Controlling Interchromophore Coupling in Diamantane-Linked Pentacene Dimers To Create a "Binary" Pair.

Two isomeric pentacene dimers, each linked by a diamantane spacer, have been synthesized. These dimers are designed to provide experimental evidence to support quantum mechanical calculations, which predict the substitution pattern on the carbon-rich diethynyldiamantane spacer to be decisive in controlling the interpentacene coupling. Intramolecular singlet fission (i-SF) serves as a probe for the existence and strength of the electronic coupling between the two pentacenes, with transient absorption spectroscopy as the method of choice to characterize i-SF. 4,9-Substitution of diamantane provides a pentacene dimer (4,9-dimer) in which the two chromophores are completely decoupled and that, following photoexcitation, deactivates to the ground state analogous to a monomeric pentacene chromophore. Conversely, 1,6-substitution provides a pentacene dimer (1,6-dimer) that exhibits sufficiently strong coupling to drive i-SF, resulting in correlated triplet M(T1T1) yields close to unity and free triplet (T1 + T1) yields of ca. 50%. Thus, the diamantane spacer effectively switches "on" or "off" the coupling between the chromophores, based on the substitution pattern. The binary control of diamantane contrasts other known molecular spacers designed only to modulate the coupling strength between two pentacenes.

Diagnostic Conundrum of a Sertoli Cell Tumor in a 2-Year-Old Girl with Peripheral Precocious Puberty and a Café-au-Lait Macule: A Case Report.

INTRODUCTION: Ovarian Sertoli cell tumors represent a subset of sex cord stromal tumors and are exceedingly rare in prepubertal children. Here, we report a girl with vaginal bleeding due to a Sertoli cell tumor who was originally thought to have McCune-Albright syndrome (MAS). CASE PRESENTATION: A previously healthy girl presented at age 2 years 6 months with breast development and vaginal bleeding. On exam, she had Tanner 4 breasts, Tanner 1 pubic hair, estrogenized vaginal mucosa, and a café-au-lait macule. Laboratory studies revealed an elevated estradiol with suppressed gonadotropins and negative tumor markers. Her bone age was advanced by more than 3 years. Pelvic ultrasound (US) revealed an enlarged uterus and a slightly larger left compared to right ovary. She was started on tamoxifen for presumed MAS. A repeat pelvic US 1 month later showed a heterogenous mass in the left ovary which was subsequently resected. Pathology revealed a Sertoli cell tumor, lipid-rich variant. Germline sequencing revealed a pathogenic STK11 variant, diagnostic for Peutz-Jeghers syndrome (PJS). CONCLUSION: The findings in our patient were strikingly similar to those encountered in MAS. To our knowledge, our patient is the youngest ever reported to present with precocious puberty due to a Sertoli cell tumor in the setting of PJS.

Frustrated Lewis pair adducts of alkynyl-capped tetrelenes.

The frustrated Lewis pair (FLP) adducts PB{ECl2} (PB = iPr2P(C6H4)BCy2; Cy = cyclohexyl; E = Si, Ge) were used to access a bis(alkynyl)-functionalized silylene and a germylene; the goal behind preparing these species was to obtain new unsaturated main group polymers [E(CCSiMe3)2]n upon heating. While the silylene adduct PB{Si(CCSiMe3)2} was stable up to 150 °C, the heavier element congener PB{Ge(CCSiMe3)2} underwent a complicated rearrangement process accompanied by Cy-group migration and Ge(II)-alkyne coordination. Density functional theory computations were performed to understand the mechanistic pathway for the unusual rearrangement of PB{Ge(CCSiMe3)2}.

Nickel-Catalyzed O-Arylation of Primary or Secondary Aliphatic Alcohols with (Hetero)aryl Chlorides: A Comparison of Ni(I) and Ni(II) Precatalysts.

