Macrocyclic Ring Size Research Articles

Tuning of Intramolecular π-π Overlap Mode of Tetrathiafulvalene Bisannulated Macrocycles in the Open-Shell Electronic State

Abstract Charge-transfer complexes of bis(methylthio)tetrathiafulvalene (DMT-TTF) bisannulated macrocycles with 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4-TCNQ) were prepared. The crystal structural analysis revealed an intramolecular dimer structure with the π-π overlap of DMT-TTF units. The magnitude of intramolecular π-π overlap depends on the ring size of macrocycles.

Synthesis and Structure−Activity Relationships of Phenylenebis(methylene)- Linked Bis-azamacrocycles That Inhibit HIV-1 and HIV-2 Replication by Antagonism of the Chemokine Receptor CXCR4

Bis-tetraazamacrocycles such as the bicyclam AMD3100 are a class of potent and selective anti-HIV-1 and HIV-2 agents that inhibit virus replication by binding to the chemokine receptor CXCR4, the co-receptor for entry of X4 viruses. With the aim of optimizing the anti-HIV-1 and HIV-2 activity of bis-azamacrocycles, a series of analogues were synthesized which contain neutral heteroatom (oxygen, sulfur) or heteroaromatic (of lower pK(a) than a secondary amine) replacements for the amino groups of AMD3100. The introduction of one or more heteroatoms such as oxygen or sulfur into the macrocyclic ring of p-phenylenebis(methylene)-linked dimers (to give N(3)X or N(2)X(2) bis-macrocycles) gave analogues with substantially reduced anti-HIV-1 (III(B)) and anti-HIV-2 (ROD) potency. In addition, the bis-sulfur analogue was also markedly more cytotoxic to MT-4 cells. However, bis-tetraazamacrocycles featuring a single pyridine group incorporated within the macrocyclic framework exhibited anti-HIV-1 and HIV-2 potency comparable to that of their saturated, aliphatic counterparts. The p-phenylenebis(methylene)-linked dimer of the py[14]aneN(4) macrocycle inhibited HIV-1 replication at a 50% effective concentration (EC(50)) of 0.5 microM while remaining nontoxic to MT-4 cells at concentrations approaching 200 microM. A series of analogues containing macrocyclic heteroaromatic groups of varying pK(a) were also synthesized, and their ability to inhibit HIV replication was evaluated. Replacing the pyridine moiety of the py[14]aneN(4) macrocyclic ring with pyrazine or pyridine groups substituted in the 4-position (with electron-withdrawing or -donating groups) either reduced antiviral potency or increased cytotoxicity to MT-4 cells. Finally, we synthesized a series of analogues in which the ring size of the bis-pyridyl macrocycles was varied between 12 and 16 members per ring including the py[iso-14]aneN(4) ring system, an isomer of the py[14]aneN(4) macrocycle. The p-phenylenebis(methylene)-linked dimer of the py[iso-14]aneN(4) (AMD3329) displayed the highest antiviral activity of the bis-azamacrocyclic analogues reported to date, exhibiting EC(50)'s against the cytopathic effects of HIV-1 and HIV-2 replication of 0.8 and 1.6 nM, respectively, that is, about 3-5-fold lower than the EC(50) of AMD3100. AMD3329 also inhibited the binding of a specific CXCR4 mAb and the Ca(2+) flux induced by SDF-1alpha, the natural ligand for CXCR4, more potently than AMD3100. Furthermore, AMD3329 also interfered with virus-induced syncytium formation at an EC(50) of 12 nM.

Triquinane-derived macrocyclic lactones and a [2]-catenane: Synthesis and characterization

cis,syn,cis-Triquinane diol 1, with its folded topology, hydrophobic posterior and inwardly directed endo,endo-hydroxy groups, readily enters into cyclooligomerization reaction with terephthaloyldichloride 4. As many as nine cyclic oligomers A-I, with macrocyclic ring size varying from 28- to 98-membered, have been isolated and characterized. The cyclic oligomers exhibit interesting spatial relationships through the relative orientation of methylene groups on the central five membered ring of the triquinane moiety. Employing X-ray crystallography and symmetry considerations, in conjunction with NMR data, stereostructures of dimers 5 and 6, trimers 7 and 8 and tetramers 9–12 could be delineated. The crystal packing in the case of 5, 6 and 7 shows some interesting motifs and many short C-H…O contacts. From the reaction of 1 and 4, a novel [2]-catenane 16, constituted through aromatic spacers and a bulky triquinane entity, has also been isolated and characterized, through the incisive analysis of the mass spectral data.

