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This work presents an integrative framework for optimizing organic fluorophores' TICT tendency and environmental sensitivities towards various applications. Two newly developed probes could detect the early phase of Aβ aggregation.

The feasibility of various bespoke guanidine-based compounds as electrochemically regenerative biomimetic hydrides for reduction of carbon dioxide to formate were assessed by Density Functional Theory (DFT).

We proposed a simple method for ratiometrically detecting the ethanol content in aqueous solutions using a low-cost and commercially available dye – acridine.

The heteroatoms could play a critical role in improving the hole transport and interfacial charge transfer of triphenylamine-based HTM.

Although super-resolution imaging offers an opportunity to visualize cellular structures and organelles at the nanoscale level, cellular heterogeneity and unpredictability still pose a significant challenge in the dynamic imaging of live cells. It is thus vital to develop better-performing and more photostable probes for long-term super-resolution imaging. Herein, we report a probe, LD-FG, for imaging lipid droplet (LD) dynamics using structured illumination microscopy (SIM). LD-FG allows wash-free imaging of LDs, owing to a hydrogen-bond sensitive fluorogenic response. The replacement of photobleached LD-FG by intact probe molecules outside the LDs ensures the long-time stability of the fluorescence imaging. With this buffering fluorogenic probe, fast and unpredictable dynamic processes of LDs can be visualized. Using this probe, two LD coalescence modes were discovered. The dynamic imaging also allowed us to propose a new model of LD maturation during adipocyte differentiation, i.e., a fast LD coalescence followed by a slow ripening step. The excellent performance of LD-FG makes the buffer strategy an effective method for designing fluorescent probes for cell dynamic imaging.

Understanding the mechanisms of aggregation-induced emission (AIE) is essential for the rational design and deployment of AIEgens toward various applications. Such a deep mechanistic understanding demands a thorough investigation of the excited-state behaviors of AIEgens. However, because of considerable complexity and rapid decay, these behaviors are often not experimentally accessible and the mechanistic comprehension of many AIEgens is lacking. Herein, utilizing detailed quantum chemical calculations, we provide insights toward the AIE mechanism of 1-(N,N-dialkylamino)-naphthalene (DAN) derivatives. Our theoretical analysis, corroborated by experimental observations, leads to the discovery that modulating the formation of the twisted intramolecular charge transfer (TICT) state (caused by the rotation of the amino groups) and managing the steric hindrance to minimize solid-state intermolecular interactions provides a plausible explanation for the AIE characteristics of DAN derivatives. These results will inspire the deployment of the TICT mechanism as a useful design strategy toward AIEgen development.

The ability to rationally design and predictably construct crystalline solids has been the hallmark of crystal engineering research. To date, numerous examples of multicomponent crystals comprising organic molecules have been reported. However, the crystal engineering of cocrystals comprising both organic and inorganic chemical units is still poorly understood and mostly unexplored. Here, we report a new diverse set of higher‐order cocrystals (HOCs) based on the structurally versatile—yet largely unexplored—phosph(V/V)azane heterosynthon building block. The novel ternary and quaternary cocrystals reported are held together by synergistic and orthogonal intermolecular interactions. Notably, the HOCs can be readily obtained either via sequential or one‐pot mechanochemical methods. Computational modelling methods reveal that the HOCs are thermodynamically driven to form and that their mechanical properties strongly depend on the composition and intermolecular forces in the crystal, offering untapped potential for optimizing material properties., Mechanosynthesis gives ternary and quaternary hybrid organic‐inorganic cocrystals held together via synergistic intermolecular interactions. Notably, higher‐order ternary and quaternary cocrystals can be readily obtained either via serial synthetic routes from the individual components or via one‐pot approaches.

Achieving wide-range tunable emission colors, especially in the solid state of single-fluorophore materials, remains a significant challenge. Herein, we report a molecular design strategy that affords wide-range excitation-dependent emissions spanning over ≈230 nm in crystalline states. Under the donor-π-acceptor configuration, we judiciously choose a rotatable acceptor fragment, o-carborane, to enrich conformational diversities in the crystalline state and generate conformation-dependent multicolor emissions. We further show that this molecular platform is generalizable in creating crystalline materials with multicolor emissions. Based on these materials, a high-capacity information storage device and a finite-state machine were fabricated to showcase multicolor displays and information storage.