A comparative experimental and computational study examining the interplay of the ancillary ligand structure and Ni oxidation state in the Ni-catalyzed C(sp2)-O cross-coupling of (hetero)aryl chlorides and primary or secondary aliphatic alcohols is presented, focusing on PAd-DalPhos (L1)-, CyPAd-DalPhos (L2)-, PAd2-DalPhos (L3)-, and DPPF (L4)-ligated [(L)NiCl]n (n = 1 or 2) and (L)Ni(o-tol)Cl precatalysts. Both L1 and L2 were found to outperform the other ligands examined, with the latter proving to be superior overall. While Ni(II) precatalysts generally outperformed Ni(I) species, in some instances the catalytic abilities of Ni(I) precatalysts were competitive with those of Ni(II). Density-functional theory calculations indicate the favorability of a Ni(0)/Ni(II) catalytic cycle featuring turnover-limiting C-O bond reductive elimination over a Ni(I)/Ni(III) cycle involving turnover-limiting C-Cl oxidative addition.

Catalyzing Singlet Fission by Transition Metals: Second versus Third Row Effects.

The synthesis and characterization of platinum(II) and palladium(II) complexes bearing two (dimers Pt(Lpc)2Cl2 and Pd(Lpc)2Cl2), one (monomers Pt(Lpc)(Lref)Cl2 and Pd(Lpc)(Lref)Cl2), or no (reference compounds Pt(Lref)2Cl2 and Pd(Lref)2Cl2) pentacene-based pyridyl ligands are presented. Photophysical properties of the dimers are probed by means of steady-state and time-resolved transient absorption measurements in comparison to the monomer and model compounds. Our results document that despite enhanced spin-orbit coupling from the presence of heavy atoms, intramolecular singlet fission (iSF) is not challenged by intersystem crossing. iSF thus yields correlated triplet pairs and even uncorrelated triplet excited states upon decoherence. Importantly, significant separation of the two pentacenyl groups facilitates decoupling of the two chromophores. Furthermore, the mechanism of iSF is altered depending on the respective metal center, that is, Pt(II) versus Pd(II). The dimer based on Pt(II), Pt(Lpc)2Cl2, exhibits a direct pathway for the iSF and forms a correlated triplet pair with singlet-quintet spin-mixing within 10 ns in variable solvents. On the other hand, the dimer based on Pd(II), Pd(Lpc)2Cl2, leads to charge transfer mixing during the population of the correlated triplet pair that is dependent on solvent polarity. Moreover, Pd(Lpc)2Cl2 gives rise to a stable equilibrium between singlet and quintet correlated triplet pairs with lifetimes of up to 170 ns. Inherent differences in the size and polarizability, when contrasting platinum(II) with palladium(II), are the most likely rationale for the underlying trends.

Tetracene Dimers: A Platform for Intramolecular Down- and Up-conversion.

Photon energy conversion can be accomplished in many different ways, including the two opposing manners, down-conversion (i.e., singlet fission, SF) and up-conversion (i.e., triplet-triplet annihilation up-conversion, TTA-UC). Both processes have the potential to help overcome the detailed balance limit of single-junction solar cells. Tetracene, in which the energies of the lowest singlet excited state and twice the triplet excited state are comparable, exhibits both down- and up-conversion. Here, we have designed meta-diethynylphenylene- and 1,3-diethynyladamantyl-linked tetracene dimers, which feature different electronic coupling, to characterize the interplay between intramolecular SF (intra-SF) and intramolecular TTA-UC (intra-TTA-UC) via steady-state and time-resolved absorption and fluorescence spectroscopy. Furthermore, we have used Pd-phthalocyanine as a sensitizer to enable intra-TTA-UC in the two dimers via indirect photoexcitation in the near-infrared part of the solar spectrum. The work is rounded off by temperature-dependent measurements, which outline key aspects of how thermal effects impact intra-SF and intra-TTA-UC in different dimers.

Monodentate Alkoxy/Aryloxy Anchored Yttrium Dihydrides; Anticipated Outcomes and Surprises.

