexCys-BTAvia the in situ thiol–ene reaction. Analysis of the system by time-resolved spectroscopy and light scattering unravels the fast dynamicity of the structures and the mechanism of depolymerization. Moreover, by intercalating the reactive Cys-BTA monomer into an unreactive inert polymer, the in situ thiol–ene reaction transforms the intercalator into a sequestrator and induces the depolymerization of the unreactive polymer. This work shows that the implementation of reactivity into supramolecular assemblies enables temporal control of depolymerization processes, which can bring us one step closer to understanding the interplay between non-covalent and covalent chemistry.

We report on the controlled depolymerization of supramolecular 1D polymers into well-defined dimers triggered by a covalent reaction on the side chains of the monomer.     

FeII4L4 tetrahedron binds and aggregates DNA G-quadruplexes

Since the discovery of the G-quadruplex (G4) structure in telomeres in 1980s, studies have established the role it plays in various biological processes. Here we report binding between DNA G4 and a self-assembled tetrahedral metal-organic cage 1 and consequent formation of aggregates, whereby the cage protects the DNA G4 from cleavage by S1 nuclease. We monitor DNA–cage interaction using fluorescence spectroscopy, firstly by quenching of a fluorescent label appended to the 5′ end of G4. Secondly, we detect the decrease in fluorescence of the G4-selective dyes thioflavin-T and Zn-PPIX bound to various DNA G4 sequences following the addition of cage 1. Our results demonstrate that 1 interacts with a wide range of G4s. Moreover, gel electrophoresis, circular dichroism and dynamic light scattering measurements establish the binding of 1 to G4 and indicate the formation of aggregate structures. Finally, we find that DNA G4 contained in an aggregate of cage 1 is protected from cleavage by S1 nuclease.

We find Fe^II₄L₄ binds to G-quadruplex and forms aggregates. G-quadruplex in the aggregates is protected from digestion by S₁ nuclease.     

Nickel-mediated N–N bond formation and N2O liberation via nitrogen oxyanion reduction

The syntheses of (DIM)Ni(NO₃)₂ and (DIM)Ni(NO₂)₂, where DIM is a 1,4-diazadiene bidentate donor, are reported to enable testing of bis boryl reduced N-heterocycles for their ability to carry out stepwise deoxygenation of coordinated nitrate and nitrite, forming O(Bpin)₂. Single deoxygenation of (DIM)Ni(NO₂)₂ yields the tetrahedral complex (DIM)Ni(NO)(ONO), with a linear nitrosyl and κ¹-ONO. Further deoxygenation of (DIM)Ni(NO)(ONO) results in the formation of dimeric [(DIM)Ni(NO)]₂, where the dimer is linked through a Ni–Ni bond. The lost reduced nitrogen byproduct is shown to be N₂O, indicating N–N bond formation in the course of the reaction. Isotopic labelling studies establish that the N–N bond of N₂O is formed in a bimetallic Ni₂ intermediate and that the two nitrogen atoms of (DIM)Ni(NO)(ONO) become symmetry equivalent prior to N–N bond formation. The [(DIM)Ni(NO)]₂ dimer is susceptible to oxidation by AgX (X = NO₃⁻, NO₂⁻, and OTf⁻) as well as nitric oxide, the latter of which undergoes nitric oxide disproportionation to yield N₂O and (DIM)Ni(NO)(ONO). We show that the first step in the deoxygenation of (DIM)Ni(NO)(ONO) to liberate N₂O is outer sphere electron transfer, providing insight into the organic reductants employed for deoxygenation. Lastly, we show that at elevated temperatures, deoxygenation is accompanied by loss of DIM to form either pyrazine or bipyridine bridged polymers, with retention of a BpinO⁻ bridging ligand.

Deoxygenation of nitrogen oxyanions coordinated to nickel using reduced borylated heterocycles leads to N–N bond formation and N₂O liberation. The nickel dimer product facilitates NO disproportionation, leading to a synthetic cycle.     