The twisted intramolecular charge transfer (TICT) mechanism has guided the development of numerous bright and sensitive fluorophores. This review briefly overviews the history of establishing the TICT mechanism, and systematically summarizes the molecular design strategies in modulating the TICT tendency of various organic fluorophores towards different applications, along with key milestone studies and representative examples. Additionally, we also succinctly review the twisted intramolecular charge shuttle (TICS) and twists during photoinduced electron transfer (PET), and compare their similarities and differences with TICT, with emphasis on understanding the structure-property relationships between the twisted geometries and how they can directly affect the fluorescence of the molecules. Such structure-property relationships presented herein will greatly aid the rational development of fluorophores that involve molecular twisting in the excited state.

Tetrazine-based fluorogenic probes are powerful tools for bioimaging, biosensing, and medical diagnostic applications. In these probes, the attachment of a tetrazine moiety generates a non-fluorescent precursor; upon the bio-orthogonal reaction of the tetrazine fragment, a strong fluorescence signal is released from the fluorophore, resulting in significant fluorescence turn-on responses. To rationally design tetrazine-based probes with enhanced turn-on ratios, one fundamental challenge is to understand their fluorescence quenching mechanism. Herein, utilizing quantum chemistry calculations, we investigated and described a generalized fluorescence quenching mechanism, coined as “energy transfer to a dark state” (ETDS). With the aid of the ETDS mechanism, we demonstrated how a large excited-state energy gap and a short distance between a tetrazine group and a fluorophore are essential for increasing the rate of energy transfer and improving turn-on ratios of tetrazine-based fluorophores. We further proposed two strategies in the rational design of highly desirable fluorogenic probes that exhibit longer emission wavelengths and higher turn-on ratios, including (1) shortening the fluorophore–tetrazine distance via “face-to-face” stacking; and (2) modulating the UV-vis absorption wavelengths. Our calculation results could provide invaluable insights into the rational design of a new generation of tetrazine-based fluorogenic probes.

Long-wavelength fluorescent proteins (LWFPs) and LWFP-based sensors are indispensable tools for bioimaging and biosensing applications. However, it remains challenging to develop LWFPs with outstanding brightness and/or sensitivities, largely due to the lack of simple and effective molecular design strategies. Herein, we rationalized the molecular origins of a multi-donor strategy that affords significant bathochromic shifts and large Stokes shifts with minimal structural changes in the resulting protein fluorophores. We analyzed three key factors that affect the spectral properties of these fluorophores, including the (1) substituent position, (2) electron-donating strength, and (3) number of electron-donating groups. We further demonstrated that this simple design strategy is generalizable to various fluorophore families. We expect that this work can provide rational guidelines for developing fluorescent proteins (and small-molecule fluorophores) with long emission wavelengths and large Stokes shifts.

Herein, we reported a simple, fast, and quantitative theoretical descriptor ΔGC-O that allows accurate predictions of a wide range of spontaneously blinking rhodamines. ΔGC-O denotes the Gibbs free energy differences between the closed and open forms of rhodamines and has a good linear relationship with experimental pKcycl values. This correlation affords an effective guide for the quantitative designs of spontaneously blinking rhodamines and eliminates trial-and-error. We have validated the predictive power of ΔGC-O via the development of two spontaneously blinking rhodamines of different colors and enhanced brightness. We also demonstrated their super-resolution imaging utilities in dynamic live-cell imaging. We expect that ΔGC-O will greatly facilitate the efficient creations of spontaneously blinking fluorophores and aid the advancements of super-resolution bioimaging techniques.

Inhibition of TICT can significantly increase the brightness of fluorescent materials. Accurate prediction of TICT is thus critical for the quantitative design of high-performance fluorophores and AIEgens. TICT of 14 types of popular organic fluorophores were modeled with time-dependent density functional theory (TD-DFT). A reliable and generalizable computational approach for modeling TICT formations was established. To demonstrate the prediction power of our approach, we quantitatively designed a boron dipyrromethene (BODIPY)-based AIEgen which exhibits (almost) barrierless TICT rotations in monomers. Subsequent experiments validated our molecular design and showed that the aggregation of this compound turns on bright emissions with ca. 27-fold fluorescence enhancement, as TICT formation is inhibited in molecular aggregates.