The synthesis, characterization, and solid-state structure of bulky alkoxy- and aryloxy-supported yttrium polynuclear hydrides are reported. Hydrogenolysis of the supertrityl alkoxy anchored yttrium dialkyl, Y(OTr*)(CH2SiMe3)2(THF)2 (1) (Tr* = tris(3,5-di-tert-butylphenyl)methyl), resulted in the clean conversion to the tetranuclear dihydride, [Y(OTr*)H2(THF)]4 (1a). X-ray analysis revealed a highly symmetrical structure (4̅ site symmetry) with the four Y atoms located on the corners of a compressed tetrahedron, each bonded to an OTr* and tetrahydrofuran (THF) ligand and the cluster held together by four face-capping, µ3-H, and four edge-bridging, µ2-H, hydrides. DFT calculations on the full system with and without THF, but also on model systems, clearly show that the structural preference for complex 1a is controlled by the presence and coordination of THF molecules. Contrary to the exclusive formation of the tetranuclear dihydride, hydrogenolysis of the bulky aryloxy yttrium dialkyl, Y(OAr*)(CH2SiMe3)2(THF)2 (2) (Ar* = 3,5-di-tert-butylphenyl) gave a mixture of the analogous tetranuclear 2a and trinuclear, [Y3(OAr*)4H5(THF)4], polyhydride, 2b. Similar results, i.e., a mixture of tetra-/tri-nuclear products, were obtained from hydrogenolysis of the even bulkier Y(OArAd2,Me)(CH2SiMe3)2(THF)2 compound. Experimental conditions were established to optimize the production of either the tetra- or trinuclear products. X-ray structure of 2b revealed a triangular array of three yttrium atoms with two face-capping µ3-H and three edge-bridging µ2-H hydrides, with one yttrium bonded to two aryloxy ligands while the other two have a complement of one aryloxy and two THF ligands; the solid-state structure is close to being C2 symmetric, with the C2 axis running through the unique Y and unique µ2-H hydride. As opposed to 2a, which shows distinct 1H NMR resonances for µ3/ µ2-H (δ = 5.83/6.35 ppm, respectively), no hydride signals for 2b were observed at room temperature, indicating hydride exchange on the NMR time scale. Their presence and assignment were secured at -40 °C from 1H SST (spin saturation) experiment.

Establishment and characterization of patient-derived xenograft of a rare pediatric anaplastic pleomorphic xanthoastrocytoma (PXA) bearing a CDC42SE2-BRAF fusion.

Pleomorphic xanthoastrocytoma (PXA) is a rare subset of primary pediatric glioma with 70% 5-year disease free survival. However, up to 20% of cases present with local recurrence and malignant transformation into more aggressive type anaplastic PXA (AXPA) or glioblastoma. The understanding of disease etiology and mechanisms driving PXA and APXA are limited, and there is no standard of care. Therefore, development of relevant preclinical models to investigate molecular underpinnings of disease and to guide novel therapeutic approaches are of interest. Here, for the first time we established, and characterized a patient-derived xenograft (PDX) from a leptomeningeal spread of a patient with recurrent APXA bearing a novel CDC42SE2-BRAF fusion. An integrated -omics analysis was conducted to assess model fidelity of the genomic, transcriptomic, and proteomic/phosphoproteomic landscapes. A stable xenoline was derived directly from the patient recurrent tumor and maintained in 2D and 3D culture systems. Conserved histology features between the PDX and matched APXA specimen were maintained through serial passages. Whole exome sequencing (WES) demonstrated a high degree of conservation in the genomic landscape between PDX and matched human tumor, including small variants (Pearson's r = 0.794-0.839) and tumor mutational burden (~ 3 mutations/MB). Large chromosomal variations including chromosomal gains and losses were preserved in PDX. Notably, chromosomal gain in chromosomes 4-9, 17 and 18 and loss in the short arm of chromosome 9 associated with homozygous 9p21.3 deletion involving CDKN2A/B locus were identified in both patient tumor and PDX sample. Moreover, chromosomal rearrangement involving 7q34 fusion; CDC42SE-BRAF t (5;7) (q31.1, q34) (5:130,721,239, 7:140,482,820) was identified in the PDX tumor, xenoline and matched human tumor. Transcriptomic profile of the patient's tumor was retained in PDX (Pearson r = 0.88) and in xenoline (Pearson r = 0.63) as well as preservation of enriched signaling pathways (FDR Adjusted P < 0.05) including MAPK, EGFR and PI3K/AKT pathways. The multi-omics data of (WES, transcriptome, and reverse phase protein array (RPPA) was integrated to deduce potential actionable pathways for treatment (FDR < 0.05) including KEGG01521, KEGG05202, and KEGG05200. Both xenoline and PDX were resistant to the MEK inhibitors trametinib or mirdametinib at clinically relevant doses, recapitulating the patient's resistance to such treatment in the clinic. This set of APXA models will serve as a preclinical resource for developing novel therapeutic regimens for rare anaplastic PXAs and pediatric high-grade gliomas bearing BRAF fusions.

