“All new is well-forgotten old”, the proverb goes. The current “fluorine boom” is news only to a novice in the field: the exceptional importance of fluorinated organic compounds in numerous areas has been known for a long time. The sharpest increase in the number of fluorine-containing pharmaceuticals and agrochemicals is dated back to 30 years ago. Also around that time (1979), the first monograph devoted to industrial applications of organofluorine compounds was published, covering not only fluorine-containing biologically active materials but also refrigerants, propellants, surfactants, textile chemicals, polymers, and dyes. The increasingly broad realization of the key role of organofluorine compounds in numerous areas has recently attracted many new scientists to the field. The development of new methods for the selective introduction of fluorine and fluorinecontaining groups into organic molecules for biologically active and other useful materials has become a hot area. Over 100 reviews, book chapters, and highlights on this subject have appeared in the literature in the past few years. As citing all of these publications in this review article is impossible, we provide references to only the most recent, general, and comprehensive ones. Molecules bearing a trifluoromethyl group constitute one of the most important classes of selectively fluorinated compounds. As early as 1928, Lehmann reported his observations of biological activity of some trifluoromethylated organic derivatives and already in 1959 Yale published a detailed review article entitled “The Trifluoromethyl Group in Medicinal Chemistry”. Since then, numerous books and reviews have appeared in the literature covering various aspects of trifluoromethylated organic and organometallic compounds. Within this family, derivatives bearing the CF3 group on aromatic rings are particularly numerous and important. Some examples of such compounds used as active ingredients of pharmaceuticals and agrochemicals are shown in Scheme 1. Trifluoromethylated building blocks and intermediates are clearly needed to make such molecules. The simplest trifluoromethylated aromatic compound, benzotrifluoride, was originally prepared by Swarts at the end of the 19th century. In his work, Swarts treated benzotrichloride with “two thirds of its weight of antimony fluoride” to obtain a mixture of PhCF2Cl and PhCF3, from which the two were separated and isolated pure by distillation. In the early 1930s, two industrial groups, one from Kinetic Chemicals, Inc. and one from I. G. Farbenindustrie AG patented their discoveries on the successful use of HF instead of SbF3 for the Swarts reaction. These inventions were the starting point for the modern large-scale manufacturing of trifluoromethylated aromatics. Other methods have been developed for conversion of various C1 units on the ring to CF3 with a variety of fluorinating agents. While representing an outstanding discovery and a classic of organic and organofluorine chemistry, the Swarts reaction is nonetheless neither atom-economical nor environmentally benign, as it deals with stoichiometric quantities of hazardous chemicals and generates large amounts of chlorine waste. To convert a CH3 group on the ring to CF3, the methyl is first exhaustively chlorinated to produce 3 equiv of HCl as a

Aromatic Trifluoromethylation with Metal Complexes

Functionalization of fluorinated molecules by transition-metal-mediated C-F bond activation to access fluorinated building blocks.

Oxidative Addition Reactions of Organoplatinum(II) Complexes with Nitrogen-Donor Ligands.

This critical review highlights the progress in (195)Pt NMR over the last 25 years. In particular, some of the recent applications of (195)Pt NMR in catalytic and mechanistic studies, intermetallics and drug binding studies are discussed. (195)Pt NMR chemical shifts obtained from both theoretical studies and experiments are presented for Pt(0), Pt(II), Pt(III) and Pt(IV) complexes. (195)Pt coupling with various nuclei (viz. coupling constants) have also been collected in addition to data on (195)Pt relaxation. The latest developments in the theoretical knowledge and experimental advances have made (195)Pt NMR into a rich source of information in many fields. (164 references.).

