We report the syntheses, reactivities, and structure evaluations of a series of Cu(I) and Cu(II) metalloenediynes of conjugated 1,6-bis(pyridine-3)hex-3-ene-1,5-diyne (PyED, 7) and 1,6-bis(quinoline-3)hex-3-ene-1,5-diyne (QnED, 8) enediyne ligands, as well as their benzoenediyne analogues. Differential scanning calorimetry demonstrates that the [Cu(PyED)(2)](NO(3))(2) (11) exhibits a Bergman cyclization temperature (156 degrees C) which is dramatically reduced from that of the corresponding [Cu(PyED)(2)](PF(6)) (19) analogue (326 degrees C), indicating that large differences in the reactivities of these metalloenediynes can be accessed by variations in metal oxidation state. The distorted, 4-coordinate dichloride compound Cu(PyED)(Cl)(2) (15) exhibits a cyclization temperature (265 degrees C) between those of 11 and 19, suggesting that variation in geometry of the copper center is responsible for the wide range of reactivities. Similar results are obtained for the benzoenediyne and quinoline analogues. The structures of the Cu(II) systems have also been evaluated by a combination of electronic absorption and EPR spectroscopies which reveal tetragonal, 6-coordinate structures for the bis(enediyne) complexes, and tetrahedrally distorted 4-coordinate Cu(enediyne)Cl(2) species. For the bis(quinoline) enediyne derivatives 12 and 14 the larger g-anisotropy (g( parallel) = 2.27-2.28; g( perpendicular) = 2.06-2.07) indicates strong oxygen coordination from counterion. Molecular mechanics/dynamics calculations reveal that the geometries of these metal centers force the alkyne termini to a wide range of distances (3.85-4.20 A), thereby accounting for the variability in Bergman cyclization temperatures. Overall, the results show that ligand rigidity plays a prominent role in the conformational response of the enediyne to metal center geometry, which results in enhanced variations in the Bergman cyclization temperatures between complexes of different geometries.

We report the preparation and thermal reactivities of unique Cu(I) and Cu(II) metalloenediyne complexes of the flexible 1,8-bis(pyridine-3-oxy)oct-4-ene-2,6-diyne ligand (bpod, 1). The thermal reactivities of these metalloenediynes are intimately modulated by metal oxidation state. Using differential scanning calorimetry (DSC), we demonstrate that the [Cu(bpod) 2 ] + complex (2) undergoes Bergman cyclization at 203 °C, whereas the Cu(II) analogue ( 3) is substantially more reactive and cyclizes at 121 °C. Similar results are also observed for mixed ligand [Cu(bpod)(pyridine) 2 ] +/2+ analogues 4 (194 °C) and 5 (116 °C), suggesting that both complexes of a given oxidation state have comparable structures. The Cu(bpod)Cl 2 compound (6) exhibits a cyclization temperature (152 °C) midway between the those of Cu(I) and Cu(II) complexes, which can be explained by the propensity for cis-CuN 2 Cl 2 structures to exhibit dihedral angle distortion. The oxidationstate-dependent thermal reactivity is unprecedented and reflects the influence of the ligand field geometry on the barrier to enediyne cyclization. On the basis of X-ray structures of Cu(pyridine) 4 + complexes, 2 and 4 are proposed to be tetrahedral. In contrast, the electronic absorption spectra of 3 and 5 each show a broad envelope that can be Gaussian resolved into three ligand field transitions characteristic of a Cu(II) center in a tetragonaloctahedral environment. This structural assignment is confirmed by the EPR spin Hamiltonian parameters (g | /A | (cm) ) 134 (3), 138 ( 5)) and is consistent with crystallographically characterized Cu(pyridine) 4 X 2 structures. Molecular mechanics calculations have independently derived comparable tetrahedral and tetragonal structures for 2 and 3, respectively, and determined the average alkyne termini separation to be 〈a〉 ) 4.0 Å for 2 and 3.6 Å for 3. Thus, the tetrahedral geometries of the copper centers in 2 and 4 increase the distance between alkyne termini relative to the tetragonal Cu(II) geometries of 3 and 5, and are therefore responsible for the increase in the thermal cyclization temperatures. The DSC and spectroscopic data for 6 support these conclusions, as the latter suggests a distorted four-coordinate structure in the solid state, and a six-coordinate geometry in solution, which gives rise to an intermediate Bergman cyclization temperature. Overall, our results emphasize the utility of newly emerging metalloenediyne complexes for controlling thermal Bergman cyclization reactions and provide insights into designing novel, pharmacologically useful metalloenediyne compounds.

