Scott A. Cameron

Stimuli-responsive Pd2L4 metallosupramolecular cages: towards targeted cisplatin drug delivery

Metallosupramolecular cages are an emerging, but as of yet relativity unexplored, drug delivery vector. Herein we show that discrete dipalladium(II) molecular cages of the formula [Pd2L4](X)4 can be quantatively self-assembled from a simple tripyridyl ligand (2,6-bis(pyridin-3-ylethynyl)pyridine) and [Pd(CH3CN)4](X)2 (X = BF4− or SbF6−). The cages have been fully characterised using 1H, 13C and DOSY NMR spectroscopy, elemental analysis, IR spectroscopy, and high resolution electrospray mass spectrometry (HR-ESMS). Additionally, the molecular structure of the [Pd2L4](SbF6)4 cage was confirmed unequivocally using X-ray diffraction. These [Pd2L4](X)4 cages are stimuli-responsive and can be reversibly disassembled/reassembled upon the addition/removal of suitable competing ligands. The central cavities of the [Pd2L4](X)4 cages are lined with four hydrogen bond accepting pyridine units which enable the encapsulation of two cisplatin molecules within the metallosupramolecular architecture through hydrogen bonding interactions between the cage and the amine ligands of the cisplatin guest. The structure of the [Pd2L4⊃(cisplatin)2](BF4)4 host–guest adduct has been confirmed by 1H NMR spectroscopy, HR-ESMS and X-ray crystallography. Additionally we have demonstrated that the cage–cisplatin host–guest adduct can be quantatively disassembled upon the addition of a competing ligand, releasing the cisplatin guest. This is the first crystallographically characterised example of a discrete metallosupramolecular cage encapsulating an FDA-approved inorganic drug molecule. This host–guest chemistry could open the way to relatively unexplored methods of drug delivery, which circumvent the malicious side effects and drug resistance associated with cisplatin and other anticancer therapeutics.

A family of 13 tetranuclear zinc(II)-lanthanide(III) complexes of a [3 + 3] Schiff-base macrocycle derived from 1,4-diformyl-2,3-dihydroxybenzene

A family of thirteen tetranuclear heterometallic zinc(II)-lanthanide(III) complexes of the hexa-imine macrocycle (L(Pr))(6-), with general formula Zn(II)(3)Ln(III)(L(Pr))(NO(3))(3)·xsolvents (Ln = La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm or Yb), were prepared in a one-pot synthesis using a 3:1:3:3 reaction of zinc(II) acetate, the appropriate lanthanide(III) nitrate, the dialdehyde 1,4-diformyl-2,3-dihydroxybenzene (H(2)L(1)) and 1,3-diaminopropane. A hexanuclear homometallic zinc(II) macrocyclic complex [Zn(6)(L(Pr))(OAc)(5)(OH)(H(2)O)]·3H(2)O was obtained using a 2:0:1:1 ratio of the same reagents. A control experiment using a 1:0:1:1 ratio failed to generate the lanthanide-free [Zn(3)(L(Pr))] macrocyclic complex. The reaction of H(2)L(1) and zinc(II) acetate in a 1:1 ratio yielded the pentanuclear homometallic complex of the dialdehyde H(2)L(1), [Zn(5)(L(1))(5)(H(2)O)(6)]·3H(2)O. An X-ray crystal structure determination revealed [Zn(3)(II)Pr(III)(L(Pr))(NO(3))(2)(DMF)(3)](NO(3))·0.9DMF has the large ten-coordinate lanthanide(III) ion bound in the central O(6) site with two bidentate nitrate anions completing the O(10) coordination sphere. The three square pyramidal zinc(II) ions are in the outer N(2)O(2) sites with a fifth donor from DMF. Measurement of the magnetic properties of [Zn(II)(3)Dy(III)(L(Pr))(NO(3))(3)(MeOH)(3)]·4H(2)O with a weak external dc field showed that it has a frequency-dependent out-of-phase component of ac susceptibility, indicative of slow relaxation of the magnetization (SMM behaviour). Likewise, the Er and Yb analogues are field-induced SMMs; the latter is only the second example of a Yb-based SMM. The neodymium, ytterbium and erbium complexes are luminescent in the solid phase, but only the ytterbium and neodymium complexes show strong lanthanide-centred luminescence in DMF solution.

Sensitivity of silver(I) complexes of a pyrimidine-hydrazone ligand to solvent, counteranion, and metal-to-ligand ratio changes.