Structural Relevance of Mixed-Donor Macrocyclic Co(II) Complexes to Chromotropism

Herein are described the synthesis and characterization of a macrocyclic series of Schiff base complexes with CoX2 (where X = Cl, NO3, SCN). All of the compounds are characterized by elemental analyses, conductometric measurements, infrared absorption and reflectance spectra. The effect of macrocyclic ring-size and counter anions on the chromotropism of the complexes, in the solid state and their solution in DMSO, have also been investigated. It is found that similar electronic spectra and conductance are maintained no matter what the size of the macrocycles is. On account of these experiments, it has been concluded that variation in the counter anions is responsible for the observed chromotropism. Referee I: K. Hegetschweiler Referee II: J. Okuda

The cation binding of benzo crown ethers in acetonitrile using fluorescence spectroscopy

The effects of Na+, K+ and Li+ cations on the fluorescence spectra of benzo[15]crown-5, benzo[18]crown-6 and dibenzo[18]crown-6 were investigated in acetonitrile. The alkali cation role observed was usually the complexation-enhanced quenching fluorescence effect (CEQF) in acetonitrile due to the increased fluorescence quenching rate of the complexed fluoroionophore. The association constants for 1 :1 stoichiometry InK a have been obtained using the relationship 1/K a[L 0] = (1 −P)2/P. It was shown that the preferential interaction rule of compatibility of cationic radii and macrocyclic ring size is in excellent agreement with the association constants obtained by fluorescence spectroscopy. The order of InK a found for benzo[15]crown-5 complexation was Li+ > Na+ > K+ and K+ > Na+ > Li+ for benzo[18]crown-6 in acetonitrile.

Synthesis and structure-activity relationships of phenylenebis(methylene)-linked bis-tetraazamacrocycles that inhibit HIV replication. Effects of macrocyclic ring size and substituents on the aromatic linker.

We have previously described the potent and selective inhibition of several strains of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) by JM2763, an n-propyl-linked dimer of the 1,4,8,11-tetraazamacrocyclic (cyclam) ring system. Upon further investigation, we have also found that incorporating an aromatic rather than aliphatic linker leads to analogs with higher antiviral potency. The prototype, JM3100 (19a, isolated as the octahydrochloride salt), which contains a p-phenylenebis(methylene) moiety linking the cyclam rings, inhibited the replication of HIV-1 (IIIB) and HIV-2 (ROD) at EC50's of 4.2 and 5.9 nM, respectively, while remaining nontoxic to MT-4 cells at concentrations exceeding 421 microM. In order to identify the structural features of bis-tetraazamacrocycles required for potent activity, we have prepared a novel series of phenylenebis(methylene)-linked analogs, in which the macrocyclic ring size was varied from 12 to 16 ring members. Depending upon the substitution of the phenylenebis(methylene) linker (para or meta), sub-micromolar anti-HIV activity was exhibited by analogs bearing macrocycles of 12-14 ring members but with varying cytotoxicity to MT-4 cells. Furthermore, while we found that identical macrocyclic rings are not required for activity, substituting an acyclic polyamine equivalent for one of the cyclam rings in 19a resulted in a substantial reduction in anti-HIV potency, clearly establishing the importance of the constrained macrocyclic structure. A short series of transition metal complexes of 19a were also prepared and evaluated. Complexes of low kinetic stability such as the bis-zinc complex retained activity comparable to that of the parent compound. Finally, the activity of bicyclam analogs appears to be insensitive to the electron-withdrawing or -donating properties of substituents introduced onto the linker, but sterically hindering groups such as phenyl markedly reduced activity. As a result, several analogs with anti-HIV potency comparable to that of 19a have been identified.

30 Potent inhibition of human immunodeficiency virus (HIV) replication by aromatic linked bis-azamacrocycles: Synthesis and effects of macrocyclic ring size: S. Padmanabhan 1, G. Bridger 1, R. Skerlj 1, D. Thornton 2, M. Abrams 1, G. Henson 1, R. Datema 3, N. Yamamoto 4, K. De Vreese 4, R. Pauwels 4 and E. De Clercq 4. 1Johnson Matthey Pharmaceutical Research,

30 Potent inhibition of human immunodeficiency virus (HIV) replication by aromatic linked bis-azamacrocycles: Synthesis and effects of macrocyclic ring size: S. Padmanabhan 1, G. Bridger 1, R. Skerlj 1, D. Thornton 2, M. Abrams 1, G. Henson 1, R. Datema 3, N. Yamamoto 4, K. De Vreese 4, R. Pauwels 4 and E. De Clercq 4. 1Johnson Matthey Pharmaceutical Research,