Sensitized Singlet Fission in Rigidly Linked Axial and Peripheral Pentacene-Subphthalocyanine Conjugates.

The goal of harnessing the theoretical potential of singlet fission (SF), a process in which one singlet excited state is split into two triplet excited states, has become a central challenge in solar energy research. Covalently linked dimers provide crucial models for understanding the role of chromophore arrangement and coupling in SF. Sensitizers can be integrated into these systems to expand the absorption bandwidth through which SF can be accessed. Here, we define the role of the sensitizer-chromophore geometry in a sensitized SF model system. To this end, two conjugates have been synthesized consisting of a pentacene dimer (SF motif) connected via a rigid alkynyl bridge to a subphthalocyanine (the sensitizer motif) in either an axial or a peripheral arrangement. Steady-state and time-resolved photophysical measurements are used to confirm that both conjugates operate as per design, displaying near unity energy transfer efficiencies and high triplet quantum yields from SF. Decisively, energy transfer between the subphthalocyanine and pentacene dimer occurs ca. 26 times faster in the peripheral conjugate, even though the two chromophores are ca. 3 Å farther apart than in the axial conjugate. Following a theoretical evaluation of the dipolar coupling, Vdip2, and the orientation factor, κ2, of both the axial (Vdip2 = 140 cm-2; κ2 = 0.08) and the peripheral (Vdip2 = 724 cm-2; κ2 = 1.46) arrangements, we establish that this rate acceleration is due to a more favorable (nearly co-planar) relative orientation of the transition dipole moments of the subphthalocyanine and pentacenes in the peripheral constellation.

A convenient route to mixed cationic group 13/14/15 compounds.

The formation of novel cationic mixed main group compounds is reported revealing a chain composed of different elements of group 13, 14, and 15. Reactions of different pnictogenylboranes R2EBH2·NMe3 (E = P, R = Ph, H; E = As, R = Ph, H) with the NHC-stabilized compound IDipp·GeH2BH2OTf (1) (IDipp = 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene) were carried out, yielding the novel cationic, mixed group 13/14/15 compounds [IDipp·GeH2BH2ER2BH2·NMe3]+ (2a E = P; R = Ph; 2b E = As; R = Ph; 3a E = P; R = H; 3b E = As; R = H) by the nucleophilic substitution of the triflate (OTf) group. The products were analysed by NMR spectroscopy and mass spectrometry and for 2a and 2b also by X-ray structure analysis. Further reactions of 1 with H2EBH2·IDipp (E = P, As) resulted in the unprecedented parent complexes [IDipp·GeH2BH2EH2BH2·IDipp][OTf] (5a E = P; 5b E = As), which were studied by X-ray structure analysis, NMR spectroscopy and mass spectrometry. Accompanying DFT computations give insight into the stability of the formed products with respect to their decomposition.