Metal complexation studies were performed with AgSO(3)CF(3) and AgBF(4) and the ditopic pyrimidine-hydrazone ligand 6-(hydroxymethyl)pyridine-2-carboxaldehyde (2-methylpyrimidine-4,6-diyl)bis(1-methylhydrazone) (1) in both CH(3)CN and CH(3)NO(2) in a variety of metal-to-ligand ratios. The resulting complexes were studied in solution by NMR spectroscopy and in the solid state by X-ray crystallography. Reacting either AgSO(3)CF(3) or AgBF(4) with 1 in either CH(3)CN or CH(3)NO(2) in a 1:1 metal-to-ligand ratio produced a double helicate in solution. This double helicate could be converted into a linear complex by increasing the metal-to-ligand ratio; however, the degree of conversion depended on the solvent and counteranion used. Attempts to crystallize the linear AgSO(3)CF(3) complex resulted in crystals with the dimeric structure [Ag(2)1(CH(3)CN)(2)](2)(SO(3)CF(3))(4) (2), while attempts to crystallize the AgSO(3)CF(3) double helicate from CH(3)CN resulted in crystals of another dimeric complex, [Ag(2)1(SO(3)CF(3))(CH(3)CN)(2)](2)(SO(3)CF(3))(2)·H(2)O (3). The AgSO(3)CF(3) double helicate was successfully crystallized from a mixture of CH(3)CN and CH(3)NO(2) and had the structure [Ag(2)1(2)](SO(3)CF(3))(2)·3CH(3)NO(2) (4). The linear AgBF(4) complex could not be isolated from the double helicate in solution; however, crystals grown from a solution containing both the AgBF(4) double helicate and linear complexes in CH(3)CN had the structure [Ag(2)1(CH(3)CN)(2)](BF(4))(2) (5). The AgBF(4) double helicate could only be crystallized from CH(3)NO(2) and had the structure [Ag(2)1(2)](BF(4))(2)·2CH(3)NO(2) (6).

A multi-component CuAAC ‘click’ approach to an exo functionalised pyridyl-1,2,3-triazole macrocycle: synthesis, characterisation, Cu(I) and Ag(I) complexes

A one-pot, multi-component CuAAC reaction was exploited for the safe generation of an exo alcohol-functionalised pyridyl-1,2,3-triazole ‘click’ macrocycle in good yield. The macrocycle was characterised by elemental analysis, HR-ES-MS, 1H and 13C NMR spectrometry, and the molecular structure was confirmed by X-ray crystallography. Efforts to use the ‘click’ macrocycle in both passive and active metal template syntheses of [2]rotaxanes were unsuccessful, and this appears to be connected to the coordinating ability of the 1,2,3-triazole units in the macrocycle. The coordination chemistry of the macrocycle with Cu(I) and Ag(I) was examined. It has been demonstrated using HR-ES-MS, 1H NMR spectrometry and X-ray crystallography that the macrocycle can form both discrete and polymeric coordination compounds with Cu(I) and Ag(I) and in all cases the 1,2,3-triazolyl units of the macrocycle are coordinated to the metal ions.

Effect of anion on Ag( i ) meso -helical chains formed with 4,4′-dipyridyl ketone: solvent versus anion bridging and anion effects on the strength of ligand binding

The synthesis and characterisation by IR spectroscopy and elemental analysis of ten new Ag(I)–L complexes are described. Of these complexes, nine are characterised by single crystal X-ray diffraction: {[Ag(L)](CF3SO3)·1/2H2O}∞ (1), {[Ag(L)](ClO4)·1/2H2O}∞ (2), {[Ag2(L)2(CH3CN)](ClO4)2·2CH3CN·H2O}∞ (3), {[Ag2(L)2(CH3CN)2](ClO4)2·CH3CN}∞ (4), {[Ag2(L)2(CH3CN)2](PF6)2·2CH3CN}∞ (5), {[Ag(L)2](CF3SO3)·1/2H2O}∞ (6), {[Ag(L)2](BF4)}∞ (7), {[Ag(L)2](PF6)}∞ (8) and {[Ag(L)2](PF6)·2CH3CN}∞ (9). The primary structures of 1–6 were meso-helical one-dimensional (1D) polymers, while 7 was a helical 1D polymer and 8 and 9 were (4,4) networks. Complexes 1–5 possessed 1 : 1 metal-to-ligand (M : L) ratios, while complexes 6–9 possessed 1 : 2 M : L ratios. The meso-helical chains of complexes 1 and 2 were di-μ-bridged at the Ag(I) nodes by the counteranions CF3SO3− and ClO4−, respectively, while the meso-helical chains of complexes 3–5 were di-μ-bridged at the Ag(I) nodes by the CH3CN molecules. The effect of counteranions and solvent molecules on delicate anion–Ag, π–π-stacking and argentophilic interactions was studied through complexes 1–5. The 1D chains of complexes 6 and 7 possessed monodentate L ligand side arms. The uncoordinated N-donors of these side arms were inclined towards the Ag(I) centre of the adjacent chains and demonstrated narrower Ag–Npy–Cg(pyridyl) angles. In the case of complexes 8 and 9, wider Ag–Npy–Cg(pyridyl) angles and stronger N⋯Ag interactions resulted in (4,4) nets. The effects of the size and the nature of the counteranions on the topology were studied through complexes 6–9.