Unexpected selectivity in the alkylation of polyazamacrocycles

Reaction of equivalent amounts of free base polyazamacrocycles with an alkyl halide in a nonpolar, aprotic solvent affords the mono-N-alkylation product as its monohydrohalide salt in high yield with excellent selectivity. This unexpected selectivity has been explained in terms of the high affinity of the alkylated product for a single proton which attenuates the nucleophilicity of the remaining nitrogen atoms. Selectivity is dependent upon a number of factors including macrocycle ring size, solvent polarity, and the steric nature of the electrophile. The approach has allowed for a short, convergent route to bifunctional lanthanide chelators which are useful in therapeutic applications

The first [14]cyclidene complexes: relationships between macrocyclic ring size, lacunar cavity shape, and dioxygen affinity of the cobalt-cyclidene dioxygen carriers

The nickel(II) and cobalt(II) complexes have been synthesized and charactetized as the first examples of metal complexes of a 14-membered cyclidene. [(2,3,16,17,19,29-Hexamethyl-3,1(,20,23,26,29-hexaazabicyclo[16.6.6]tiaconta-1,17,19,23,25,29-hexaene-k 4 N 20,23,26,29 )nickel(II)] hexafluoxophosphate, NiC 30 H 52 N 6 P 2 F 12 tallized in the orthorhombic space group Pna2 1 .

Structurally reinforced macrocyclic ligands

Abstract

Potential ATPase mimics by polyammonium macrocycles: Criteria for catalytic activity

A series of polyammonium macrocycles, ranging in size from the 18-membered ring [18]aneN 6 to the 36-membered [36]aneN 12 were examined as potential ATPase mimics. The rates of hydrolysis of ATP were followed at pH 3.0 and 7.0 using 31P NMR and HPLC techniques. Stability constants as a function of degree of protonation, distribution curves for the ligands as a function of pH, and distribution curves for the mixed species of nucleotides, inorganic phosphate, and macrocycle were also determined. All of the macrocycles catalyzed the hydrolysis of ATP to some extent compared to noncatalyzed hydrolysis. A critical dependence on macrocyclic ring size was observed, with [21]aneN 7 being the best catalyst at both pHs. Stability constants of the complexes formed between the phosphate species and macrocycle increase with increasing degree of protonation and decreasing ring size. The trend in stability constants for phosphate species was found to be PO 4 3− > P 2O 7 4− > ATP 4− > ADP 3− > AMP 2− for a given degree of protonation. The crystal structure of tetraprotonated [21]aneN 7 was determined. The compound N 7C 14Cl 4H 41O crystallizes in the monoclinic space group P2 1 (#4) with unit cell dimensions a = 7.472(1), b = 19.480(2), c = 8.3638(9) A ̊ , β = 100.38(1) o, and V = 1197.4(3) A ̊ 3 . The structure was solved by direct methods and refined using full-matrix least-squares techniques to give a final R = 0.041 and R w = 0.055.

Metal ion complexation studies in an aqueous solution of 1-thia-4,7-diazacyclononane, 1- thia-4,8-diazacyclodecane and 5-thia-2,8- diazanonane

The stability constants of the macrocyclic 1-thia-4,7- diazacyclononane ([9]aneN 2S) and 1-thia-4,8-diazacyclodecane ([10]aneN 2S) and of the open-chain 5-thia-2,8-diazanonane (atan) with cobalt(II), nickel(II), copper(II), zinc(II), cadmium(II) and lead(II) have been determined in aqueous solution (25°C, 0.1 mol dm −3 KNO 3) by pH potentiometry. The complexation enthalpies with copper(II) have been determined by adiabatic calorimetry. The electronic spectra of the copper(II) and nickel(II) complexes were recorded. The magnitude of the macrocyclic effect for the copper(II) complexes is dependent upon the choice of the open-chain reference ligand and is analysed for its enthalpic and entropic contributions: a positive entropy contribution is found irrespective of the reference ligand, while the enthalpy contribution may be exothermic or endothermic. The metal ion size-based selectivity upon increase in the chelate ring size from five-membered in [9]aneN 2S to six-membered in [10]aneN 2S is controlled by the macrocyclic ring size: the largest drop in stability is observed for the smaller metal ions [copper(II) and nickel(II)] when [9]aneN 2S is replaced by [10]aneN 2S in the 1: 1 complexes. This drop in stability in the case of the 1: 1 complex with copper(II) is entirely due to an unfavourable entropy change, the complexation heat and the LF strength being higher for [10]aneN 2S than for [9]aneN 2S.