There are many active pharmaceutical ingredients that lack N-H, O-H and S-H hydrogen-bond donor functional groups. N,N-disubstituted O-thiocarbamates are examples of molecules that display such a feature. Despite the desirable medicinal properties displayed by some N,N-disubstituted O-thiocarbamates, the study of the solid-state properties of these compounds has been relatively unexplored. Herein, we report the synthesis and analysis of the structures and properties of a series of N,N-dimethyl-O-thiocarbamates, and use X-ray diffraction techniques to gain insight into how these molecules self-assemble in the solid-state. As part of our work, we report for the first time the crystal structure of Tolnaftate, an active pharmaceutical ingredient that is indicated for the treatment of fungal infections. It was observed that the aryl-thiocarbamate C-O bonds are twisted such that the planar aryl and carbamate moieties are orthogonal. Such a non-planar molecular geometry affects the way the molecules pack and crystal structure analyses revealed four general modes in which the molecules can assemble in the solid-state, with some members of the series displaying isostructural relationships. Computational modelling of the cohesive energy densities in the crystals suggests that there is no single stacking type that is associated with greater stability. However, crystals with a combination of high packing index and π···π stacking interactions appear to display large cohesive energy densities. The lack of strong hydrogen bonding interactions in the crystals also leads to relatively low Young’s moduli that are within a narrow range of 10-15 GPa for all 14 crystal structures reported. Agency for Science, Technology and Research (A*STAR) Accepted version F.G. would like to thank A*STAR AME IRG (A1783c0003) and a NTU start-up grant (M4080552) for financial support. H.S.S. is grateful for the Singapore Ministry of Education Academic Research Fund Tier 1 grants RG 111/18 and RT 05/19. H.S.S. also acknowledges that this project is supported by A*STAR under the AME IRG grants A1783c0003, A1783c0002, and A1783c0007 D.T. would like to thank A*STAR for a postdoctoral research fellowship. .M. would like to acknowledge Khalifa University for financial support under the CIRA program (Project Code: CIRA-2018-068). The theoretical calculations were performed using the high-performance computing clusters of Khalifa University and the authors would like to acknowledge the support of the research computing department.

Although doping can induce room-temperature phosphorescence (RTP) in heavy-atom free organic systems, it is often challenging to match the host and guest components to achieve efficient intersystem crossing for activating RTP. In this work, we developed a simple descriptor ΔE to predict host molecules for matching the guest RTP emitters, based on the intersystem crossing via higher excited states (ISCHES) mechanism. This descriptor successfully predicted five commercially available host components to pair with naphthalimide (NA) and naphtho[2,3-c]furan-1,3-dione (2,3-NA) emitters with a high accuracy of 83 %. The yielded pairs exhibited bright yellow and green RTP with the quantum efficiency up to 0.4 and lifetime up to 1.67 s, respectively. Using these RTP pairs, we successfully achieved multi-layer message encryption. The ΔE descriptor could provide an efficient way for developing doping-induced RTP materials.

Understanding the mechanisms of aggregation-induced emission (AIE) is essential for the rational design and deployment of AIEgens toward various applications. Such a deep mechanistic understanding demands a thorough investigation of the excited-state behaviors of AIEgens. However, because of considerable complexity and rapid decay, these behaviors are often not experimentally accessible and the mechanistic comprehension of many AIEgens is lacking. Herein, utilizing detailed quantum chemical calculations, we provide insights toward the AIE mechanism of 1-(

