Metal coordination polymer chemistry is a growing field, its exploration driven in part by the search for novel magnetic materials 1,2 as well as for new microporous phases 3 and catalysts 4 which are complementary to zeolites. Recently, we reported the solvothermal synthesis of a highly porous yet stable coordination polymer from copper ions and trimesic acid [Cu 3 {1,3,5- 5 Central to the stability of 1 is the structural rigidity of its [Cu 2 (µ-O 2 CR) 4 L 2 ] dimer units (Figure 1). A recent report by Japanese workers of a related sorption polymer [Cu-{1,4-C 6 H 4 (COO) 2 }(H 2 O) x ] n , 6 prompted us to explore the solvothermal chemistry of the copper terephthalate system.Herein we report that under solvothermal or hydrothermal conditions, reaction of copper(II) nitrate, terephthalic acid, and 4,4′-bipyridine 7 results in the formation of an air-stable, openframework coordination polymer with mixed-valence [Cu 2 ] 3+ dimer subunits, [Cu 4 {1,4-C 6 H 4 (COO) 2 } 3 (4,4′-bipy) 2 ] n , 2. We believe that the polymer represents the trapping through "supramolecular precipitation" of the unstable Cu(I)-Cu(II) dimers which are produced under the reducing conditions prevalent in the reaction media at high temperatures.Compound 2 is formed phase-pure as small dark-blue blocks of ∼100 µm dimension in ∼65% yield from a solvothermal reaction (180 °C, 1 day) of [Cu(NO 3 ) 2 ]‚H 2 O, [1,4-C 6 H 4 (COOH) 2 ] and [4,4′-bipy] of 1:1:1 ratio in 50% aqueous ethanol. Larger crystal specimens up to 1 mm are formed, although in much reduced yield ( ∼20% of the isolated solids) from a parallel hydrothermal reaction with copper sulfate. The dark coloration suggested a rather novel structure for 2 which was confirmed by single-crystal diffraction. 8 Rather than the expected "paddle-wheel" arrangement of four bridging carboxylates, found in 1, an open-framework polymer containing dimeric [Cu 2 (µ-O 2 CR) 3 L 2 ] units with only three carboxylate bridges is found in compound 2. (Figure 2) Once the framework atoms had been refined, difference Fourier maps revealed no peaks of chemical significance, residual electron density maxima and minima were +0.92/-0.97 e Å -3 , both less than 1 Å from Cu. The necessity to charge balance the ligands in 2, indicate that the metals have a mixed Cu(I)-Cu(II) formulation. Other structural evidence for this comes from the unusually short Cu-Cu separation of 2.442(1) Å. This is consistent with the majority of [Cu 2 ] 3+ complexes determined previously, 9-11 which also have short "bonds". 12 Furthermore the bond valence sums indicate equivalence of the Cu centers and a delocalized 1.5+ "oxidation state" for each site.
Artesunate drug substance, for which a rectal capsule formulation is under development for the treatment of severe malaria, when heated at 100 degrees C for 39 h gives beta-artesunate, artesunate dimers, 9,10-anhydrodihydroartemisinin (glycal), a DHA beta-formate ester, and smaller amounts of other products that arise via intermediate formation of dihydroartemisinin (DHA) and subsequent thermal degradation. Solid DHA at 100 degrees C provides an epimeric mixture of a known peroxyhemiacetal, arising via ring opening to a hydroperoxide and re-closure, smaller amounts of a 3:1 mixture of epimers of a known tricarbonyl compound, and a single epimer of a new dicarbonyl compound. The latter arises via homolysis of the peroxide and an ensuing cascade of alpha-cleavage reactions which leads to loss of formic acid incorporating the C10 carbonyl group of DHA exposed by this 'unzipping' cascade. The tricarbonyl compound that arises via peroxide homolysis and extrusion of formic acid from a penultimate hydroxyformate ester incorporating C12 of the original DHA, is epimeric at the exocyclic 1''-aldehyde, and not in the cyclohexanone moiety. It is converted into the dicarbonyl compound by peroxide-induced deformylation. The dicarbonyl compound is not formed during anhydrous ferrous bromide mediated decomposition of DHA at room temperature, which provides the 1''-R epimer of the tricarbonyl compound as the dominant product; this equilibrates at room temperature to the 3:1 mixture of epimers of the tricarbonyl compound obtained from thermolysis. Each of artesunate and DHA decomposes readily under aqueous acidic conditions to provide significant amounts of the peroxyhemiacetal, which, like DHA, decomposes to the inert end product 2-deoxyartemisinin under acidic or basic conditions. DHA and the peroxyhemiacetal are the principal degradants in aged rectal capsule formulations of artesunate. TGA analysis and thermal degradation of DHA reveals a thermal lability which would pose a problem not only in relation to ICH stability testing guidelines, but in the use of DHA in fixed formulations currently under development. This thermolability coupled with the poor physicochemical properties and relative oral bioavailability of DHA suggests that it is inferior to artesunate in application as an antimalarial drug.
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