Formazans: a Structural and Spectroscopic Study of 3-Substituted-1,5-Diphenylformazans

<p>A series of thirteen isomeric 1,5-diphenylformazans have been structurally characterised both in the solid state and in solution by the combined techniques of x-ray crystallography, nuclear magnetic resonance, Raman, mass and absorption spectroscopies. 1,5-Diphenylformazan is known to exist in the anti, s-trans configuration in the solid state and this is shown to be the solution dominant species. In aprotic solvents an equilibrium involving the anti, s-trans and syn, s-cis configurations is evidenced. 3-Methyl-1,5-diphenylformazan has been characterised by an x-ray crystal analysis. C14H14N4 belongs to the monoclinic space group P2/c, a = 8.133(1), b = 19.085(4), c = 9.364(2) A, beta = 105.93 degrees,U = 1397.6(5) A3, Z = 4. The anti, s-trans configuration of the solid state is also preferred in solution where it is in equilibrium with the syn, s-cis configuration. 3-Ethyl-1,5-diphenylformazan exists in two isomers in the solid state, both of which have been characterised by an x-ray crystal analysis. The red isomer of 3-ethyl-1,5-diphenylformazan belongs to the orthorhombic space group P2l2l2l and adopts the syn, s-trans configuration in the solid state. The orange, light stable isomer of 3-ethyl-1,5-diphenylformazan belongs to the monoclinic space group P2l/c and adopts the anti, s-trans configuration in the solid state. The rate of return of the photo-activated orange isomer to the dark-stable red isomer follows first order kinetics dependent upon the total concentration of the formazan and the water content of the solvent. 3-Tertiary-butyl-1,5-diphenylformazan has been characterised by an x-ray crystal analysis. C17H20N4, belongs to the monoclinic space group P2/c, a = 11.235(3), b = 20.117(5), c = 14.176(3) A, beta = 92.14(2) degrees, U = 3202(1) A3, Z = 8. The syn, s-cis configuration of the solid state is maintained in solution. 1,3,5-Triphenylformazan is shown to exist in two red forms in the solid state. The syn, s-cis and syn, s-trans isomers are both present in the crystalline sample. These isomers are also evident in solution with the syn, s-trans configuration becoming more dominant in aprotic solvents. 1,5-Diphenylformazan reacts with bromine in solution in a single reaction to give di(3-bromo-1,5-diphenyltetrazolium)-decabromide and 3-bromo-1,5-di-para-phenylformazan, both of which have been characterised by an x-ray crystal analysis. C13H10.6N4Br5.3 belongs to the triclinic space group Pl, a = 8.572(1), b = 9.711(1), c = 14.166(3) A, alpha = 75.18(1), beta = 89.84(1), gamma = 70.42(1) degrees, Z = 2. Stacks of anti-parallel pairs of 3-bromo-1,5-diphenyltetrazolium cations are interleaved by pairs of Br102- anions. The polybromide represents a new type of polyhalogen network for bromine, Br102-, the Raman spectrum of which has been recorded for the first time. C13H9N4Br3 belong to the orthorhombic space group Pnma, a = 7.343(2), b = 32.793(12), c = 5.912(1) A, Z = 4. The formazan adopts the anti, s-trans configuration in the solid state. 3-Chloro-1,5-diphenylformazan has been characterised by an x-ray crystal analysis. Preliminary results indicate that the formazan adopts the anti, s-trans configuration in the solid state. 3-Mercapto-1,5-diphenylformazan is shown to exist in the anti, s-trans configuration in CDCl3, solution. 3-Methylthio-1,5-diphenylformazan is shown to exist in an equilibrium mixture of syn, s-trans and anti, s-trans configurations in solution. The ratio of the two isomers is approximately equal. 3-Ethylthio-1,5-diphenylformazan exists in two isomers in the solid state, one of which has been characterised by an x-ray crystal analysis. Preliminary results indicate that the orange isomer of 3-ethylthio-1,5-diphenylformazan. C15H16N4S belongs to the monoclinic space group P2l/a, a = 11.027(6). b = 8.627(7), c = 15.487(8) A, b = 93.70(5) degrees, U = 1470 A3, Z = 4, and exists in the anti, s-trans configuration on the solid state. The orange and red isomers are both present in an equilibrium mixture in solution. The red isomer is shown to exist in the syn, s-trans configuration in the solid. 3-isopropylthio-1,5-diphenylformazan is shown to exist in an equilibrium mixture of anti, s-trans and syn, s-trans configurations in solution. 1-Methyl-1,5-diphenylformazan has been characterised by an x-ray crystal analysis. C14H14N4 belongs to the monoclinic space group 12/1, a = 28.402(7), b = 5.640(1), c = 15.688(4) A, beta = 97.34 degrees, U = 2493(1) A3, Z = 8. The formazan adopts the anti, s-trans configuration in the solid state. The formazan retains its configurational integrity in both protic and aprotic solutions. The excitation profile of the Raman active phonons based upon coupled vibrations of the formazan backbone indicate a maximum corresponding to the absorption spectra in both the solid state and in solution. Preliminary results of a kinetic investigation of some primary metal dithizonates indicate that the thermal-path return is strictly first order. The mechanism would appear to be essentially similar to that operating in 3-ethyl-1,5-diphenylformazan. The mass spectra of the series of formazan follow similar splitting schemes irrespective of the solid-state configuration.</p>

