Arene Ligand Research Articles

Synthesis of Novel Photochromic Calix[4]arene Ligand Bearing a Spirobenzopyran and Three Ethyl-Ester Moieties and Photocontrol of Its Alkali Metal Ion Extractability

Abstract A novel photochromic calix[4]arene ligand bearing a spirobenzopyran and three ethyl-ester moieties (compound 1) was synthesized, and photocontrol of its alkali metal ion extractability was studied. In the dark, compound 1 showed the largest changes of absorption spectra for Na+ among alkali metal ions. When Na+ was gradually added to the solution of compound 1, its complexation behavior was evaluated by 1H NMR, which suggests that Na+ was taken into the cavity formed by four carbonyl oxygens and four ether oxygens, and that compound 1 formed a 1:1 complex with Na+. The proton signals originating from the spirobenzopyran moiety were slightly changed by metal-ion complexation. This means that the spirobenzopyran moiety was not very close to Na+ under dark conditions. Liquid–liquid extraction experiments with alkali metal ion using compound 1 made it clear that the extractability of Na+ was enhanced under UV-light irradiation, compared with that under visible-light irradiation. This suggests that the electrostatic interaction between a phenolate anion of the merocyanine moiety generated by UV-light irradiation and Na+ promotes the extractability to some extent.

The Effect of Ligand Denticity in Size‐Selective Synthesis of Calix[n]arene‐Stabilized Gold Nanoparticles: A Multitechnique Approach

A series of gold nanoparticles (AuNPs) stabilized by monodentate, bidentate, and tridentate thiolate calix[n]arene ligands 1-3 was prepared by using the Brust-Schiffrin two-phase direct synthesis and characterized with NMR spectroscopy, elemental analysis, transmission electron microscopy (TEM), and X-ray photoelectron spectroscopy (XPS). The experimental data show that the particular multidentate structure of calix[n]arene derivatives 2 and 3 introduces a control element in the preparation of the gold nanoparticles that allows, in the particular experimental conditions here reported, to obtain very small (≈1 nm) AuNPs. These are the first experimental findings that identify a role of ligand "denticity" in the determination of the nuclearity of nanoparticles.

Nickel Complexes with Bis(8-quinolyl)silyl Ligands. An Unusual Ni3Si2 Cluster Containing Six-Coordinate Silicon

Efforts to install the bis(8-quinolyl)methylsilyl (Me-NSiN; 1 = Me-NSiNH) and bis(8-quinolyl)phenylsilyl (Ph-NSiN; 2 = Ph-NSiNH) ligands onto nickel are described. Reaction of 1 with NiCl2(DME) and NiPr2Et afforded [(iPr2EtNH)2Cl][(QnH)NiCl3] (3; Qn = quinolyl) via degradation of the silane. Reaction of 2 with Ni(COD)2 in chlorobenzene yielded [Ph-NSiN]2Ni3Cl2 (5), which is a rare example of a silylnickel cluster with a [Ni3Si2] core. An X-ray structure determination reveals the presence of a triangular Ni3 core with two face-capping silyl groups: one that is bonded symmetrically to the three nickel atoms, while the other is unsymmetrically bound. The bonding in 5 has been investigated by computational methods to obtain descriptions of the molecular orbitals. The unsymmetrical bonding of Si(1) results from a two-electron bonding interaction with Ni(1), and this explains the short Si(1)−Ni(1) contact (2.2688(6) Å). The symmetrical bonding of Si(2) appears to result from its interaction with a delocalized Ni3 skeletal orbital. Complex 5 slowly decomposes in dichloromethane-d2 to (PhClSiQn2)NiCl (6), a Ni(I) chloride complex in which the phenyl group is bonded to the nickel with an intramolecularly coordinated (silyl)arene ligand. The η2-coordination of the aryl group involves interaction of ipso and ortho carbon atoms with the metal center. Theoretical studies of 6 support a very weak Ni−Si interaction (2−3 kcal/mol at the NBO level) that is supported by the arene coordination. The strength of the η2-coordination of the arene was estimated at the second-order donor−acceptor NBO level to be 25 kcal/mol.

ChemInform Abstract: Ruthenium Cluster - [2.2]Paracyclophane Complexes

Abstract The last few years have seen a rapid expansion in the synthesis and characterisation of cluster–arene complexes. One arene ligand which has been found to be particularly versatile in cluster chemistry is [2.2]paracyclophane. In this article we review the chemistry of [2.2]paracyclophane clusters with regard to their synthesis, reactivity and structure.