Heavy-atom-based photosensitizers usually exhibit shortened triplet-state lifetimes, which is not ideal for hypoxic tumor photodynamic therapy. Although several heavy-atom-free photosensitizers possess long triplet-state lifetimes, the clinical applicability is limited by their short excitation wavelengths, poor photon capture abilities, and intrinsically hydrophobic structures. Herein we developed a novel NIR heavy-atom-free photosensitizer design strategy by introducing sterically bulky and electron-rich moieties at the meso position of the pentamethine cyanine (Cy5) skeleton, which simultaneously enhanced intersystem crossing (ISC) and prolonged excited-state lifetime. We found that the 1O2 generation ability is directly correlated to the electron-donating ability of the meso substituent in cyanine, and the excited-state lifetime was simultaneously much elongated when the substituents were anthracene derivatives substituted at the 9-position. Our star compound, ANOMe-Cy5, exhibits intense NIR absorption, the highest 1O2 quantum yield (4.48-fold higher than Cy5), the longest triplet-state lifetime (9.80-fold longer than Cy5), and lossless emission intensity (nearly no change compared with Cy5). Such excellent photophysical properties coupled with its inherently cationic and hydrophilic nature enable the photosensitizer to realize photoablation of solid tumor and antitumor lung metastasis. This study highlights the design of a new generation of NIR photosensitizers for imaging-guided photodynamic cancer treatment.

Advances in processing capabilities of computer clusters have allowed for the full modeling of organometallic complexes that previously would have been simplified to reduce computational cost. Increased feasibility of computational modeling offers new challenges, not only in terms of limitations of methods and theory, but attention should be paid to complexes that can exist in many conformations, as the appropriate choice of conformer may be easily overlooked. In this work a series of pincer complexes with isopropyl and cyclopentyl substituents have been chosen as examples to demonstrate the importance of conformational analysis. The complexes examined contain four isopropyl or cyclopentyl groups on phosphor atoms generating between 27 and 324 possible rotamers. The importance of conformational search in a mechanistic investigation is demonstrated with the CO2 insertion into a nickel hydride bond of POCOP iPr nickel hydride complex. Results show that the reaction energy profile can be both exergonic and endergonic depending on rotamer choice. Specifically, the POCOPiPr Ni-formato complex product of the CO2 insertion reaction had an energy difference between the lowest and highest energy rotamer as high as 16.8 kcal/mol. The significant energy differences between rotamers highlight the importance of thorough conformational analysis and should be taken into consideration when evaluating the energy profile of related reactions. Keywords: Conformational analysis, DFT, Pincer, Mechanism, Rotamers

Bimolecular nucleophilic substitution (SN2) plays a central role in organic chemistry. In the conventionally accepted mechanism, the nucleophile displaces a carbon-bound leaving group X, often a halogen, by attacking the carbon face opposite the C–X bond. A less common variant, the halogenophilic SN2X reaction, involves initial nucleophilic attack of the X group from the front and as such is less sensitive to backside steric hindrance. Herein, we report an enantioconvergent substitution reaction of activated tertiary bromides by thiocarboxylates or azides that, on the basis of experimental and computational mechanistic studies, appears to proceed via the unusual SN2X pathway. The proposed electrophilic intermediates, benzoylsulfenyl bromide and bromine azide, were independently synthesized and shown to be effective. Ministry of Education (MOE) Nanyang Technological University We acknowledge support from Nanyang Technological University (M4011663 and M4080946); Ministry of Education, Singapore (MOE2016-T2-1-087); and Singapore University of Technology and Design (T1MOE1706 and IDG31800104) as well as computational resources from National Supercomputing Centre (Singapore).

In the last few decades, mechanochemistry has become rapidly established as a powerful tool enabling environmentally-benign and sustainable chemical syntheses. Not only have these techniques been demonstrated as viable alternatives to traditional solution-based syntheses, but they have also received attention for their ability to enable new reactivity and “unlocking” novel compounds inaccessible by conventional methods. Reflecting the rising popularity of mechanochemistry, many excellent reviews highlighting its benefits have recently been published. Whilst the scope of most of these focuses on organic chemistry, transition-metal catalysis, porous framework materials, coordination compounds and supramolecular synthesis, few have addressed the use of mechanochemical ball milling for the synthesis of compounds containing s- and p-block elements. This tutorial review turns the spotlight towards mechanochemical research in the field of inorganic main group chemistry, highlighting significant advantages that solid-state inorganic reactions often possess, and the potential for these to drive the development of greener methodologies within the modern main group arena. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) Nanyang Technological University Published version The authors would like to thank A*STAR AME IRG(A1783c0003), NTU start-up grant (M4080552), and MOE AcRFTier 1 grants (M4011441 and M4011709) for financial support.

