John Desper

Using Cocrystals To Systematically Modulate Aqueous Solubility and Melting Behavior of an Anticancer Drug

Five cocrystals of an anticancer compound have been assembled using a well-defined hydrogen-bond-based supramolecular approach that produced the necessary structural consistency in the resulting solids. These cocrystals contain aliphatic even-numbered dicarboxylic acids of increasing chain length, and as a result, the physical properties of the cocrystals can be related to the molecular structure of the acid. The melting points of the five cocrystals show an excellent correlation with the melting points of the individual acids, and it has also been shown that aqueous solubility can be increased by a factor of 2.5 relative to that of the individual drug. Consequently, cocrystals can offer a range of solid forms from which can be chosen an active ingredient where a particular physical property can be dialed in, provided that the cocrystals show considerable structural consistency and that systematic changes are made to the participating cocrystallizing agents.

Bis-N-heterocyclic Carbene Palladium(IV) Tetrachloride Complexes: Synthesis, Reactivity, and Mechanisms of Direct Chlorinations and Oxidations of Organic Substrates

This Article describes the preparation and isolation of novel octahedral CH(2)-bridged bis-(N-heterocyclic carbene)palladium(IV) tetrachlorides of the general formula LPd(IV)Cl(4) [L = (NHC)CH(2)(NHC)] from LPd(II)Cl(2) and Cl(2). In intermolecular, nonchelation-controlled transformations LPd(IV)Cl(4) reacted with alkenes and alkynes to 1,2-dichlorination adducts. Aromatic, benzylic, and aliphatic C-H bonds were converted into C-Cl bonds. Detailed mechanistic investigations in the dichlorinations of alkenes were conducted on the 18VE Pd(IV) complex. Positive solvent effects as well as kinetic measurements probing the impact of cyclohexene and chloride concentrations on the rate of alkene chlorination support a Pd(IV)-Cl ionization in the first step. Product stereochemistry and product distributions from various alkenes also support Cl(+)-transfer from the pentacoordinated Pd(IV)-intermediate LPd(IV)Cl(3)(+) to olefins. 1-Hexene/3-hexene competition experiments rule out both the formation of π-complexes along the reaction coordinate as well as in situ generated Cl(2) from a reductive elimination process. Instead, a ligand-mediated direct Cl(+)-transfer from LPd(IV)Cl(3)(+) to the π-system is likely to occur. Similarly, C-H bond chlorinations proceed via an electrophilic process with in situ formed LPd(IV)Cl(3)(+). The presence of a large excess of added Cl(-) slows cyclohexene chlorination while the presence of stoichiometric amounts of chloride accelerates both Pd(IV)-Cl ionization and Cl(+)-transfer from LPd(IV)Cl(3)(+). (1)H NMR titrations, T1 relaxation time measurements, binding isotherms, and Job plot analysis point to the formation of a trifurcated Cl(-)···H-C bond in the NHC-ligand periphery as a supramolecular cause for the accelerated chemical events involving the metal center.

Establishing amide...amide reliability and synthon transferability in the supramolecular assembly of metal-containing one-dimensional architectures.

On the basis of a combination of new structural data (eleven single-crystal structure determinations are presented) and information from the Cambridge Structural Database, it has been shown that self-complementary hydrogen-bond based amide...amide dimers can be relied upon as effective supramolecular synthons for the assembly and organization of acac- and paddle-wheel complexes of a variety of metal(II) ions. The targeted molecular recognition event and intended extended one-dimensional motif appear with a supramolecular yield of 78% (a total of 28 structures were examined). Despite the fact that the hydrogen bonds that give rise to the R2(2)(8) motif can be disrupted by both carboxylate- and acac-ligands, as well as by solvent molecules, they remain remarkably resilient and therefore represent useful synthetic tools in inorganic crystal engineering.

Co-crystal screening of diclofenac.