Metabolization of [Ru(η6-C6H5CF3)(pta)Cl2]: a cytotoxic RAPTA-type complex with a strongly electron withdrawing arene ligand

The anticancer ruthenium-arene compound [Ru(eta(6)-C(6)H(5)CF(3))(pta)Cl(2)] (where pta is 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane), termed RAPTA-CF3, with the electron-withdrawing alpha,alpha,alpha-trifluorotoluene ligand, is one of the most cytotoxic RAPTA compounds known. To rationalize the high observed cytotoxicity, the hydrolysis of RAPTA-CF3 in water and brine (100 mM sodium chloride) and its reactions with the protein ubiquitin and a double-stranded oligonucleotide (5'-GTATTGGCACGTA-3') were studied using NMR spectroscopy, high-resolution Fourier transform ion cyclotron resonance mass spectrometry, and gel electrophoresis. The aquation of the ruthenium-chlorido complex was accompanied by a loss of the arene ligand, independent of the chloride concentration, which is a special property of the compound not observed for other ruthenium-arene complexes with relatively stable ruthenium-arene bonds. Accordingly, the mass spectra of the biomolecule reaction mixtures contained mostly [Ru(pta)]-biomolecule adducts, whereas [Ru(pta)(arene)] adducts typical of other RAPTA compounds were not observed in the protein or DNA binding studies. Gel electrophoresis experiments revealed a significant degree of decomposition of the oligonucleotide, which was more pronounced in the case of RAPTA-CF3 compared with RAPTA-C. Consequently, facile arene loss appears to be responsible for the increased cytotoxicity of RAPTA-CF3.

Chiral Amino Alcohol Derived Bis-phosphoramidite Pincer Palladium Complexes and Their Applications in Asymmetric Allylation of Aldimines

Novel P-stereogenic bis-phosphoramidite pincer palladium complexes 1 and 2 derived from (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol and (S)-(+)-indolinemethanol, respectively, were synthesized in reasonable yields (i.e., 55−62%) by using a flexible, modular synthetic approach and were characterized by X-ray crystal structure determination. Reacting (S)-(+)-indolinemethanol with PCl3 leads to the formation of a novel P-chiral building block, which exhibits good thermal stability of its stereochemical features. This enabled the design and development of new P-chiral bis-phosphoramidite pincer arene ligands and their corresponding metal complexes. The molecular structure of the new indolinemethanol-derived phosphoramidite pincer metal complex screens quadrants I and III, which is in contrast to the previously reported l-proline-derived P-chiral ligands that screen quadrants II and IV. The bis-phosphoramidite pincer palladium complexes 1 and 2 are active catalysts for asymmetric homoallylation of sulfonimines,...

Low-Valent Ruthenium Complexes of the Non-innocent 2,6-Bis(imino)pyridine Ligand

A series of low-valent ruthenium complexes bearing 2,6-bis(imino)pyridyl (“[N3]”) ligands has been synthesized and characterized. Reduction of [N3]RuCl2(C2H4) ([N3xyl] = 2,6-(XylNCMe)2C5H3N, 1a; [N3mes] = 2,6-(MesNCMe)2C5H2N, 1b; [tBu-N3mes] = 2,6-(MesNCMe)2p-tBuC5H2N, 1c) with hydridosilanes in an arene solvent such as toluene yields new 18e− η6-arene complexes [κ2-N3]Ru(η6-MeC6H5), 2a,b,c, in which the [N3] ligand is bidentate and only one imine group is coordinated to the metal. The arene ligand can be displaced with dinitrogen in non-arene solvents to yield the binuclear, four-coordinate, formally Ru(0) complexes {[N3]Ru}2(μ-N2), 3a,b,c. Pyrophoric complex 3c is a rare example of a structurally characterized Ru(0) dinitrogen complex. Treatment of low-valent complexes 2 or 3 with donor ligands generates five-coordinate complexes [N3xyl]RuL1,2 (L1,2 = C2H4, 4a; L1,2 = PMe3, 5a; L1,2 = CO, 6a; L1 = PMe3, L2 = CO, 7a). Complexes 2a, 3c, 5a, 6a, and 7a are diamagnetic and have been structurally characterized by single-crystal X-ray diffraction methods. New six-coordinate Ru(II) complexes [N3xyl]RuCl2(L) (L = PMe3, CO) were also isolated and structurally characterized. The infrared data, observed geometrical parameters, and reactivity patterns of the formally Ru(0) centers suggest varying degrees of electron delocalization to the “non-innocent” bis(imino)pyridyl, but probably not to the extent implied by the valence tautomeric [N3]2−/Ru(II) canonical form. Although the [N3]−/Ru(I) representation may portray the electron distribution more accurately than “Ru(0)”, the inherent odd electron counts on both ligand and metal—and requisite antiferromagnetic coupling—provides little in the way of “useful” distinctions or predictive value for the low-valent [N3]Ru(L)2 complexes with strong-field co-ligands such as CO and PMe3. These five-coordinate adducts seem to be adequately described as Ru(0) complexes of the neutral [N3] ligand. However, “non-innocent” valence tautomeric canonical forms such as [N3]−/Ru+ may be more applicable to the four-coordinate dinitrogen complexes {[N3]Ru}2(μ-N2).