Fluorescent thermometers based on organic dyes play an important role in the visualization of dynamic temperature topography with high resolution. Many molecular thermometers contain two fluorophores with different temperature responses to achieve ratiometric temperature detection. However, the stability and reliability of such ratiometric thermometers are highly dependent on the susceptibility of the fluorophores towards photobleaching. Despite the use of single-fluorophore ratiometric thermometers in previous reports, the difficulty and complexity in their molecular design and synthesis severely hinder their widespread applicability. In this work, we have investigated the use of commercially available dyes (i.e., BD140 and LD688) with conformational isomers as ratiometric thermometers. Each of these dyes consists of a mixture of conformers with distinct UV-vis absorption and emission spectra. The thermal equilibrium of these conformers successfully enabled the development of ratiometric thermometers with good stability and reliability.

The ability to rationally design and predictably construct crystalline solids has been the hallmark of crystal engineering research over the past two decades. When building higher-order multicomponent cocrystals (i.e. crystals containing more than two constituents), the differential and hierarchical way molecules interact and assemble in the solidstate is of pinnacle importance. To date, numerous examples of multicomponent crystals comprising organic molecules leading to salts, cocrystals or ionic cocrystals have been reported. However, the crystal engineering of hybrid organicinorganic cocrystals with sophisticated inorganic building blocks is still poorly understood and mostly unexplored. Here, we reveal the first efficient mechanochemical synthesis of higher-order hybrid organic-inorganic cocrystals based on the structurally versatile – yet largely unexplored – cyclodiphos(V/V)azane heterosynthon building block. The novel hybrid ternary and quaternary multicomponent cocrystals herein reported are held together by synergistic intermolecular interactions (e.g., hydrogen- and halogen-bonding, Se-π and ion-dipole interactions). Notably, higher-order ternary and quaternary cocrystals can be readily obtained either via direct synthetic routes from its individual components, or via unprecedented telescopic approaches from lower-order cocrystal sets. In addition, computational modelling has also revealed that the formation of higher-order cocrystals is thermodynamically driven, and that bulk moduli and compressibilities are strongly dependent on the chemical composition and intermolecular forces present in the crystals, which offer untapped potential for optimizing material properties.

International audience; Colloidal bismuth therapeutics have been used for hundreds of years, yet remain mysterious. Here we report an X-ray pair distribution function (PDF) study of the solvolysis of bismuth disalicylate, a model for the metallodrug bismuth subsalicylate (Pepto-Bismol). This reveals catalysis by traces of water, followed by multistep cluster growth. The ratio of the two major species, {Bi9O7} and {Bi38O44}, depends on exposure to air, time, and the solvent. The solution-phase cluster structures are of significantly higher symmetry in comparison to solid-state analogues, with reduced off-center Bi3+ displacements. This explains why such “magic-size” clusters can be both stable enough to crystallize and sufficiently labile for further growth.

There are many pharmaceutical compounds that do not contain N-H, O-H, and S-H hydrogen-bond donor functional groups. Some of these compounds are N,N-disubstituted O-thiocarbamates which exhibit desirable medicinal properties, yet the study of these important molecules in the solid-state has been relatively unexplored. Herein, we report the synthesis and analysis of a series of N,N-dimethyl-O-thiocarbamates, and use X-ray diffraction techniques to gain insight into how these molecules self-assemble in the solid-state and discern certain packing patterns. It was observed that the aryl-thiocarbamate C-O bonds are twisted such that the planar aryl and carbamate moieties are orthogonal. Such a non-planar molecular geometry affects the way the molecules pack and crystal structure analyses revealed four general modes in which the molecules can associate in the solid-state, with some members of the series displaying isostructural relationships. The crystal structure of a well-known yet unreported O-thiocarbamate drug, Tolnaftate, is also reported. Additionally, Hirshfeld surface analysis was also performed on these compounds as well as several related O-thiocarbamates in the literature.