An indium(I) tetramer bound by anionic N-heterocyclic olefins: ambiphilic reactivity, transmetallation and a rare indium-imide.

An organometallic tetrahedron-shaped indium(I) tetramer [(MeIPrCH)In]4 (MeIPrCH = [(MeCNDipp)2CCH]-; Dipp = 2,6-iPr2C6H3) supported by anionic N-heterocyclic olefin (aNHO) ligands is reported. The monomeric unit of this species exhibits both Lewis acidic and basic character at indium, while the steric profile of the aNHO ligand enables isolation of a rare monomeric imide, RInNR'.

Targeted treatment of refractory primitive neuroectodermal tumor arising from an immature teratoma with crizotinib leading to a sustained response.

Here we present a case of metastatic PNET which arose from an immature teratoma that was refractory to standard Ewing sarcoma chemotherapy. This PNET was determined to have elevated levels of ALK protein via IHC. The patient was treated with crizotinib on a palliative basis with a sustained response.

Frustrated Lewis Pair Adduct of Atomic P(-1) as a Source of Phosphinidenes (PR), Diphosphorus (P2 ), and Indium Phosphide.

We report phosphinidenes (PR) stabilized by an intramolecular frustrated Lewis pair (FLP) chelate. These adducts include the parent phosphinidene, PH, which is accessed via thermolysis of coordinated HPCO. The reported FLP-PH species acts as a springboard to other phosphorus-containing compounds, such as FLP-adducts of diphosphorus (P2 ) and InP3 . Our new adducts participate in thermal- or light-induced phosphinidene elimination (of both PH and PR, R=organic group), transfer P2 units to an organic substrate, and yield the useful semiconductor InP at only 110 °C from solution.

Molecular Sn(II) precursors for room temperature deposition of crystalline elemental tin.

We report mild routes for the deposition of crystalline films of elemental tin via the formation and subsequent decomposition of unstable tin(II) hydrides. Specifically, we take advantage of efficient OtBu/H metathesis involving Sn(II) alkoxide precursors and the hydride source pinacolborane (HBpin); related -N(SiMe3)2/H exchange also afforded elemental tin as a final (insoluble) product.

Frustrated Lewis pair-ligated tetrelenes.

The reactivity of [PB{SiX2}] (X = Cl, Br; PB = 1,2-iPr2(C6H4)BCy2; E = Si, Ge) adducts is described, with an initial focus on reduction attempts to access [PB{E}]x species; however, in all cases only free PB ligand was formed as the soluble product. Moreover, computations were performed to evaluate the energy penalty associated with EX2 dissociation from the PB chelates. Moving up the periodic table, the formal methylene adduct [PB{CH2}] was isolated and its reactivity was compared with its heavier element congeners of [PB{EH2}]. We also introduce new phosphine-borane frustrated Lewis pair (FLP) chelates and explore preliminary coordination chemistry with these ligands.

Pentacenones as Divergent Intermediates to Unsymmetrically Substituted Pentacenes: Synthesis and Crystallographic Analysis.

We report a general method for the desymmetrization of 6,13-pentacenequinone to access ethynylated pentacene ketones, namely, 13-hydroxy-13-(ethynylated)pentacene-6(13H)-ones. These pentacene ketones ("pentacenones") serve as divergent intermediates to unsymmetrically 6,13-disubstituted pentacenes, commonly used for studying singlet fission processes and charge transport phenomena in organic field effect transistors. We report a synthetic method to access pentacenones, which utilizes a precipitation/crystallization from the crude mixture to enable facile purification on a multigram scale. X-ray crystallographic analysis of the pentacenones reveals key noncovalent interactions that contribute to the crystallization, specifically, hydrogen bonding between the ketone and alcohol functional groups as well as π-π-stacking and dipole-dipole interactions.

Frustrated Lewis Pair Chelation and Reactivity of Complexed Parent Iminoborane and Aminoborane.