Ligand design and metal-ion recognition. Comparison of the interaction of cobalt(II) and nickel(II) with 16- to 19-membered mixed-donor macrocycles

The interaction of cobalt(II) and nickel(II) with a range of 16- to 19-membered ring macrocycles incorporating nitrogen, oxygen and/or sulfur heteroatoms is reported. These ligands constitute an extensive array of related macrocyclic structures in which the positions of the donor atoms, their spacing, and the macrocyclic ring size all vary in a systematic manner. Emphasis has been given to the examination of structure–function relationships in the complexation behaviour. Physical measurements confirm the 1 : 1 metal to macrocyclic ligand stoichiometry of the respective complexes. Stability constants for the metal complexes have been determined potentiometrically in 95% methanol (I= 0.1 mol dm–3, NEt4ClO4). An X-ray crystallographic study of [NiL18(H2O)][NO3]2(L18= 5,6,7,8,10,11,12,13,19,20-decahydrodibenzo[f,I][1,8,11,4,15]oxadithiadiazacycloheptadecine) confirms that the nickel ion is six-co-ordinate with the complex cation exhibiting a distorted-octahedral geometry defined by all five donor atoms of the ON2S2 macrocycle and a water molecule; the macrocyclic backbone incorporating the N–O–N donor fragment is arranged meridionally. Molecular mechanics modelling of selected nickel(II) complexes has also been undertaken. As well as their considerable intrinsic interest, the results provide a potentially useful background upon which the design of new reagents for metal-ion discrimination may be based.

Macrocyclic ligand ring size effects. Part 2. Synthetic, structural and electrochemical studies of the interaction of Ni II with 14-membered tetraaza macrocycles containing fused dibenzo substituents

A comparative study of the high- and low-spin complexes of NiII with two tetraaza dibenzo-substituted macrocycles incorporating 14-membered inner rings has been carried out. The results obtained are also compared with those for the analogous nickel(II) derivatives of 1,4,8,11-tetraazacyclotetradecane. Four X-ray structures of nickel complexes as well as the structure of one free ligand have been determined. These structures taken together with previous X-ray structural data and selected molecular mechanics calculations have enabled a detailed assessment of the effects of spin state and ligand substituent on the hole size and ring conformations adopted by individual complexes. A comparative electrochemical investigation of individual high- and low-spin complexes in the series has been performed.

Stability of complexes of the macrocycles 1,5,9,13-tetraazacyclohexadecane and 1,4,7,11-tetraazacyclotetradecane with metal ions. Effect of large hole size and of chelate ring sequence

A glass-electrode study of the formation constants of [16]aneN4(1,5,9,13-tetraazacyclohexadecane) and isocyclam (1,4,7,11-tetraazacyclotetradecane) with several metal ions is reported. The formation constants, log K1 for the complexes of [16]aneN4 at 25°C and in 0.1 mol dm–3 NaNO3 are ZnII, 13.02; CdII, 12.65; PbII, 9.29. With isocyclam, log K1 at 25°C in 0.1 mol dm–3 NaNO3 is: ZnII, 15.44; CdII, 11.84; PbII, 10.86. A spectroscopic study of the copper(II) complex of isocyclam at 25°C in 0.5 mol dm–3 NaNO3 gave log K1 as 27.3. The surprising result of the complexes of isocyclam being of almost identical stability to those of cyclam (1,4,8,11-tetraazacyclotetradecane) is discussed, as is the pattern of complex stability of the tetraaza macrocycles as a function of macrocyclic ring size.

Macrocyclic ligand ring size effects. Part 1. Complexation of tetra-aza ligands containing fused dibenzo substituents with Zn II and Cd II : a solution stability, X-ray crystal structure, and molecular mechanics study

The interaction of ZnII and CdII with an extensive series of dibenzo-substituted macrocyclic and open-chain tetra-amines has been investigated. All ligands form 1 : 1 (metal : ligand) complexes in solution with these metal ions; the thermodynamic stabilities of the complexes in 95% methanol (I= 0.1 mol dm–3, NEt4ClO4) have been determined. Along one series of 14- to 16-membered macrocyclic systems a dislocation in the stability pattern occurs for ZnII at the 16-membered ring complex while, for CdII, the dislocation corresponded to the 15-membered ring species. As a consequence there is an enhanced stability difference (ZnII > CdII) between the complexes of this latter ring. The observed discrimination shown by the 15-membered ring is largely maintained when bulky alkyl substituents are appended to carbons adjacent to two of the secondary amine donors; however, the absolute magnitudes of the respective stabilities are decreased because of steric effects. In an extension of this study it has been found that open-chain analogues show no unusual discrimination between ZnII and CdII. Other macrocyclic and open-chain ligands containing only anilino nitrogen donors have been shown to form only very weak complexes with ZnII and CdII. The X-ray structures and molecular mechanics investigation of two free ligands and three metal complexes are reported.