In the pharmaceutical industry, co-crystals are becoming increasingly valuable as crystalline solids that can offer altered/improved physical properties of an active pharmaceutical ingredient (API) without changing its chemical identity or biological activity. In order to identify new solid forms of diclofenac—an analgesic with extremely poor aqueous solubility for which few co-crystal structures have been determined—a range of pyrazoles, pyridines, and pyrimidines were screened for co-crystal formation using solvent assisted grinding and infrared spectroscopy with an overall success rate of 50%. The crystal structures of three new diclofenac co-crystals are reported herein: (diclofenac)·(2-aminopyrimidine), (diclofenac)·(2-amino-4,6-dimethylpyrimidine), and (diclofenac)·(2-amino-4-chloro-6-methylpyrimidine).

Synthesis of Cyclododeciptycene Quinones

Cycloiptycenes are elusive and synthetically challenging molecules. We report the first synthesis of two substituted cyclododeciptycene tetraquinones via a sequence of intermolecular and intramolecular Diels-Alder reactions from cis,cis-heptiptycene tetraquinone 2 and substituted 7,16-dihydro-7,16-(o-benzeno)heptacenes 3. Heptiptycene tetraquinone 2 was made from triptycene bisquinone 4 and 1,4-dimethoxyanthracene in three steps, and 6,8,15,17-tetramethoxy-7,16-dihydro-7,16-(o-benzeno)heptacene (3a) was synthesized from triptycene bisquinone 4 and 1,4-dihydro-2,3-benzoxathiin-3-oxide in four steps. The structure of a cyclododeciptycene, 1a, was determined by a single-crystal X-ray analysis. The synthetic sequence is general and should allow the incorporation of various alkoxy and acetoxy substituents appended to the cycloiptycene framework.

Macrocycles containing sulfur and phosphorus: Structure and complexation properties

Abstra: The structure and complexation properties of macrocycles containing atoms from the second row of the periodic table (e.g., sulfur and phosphorus) have received less attention than the corresponding properties of macrocycles containing only first row atoms (e.g., oxygen and nitrogen). We describe results in two areas: macrocyclic thioethers for chelation of late transition metal ions, and macrocycles containing sulfoxide and phosphine oxide groups for complexation of monosaccharide derivatives via multipoint hydrogen bonding.

An unusual hydrogen bonding pattern in a crystallographically observed β-turn

Abstract In the crystalline state, tBoc-glycylglycine-cyclohexylamide adopts a β-turn conformation that has several interesting features: the ten-membered ring CO—H-N interaction is characterized by a very long O—H distance, and two of the amide protons appear to be within hydrogen bonding distance of the preceding amidic nitrogen.

Metal insertion into a CH bond as a route to the heterobimetallic μ-methylidene complex C5H5(CO)2Re(μ-CH2)Pt(PPh3)2

Abstract The reaction of C 5 H 5 (CO) 2 Re(CH 3 )−Li + -THF ( 5 ) with (Ph 3 P) 3 Pt[( E )-C(CH 3 )CHCH 3 ] + CF 3 SO 3 − ( 3E ) in an attempt to prepare the heterobimetallic complex C 5 H 5 (CO) 2 (CH 3 )RePt[( E )-C(CH 3 )CHCH 3 ](PPh 3 ) 2 ( B ) led to the formation of the new heterobimetallic μ-methylene complex C 5 H 5 (CO) 2 Re(μ-Ch 2 )Pt(PPh 3 ) 2 ( 4 ), which was characterized by X-ray crystallography. A mechanism involving initial generation of intermediate B followed by insertion of Pt into a CH bond and reductive elimination is suggested. The related substituted alkylidene complexes C 5 H 5 (CO) 2 Re[μ-CH( E -CH 3 CCHCH 3 )]Pt(PPh 3 ) 2 ( 9 ) and C 5 H 5 (CO) 2 Re(μ-CHCH 3 )Pt(PPh 3 ) 2 ( 11 ) were prepared from Pt(C 2 -H 4 )(PPh 3 ) 2 and the appropriate rhenium alkylidene complexes C 5 H 5 (CO) 2 ReCHR.

Stereoselective oxidation of an eleven-membered heterocycle

Abstract Oxidation of macrocyclic phosphine oxide-dithioether 1 produces only the dl form of disulfoxide 2. This selectivity can be rationalized by comparing the crystal structures of starting material and product, and on the basis of VT NMR data, which suggest that the starting macrocycle is conformationally constrained in solution.