Formazans: a Structural and Spectroscopic Study of 3-Substituted-1,5-Diphenylformazans

<p>A series of thirteen isomeric 1,5-diphenylformazans have been structurally characterised both in the solid state and in solution by the combined techniques of x-ray crystallography, nuclear magnetic resonance, Raman, mass and absorption spectroscopies. 1,5-Diphenylformazan is known to exist in the anti, s-trans configuration in the solid state and this is shown to be the solution dominant species. In aprotic solvents an equilibrium involving the anti, s-trans and syn, s-cis configurations is evidenced. 3-Methyl-1,5-diphenylformazan has been characterised by an x-ray crystal analysis. C14H14N4 belongs to the monoclinic space group P2/c, a = 8.133(1), b = 19.085(4), c = 9.364(2) A, beta = 105.93 degrees,U = 1397.6(5) A3, Z = 4. The anti, s-trans configuration of the solid state is also preferred in solution where it is in equilibrium with the syn, s-cis configuration. 3-Ethyl-1,5-diphenylformazan exists in two isomers in the solid state, both of which have been characterised by an x-ray crystal analysis. The red isomer of 3-ethyl-1,5-diphenylformazan belongs to the orthorhombic space group P2l2l2l and adopts the syn, s-trans configuration in the solid state. The orange, light stable isomer of 3-ethyl-1,5-diphenylformazan belongs to the monoclinic space group P2l/c and adopts the anti, s-trans configuration in the solid state. The rate of return of the photo-activated orange isomer to the dark-stable red isomer follows first order kinetics dependent upon the total concentration of the formazan and the water content of the solvent. 3-Tertiary-butyl-1,5-diphenylformazan has been characterised by an x-ray crystal analysis. C17H20N4, belongs to the monoclinic space group P2/c, a = 11.235(3), b = 20.117(5), c = 14.176(3) A, beta = 92.14(2) degrees, U = 3202(1) A3, Z = 8. The syn, s-cis configuration of the solid state is maintained in solution. 1,3,5-Triphenylformazan is shown to exist in two red forms in the solid state. The syn, s-cis and syn, s-trans isomers are both present in the crystalline sample. These isomers are also evident in solution with the syn, s-trans configuration becoming more dominant in aprotic solvents. 1,5-Diphenylformazan reacts with bromine in solution in a single reaction to give di(3-bromo-1,5-diphenyltetrazolium)-decabromide and 3-bromo-1,5-di-para-phenylformazan, both of which have been characterised by an x-ray crystal analysis. C13H10.6N4Br5.3 belongs to the triclinic space group Pl, a = 8.572(1), b = 9.711(1), c = 14.166(3) A, alpha = 75.18(1), beta = 89.84(1), gamma = 70.42(1) degrees, Z = 2. Stacks of anti-parallel pairs of 3-bromo-1,5-diphenyltetrazolium cations are interleaved by pairs of Br102- anions. The polybromide represents a new type of polyhalogen network for bromine, Br102-, the Raman spectrum of which has been recorded for the first time. C13H9N4Br3 belong to the orthorhombic space group Pnma, a = 7.343(2), b = 32.793(12), c = 5.912(1) A, Z = 4. The formazan adopts the anti, s-trans configuration in the solid state. 3-Chloro-1,5-diphenylformazan has been characterised by an x-ray crystal analysis. Preliminary results indicate that the formazan adopts the anti, s-trans configuration in the solid state. 3-Mercapto-1,5-diphenylformazan is shown to exist in the anti, s-trans configuration in CDCl3, solution. 3-Methylthio-1,5-diphenylformazan is shown to exist in an equilibrium mixture of syn, s-trans and anti, s-trans configurations in solution. The ratio of the two isomers is approximately equal. 3-Ethylthio-1,5-diphenylformazan exists in two isomers in the solid state, one of which has been characterised by an x-ray crystal analysis. Preliminary results indicate that the orange isomer of 3-ethylthio-1,5-diphenylformazan. C15H16N4S belongs to the monoclinic space group P2l/a, a = 11.027(6). b = 8.627(7), c = 15.487(8) A, b = 93.70(5) degrees, U = 1470 A3, Z = 4, and exists in the anti, s-trans configuration on the solid state. The orange and red isomers are both present in an equilibrium mixture in solution. The red isomer is shown to exist in the syn, s-trans configuration in the solid. 3-isopropylthio-1,5-diphenylformazan is shown to exist in an equilibrium mixture of anti, s-trans and syn, s-trans configurations in solution. 1-Methyl-1,5-diphenylformazan has been characterised by an x-ray crystal analysis. C14H14N4 belongs to the monoclinic space group 12/1, a = 28.402(7), b = 5.640(1), c = 15.688(4) A, beta = 97.34 degrees, U = 2493(1) A3, Z = 8. The formazan adopts the anti, s-trans configuration in the solid state. The formazan retains its configurational integrity in both protic and aprotic solutions. The excitation profile of the Raman active phonons based upon coupled vibrations of the formazan backbone indicate a maximum corresponding to the absorption spectra in both the solid state and in solution. Preliminary results of a kinetic investigation of some primary metal dithizonates indicate that the thermal-path return is strictly first order. The mechanism would appear to be essentially similar to that operating in 3-ethyl-1,5-diphenylformazan. The mass spectra of the series of formazan follow similar splitting schemes irrespective of the solid-state configuration.</p>