Aggregation-induced phosphorescence sensitization in two heptanuclear and decanuclear gold–silver sandwich clusters

The strategy of aggregation-induced emission enhancement (AIEE) has been proven to be efficient in wide areas and has recently been adopted in the field of metal nanoclusters. However, the relationship between atomically precise clusters and AIEE is still unclear. Herein, we have successfully obtained two few-atom heterometallic gold–silver hepta-/decanuclear clusters, denoted Au₆Ag and Au₉Ag, and determined their structures by X-ray diffraction and mass spectrometry. The nature of the Au^I⋯Ag^I interactions thereof is demonstrated through energy decomposition analysis to be far-beyond typical closed-shell metal–metal interaction dominated by dispersion interaction. Furthermore, a positive correlation has been established between the particle size of the nanoaggregates and the photoluminescence quantum yield for Au₆Ag, manifesting AIEE control upon varying the stoichiometric ratio of Au : Ag in atomically-precise clusters.

The strategy of aggregation-induced emission enhancement (AIEE) has been proven to be efficient in wide areas and has recently been adopted in the field of metal nanoclusters.     

Enhanced photoreduction of water catalyzed by a cucurbit[8]uril-secured platinum dimer

A cucurbit[8]uril (CB[8])-secured platinum terpyridyl chloride dimer was used as a photosensitizer and hydrogen-evolving catalyst for the photoreduction of water. Volumes of produced hydrogen were up to 25 and 6 times larger than those obtained with the corresponding free and cucurbit[7]uril-bound platinum monomer, respectively, at equal Pt concentration. The thermodynamics of the proton-coupled electron transfer from the Pt(ii)–Pt(ii) dimer to the corresponding Pt(ii)–Pt(iii)–H hydride key intermediate, as quantified by density functional theory, suggest that CB[8] secures the Pt(ii)–Pt(ii) dimer in a particularly reactive conformation that promotes hydrogen formation.

The cucurbit[8]uril macrocycle can secure a platinum terpyridyl complex into a particularly reactive dimer that catalyzes the photoreduction of water.     

Accelerating the insertion reactions of (NHC)Cu–H via remote ligand functionalization

Most ligand designs for reactions catalyzed by (NHC)Cu–H (NHC = N-heterocyclic carbene ligand) have focused on introducing steric bulk near the Cu center. Here, we evaluate the effect of remote ligand modification in a series of [(NHC)CuH]₂ in which the para substituent (R) on the N-aryl groups of the NHC is Me, Et, ^tBu, OMe or Cl. Although the R group is distant (6 bonds away) from the reactive Cu center, the complexes have different spectroscopic signatures. Kinetics studies of the insertion of ketone, aldimine, alkyne, and unactivated α-olefin substrates reveal that Cu–H complexes with bulky or electron-rich R groups undergo faster substrate insertion. The predominant cause of this phenomenon is destabilization of the [(NHC)CuH]₂ dimer relative to the (NHC)Cu–H monomer, resulting in faster formation of Cu–H monomer. These findings indicate that remote functionalization of NHCs is a compelling strategy for accelerating the rate of substrate insertion with Cu–H species.

Remote modification of an N-heterocyclic carbene ligand with bulky or electron-rich groups in [(NHC)Cu(μ-H)]₂ increases the rate of substrate insertion, which kinetics studies suggest arises from changes in the Cu–H monomer–dimer equilibrium.     

Oxa-spirocycles: synthesis,properties and applications

A general approach to a new generation of spirocyclic molecules – oxa-spirocycles – was developed. The key synthetic step was iodocyclization. More than 150 oxa-spirocyclic compounds were prepared. Incorporation of an oxygen atom into the spirocyclic unit dramatically improved water solubility (by up to 40 times) and lowered lipophilicity. More potent oxa-spirocyclic analogues of antihypertensive drug terazosin were synthesized and studied in vivo.

A general practical approach to a new generation of spirocyclic molecules – oxa-spirocycles – is developed.     

Inhibition of (dppf)nickel-catalysed Suzuki–Miyaura cross-coupling reactions by α-halo-N-heterocycles

A nickel/dppf catalyst system was found to successfully achieve the Suzuki–Miyaura cross-coupling reactions of 3- and 4-chloropyridine and of 6-chloroquinoline but not of 2-chloropyridine or of other α-halo-N-heterocycles. Further investigations revealed that chloropyridines undergo rapid oxidative addition to [Ni(COD)(dppf)] but that α-halo-N-heterocycles lead to the formation of stable dimeric nickel species that are catalytically inactive in Suzuki–Miyaura cross-coupling reactions. However, the corresponding Kumada–Tamao–Corriu reactions all proceed readily, which is attributed to more rapid transmetalation of Grignard reagents.

