1,3-Bis(2,6-diisopropyl­phen­yl)imidazolidinium tetra­phenyl­borate dichloro­methane disolvate

The title compound, C27H39N2 +·C24H20B−·2CH2Cl2, is the first reported imidazolidinium cation with the sterically demanding 2,6-diisopropyl­phenyl groups in the 1,3-positions. The crystal structure is stabilized by weak inter­molecular C—H⋯π(arene) inter­actions. Due to the bulky nature of both the flanking 2,6-diisopropyl­phenyl substituents and the tetra­phenyl­borate counter-ion, anion inter­actions with the imidazolidinium H atom in the 2-position are not observed, also a first for this class of ortho-alkyl-substituted Arduengo-type carbene precursors

A new polymorph of 2,6-bis(trifluoromethyl)benzoic acid

Publisher's version/PDFThe asymmetric unit of a second polymorph of the title compound, C[subscript 9]H[subscript 4]F[subscript 6]O[subscript 2], contains five independent molecules, which form hydrogen-bonded O—H[ellipsis]O dimers about inversion centers. The most significant structural difference between this structure and that of the first polymorph [Tobin & Masuda (2009). Acta Cryst. E65, o1217] is the hydrogen-bonded, dimeric orientation of the carboxylic acid functionalities

1,3-Bis(2,6-diisopropyl­phen­yl)imidazolidin-2-yl­idene

The title compound, C27H38N2, is the first reported free imidazolidin-2-yl­idene carbene with 2,6-diisopropyl­phenyl groups in the 1,3-positions. The five-membered ring adopts a twisted conformation and the dihedral angle between the aromatic rings is 48.81 (6)°. Both isopropyl groups attached to one of the benzene rings are disordered over two sets of sites in 0.74 (2):0.26 (2) and 0.599 (8):0.401 (8) ratios

Crystal Structure of Bis(2,4,6-trimethylphenyl)-phosphine Oxide

Published VersionThe single crystal structure of bis(2,4,6-trimethylphenyl) phosphine oxide has been determined. All interatomic distances and angles can be considered normal. The aryl substituents adopt an intermediate configuration when compared to both sterically unhindered (e.g., diphenylphosphine oxide) and congested (e.g., bis(2,4,6-tri-tert-butylphenyl)phosphine oxide) secondary phosphine oxides, illustrating the influence of steric congestion on the molecular structure

Anhydrous TEMPO-H: reactions of a good hydrogen atom donor with low-valent carbon centres

Publisher's version/PDFIn this paper, we report a novel synthesis of anhydrous 1-hydroxy-2,2,6,6-tetramethyl-piperidine (TEMPO-H). An X-ray crystal structure and full characterization of the compound are included. Compared to hydrated TEMPO-H, its anhydrous form exhibits improved stability and a differing chemical reactivity. The reactions of anhydrous TEMPO-H with a variety of low-valent carbon centres are described. For example, anhydrous TEMPO-H was reacted with 1,3-bis(2,4,6-trimethylphenyl)-imidazol-2-ylidene (IMes), an unsaturated NHC. Crystals of CHNC[subscript 6H[subscript 2](CH[subscript 3])[subscript 3]][subscript 2]C...HO-(NC[subscript 5]H[subscript 6](CH[subscript 3])[subscript 4]), IMes...TEMPO-H, were isolated and a crystal structure determined. The experimental structure is compared to the results of theoretical calculations on the hydrogen-bonded dimer. Anhydrous TEMPO-H was also reacted with the saturated NHC, 1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene (SIPr), giving the product [CH[subscript 2]Ni-Pr[subscript 2]C[subscript 6]H[subscript 3]][subscript 2]CH...O(NC[subscript 5]H[subscript 6](CH[subscript 3])[subscript 4]). In contrast, the reaction of hydrated TEMPO-H with 1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene gave small amounts of the hydrolysis product, N-(2,6-diisopropylphenyl)-N-[2-(2,6-diisopropylphenylamino)ethyl]formamide. Finally, anhydrous TEMPO-H was reacted with (triphenylphosphoranylidene)ketene to generate Ph[subscript 3]PC(H)C(=O)O(NC[subscript 5]H[subscript 6](CH[subscript 3])[subscript 4]). A full characterization of the product, including an X-ray crystal structure, is described