Page 7210: The syntheses of metalloenediyne precursors 1,8-bis(tetrahydropyran-2-yloxy)oct-4-ene-2,6-diyne and 1,8-dibromooct-4-ene-2,6-diyne were prepared from a modified literature procedure (König, B.; Pitsch, W.; Dix, I.; Jones, P. G. Synthesis 1996, 446-448) which was inadvertently omitted from the references. We thank Dr. Burkhard König for preprints regarding these procedures and bringing the oversight to our attention. Solubility and solubilization are important and critical areas in the design of drug delivery systems. This book is expertly written and provides the reader with both a theoretical and practical approach to solubility and techniques of solubilization.The book is divided into 10 instructive and well-referenced chapters. The contents of Chapter 1 provide information about the thermodynamics of mixing and the properties of mixtures. Ideal and real mixtures are compared and contrasted from a theoretical viewpoint. A concise discussion of colligative properties is also presented. The next chapter contains an in-depth characterization of solutions. The reader is led through a logical presentation of the modeling of solutions, with a discussion including models for ideal, athermal, regular, solvated, and self-associated solutions.Chapter 3 begins the discussion of the parameters that determine the miscibility of one liquid with another. A highlight is an instructive review of the influence of temperature and solution composition on solubility. The following chapter offers a relevant discussion of solute modification for enhancing the dissolution rate of drugs, especially poorly soluble ones. The next chapters provide the reader with a fundamental understanding of the techniques used to enhance the solubilization of a solute and gives practical examples of each. These chapters are particularly important for pharmaceutical scientists working to increase the bioavailability of drugs by enhancing their aqueous solubility through strategies such as pH control, the use of cosolvents and surface-active agents, and complexation.Chapter 9 summarizes the influence of a cosoluteswhich includes isomers, racemates, solvates, reaction-starting materials, intermediates, degradation products, impurities, or deliberately introduced materialsson solubility of the solute of interest. A strategy for solubilization is presented in detail in the concluding chapter. This chapter provides the reader with a well-thought-out approach to follow for enhancing the solubility of a solute based on information presented in the previous chapters.Overall, this book is highly recommended for scientists involved with enhancing solute solubility, especially those working in the field of pharmaceutical drug delivery.

Metal-to-ligand charge-transfer (MLCT) photolyses (lambda > or = 395 nm) of copper complexes of cis-1,8-bis(pyridin-3-oxy)oct-4-ene-2,6-diyne (bpod, 1), [Cu(bpod)(2)]PF(6) (2), and [Cu(bpod)(2)](NO(3))(2) (3) yield Bergman cyclization of the bound ligands. In contrast, the uncomplexed ligand 1 and Zn(bpod)(2)(CH(3)COO)(2) compound (4) are photochemically inert under the same conditions. In the case of 4, sensitized photochemical generation of the lowest energy (3)pi-pi state, which is localized on the enediyne unit, leads to production of the trans-bpod ligand bound to the Zn(II) cation by photoisomerization. Electrochemical studies show that 1, both the uncomplexed and complexed, exhibits two irreversible waves between E(p) values of -1.75 and -1.93 V (vs SCE), corresponding to reductions of the alkyne units. Irreversible, ligand-based one-electron oxidation waves are also observed at +1.94 and +2.15 V (vs SCE) for 1 and 3. Copper-centered oxidation of 2 and reduction of 3 occur at E(1/2) = +0.15 and +0.38 V, respectively. Combined with the observed Cu(I)-to-pyridine(pi) MLCT and pyridine(pi)-to-Cu(II) ligand-to-metal charge transfer (LMCT) absorption centered near approximately 315 nm, the results suggest a mechanism for photo-Bergman cyclization that is derived from energy transfer to the enediyne unit upon charge-transfer excitation. The intermediates produced upon photolysis degrade both pUC19 bacterial plasmid DNA, as well as a 25-base-pair, double-stranded oligonucleotide. Detailed analyses of the cleavage reactions reveal 5'-phosphate and 3'-phosphoglycolate termini that are derived from H-atom abstraction from the 4'-position of the deoxyribose ring rather than redox-induced base oxidation.