Herein, we reported a simple, fast, and quantitative theoretical descriptor ΔG

Highly enantioselective allylic alkynylation of racemic bromides under biphasic condition is furnished in this report. This approach employs functionalized terminal alkynes as pro-nucleophiles and provides 6- and 7-membered cyclic 1,4-enynes with high yields and excellent enantioselectivities (up to 96% ee) under mild conditions. Enantioretentive derivatizations highlight the synthetic utility of this transformation. Cold-spray ionization mass spectrometry (CSI-MS) and X-ray crystallography were used to identify some catalytic intermediates, which include guanidinium cuprate ion pairs and a copper-alkynide complex. A linear correlation between the enantiopurity of the catalyst and reaction product indicates the presence of a copper complex bearing a single guanidine ligand at the enantio-determining step. Further experimental and computational studies supported that the alkynylation of allylic bromide underwent an anti-SN2' pathway catalyzed by nucleophilic cuprate species. Moreover, metal-assisted racemization of allylic bromide allowed the reaction to proceed in a dynamic kinetic fashion to afford the major enantiomer in high yield. Accepted version

Noble metals are valued, critical elements whose chemical activation or recycling is challenging, and traditionally requires high temperatures, strong acids or bases, or aggressive complexation agents. By using elementary palladium and gold, demonstrated here is the use of mechanochemistry for noble-metal activation and recycling by mild, clean, solvent-free, and room-temperature chemistry. The process leads to direct, efficient, one-pot conversion of the metals, including spent catalysts, into either simple water-soluble salts or metal-organic catalysts.

International research suggests that a proportion of youth facing legal charges are at risk of being unfit (or incompetent) to stand trial. In New Zealand, only a fraction of youth coming before Youth Court are referred for fitness to stand trial evaluations. Amid debate surrounding notions that youth offending could be deterred by providing harsher penalties, it is important to consider fitness to stand trial in youth facing criminal proceedings. This study sought to capture a cross-sectional view of how fitness (competency) to stand trial is addressed in the Youth Court, and how evaluator opinions relate to ultimate court findings. A retrospective review of reports for fitness to stand trial in 79 youth consecutively referred to the Regional Youth Forensic Service from 2010 to 2015 was conducted. Data were combined with Youth Court outcomes obtained from the Ministry of Justice. The mean age is 15.6 years. Intellectual disability is associated with unfit opinions and legal findings (p = .002 and p = .03, respectively), and cases disposed through the Intellectual Disability (Compulsory Care and Rehabilitation) Act 2003. Immaturity itself does not appear to have a significant effect on evaluator opinions or court findings of fitness to stand trial. The majority of the referred youth were both opined and found fit.

We provide a brief overview of recent advances in the use of mechanochemical techniques for the synthesis of organic molecules and materials, highlighting selected examples of mechanochemical organic transformations and mechanistic studies, and especially those that illustrate chemical reactions or syntheses of molecular targets that have remained elusive to conventional solution techniques.

Mechanistic insights into the selective C–H terminal activation of n -pentane with tungsten allyl nitrosyl complex reported by Legzdins were gained by employing density functional theory with B3LYP hybrid functional. Using Bader’s atom in molecules (AIM) analysis on the elementary steps of the hydrogen transfer process, TS1 and TS2 , it was observed that the calculated H-transfer models were closely similar to Hall’s metal-assisted σ-bond metathesis through bond critical point (BCP) comparisons. One distinguishable feature was the fact that the formal oxidation state of the W changed in the concerted H-transfer process. To better differentiate, we term these processes as ‘Formal Reductive Hydrogen Transfer’ (FRHT) for TS1 and ‘Formal Oxidative Hydrogen Transfer’ (FOHT) for TS2 .

A previously unknown insertion of carbodiimides into sulfonimides enables the first one-step, two-atom expansion of the saccharin 5-membered ring into a 7-membered benzo[1,2,4]thiadiazepine, and a two-atom chain extension of a non-cyclic sulfonimide. This reaction is enhanced by copper salts, which allow it to be conducted mechanochemically, in a solvent-free manner.

A mechanochemical route is developed for room-temperature and solvent-free derivatization of different types of amides into carbamoyl isatins (up to 96 % conversion or yield), benzamides (up to 81 % yield), and imides (up to 92 % yield). In solution, this copper-catalyzed coupling either does not take place or requires high temperatures at which it may also be competing with alternative thermal reactivity, highlighting the beneficial role of mechanochemistry for this reaction. Such behavior resembles the previously investigated coupling with sulfonamide substrates, suggesting that this type of C-N coupling is an example of a mechanochemically favored reaction, for which mechanochemistry appears to be a favored environment over solution.

