Free Macrocycle Research Articles

Biosynthetic Preparation of Isotopically Labeled Heme

An efficient method for the preparation of isotopically enriched heme has been developed. This method utilizes a commercially available bacterial host and plasmid, into which a synthetic gene encoding for rat liver outer mitochondrial membrane cytochrome b 5 a heme-binding protein, has been inserted. The method described in this report utilizes the efficient synthesis of the cytochrome b 5 polypeptide together with the enhanced biosynthesis of heme brought about by addition of the first committed precursor in heme biosynthesis, δ-aminolevulinic acid. Apocytochrome b 5 sequesters heme as the macrocycle is being synthesized in order to form holocytochrome b 5, thus avoiding toxic concentrations of free macrocycle in the cell. Relatively high concentrations of free heme in the cell have been shown to stimulate excretion of heme precursors such as coproporphyrinogen and uroporphyrinogen (W. F. Harris III, R. S. Burkhalter, W. Lin and R. Timkovich, (1993) Bioorg. Chem. 21, 209-220), therefore causing isotopic dilution of the labeled material. The heme obtained using this methodology was determined to be >85% enriched. Because the heme in cytochrome b 5 is not covalently attached to the polypeptide, it can be extracted and used in other applications. Use of glutamate, a precursor of δ-aminolevulinate biosynthesis in Escherichia coli, did not result in high levels of isotopic incorporation into heme, thus pointing out to the importance of using a labeled precursor that is committed to heme biosynthesis in order to obtain high levels of isotopic labeling.

The synthesis of oxotitanium (IV), oxochromium (IV) and dioxomolybdenum (VI) complexes with 7,16-disubstituted dibenzo- and dipyridotetraazaannulenes

The synthesis of oxotitanium(IV) complexes of 7,16(γ)-substituted dibenzo- and dipyridotetraazaannulenes are reported for the first time from the reaction of the free macrocycles with TiCl 4. These complexes show a ν(TiO) at around 920 cm −1 and the titanyl moiety in these complexes is also quite reactive. Oxochromium(IV) and dioxomolybdenum(VI) complexes of dibenzotetraazaannulenes were prepared by the reaction of Cr(CO) 6 and Mo(CO) 4(pip) 2, respectively, with the free macrocycles. Cyclic voltammetric experiments show the occurrence of reversible oxidations for the oxochromium and dioxomolybdenum complexes but only irreversible oxidations for the titanium complexes.

Synthesis and characterization of various unsubstituted and mono-N-substituted tetraazamacrocycles

Syntheses of tetraazamacrocycles have been carried out by using p-toluenesulfonyl chloride as protective group. The [14(ane) N4] and [15(ane) N4] were also obtained by the template synthesis. Mono-N-functionalization of tetraazamacrocycles was accomplished by reaction of a fivefold excess of the free macrocycles with 1 equivalent of a suitable alkylating or arylating reagent. The key point of the synthesis lies in the use of an excess of the macrocycle over the substituting reactants to reduce the formation of polysubstituted derivatives, and in the easy separation of the excess of unreacted macrocycle. All the products were characterized on the basis of spectral studies (1H and l3C NMR, including 2D NMR and NOE difference studies) and mass spectrometry. Keywords: tetraazamacrocycles, improved synthesis, protective group, N-tosylation, template synthesis, NOE difference spectroscopy.

Chelating behaviour of new 12-membered Schiff base macrocycles containing pendant groups

The free Schiff base macrocycles 1,4,7,10-tetraazacyclo-dodeca-5,6,11,12-tetraaminoacetic acid-4,6,10,12-tetraene (L1), 1,4,7,10-tetraazacyclododeca-5,6,11,12-tetraamino-phenyl-4,6,10,12-tetraene (L2) and 1,4,7,10-tetraazacyclo-dodeca-5,6,11,12-tetraaminopyridyl-4,6,10,12-tetraene (L3) have been prepared by the reaction of oxamidediacetic acid, oxamidediphenyl and oxamidedipyridyl, respectively, with ethylenediamine. Their complexes with first row transition metal ions, of types [MLCl2] and [MLCl2]Cl, have also been prepared and characterized by physico-chemical and spectroscopic methods. The complexes of divalent metal ions are non-ionic while those of trivalent metal ions appear to be 1∶1 electrolytes. An octahedral geometry is proposed for all the complexes.

