A new route to N-aromatic heterocycles from the hydrogenation of diesters in the presence of anilines.

The hydrogenation of dicarboxylic acids and their esters in the presence of anilines provides a new synthesis of heterocycles. [Ru(acac)3] and 1,1,1-tris(diphenylphosphinomethyl)ethane (triphos) gave good to excellent yields of the cyclic amines at 220 °C. When aqueous ammonia was used with dimethyl 1,6-hexadienoic acid, ε-caprolactam was obtained in good yield. A side reaction involving alkylation of the amine by methanol was suppressed by using diesters derived from longer chain and branched alcohols. Hydrogenation of optically pure diesters (dimethyl (R)-2-methylbutanedioate and dimethyl (S)-2-methylbutanedioate) with aniline afforded racemic 3-methyl-1-phenylpyrrolidine in 78% yield.

Connecting defects and amorphization in UiO-66 and MIL-140 metal­organic frameworks: a combined experimental and computational study.

The mechanism and products of the structural collapse of the metal­organic frameworks (MOFs) UiO-66, MIL-140B and MIL-140C upon ball-milling are investigated through solid state 13C NMR and pair distribution function (PDF) studies, finding amorphization to proceed by the breaking of a fraction of metal­ligand bonding in each case. The amorphous products contain inorganic­organic bonding motifs reminiscent of the crystalline phases. Whilst the inorganic Zr6O4(OH)4 clusters of UiO-66 remain intact upon structural collapse, the ZrO backbone of the MIL-140 frameworks undergoes substantial distortion. Density functional theory calculations have been performed to investigate defective models of MIL-140B and show, through comparison of calculated and experimental 13C NMR spectra, that amorphization and defects in the materials are linked.

A comparison of the amorphization of zeolitic imidazolate frameworks (ZIFs) and aluminosilicate zeolites by ball-milling.

X-ray diffraction has been used to investigate the kinetics of amorphization through ball-milling at 20 Hz, for five zeolitic imidazolate frameworks (ZIFs) - ZIF-8, ZIF-4, ZIF-zni, BIF-1-Li and CdIF-1. We find that the rates of amorphization for the zinc-containing ZIFs increase with increasing solvent accessible volume (SAV) in the sequence ZIF-8 > ZIF-4 > ZIF-zni. The Li-B analogue of the dense ZIF-zni amorphizes more slowly than the corresponding zinc phase, with the behaviour showing a correlation with their relative bulk moduli and SAVs. The cadmium analogue of ZIF-8 (CdIF-1) amorphizes more rapidly than the zinc counterpart, which we ascribe primarily to its relatively weak M-N bonds as well as the higher SAV. The results for the ZIFs are compared to three classical zeolites - Na-X, Na-Y and ZSM-5 - with these taking up to four times longer to amorphize. The presence of adsorbed solvent in the pores is found to render both ZIF and zeolite frameworks more resistant to amorphization. X-ray total scattering measurements show that amorphous ZIF-zni is structurally indistinguishable from amorphous ZIF-4 with both structures retaining the same short-range order that is present in their crystalline precursors. By contrast, both X-ray total scattering measurements and (113)Cd NMR measurements point to changes in the local environment of amorphous CdIF-1 compared with its crystalline CdIF-1 precursor.

Drug delivery and controlled release from biocompatible metal-organic frameworks using mechanical amorphization.

We have used a family of Zr-based metal-organic frameworks (MOFs) with different functionalized (bromo, nitro and amino) and extended linkers for drug delivery. We loaded the materials with the fluorescent model molecule calcein and the anticancer drug α-cyano-4-hydroxycinnamic acid (α-CHC), and consequently performed a mechanical amorphization process to attempt to control the delivery of guest molecules. Our analysis revealed that the loading values of both molecules were higher for the MOFs containing unfunctionalized linkers. Confocal microscopy showed that all the materials were able to penetrate into cells, and the therapeutic effect of α-CHC on HeLa cells was enhanced when loaded (20 wt%) into the MOF with the longest linker. On one hand, calcein release required up to 3 days from the crystalline form for all the materials. On the other hand, the amorphous counterparts containing the bromo and nitro functional groups released only a fraction of the total loaded amount, and in the case of the amino-MOF a slow and progressive release was successfully achieved for 15 days. In the case of the materials loaded with α-CHC, no difference was observed between the crystalline and amorphous form of the materials. These results highlight the necessity of a balance between the pore size of the materials and the size of the guest molecules to accomplish a successful and efficient sustained release using this mechanical ball-milling process. Additionally, the endocytic pathway used by cells to internalize these MOFs may lead to diverse final cellular locations and consequently, different therapeutic effects. Understanding these cellular mechanisms will drive the design of more effective MOFs for drug delivery applications.

Combined experimental and computational NMR study of crystalline and amorphous zeolitic imidazolate frameworks.

Zeolitic imidazolate frameworks (ZIFs) have attracted great interest in recent years due to their high chemical and thermal stability with promising applications in gas storage and separations. We investigate the structures of three different crystalline ZIFs - ZIF-4, ZIF-8, ZIF-zni - and their amorphous counterparts using high field (13)C and (15)N CP MAS NMR. The high field (20 T) allows for the observation of all crystallographically independent carbon and nitrogen atoms in the crystalline ZIFs. Combining our experimental results with density functional theory calculations enabled the assignment of all chemical shifts. The crystalline spectra reveal the potential of high field NMR to distinguish between two ZIF polymorphs, ZIF-4 and ZIF-zni, with identical [Zn(C3H3N2)2] chemical compositions. (13)C and (15)N CP MAS NMR data obtained for the amorphous ZIFs clearly showed signal broadening upon amorphization, confirming the retention of chemical composition and the structural similarity of amorphous ZIF-4 and ZIF-zni. In the case of amorphous ZIF-8, we present evidence for the partial de-coordination of the 2-methyl imidazole linker.

Amorphous metal-organic frameworks for drug delivery.

We report the encapsulation of the hydrophilic model molecule calcein in the Zr-based MOF UiO-66, followed by amorphization of the framework by ball-milling. We show controlled release of calcein over more than 30 days, compared with the 2 day release period from crystalline UiO-66.