Nickel complexes with a dppf ligand can form inactive dinickel(ii) complexes during Suzuki–Miyaura cross-coupling reactions. However, these complexes can react with Grignard reagents in Kumada–Tamao–Corriu cross-coupling reactions.     

A unified strategy to prostaglandins: chemoenzymatic total synthesis of cloprostenol,bimatoprost, PGF2α, fluprostenol,and travoprost guided by biocatalytic retrosynthesis

Development of efficient and stereoselective synthesis of prostaglandins (PGs) is of utmost importance, owing to their valuable medicinal applications and unique chemical structures. We report here a unified synthesis of PGs cloprostenol, bimatoprost, PGF_2α, fluprostenol, and travoprost from the readily available dichloro-containing bicyclic ketone 6a guided by biocatalytic retrosynthesis, in 11–12 steps with 3.8–8.4% overall yields. An unprecedented Baeyer–Villiger monooxygenase (BVMO)-catalyzed stereoselective oxidation of 6a (99% ee), and a ketoreductase (KRED)-catalyzed diastereoselective reduction of enones 12 (87 : 13 to 99 : 1 dr) were utilized in combination for the first time to set the critical stereochemical configurations under mild conditions. Another key transformation was the copper(ii)-catalyzed regioselective p-phenylbenzoylation of the secondary alcohol of diol 10 (9.3 : 1 rr). This study not only provides an alternative route to the highly stereoselective synthesis of PGs, but also showcases the usefulness and great potential of biocatalysis in construction of complex molecules.

We report a unified chemoenzymatic asymmetric synthesis of five prostaglandins, featuring two enzymatic redox transformations and a copper(ii)-catalyzed regioselective p-phenylbenzoylation.     

Organic amine mediated cleavage of Caromatic–Cα bonds in lignin and its platform molecules

The activation and cleavage of C–C bonds remains a critical scientific issue in many organic reactions and is an unmet challenge due to their intrinsic inertness and ubiquity. Meanwhile, it is crucial for the valorization of lignin into high-value chemicals. Here, we proposed a novel strategy to enhance the C_aromatic–C_α bond cleavage by pre-functionalization with amine sources, in which an active amine intermediate is first formed through Markovnikov hydroamination to reduce the dissociation energy of the C_aromatic–C_α bond which is then cleaved to form target chemicals. More importantly, this strategy provides a method to achieve the maximum utilization of the aromatic nucleus and side chains in lignin or its platform molecules. Phenols and N,N-dimethylethylamine compounds with high yields were produced from herbaceous lignin or the p-coumaric acid monomer in the presence of industrially available dimethylamine (DMA).

Pre-functionalization with amine sources mediated the cleavage of C_aromatic–C_α bonds to produce two valuable chemicals with high yields, for the full utilization of the aromatic rings and side-chains in lignin and its platform molecules.     

Covalent flexible peptide docking in Rosetta

Electrophilic peptides that form an irreversible covalent bond with their target have great potential for binding targets that have been previously considered undruggable. However, the discovery of such peptides remains a challenge. Here, we present Rosetta CovPepDock, a computational pipeline for peptide docking that incorporates covalent binding between the peptide and a receptor cysteine. We applied CovPepDock retrospectively to a dataset of 115 disulfide-bound peptides and a dataset of 54 electrophilic peptides. It produced a top-five scoring, near-native model, in 89% and 100% of the cases when docking from the native conformation, and 20% and 90% when docking from an extended peptide conformation, respectively. In addition, we developed a protocol for designing electrophilic peptide binders based on known non-covalent binders or protein–protein interfaces. We identified 7154 peptide candidates in the PDB for application of this protocol. As a proof-of-concept we validated the protocol on the non-covalent complex of 14-3-3σ and YAP1 phosphopeptide. The protocol identified seven highly potent and selective irreversible peptide binders. The predicted binding mode of one of the peptides was validated using X-ray crystallography. This case-study demonstrates the utility and impact of CovPepDock. It suggests that many new electrophilic peptide binders can be rapidly discovered, with significant potential as therapeutic molecules and chemical probes.