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Crystal Structure of Bis(2,4,6-trimethylphenyl)-phosphine Oxide

The single crystal structure of bis(2,4,6-trimethylphenyl)phosphine oxide has been determined. All interatomic distances and angles can be considered normal. The aryl substituents adopt an intermediate configuration when compared to both sterically unhindered (e.g., diphenylphosphine oxide) and congested (e.g., bis(2,4,6-tri-tert-butylphenyl)phosphine oxide) secondary phosphine oxides, illustrating the influence of steric congestion on the molecular structure

Reaction of sterically encumbered phenols, TEMPO-H, and organocarbonyl insertion reactions with L-AlH2 (L ¼HC(MeCNDipp)2, Dipp ¼2,6- diisopropylphenyl)

Published VersionThe reaction of L-AlH2 (L = HC(MeCNDipp)2, Dipp = 2,6-diisopropylphenyl) with sterically bulky phenols (2,4,6-trimethylphenol, MesOH; 2,6-diisopropylphenol, DippOH) and an N-hydroxylamine (1-hydroxy-2,2,6,6-tetramethyl-piperidine, TEMPO-H) forms an Al–O bond with concomitant loss of hydrogen gas to give L-Al(H)OMes, L-Al(H)ODipp and L-Al(H)TEMPO, respectively. Reaction with 1 or 2 equivalents of benzaldehyde or 1 equivalent of benzophenone results in insertion of carbonyl into the Al–H bond(s) to give the related benzylate and diphenylmethoxide products. Compounds L-Al(H)OMes, L-Al(H)ODipp, L-Al(H)TEMPO, L-Al(H)OBn, L-Al(OBn)2, and L-Al(H)OCHPh2 have been characterized by NMR spectroscopy, elemental analysis, infrared spectroscopy and single crystal X-ray diffraction. The reaction of L-Al(H)OBn with pinacol borane gives a complex mixture of unidentifiable products, providing evidence of the importance of the triflate group in the known aldehyde and ketone hydroboration catalyst L-Al(H)OTf (OTf = CF3SO3−)

Preparation of a Diphosphine with Persistent Phosphinyl Radical Character in Solution: Characterization, Reactivity with O₂, S₈, Se, Te, and P₄, and Electronic Structure Calculations

A new, easily synthesized diphosphine based on a heterocyclic 1,3,2-diazaphospholidine framework has been prepared. Due to the large, sterically encumbering Dipp groups (Dipp = 2,6-diisopropylphenyl) on the heterocyclic ring, the diphosphine undergoes homolytic cleavage of the P–P bond in solution to form two phosphinyl radicals. The diphosphine has been reacted with O₂, S₈, Se, Te, and P₄, giving products that involve insertion of elements between the P–P bond to yield the related phosphinic acid anhydride, sulfide/disulfide, selenide, telluride, and a butterfly-type perphospha-bicyclobutadiene structure with a <i>trans</i>,<i>trans</i>-geometry. All molecules have been characterized by multinuclear NMR spectroscopy, elemental analysis, and single-crystal X-ray crystallography. Variable-temperature EPR spectroscopy was utilized to study the nature of the phosphinyl radical in solution. Electronic structure calculations were performed on a number of systems from the parent diphosphine [H₂P]₂ to amino-substituted [(H₂N)₂P]₂ and cyclic amino-substituted [(H₂C)₂(NH)₂P]₂; then, bulky substituents (Ph or Dipp) were attached to the cyclic amino systems. Calculations on the isolated diphosphine at the B3LYP/6-31+G* level show that the homolytic cleavage of the P–P bond to form two phosphinyl radicals is favored over the diphosphine by ∼11 kJ/mol. Furthermore, there is a significant amount of relaxation energy stored in the ligands (52.3 kJ/mol), providing a major driving force behind the homolytic cleavage of the central P–P bond