Synthesis of 1-(2,4-Dinitrophenyl)-3,5-diphenyl-1H-pyrazol-4-ol via trans-1,3-Diphenyl-2,3-epoxy-1-propanone

The trans-1,3-diphenyl-2,3-epoxy-1-propanone was synthesized from benzaldehyde and 2-bromoacetophenone in 20 min which is more economical. The presence of ethanol and Br in 2-bromoacetophenone facilitated the reaction. The vicinal diaxial coupling constant of trans-1,3-diphenyl-2,3-epoxy-1-propanone was zero, an indication of trans configuration for a rigid 3-membered ring at ~90o dihedral angle. 1-(2,4-Dinitrophenyl)-3,5-diphenyl-1H-pyrazol-4-ol was synthesized from trans-1,3-diphenyl-2,3-epoxy-1-propanone and 2,4-dinitro phenylhydrazine in glacial CH3COOH to give 85.5% yield and characterized using FTIR, 1H, 13C NMR, DEPT 135 and MS spectra. The 1-(2,4-dinitrophenyl)-3,5-diphenyl-1H-pyrazol-4-ol can be exploited for unique biological activities and in the synthesis of synthetic fibers. Keywords: 1-(2,4-dinitrophenyl)-3,5-diphenyl-1H-pyrazol-4-ol, trans-1,3-diphenyl-2,3-epoxy-1-propanone; synthesis; 2,4-dinitro phenylhydrazine

Controlling One-Electron vs Two-Electron Pathways in the Multi-Electron Redox Cycle of Nickel Diethyldithiocarbamate

This manuscript describes electrochemical experiments in which a Nickel(III) intermediate is kinetically trapped by the addition of derivatized pyridine ligands to the electrolyte solution. EPR and DFT studies support the conclusion that pyridine coordinates in a trans- configuration and contains a small equilibrium between mono- and bis-pyridine structures. Electrochemical kinetic data provides evidences for decomposition pathways which ultimately result in Ni(IV) complexes.

Controlling One-Electron vs Two-Electron Pathways in the Multi-Electron Redox Cycle of Nickel Diethyldithiocarbamate

This manuscript describes electrochemical experiments in which a Nickel(III) intermediate is kinetically trapped by the addition of derivatized pyridine ligands to the electrolyte solution. EPR and DFT studies support the conclusion that pyridine coordinates in a trans- configuration and contains a small equilibrium between mono- and bis-pyridine structures. Electrochemical kinetic data provides evidences for decomposition pathways which ultimately result in Ni(IV) complexes.

Synthesis of trans-Mono(silyl)palladium(II) Bromide Complexes

The stoichiometric reaction of cis-[Pd(ITMe)2(SiR3)2], where (SiR3 = SiMe3 and SiMe2Ph and ITMe = 1,3,4,5-tetramethylimidazol-2-ylidene) with allyl bromide affords the corresponding allylsilanes along with complexes of the type trans-[Pd(ITMe)2(SiR3)(Br)]. The structure of trans-[Pd(ITMe)2(SiMe2Ph)Br] 2b has been determined in the solid state and displays a slightly distorted square-planar geometry with the two N-heterocyclic carbene ligands in a trans-configuration.