Probing CH-π(alkyne) interactions in a series of ethynylferrocenes

A neoteric correlation between the cyclopentadienyl (Cp)-aryl dihedral angle and crystal packing arrangement is confirmed in the structural determination of three ethynylferrocene substituted naphthalenes. Two of the naphthalenes have approximately orthogonal Cp and aryl ring systems and feature an inversion dimer motif with CH⋯π(alkyne) short contacts. This motif is found in other arylethynylferrocenes. DFT calculations suggest the difference in energy between different dihedral conformations is of the same order as a weak hydrogen bond. Focussing on weak hydrogen bonds that involve the ethynyl group, other comparisons are made with a new polymorph of diferrocenylbutadiyne and the trans-isomer of 1,4-diferrocenylbut-1-ene-3-yne. Although the intermolecular forces described for the subject ethynylferrocenes are weak, they nonetheless give rise to distinctive structural motifs that may be exploitable in future supramolecular design.

Improved Access to 1,8-Diformyl-carbazoles Leads to Metal-Free Carbazole-Based [2 + 2] Schiff Base Macrocycles with Strong Turn-On Fluorescence Sensing of Zinc(II) Ions

Development of a new and high yielding synthetic route to 1,8-diformyl-carbazoles 3 (3a 3,6-di- tert-butyl substituted; 3b 3,6-unsubstituted) is reported. Use of a Heck coupling reaction, followed by ozonolysis, has greatly facilitated the preparation of these interesting head units in useful quantities. An initial foray into the new generations of Schiff base macrocycles that ready access to these head units (3) opens up, has led to the direct (i.e., metal-free) synthesis of two [2 + 2] macrocycles from 3a or 3b with 1,2-diaminoethane, H2LtBu (4a) and H2LH (4b), respectively, obtained as yellow powders in high yields (87-88%). The dizinc complex [Zn2LH(OAc)2] (5b) was isolated as a bright yellow solid in 83% yield, by 1:2:2 reaction of H2LH with zinc(II) acetate and triethylamine. Aldehydes 3a and 3b, macrocycle H2LH, and complex [Zn2LH(OAc)2] (5b) have been structurally characterized. The carbazole NH makes bifurcated hydrogen bonds with the pair of flanking 1,8-diformyl-moieties in 3, or 1,8-diimine-moieties in H2LH, leading to a flat, all- cis conformation. The stepped conformation of the metal-free macrocycle H2LH is retained in [Zn2LH(OAc)2], despite deprotonation and binding of two zinc(II) centers within the two tridentate pockets. The N3O2 coordination of the zinc ions is completed by one μ1,1- and one μ1,3- bridging acetate anion. Excitation of nanomolar [Zn2LH(OAc)2] in DMF at 335 nm results in clearly visible blue fluorescence (λmax = 460 nm). Further studies on the H2LH macrocycle revealed turn-on fluorescence, with selectivity (over Ca2+, Mg2+ and a range of 3d dications) and nanomolar sensitivity for zinc(II) ions, highlighting one of the many potential applications for these new carbazole-based Schiff base macrocycles.

5-Chloro-6-hy­droxy-7,8-dimethyl­chroman-2-one

In the title molecule, C11H11ClO3, the fused pyran ring adopts a half-chair conformation. In the crystal, intermolecular O—H⋯O hydrogen bonds link molecules into chains along [100]. These chains are interconnected by weak intermolecular C—H⋯O contacts which generate R 2 2(8) ring motifs, forming sheets parallel to (001). Tetragonal symmetry generates an equivalent motif along b. Furthermore, the sheets are linked along the c axis by offset π–π stacking interactions involving the benzene rings of adjacent molecules [with centroid–centroid distances of 3.839 (2) Å], together with an additional weak C—H⋯O hydrogen bond, resulting in an overall three-dimensional network.