Synthesis and properties of transition metal complexes with a novel tetradentate macrocyclic ligand containing 1,10-phenanthroline derivatives

Abstract Complexes of a tetradentate macrocyclic ligand L with manganese(II), cobalt(II), nickel(II) and copper(II) ions have been prepared by condensation of 2,9-diamino-1,10-phenanthroline and 1,10-phenanthroline-2,9-dicarboxalehyde in the presence of metal ion templates. Electrical conductivity measurements, ir and 1H NMR spectral data are reported and evaluated to show that ring closure rather than polymer formation has occurred. The template condensation in the presence of chromium(III) chloride and hydrochloric acid (pH = 1) leads to the formation of the free macrocycle rather than the expected metal complex.

Synthesis, complexation behaviour and reactions of thia-crown ethers incorporating propan-2-one units

Thia-crown ethers containing ketone functionality derived from 1,3-dichloroacetone have been prepared in 70–80% yields; the crystal structures of one free macrocycle and two AgI complexes have been determined.

Metal-ion selectivity by macrocyclic ligands. Part 1. The interaction of Ni II and Cu II with pyridinyl-derived N3O2 macrocycles; the X-ray structures of a free macrocycle, its endomacrocyclic complexes of Ni II and Cu II and an exomacrocyclic nickel(II) complex

The interaction of CuII and NiII with two macrocycles L1 and L2, each containing an N3O2 donor set, has been investigated. Spectrophotometric studies in dimethyl sulphoxide reveal the formation of complexes with 1 : 1 and 1 : 2 metal : ligand ratios and conductometric studies in the same solvent indicated that all of the complexes were 1 : 2 electrolytes. Conductometric titration of the 1 : 1 copper(II) complexes with chloride in each case indicated the formation of a 1 : 1 electrolyte, presumably through co-ordination of a chloride ion to the central copper of each complex. Similar titration of the nickel(II) complexes gave evidence for the formation of dinuclear species; each of these was postulated to contain a bridging chloride anion. The stability constants of the complexes together with their enthalpies of co-ordination have been determined in 95% methanol. Extraction and related transport experiments were carried out and under the conditions employed CuII was favoured over NiII. The X-ray crystal structures of the free macrocycle L1, the 1 : 1 complexes [CuL1(H2O)][ClO4]2 and [NiL1(I)]I·MeOH, and the 1 : 2 complex [NiL12(NO3)]NO3·2MeOH have been determined. The metal in [CuL1(H2O)][ClO4]2 is six-co-ordinate and lies within the folded macrocyclic cavity. The donor set comprises the five macrocyclic donor atoms and a water molecule. Overall, the co-ordination sphere corresponds to a restricted tetragonal rhombic arrangement. The complex [NiL1(I)]I·MeOH also has all donors of the macrocycle co-ordinated with an iodide anion occupying the sixth site to yield a distorted-octahedral geometry. The structure of [NiL12(NO3)]NO3·2MeOH shows that the nickel is again six-co-ordinated, to the aliphatic nitrogen atoms from two macrocycles (each showing exo co-ordination) and a bidentate nitrate anion.

ChemInform Abstract: Synthesis and Characterization of New Cobalt Dioxygen Carriers Based on a Familiar Macrocyclic Ligand.

AbstractA new class of macrocyclic Co(II) dioxygen carriers, the bisacylated complexes (Ib)‐(Id) are prepared by reaction of Co(II) acetate tetrahydrate with the corresponding free macrocycles in MeOH/MeCN in the case of (Ib) and (Id) or by acylation of (Ia) with trifluoroacetic anhydride in benzene in the case of (Ic).

Polarographic Study of the Rates of the Dissociation Reactions of the Eu(III)-HAHA Complex and of the Eu(III)-, Gd(III)-, and Ho(III)-PAPA Complexes

Abstract Polyaza macrocycles carrying acetate groups, HAHA and PAPA, were found to form solely 1:1 ratio complexes with Eu(III), Gd(III), or Ho(III) ions. The PAPA complexes of the Eu(III), Gd(III), and Ho(III) ions and the HAHA complex of the Eu(III) ion in acetate buffer solutions containing an excess of the Eu(III), Gd(III), or Ho(III) ion produce anodic waves, which are kinetic in nature. They can be ascribed to the free macrocycles formed upon the dissociations of the complexes preceding electron-transfer steps at the electrode surface. From an experimental examination of the nature of these kinetic waves, the reaction mechanisms and rates for the dissociation reactions were determined. The dissociation reactions for the HAHA and PAPA complexes were found to proceed through (A) and (B), respectively. The (kd)o values for the Eu(III)-HAHA and -PAPA complexes were 5.1×10−1 and 3.9×10−2 (sec−1), respectively, and those for the Gd(III)- and Ho(III)-PAPA complexes, 4.04×10−2 and 1.2×10−2 (sec−1). (Remark: Graphics omitted.) The (kd) values for the Eu(III)-HAHA abd -PAPA complexes were 3.70×102 and 4.24×105 (mol−1dm3s−1) and those for the Gd(III)-and Ho(III)-PAPA complexes, 2.45×104 (mol−1dm3s−1).