We developed Rosetta CovPepDock, a computational pipeline for covalent peptide docking. We showed it is highly accurate in retrospective benchmarks, and applied it prospectively to design potent and selective covalent binders of 14-3-3σ.     

Uncommon carbene insertion reactions

Transition-metal-catalysed carbene insertion reaction is a straightforward and efficient protocol for the construction of carbon–carbon or carbon–heteroatom bonds. Compared to the intensively studied and well-established “common” carbene insertion reactions, including carbene insertion into C–H, Si–H, N–H, O–H, and S–H bonds, several “uncommon” carbene insertion reactions, including carbene insertion into B–H, Sn–H, Ge–H, P–H, F–H, C–C, and M–M bonds, have been neglected for a long time. However, more and more studies on uncommon carbene insertion reactions have been disclosed recently, and clearly demonstrate the great synthetic potential of these reactions. The current perspective reviews the history and the newest advances of uncommon carbene insertion reactions, discusses their potential applications and challenges, and also presents an outlook of this promising field.

Transition-metal-catalysed carbene insertion reaction is a straightforward and efficient protocol for the construction of carbon–carbon or carbon–heteroatom bonds.     

The mechanism of Raf activation through dimerization

Raf, a threonine/serine kinase in the Raf/MEK/ERK pathway, regulates cell proliferation. Raf''s full activation requires dimerization. Aberrant activation through dimerization is an important therapeutic target. Despite its clinical importance, fundamental questions, such as how the side-to-side dimerization promotes the OFF-to-ON transition of Raf''s kinase domain and how the fully activated ON-state kinase domain is stabilized in the dimer for Raf signaling, remain unanswered. Herein, we decipher an atomic-level mechanism of Raf activation through dimerization, clarifying this enigma. The mechanism reveals that the replacement of intramolecular π–π stacking by intermolecular π–π stacking at the dimer interface releases the structural constraint of the αC-helix, promoting the OFF-to-ON transition. During the transition, the inhibitory hydrophobic interactions were disrupted, making the phosphorylation sites in A-loop approach the HRD motif for cis-autophosphorylation. Once fully activated, the ON-state kinase domain can be stabilized by a newly identified functional N-terminal basic (NtB) motif in the dimer for Raf signaling. This work provides atomic level insight into critical steps in Raf activation and outlines a new venue for drug discovery against Raf dimerization.

We decipher an atomic-level mechanism of Raf activation through dimerization, revealing that the disruption of intramolecular π–π stacking at the dimer interface promotes the OFF-to-ON transition.     

Carbon–carbon bond activation by B(OMe)3/B2pin2-mediated fragmentation borylation

Selective carbon–carbon bond activation is important in chemical industry and fundamental organic synthesis, but remains challenging. In this study, non-polar unstrained Csp²–Csp³ and Csp²–Csp² bond activation was achieved by B(OMe)₃/B₂pin₂-mediated fragmentation borylation. Various indole derivatives underwent C2-regioselective C–C bond activation to afford two C–B bonds under transition-metal-free conditions. Preliminary mechanistic investigations suggested that C–B bond formation and C–C bond cleavage probably occurred in a concerted process. This new reaction mode will stimulate the development of reactions based on inert C–C bond activation.

Non-polar unstrained Csp²–Csp³ and Csp²–Csp² bond activation was achieved via B(OMe)₃/B₂pin₂-mediated fragmentation borylation, in which C–C bond activation occurred regioselectively at the C2-position in various substituted indoles.     