195Pt NMR—theory and application

Multicomponent chemotherapy has increasingly become a strategy of great importance in clinical cancer treatments. However, this type of chemotherapy has not been demonstrated in nanoscale delivery vehicles where two cytotoxic agents can be packaged together, potentially leading to synergistic drug activities. Herein, we present the codelivery of doxorubicin and cisplatin via a single polymer-caged nanobin (PCN) and show that copackaging can yield strong synergy in the efficacy of these agents. Such a PCN comprises a doxorubicin-encapsulated liposomal core protected by a pH-responsive cisplatin prodrug-loaded polymer shell with tunable drug ratios and surface charge potentials. This dual-agent Pt-PCNDXR formulation dramatically enhances the overall cytotoxicity of each drug against cancer cells at reduced doses and exhibits higher synergy than combinations of either the free drugs or separately nano-packaged drugs. These results clearly indicate that the polymer-caged nanobin platform can offer new means f...

Polymer-caged nanobins for synergistic cisplatin-doxorubicin combination chemotherapy.

Displacement of norbornadiene (NBD) from Pt(CF3)2(NBD) by weak donor ligands L, and reactions of cis-Pt(CF3)2L2 with water and acids

Oxidative addition to bis(trifluoromethyl)platinum(II) complexes with N-donor ligands

Reactions of cis-Pt(NH 3) 2(H 2O) 2 2+ (1) with 2-aminomalonic acid (amalH 2), aspartic acid (aspH 2), and glutamic acid (gluH 2) have been studied by multinuclear ( 1H, 13C, 195Pt, 15N) NMR spectroscopy. With aspH 2 or gluH 2, 1 gives initially a complex in which the ligand is bound through only one carboxylate group, cis-Pt(NH 3) 2(LH 2-O)(H 2O) 2+. At pH <2, the α-carboxyl group is bound predominantly, but at pH 4-5, both carboxylate groups are involved to a similar extent. Over 2-3 days at pH 1.5, a complex with five-membered N,αO-chelate ring is formed, Pt(NH 3) 2(LH-N,αO) +. Reaction of aminomalonate with 1 gives initially a complex Pt(NH 3) 2(amalH-O,O′) +, with a six-membered chelate ring. Over 2-3 days at pH 1.5, this complex converts to Pt(NH 3) 2(amalH-N,O) +, with a five-membered ring. In solutions sufficiently acidic to protonate the uncoordinated carboxyl group, decarboxylation then occurs over several days to give the glycinate complex Pt(NH 3) 2(gly-N,O) +. The carboxylate group that is not part of the five-membered chelate ring in each of the three complexes Pt(NH 3) 2(L-N,O) is able to coordinate to platinum from excess 1. With aspartic and glutamic acids, one or two Pt(NH 3) 2(L) moieties can coordinate to one diammineplatinum(II) cation, to give [{Pt(NH 3) 2(L)}{Pt(NH 3) 2(H 2O)}] 2+ or [{Pt(NH 3) 2(L)} 2{Pt(NH 3) 2}] 2+, respectively. One Pt(NH 3) 2(amal) molecule can react with 1 to give [{Pt(NH 3) 2(amal)}{Pt(NH 3) 2(H 2O)}] 2+, which is in equilibrium with [{Pt(NH 3) 2} 2(amal)] 2+, in which the carboxylate group involved in a five-membered N,O-chelate ring with one Pt atom also bridges to the second Pt atom to complete a six-membered O,O′-chelate ring.

Reactions of the cis-diamminediaquaplatinum(II) cation with 2-aminomalonic acid and its homologs, aspartic and glutamic acids. Rearrangements of metastable complexes with carboxylate-bound ligands to N,O-chelates and formation of di- and trinuclear complexes

Donald W. Neale

Papers

Displacement of norbornadiene (NBD) from Pt(CF3)2(NBD) by weak donor ligands L, and reactions of cis-Pt(CF3)2L2 with water and acids

Oxidative addition to bis(trifluoromethyl)platinum(II) complexes with N-donor ligands

Reactions of the cis-diamminediaquaplatinum(II) cation with 2-aminomalonic acid and its homologs, aspartic and glutamic acids. Rearrangements of metastable complexes with carboxylate-bound ligands to N,O-chelates and formation of di- and trinuclear complexes

NMR spectra of platinum(III) complexes with sulfato- and phosphato-bridges

195Pt chemical shifts and PtPt coupling constants for sulfato- and phosphato-bridged platinum(III) dimeric anions