An intramolecular phosphine-borane frustrated Lewis pair (FLP) chelate, iPr2P(C6H4)BCy2 or PB (Cy = cyclohexyl), was used to coordinate aminoborane (H2BNH2) and iminoborane (HBNH) units via donor-acceptor stabilization. Attempts to induce dehydrogenation from these B-N adducts with known metal catalysts (or pre-catalysts) have been unsuccessful thus far, and related observations were noted with an H2BNH2 complex supported by a modified FLP chelate bearing a geometrically constrained bicyclic 9-borabicyclo(3.3.1)nonane (BBN) unit. Treatment of the iminoborane adduct [PB{HBNH}] with a chlorinating agent led to ligand activation via B-C bond cleavage instead of the expected H/Cl exchange at boron to give [PB{ClBNH}]. Nucleophilic attack at the boron center in [PB{HBNH}] was observed upon addition of BnK (Bn = benzyl), yielding the amidoborate complex [PB{H(Bn)BNH}{K(THF)2}].

Precision Medicine Highlights Dysregulation of the CDK4/6 Cell Cycle Regulatory Pathway in Pediatric, Adolescents and Young Adult Sarcomas.

Despite improved therapeutic and clinical outcomes for patients with localized diseases, outcomes for pediatric and AYA sarcoma patients with high-grade or aggressive disease are still relatively poor. With advancements in next generation sequencing (NGS), precision medicine now provides a strategy to improve outcomes in patients with aggressive disease by identifying biomarkers of therapeutic sensitivity or resistance. The integration of NGS into clinical decision making not only increases the accuracy of diagnosis and prognosis, but also has the potential to identify effective and less toxic therapies for pediatric and AYA sarcomas. Genome and transcriptome profiling have detected dysregulation of the CDK4/6 cell cycle regulatory pathway in subpopulations of pediatric and AYA OS, RMS, and EWS. In these patients, the inhibition of CDK4/6 represents a promising precision medicine-guided therapy. There is a critical need, however, to identify novel and promising combination therapies to fight the development of resistance to CDK4/6 inhibition. In this review, we offer rationale and perspective on the promise and challenges of this therapeutic approach.

Molecular rotational conformation controls the rate of singlet fission and triplet decay in pentacene dimers.

Three pentacene dimers have been synthesized to investigate the effect of molecular rotation and rotational conformations on singlet fission (SF). In all three dimers, the pentacene units are linked by a 1,4-diethynylphenylene spacer that provides almost unimpeded rotational freedom between the pentacene- and phenylene-subunits in the parent dimer. Substituents on the phenylene spacer add varying degrees of steric hindrance that restricts both the rotation and the equilibrium distribution of different conformers; the less restricted conformers exhibit faster SF and more rapid subsequent triplet-pair recombination. Furthermore, the rotational conformers have small shifts in their absorption spectra and this feature has been used to selectively excite different conformers and study the resulting SF. Femtosecond transient absorption studies at 100 K reveal that the same dimer can have orders of magnitude faster SF in a strongly coupled conformer compared to a more weakly coupled one. Measurements in polystyrene further show that the SF rate is nearly independent of viscosity whereas the triplet pair lifetime is considerably longer in a high viscosity medium. The results provide insight into design criteria for maintaining high initial SF rate while suppressing triplet recombination in intramolecular singlet fission.

The Effects of Ring Strain on Cyclic Tetraaryl[5]cumulenes.

Cyclic tetraaryl[5]cumulenes (1 a-f) have been synthesized and studied as a function of increasing ring strain. The magnitude of ring strain is approximated by the extent of bending of the cumulenic core as assessed by a combination of X-ray crystallographic analysis and DFT calculations. Trends are observed in 13 C NMR, UV-vis, and Raman spectra associated with ring strain, but the effects are small. In particular, the experimental HOMO-LUMO gap is not appreciably affected by bending of the [5]cumulene framework from ca. 174° (λmax =504 nm) in 1 a to ca. 178° (λmax =494 nm) in 1 f.