Enantioselective palladium-catalyzed C(sp2)–C(sp2) σ bond activation of cyclopropenones by merging desymmetrization and (3 + 2) spiroannulation with cyclic 1,3-diketones

Catalytic asymmetric variants for functional group transformations based on carbon–carbon bond activation still remain elusive. Herein we present an unprecedented palladium-catalyzed (3 + 2) spiro-annulation merging C(sp²)–C(sp²) σ bond activation and click desymmetrization to form synthetically versatile and value-added oxaspiro products. The operationally straightforward and enantioselective palladium-catalyzed atom-economic annulation process exploits a TADDOL-derived bulky P-ligand bearing a large cavity to control enantioselective spiro-annulation that converts cyclopropenones and cyclic 1,3-diketones into chiral oxaspiro cyclopentenone–lactone scaffolds with good diastereo- and enantio-selectivity. The click-like reaction is a successful methodology with a facile construction of two vicinal carbon quaternary stereocenters and can be used to deliver additional stereocenters during late-state functionalization for the synthesis of highly functionalized or more complex molecules.

An unprecedented palladium-catalyzed (3 + 2) spiro-annulation merging C–C bond activation and desymmetrization was developed for the enantioselective construction of synthetically versatile and value-added oxaspiro products with up to 95% ee.     

Dibenzocycloheptanones construction through a removable P-centered radical: synthesis of allocolchicine analogues

Dibenzocycloheptanones containing a tricyclic 6–7–6-system are present in numerous biologically active natural molecules. However, the simple and efficient preparation of derivatives containing a dibenzocycloheptanone scaffold remains difficult to date. Herein, we report a versatile strategy for the construction of these challenging seven-membered rings using a 7-endo-trig cyclization which is initiated by a phosphorus-centered radical. This approach provides a step-economical regime for the facile assembly of a wide range of phosphorylated dibenzocycloheptanones. Remarkably, we also have devised a traceless addition/exchange strategy for the preparation of dephosphorylated products at room temperature with excellent yields. Therefore, this protocol allows for the concise synthesis of biorelevant allocochicine derivatives.

Dibenzocycloheptanones containing a tricyclic 6–7–6-system are present in numerous biologically active natural molecules.     

Coexistence of magnetic and electric orderings in a divalent Cr2+-based multiaxial molecular ferroelectric

Multiferroic materials have attracted great interest because of their underlying new science and promising applications in data storage and mutual control devices. However, they are still very rare and highly imperative to be developed. Here, we report an organic–inorganic hybrid perovskite trimethylchloromethylammonium chromium chloride (TMCM–CrCl₃), showing the coexistence of magnetic and electric orderings. It displays a paraelectric–ferroelectric phase transition at 397 K with an Aizu notation of 6/mFm, and spin-canted antiferromagnetic ordering with a Néel temperature of 4.8 K. The ferroelectricity originates from the orientational ordering of TMCM cations, and the magnetism is from the [CrCl₃]⁻ framework. Remarkably, TMCM–CrCl₃ is the first experimentally confirmed divalent Cr²⁺-based multiferroic material as far as we know. A new category of hybrid multiferroic materials is pointed out in this work, and more Cr²⁺-based multiferroic materials will be expectedly developed in the future.

An organic–inorganic hybrid perovskite Trimethylchloromethylammonium chromium(ii) chloride (TMCM–CrCl₃) can simultaneously show excellent ferroelectricity and antiferromagnetism, which is the first experimentally confirmed Cr²⁺-based multiferroic material.     

Structure–function relationships in aryl diazirines reveal optimal design features to maximize C–H insertion

Diazirine reagents allow for the ready generation of carbenes upon photochemical, thermal, or electrical stimulation. Because carbenes formed in this way can undergo rapid insertion into any nearby C–H, O–H or N–H bond, molecules that encode diazirine functions have emerged as privileged tools in applications ranging from biological target identification and proteomics through to polymer crosslinking and adhesion. Here we use a combination of experimental and computational methods to complete the first comprehensive survey of diazirine structure–function relationships, with a particular focus on thermal activation methods. We reveal a striking ability to vary the activation energy and activation temperature of aryl diazirines through the rational manipulation of electronic properties. Significantly, we show that electron-rich diazirines have greatly enhanced efficacy toward C–H insertion, under both thermal and photochemical activation conditions. We expect these results to lead to significant improvements in diazirine-based chemical probes and polymer crosslinkers.

Electron-rich aryl diazirines have lower activation temperatures and a longer λ_max than electron-poor analogues, and undergo C–H insertion up to ten-fold more efficiently—suggesting improved performance for biological probes and polymer crosslinkers.