Reductive and Oxidative DNA Damage by Photoactive Platinum(II) Intercalators

Several photoactive platinum R-diimine intercalators have been prepared to develop new probes of DNA oxidation and reduction chemistry. Five water-soluble bis(mes')Pt(II) complexes (mes') N,N,N,3,5-pentamethylaniline) with various aromatic α-diimine ligands (dppz= dipyridophenazine, np = naphtha[2,3-f][1,ω]phenanthroline, CN-np = naphtho[2,3-f][1,10]phenanthroline-9-carbonitrile, CN_2-np = naphtho[2,3-f][1,10]phenanthroline-9,14-dicarbonitrile, and bp = benzo-[f][1,10]phenanthroline) were synthesized. The complex [(np)Pt(mes')_2]Cl_2 was also characterized by X-ray crystallography, and the crystal structure shows that the ortho-methyl groups of the mes' ligands conveniently block substitution at the vacant sites of platinum without overlapping with the intercalating α-diimine ligand. The Pt(II) complexes were found to have excited-state oxidation and reduction potentials of -0.6 to -1.0 and 1.0 to 1.5 V versus NHE, respectively, making them potent photoreductants as well as photooxidants. Many of the complexes are found to promote the photooxidation of N^2-cyclopropyldeoxyguanosine (d^(Cp)G). Photoexcited [(dppz)Pt(mes')_2]^(2+) is found to be most efficient in this photooxidation, as well as in the photoreduction of N^4-cyclopropylcytidine (^(Cp)C); these modified nucleosides rapidly decompose in a ring-opening reaction upon oxidation or reduction. Photoexcited [(dppz)Pt(mes')_2]Cl_2, upon intercalation into the DNA π stack, is found, in addition, to promote reductive and oxidative damage within the DNA duplex, as is also probed using the kinetically fast electron and hole traps, ^(Cp)C and ^(Cp)G. These Pt complexes may therefore offer useful reactive tools to compare and contrast directly reductive and oxidative chemistry in double helical DNA

Mild Catalytic methods for Alkyl-Alkyl Bond Formation

Overview of Research Goals and Accomplishments for the Period 07/01/06 – 06/30/07: Our overall research goal is to transform the rapidly emerging synthetic chemistry involving alkyl-alkyl cross-couplings into more of a mechanism-based field so that that new, rationally-designed catalysts can be performed under energy efficient conditions. Our specific objectives for the previous year were 1) to obtain a proper electronic description of an active catalyst for alkyl-alkyl cross-coupling reactions and 2) to determine the effect of ligand structure on the rate, scope, selectivity, and functional group compatibility of C(sp3)-C(sp3) cross-coupling catalysis. We have completed both of these initial objectives and established a firm base for further studies. The specific significant achievements of the current grant period include: 1) we have performed magnetic and computational studies on (terpyridine)NiMe, an active catalyst for alkyl-alkyl cross couplings, and have discovered that the unpaired electron resides heavily on the terpyridine ligand and that the proper electronic description of this nickel complex is a Ni(II)-methyl cation bound to a reduced terpyridine ligand; 2) we have for the first time shown that alkyl halide reduction by terpyridyl nickel catalysts is substantially ligand based; 3) we have shown by isotopic labeling studies that the active catalyst (terpyridine)NiMe is not produced via a mechanism that involves the formation of methyl radicals when (TMEDA)NiMe2 is used as the catalyst precursor; 4) we have performed an extensive ligand survey for the alkyl-alkyl cross-coupling reactions and have found that electronic factors only moderately influence reactivity in the terpyridine-based catalysis and that the most dramatic effects arise from steric and solubility factors; 5) we have found that the use of bis(dialkylphosphino)methanes as ligands for nickel does not produce active catalysts for cross-coupling but rather leads to bridging hydride complexes of varying geometries; 6) we have determined that the geometry of aforementioned bridging hydride complexes is largely determined by external forces such as hydrogen bonding interactions and crystal packing forces; 7) we have found that the rate of reductive elimination of alkane from a (pyridyl-2-pyrrolide)AuMe2 complex is severely inhibited due to the rigid geometry of the pyridyl-2-pyrrolide ligand; 8) we have prepared, structurally characterized, and explored the reactivity of 1-adamantylzinc reagents as model nucleophiles for sterically challenging alkyl-alkyl cross-coupling reactions. The continued success of this work will lead to alkyl-alkyl cross-coupling catalysts with broad scope and selectivities. The work has potential to significantly impact science and technologies of interest to the DOE as the chemistry is focused on developing useful reactions using reagents that can be directly prepared from petroleum and natural gas feedstocks. Moreover, the developing synthetic chemistry can profoundly affect the way materials, fine chemicals, and drugs are made. Since the methodology we are developing can shorten existing synthetic protocols, proceed at room temperature, and operate under environmentally benign conditions, it can greatly reduce energy expenditures, especially considering the contribution of the chemical manufacturing field to the gross domestic product

Versatile Route to Arylated Fluoroalkyl Bromide Building Blocks

New difunctionalized and fluoroalkylated silyl reagents have been prepared that react with silver and copper salts to afford active catalysts that can be used to synthesize arylated fluoroalkyl bromide building blocks. It has been shown that the [(phen)­Ag­(CF₂)_<i>n</i>Br] intermediates are capable of transferring both the phenanthroline ligand and the fluoroalkyl bromide chain to copper iodide, eliminating the need for a preligated copper salt precursor. The methodology is compatible with various chain lengths of the fluoroalkyl halide functionality

Exploring Mechanisms in Ni Terpyridine Catalyzed C-C Cross-Coupling Reactions-A Review

In recent years, nickel has entered the stage for catalyzed C-C cross-coupling reactions, replacing expensive palladium, and in some cases enabling the use of new substrate classes. Polypyridine ligands have played an important role in this development, and the prototypical tridentate 2,2':6',2 ''-terpyridine (tpy) stands as an excellent example of these ligands. This review summarizes research that has been devoted to exploring the mechanistic details in catalyzed C-C cross-coupling reactions using tpy-based nickel systems

Direct Difluoromethylation of Aryl Halides via Base Metal Catalysis at Room Temperature

A stable and isolable difluoro­methyl zinc reagent has been prepared through the reaction of ICF₂H with diethyl zinc and DMPU. This new zinc reagent is a free-flowing solid and can be used in combination with a nickel catalyst to difluoro­methylate aryl iodides, bromides, and triflates at room temperature. Such mild conditions for the catalytic difluoro­methylation of these substrates are unprecedented

Oxygen-Bound Trifluoromethoxide Complexes of Copper and Gold

Well-defined copper and gold complexes have been prepared which contain the shortest structurally characterized metal–oxygen bonds between transition metals and a trifluoromethoxide moiety. The trifluoromethoxide ligand is O-bound to both the copper and gold centers, with a copper–oxygen distance of 1.849(4) Å and a gold–oxygen distance of 2.058(4) Å. Density functional theory (DFT) calculations on all new trifluoromethoxy complexes were performed in order to obtain bond lengths and angles that are not influenced from any intermolecular contacts in the solid state and also to provide a first glimpse of the electronic features of this previously unknown ligand