Interaction of Zn(II) and Cd(II) with large polyazacycloalkanes in dmso/H 2O (80:20 vol./vol.). A potentiometric study

A potentiometric study on the interaction at 25 °C and 0.15 mol dm −3 between large polyazacycloalkanes of the series [3 k]aneN k and Zn(II) and Cd(II) ions in dmso:H 2O (80:20 vol./vol.) is reported. The protonation behavior of the free macrocycles and coordination trends are compared with those previously observed in aqueous solution. The main features observed in the mixed solvent are: similar protonation behavior of the free polyamines, greater tendency to form binuclear and protonated complexes and a lower tendency to bear hydrolytic reactions.

Complexes of ligands providing endogenous bridges. Part 8. Metal complexes of oxa-azamacrocycles derived from 1,5-diamino-3-pentanol; the X-ray crystal structure of a free macrocyclic ligand

A series of oxa-azamacrocycles derived from 1,5-diamino-3-pentanol and acyclic dialdehydes have been prepared by non-template procedures and used to synthesise mononuclear complexes of CoII, NiII, CuII, and ZnII. The crystal structure of the free macrocycle C21H28N2O3 is reported. The compound crystallises in the triclinic space group P(Ci, no. 2) with unit-cell dimensions a= 9.028(6), b= 10.207(7), c= 11.314(9)Å, α= 108.52(6), β= 85.51(6), γ= 100.09(6)°, and Z= 2; 922 independent reflections with |F|/σ(|F|) > 6.0 gave R= 0.0473.

Macrocycle-metal cation interactions involving polyaza macrocycles bonded to silica gel via a nitrogen donor atom

Abstract

The preparation and coordination chemistry of 2,2′:6′,2″-terpyridine macrocycles—VI. Planar hexadentate macrocycles incorporating 2,2′: 6′,2″-terpyridine

The template condensation of 6,6″-bis(α-methylhydrazino)-2,2′: 6′,2″-terpyridines L 2 and L 3 with 2,6-pyridinedialdehyde may give a number of different products depending upon the metal ion which is used. In the presence of nickel(II) the products are either the nickel(II) complexes of the 18-membered ring macrocycles L 4 or L 5 or the free macrocycles. The metal ion acts as a transient template and is removed in a chloride ion specific demetallation. The use of dimethyltin(IV) as a template results in the formation of complexes of the ring contracted macrocycles L 6 or L 7.

An Oxygen-Nitrogen Donor Macrocycle Immobilized on Silica Gel. A Reagent Showing High Selectivity for Copper(II) in the Presence of Cobalt(II), Nickel(II), Zinc(II) or Cadmium(II)

A 17-membered O2N3-donor macrocycle has been appended to a derivatized silica gel substrate, and the binding and selectivity properties of the functionalized surface towards CO11, Ni11 CU11, Zn11 and Cd11 in aqueous solution have been investigated. Metal uptake was found to be concentration-dependent with the maximun (saturation) loading capacity in all cases being less than the 'theoretical' amount based on the calculated degree of polymer functionalization present. Metal loading and leaching both occurred readily in aqueous media; the loading studies were performed at near-neutral pH whereas metal leaching was carried out by using either dilute (hydrochloric) acid or aqueous ammonia solution. The functionalized silica underwent no degradation during repeated loading/leaching cycles, and, under similar conditions, its binding capacity is highest for CU11 relative to the other ions investigated. The observed binding order was CO11 < Ni11 < CUII > ZnIIand this sequence parallels the respective log K values for the complexes of the free macrocycle. However, the loading order of ZnII > CdII which was observed is the opposite to the corresponding log K values for the unattached complexes. Steric effects involving the silica backbone appear to influence the binding in this case. The insolubilized product may be used to remove selectively CuII in the presence of the other ions mentioned above.

ChemInform Abstract: Complexation of Crown Ethers with Neutral Molecules. Part 2. Comparison of Free Macrocycles and Their Complexes with Malononitrile in Solution.

ChemInform Abstract: Complexation of Crown Ethers with Neutral Molecules. Part 2. Comparison of Free Macrocycles and Their Complexes with Malononitrile in Solution.