The dependence of the solid state structures of bisparaphenylene-(3n+ 4)-crown-n ethers upon macrocyclic ring size

X-Ray crystallography on the free BPP(3n+4)Cn ethers where n= 7,8,10,11, and 12 reveals a conformational dependence for the macrocycles which is reflected in their cavity sizes, with a maximum for n= 10, and in the relative orientations of the two hydroquinol rings, almost orthogonal for n= 7 and parallel or nearly parallel for n= 8,10,11, and 12, with respect to each other.

The Stabilization of High Oxidation States of Metals Through Coordination by Poly-aza Macrocycles

Abstract The incorporation of a transition metal ion into a poly-aza macrocyle favors the access to unusually high oxidation states (e.g. NiIII, CuIII). The tendency to stabilize trivalent cations, which is expressed by the value of the potential of the MIII/MIII redox couple, is regulated by the structural features of the macrocycle (ring size, number and type of the donor nitrogen atoms). In general, formation of trivalent complexes is favored by strong equatorial interactions and the CuII/CuIII oxidation process profits from the ligand-field contribution to a larger extent than does the corresponding NiII/NiIII process. The solvent may profoundly influence the MIII/MIII redox change through axial coordination of one of the redox-active macrocyclic complexes.

Tetracyanonickelate(II) compounds of some (tetraazamacrocycle)nickel(II) cations. The structure of catena-Di(μ-cyano)dicyano(N-meso-5,7,7,12,14,14-hexamethy1-1,4,8,11-tetraazacyclotetradeca-1, 11-diene)dinicke1(II) hydrate

Tetracyanonickelate(II) compounds of several (tetraazamacrocycle)nickel(II) cations have been prepared. The structure of the N-meso-5,7,7,12,14,14-hexamethyl-1,4,8,11-tetraazacyclotetradeca- 4,11-diene, hmtd, compound [Ni(hmtd)Ni(CN)4].H2O has been determined by X-ray diffractometry [monoclinic, a 1780.3(3), b 1063.41(7), c 1409.3(2) pm, β 120.54(1)�, 24, space group C2/c, R 0.021, Rw 0.030 for 2178 reflections] and shows a chain polymeric structure with trans singlet ground state [Ni(CN)4]2- groups linking parallel stacked triplet ground state [Ni(hmtd)]2+ groups. The triplet ground state nickel(II) ions have a tetragonally elongated coordination environment [Ni-N (mean macrocycle) 204.5(1) pm, Ni-N (N≡C) 220.7(1) pm]. Tetracyanonickelate compounds of macrocycles related to hmtd but with different substituents, macrocycle ring size, and/or numbers of imine and amine donor groups were prepared. Some are diamagnetic, with discrete cation and anion, while others are similar to the hmtd compound, and for the latter, tetragonal distortions were evaluated from the reflectance spectra. Magnetic susceptibilities and infrared spectra are reported.

An electrochemical investigation of the effect of macrocycle ring size on the binding of di- and trivalent lanthanide cations by 12-crown-4, 15-crown-5, 4-tert-butylbenzo-15-crown-5, and dibenzo-30-crown-10 in propylene carbonate

The complexation in anhydrous proplene carbonate of the lanthanide ions by various macrocylic polyethers featuring from four to ten oxygen atoms has been investigated by a competitive potentiometric technique with lead(II) or thallium(I) as auxilliary ions. The stability of the complexes appears to depend primarily on the relative sizes of the metal ions and of the internal cavity of each macrocycle. It depends also on the rigidity of the ligands and is influenced by solvation effects. The small ligands 12-crown-4 (1) and 15-crown-5 (2) exhibit a similar behavior: they form 1:2 lanthanide complexes, the stability of which decreases with decreasing ionic radius despite the higher charge density of the metal ions. The presence of an electron-withdrawing phenyl group, as in 4-tert-butylbenzo-15-crown-5 (3), leads to a strong reduction of the stability constants. A maximum stability of 1:1 complexes of 3 is found at Nd(III) while a marked minimum is observed at Gd(III) in the complexation curve of dibenzo-30-crown-10 (5). Divalent samarium and ytterbium are more strongly coordinated than the corresponding trivalent ions by the crown ethers 1-5. The larger divalent ions fit better into the internal cavity of 5 and they form stable 1:2 sandwich complexes with 1 and 3. Themore » properties of the complexes described in the present work are completely different from those reported so far in the case of noncylic ligands.« less