JAK2 R1063H Variant Enhances V617F Constitutive Signaling and Favors Development of Essential Thrombocythemia with Increased Hemoglobin and Neutrophils

The clinical consequences of the highly prevalent JAK2 V617F mutation in Ph-negative myeloproliferative neoplasms (MPNs) are well studied. However, the impact on the MPN phenotype of co-occurring JAK2 variants is less well characterized. In this study, we focused on JAK2 R1063H, a variant previously reported in a pediatric case of hereditary erythrocytosis (Kapralova et al, Blood 2016) and in 3 out of 93 polycythemia vera patients that were JAK2 V617F-positive (Levine et al, Cancer Cell 2005). It has been described as a very rare polymorphism in population (frequency 0.004377). In order to gain insight into the clinical and functional relevance of coexisting JAK2 mutations, we tested a cohort of 390 JAK2 V617F-positive MPN patients for JAK2 R1063H and identified 14 carriers of both mutations. From the clinical perspective, the double-positive patients exhibited predominantly an essential thrombocythemia phenotype that was accompanied by significantly higher neutrophil granulocyte counts and hemoglobin values, when compared to those harboring only JAK2 V617F mutation. By employing targeted NGS for genes known to be involved in myeloid malignancies we found that the mutational profile and the number of additional somatic mutations in double-mutant patients seemed to be comparable to previous studies of JAK2 V617F-positive MPNs. Next, we used digital droplet PCR (ddPCR) for JAK2 R1063H and JAK2 V617F allele burden assessment. Quantification of JAK2 R1063H allele indicated that in 8 patients the variant was heterozygous, likely inherited (the percentage of the mutant allele being around 50%). In 3 patients with a high JAK2 V617F allelic burden a nearly homozygous status for R1063H was identified (a fractional abundance >80%) suggesting that one R1063H allele was inherited and the second one was acquired by uniparental disomy, as a result of mitotic recombination. In 3 other patients, the JAK2 R1063H mutation was most likely acquired due to the low percentage of the mutant allele (between 20.7% and 31.5%). For cis/trans configuration analysis of JAK2 V617F and R1063H mutations, we performed single-colony sequencing of subcloned JAK2 cDNA from 9 out of 14 patients. A cis configuration of the mutations was detected in 7 and a trans configuration in 2 cases. In one patient, the cis configuration of JAK2 mutations combined with results obtained by ddPCR (the allele burdens for R1063H and V617F were 31.5% and 52.8%, respectively) suggested that R1063H was acquired, following V617F acquisition. To assess the effect on JAK2 signaling of coexisting JAK2 V617F and R1063H mutations in cis or trans, we created human cDNA JAK2 mutants (V617F, R1063H and V617F/R1063H). STAT5 transcriptional activity of the JAK2 WT and JAK2 mutants in the presence of myeloid dimeric cytokine receptors (EPOR, given the higher hemoglobin levels, G-CSFR, given the observed neutrophilia in patients carrying JAK2 V617F and R1063H, and TPOR) measured in JAK2-deficient γ-2A cells by dual luciferase assay revealed a significantly higher constitutive activity of JAK2 V617F/R1063H (cis mutant) compared to that of JAK2 V617F, in both homozygous and heterozygous configurations and with either of the dimeric myeloid cytokine receptors. In the trans configuration of JAK2 V617F and JAK2 R1063H, we did not observe a significant difference compared to combination of JAK2 V617F and JAK2 WT. Western blot analysis assessing activated phosphorylated forms of JAK2, STAT5 and ERK1/2 demonstrated a higher level of constitutive activation of JAK2 and STAT5 generated by the double V617F/R1063H mutant versus JAK2 V617F and similar effect was shown also for ERK1/2 signaling. Our results suggest that either an acquisition of V617F in cis on a germline R1063H allele or a gain of additional JAK2 R1063H on JAK2 V617F will lead to an increase in downstream signaling by the driver JAK2 V617F. The oncogenic signaling of JAK2 V617F enhanced by the R1063H mutation has a clinical effect, leading to a significantly increased number of neutrophilic granulocytes and hemoglobin values, in agreement with higher levels of signaling via EPOR and G-CSFR. The work was supported by projects COP A1.1.4. ID: P_37_798, Contract 149/26.10.2016, (MySMIS2014+: 106774), MyeloAL, WELBIO F 44/8/5-MCF/UIG-10955, ARC: N° 16/21-073, by Ludwig Institute for Cancer Research, Salus Sanguinis Foundation, Fondation Les avions de Sébastien, Belgium and by GACR 17-05988S and MSMT LTAUSA17142. Disclosures No relevant conflicts of interest to declare.