This overview highlights the emergent area of mechanochemical reactions for making active pharmaceutical ingredients (APIs), and covers the latest advances in the recently established area of mechanochemical screening and synthesis of pharmaceutical solid forms, specifically polymorphs, cocrystals, salts and salt cocrystals. We also provide an overview of the most recent developments in pharmaceutical uses of mechanochemistry, including real-time reaction monitoring, techniques for polymorph control and approaches for continuous manufacture using twin screw extrusion, and more. Most importantly, we show how the overlap of previously unrelated areas of mechanochemical screening for API solid forms, organic synthesis by milling, and mechanochemical screening for molecular recognition, enables the emergence of a new research discipline in which different aspects of pharmaceutical and medicinal chemistry are addressed through mechanochemistry rather than through conventional solution-based routes. The emergence of such medicinal mechanochemistry is likely to have a strong impact on future pharmaceutical and medicinal chemistry, as it offers not only access to materials and reactivity that are sometimes difficult or even impossible to access from solution, but can also provide a general answer to the demands of the pharmaceutical industry for cleaner, safer and efficient synthetic solutions.

Bimolecular nucleophilic substitution (S

Mechanochemistry has been established to be an environmentally-friendly way of conducting reactions in a solvent-free manner. The development of mechanochemical orthogonal reactions, in which multiple reagents are milled together, can be a powerful strategy to selectively yield the desired product. Such orthogonal syntheses are rare, especially those involving main group frameworks - based on bonds other than carbon - which are yet to be reported. Herein, we demonstrate the direct formation of air- and moisture-stable cyclophosph(v)azanes enabled by an orthogonal "one-step one-pot" mechanochemical reaction. In addition, detailed hydrolytic- and air-stability studies, conducted over one and 12 months, respectively, revealed high robustness of these compounds.

Highly enantioselective bisguanidinium-catalyzed tandem rearrangements of acylsilanes are reported. The acylsilanes were activated via an addition of fluoride on the silicon to form a penta-coordinate anionic silicate intermediate. The silicate then underwent alkyl or aryl group migration from the silicon atom to the neighboring carbonyl carbon atom (1,2-anionotropic rearrangement), followed by [1,2]-Brook rearrangement to provide the secondary alcohols in high yields with excellent enantioselectivities (up to 95% ee). The isolation of an α-silylcarbinol intermediate as well as DFT calculations revealed that the 1,2-anionotropic rearrangement occurred via a bisguanidinium silicate ion pair, which is the stereodetermining step. The chiral center formed is then retained without inversion through the subsequent [1,2]-Brook rearrangement. Crotyl acylsilanes were smoothly transformed into homoallylic linear crotyl alcohols with retention of E/Z geometry, and no branched alcohols were detected. This clearly suggested that the 1,2-anionotropic rearrangement occurred through a three-membered instead of a five-membered transition state. Accepted version

Cyclophosphazanes have been extensively studied over the past decades due to their topological flexibility and unique chemical versatility. However, their use in supramolecular chemistry and crystal engineering is still in its infancy. Here, we report the synthesis of cis-Se-oxidized cyclodiphosph(V/V)azane 1 as a model cyclophosphazane compound and its use as supramolecular building blocks. The displayed cis-conformation, along with its tendency to adopt an exo, exo configuration of the terminal tert-butylamino substituents, enables the formation of highly reproducible supramolecular synthons via R21(8) bifurcated hydrogen bonds. Such bifurcated hydrogen bonds formed by the cyclodiphosphazane scaffold contain larger bite angles than those of their more well-known urea, thiourea and squaramide counterparts. We obtained five different solvate crystals as well as three different cocrystals that all contain similar hydrogen bonding motifs. In addition, we envisioned that the Se atoms in the oxidized cyclodiphosph(V/V)azane can act as halogen bond acceptors, and we were able to successfully obtain a cocrystal with 1,4-dibromo-tetrafluorobenzene, via the formation of P[double bond, length as m-dash]Se⋯Br halogen bonds. Such interaction had only been reported once before and warrants further exploration. Our results demonstrate the versatility and robustness of the cyclodiphosph(V/V)azane scaffold and highlights its potential as a prospective building block for creating reproducible supramolecular synthons for main group crystal engineering purposes.