ChemInform Abstract: Molecular Mechanics Studies of the Conformation of the Macrocycle β‐2,12‐Dimethyl‐3,7,11,17‐tetra‐azabicyclo[11.3.1]heptadeca‐1(17),13,15‐triene (L1) in the Free State and in a Series of Nickel Complexes.

AbstractThe free macrocycle (I) crystallizes in the space group P2,/ a with Z=4 and has a folded shape very different from the Conformation that is found in metal Complexes.

Complexation of crown ethers with neutral molecules. 2. Comparison of free macrocycles and their complexes with malononitrile in solution

Thermodynamic parameters for the complexation of a neutral guest (malononitrile) with crown ethers having ring sizes of 15 to 33 ring atoms and various functionalities were obtained. The results give useful information about the conformations of the free crown ethers and their interactions with solvent molecules. 18-Membered macrocycles form the most stable complexes with malononitrile. Crown ethers in which the uncomplexed form strong intraannular interactions are present form weaker complexes while macrocycles in which additional binding sites (e.g., C=O) are available for complexation form more stable complexes with malononitrile than expected. A compensating effect of T ..delta.. S/sup 0/ and ..delta.. H/sup 0/ of complexation was found for all complexes. The crystal structure of 2,6-pyrido-18-crown-6-CH/sub 2/(CN)/sub 2/ (1:2) was determined; it shows a hydrogen bond to the pyridyl nitrogen atom.

Molecular mechanics studies of the conformation of the macrocycle β-2,12-dimethyl-3,7,11,17-tetra-azabicyclo[11.3.1]heptadeca-1(17),13,15-triene (L1) in the free state and in a series of nickel complexes. Crystal and molecular structure of L1

The crystal structure of the free macrocycle β-2,12-dimethyl-3,7,11,17-tetra-azabicyclo[11.3.1]heptadeca-1 (17),13,15-triene (L1) is reported. Crystals are monoclinic, space group P21/a, with a= 8.433(9), b= 23.697(12), c= 8.653(10)A, β= 113.9(1)°, and Z= 4. A total of 810 independent reflections above background have been refined to R 0.077. The free macrocycle has a folded shape very different from the conformation that is found in metal complexes. Empirical force-field methods have been used to calculate the steric energies of the various conformations of this ligand in the free state and in a series of nickel complexes, viz. [NiL1]2+, [NiL1(NO2)(ONO)], and [NiL1(en)]2+(en = ethylenediamine), and also to provide a hole-size profile for the macrocycle.

Structural characterisation of a pentagonal bipyramidal macrocyclic chromium(III) complex; an explanation of a chromium-mediated ‘transient-template’ effect

The template condensation of 6,6′-bis(hydrazino)-2,2′-bipyridines or 2,9-bis(hydrazino)-1,10-phenanthrolines with 2,6-pyridine dicarbonyl in the presence of chromium(III) chloride leads to the formation of free macrocycles rather than the expected metal complexes; the origin of this ‘transient-template’ effect is discussed and the crystal structural analysis of a chromium(III) macrocyclic complex is described.

Dinucleating macrocyclic Schiff bases derived from thiophene and their metal complexes: the crystal structures of a free macrocycle and of a disilver complex

Dinucleating macrocyclic Schiff bases derived from the condensation of thiophene-2,5-dicarbaldehyde and a number of α,ω-alkanediamines are reported together with their barium and silver complexes. The crystal structure of the macrocycle derived from 3-oxapentane-1,5-diamine, 6,19-dioxa-27,28-dithia-3,9,16,22-tetra-azatricyclo[22.2.1.1 11,14]octacosa-2,9,11,13,15,22,24,26-octaene, has been determined. Crystals are orthorhombic of space group P212121, with a= 25.820(13), b= 14.275(6), c= 5.938(2)A, and Z= 4. 1 629 Independent reflections with I/σ(I) > 3.0 gave R= 0.0442. The crystal structure of the dinuclear silver complex of the macrocycle derived from 3,6-dioxaoctane-1,8-diamine, [6,9,22,25-tetraoxa-33,34-dithia-3,12,19,28-tetra-azatricyclo[28.2.1.1 14,17]tetratriaconta-2,12,14,16,18,28,30,32-octaene-N3N12 : N19N28]–bis[aquaperchloratosilver(I)], has also been determined. Crystals are monoclinic of space group C2/c, with a= 27.941(16), b= 8.612(6), c= 15.359(9)A, β= 102.92(5)°, and Z= 4. 855 Independent reflections with I/σ(I) > 2.0 gave R= 0.1227. In the latter structure the silver atoms are strongly co-ordinated by a pair of imine nitrogen atoms (2.27 and 2.17 A) and by a water molecule (2.72 A).