Density Functional Analysis of the Trigonal Uranyl Equatorial Coordination in Hexahomotrioxacalix[3]arene-based Macrocyclic Complexes

Representative models of the different geometries observed for uranyl complexes with fully deprotonated p-R-hexahomotrioxacalix[3]arene (R = tert-Bu, Me) ligands, among which is the rare trigonal geometry, have been investigated using all-electron scalar relativistic density functional theory (DFT). Optimized structures of complexes incorporating triethylammonium (HNEt3+) and 4-methylpiperidinium (HMePi+) cations are in close agreement with experimental crystal diffraction data. Possible explanations for the structural differences between these uranyl complexes are discussed in terms of varying degrees of bonding between uranium and oxygen atoms from the ether and phenoxide groups. In particular, molecular orbital analysis highlights the central role of 5f-2p hybridization in the U-O bonding.

Influence of the Arene Ligand and the Leaving Group on the Anticancer Activity of (Thio)maltol Ruthenium(II)–(η6-Arene) Complexes

Maltol and its metal complexes have shown promising applications in medicinal chemistry. We report here the synthesis and characterization of Ru(η6-arene)(halido) coordination compounds bearing maltol or thiomaltol ligands and studies on their behaviour in aqueous solution, their reactions with the DNA model guanosine 5′-monophosphate (5′-GMP) and their in vitro anticancer activity in human tumour cell lines. The compounds hydrolyze rapidly and quantitatively to the respective aqua species by exchange of the halido ligand. With pKa values of >8, such species would also be present in biological media and they proved reactive to 5′-GMP. The thiomaltol compounds show promising in vitro activity with IC50 values (50% inhibitory concentration) in the low micromolar range, whereas activity of the maltol complexes is marginal. Variation of the arene ligand (benzene, toluene, p-cymene or biphenyl) resulted only in minor changes in activity.

Cytotoxicity, Hydrophobicity, Uptake, and Distribution of Osmium(II) Anticancer Complexes in Ovarian Cancer Cells

The cytotoxicity, hydrophobicity (log P), cellular uptake, aqueous reactivity, and extent of DNA adduct formation in the A2780 ovarian carcinoma cells for four osmium(II) arene complexes [(eta(6)-arene)Os(4-methyl-picolinate)Cl] that differ only in their arene ligands as benzene (1), p-cymene (2), biphenyl (3), or tetrahydroanthracene (4) are reported. There is a correlation between hydrophobicity (log P), cellular uptake, nucleus uptake, and cytotoxicity of the complexes, following the order 3 approximately 4 > 2 > 1, suggesting that the arene plays an important role in the biological activity of these types of compounds. Cell distribution studies using fractionation showed that all four compounds distribute similarly within cells. DNA binding of osmium did not correlate with cytotoxicity, indicating that the nature of the DNA lesion may also be crucial to activity. TEM images of ovarian cells treated with 3 revealed morphological changes associated with apoptosis with possible involvement of mitochondria.

Protonation of electroneutral p-tert-butylcalix[4]arenetetraacetic acid

AbstractUsing 1 H NMR spectroscopy together with density functional theoretical calculations, it is shown that electroneutral p-tert-butylcalix[4]arenetetraacetic acid forms an equimolar complex with a proton in the form of the H 3 O + ion in nitrobenzene-d 5 . Protons were offered by hydrogen bis(1,2-dicarbollyl)cobaltate and converted to hydroxonium ions by traces of water. In the resulting complex, the H 3 O + cation is bound by strong hydrogen bonds to two phenoxy oxygen atoms of the parent calix[4]arene ligand and to one carbonyl oxygen of the corresponding COOH group of this ligand.Graphical Abstract[IMAGE]

Systematic Method for the Incorporation of the {(η6-Arene)Fe} Fragment into Carborane Cages via [(η6-Arene)Fe]2+ Dications. A Series of [3-(η6-Arene)-closo-3,1,2-FeC2B9H11] Complexes. Reliable Synthesis of Polymethylated [(η6-Arene)2Fe]2+ Cations

Developed was a systematic method for the incorporation of the {(eta(6)-arene)Fe} fragment into a carborane cage. Reactions between [(eta(6)-arene)(2)Fe](PF(6))(2) salts and Tl(2)[nido-7,8-C(2)B(9)H(11)] in refluxing (CH(2))(2)Cl(2) generated a series of [3-(eta(6)-arene)-closo-3,1,2-FeC(2)B(9)H(11)] neutral complexes with variable types of polymethylated arene ligands in the structure. The structures of durene and hexamethylbenzene complexes were established by X-ray diffraction analyses. The work also shows that the original high-temperature method for the preparation of the [(eta(6)-arene)(2)Fe](2+) dications fails for mesitylene and durene compounds, which was overcome by a reliable room-temperature modification.

Directional Control and Supramolecular Protection Allowing the Chemo‐ and Regioselective Transformation of a Triamine

A Zn(II)-funnel complex based on a calix[6]arene ligand decorated with three tris(imidazolyl) arms at one end of the cone and three NH(2) substituents at the other end, acts as a multipoint recognition host for polyfunctionalized guests. The selectivity is ensured by coordination to Zn(II), CH-pi interaction within the calix cone, and H-bonding at both rims of the cavity. As a result of these multiple interactions, the host can wrap and orient an unsymmetrical triamine guest with a high selectivity. Furthermore, a proton-monitored switch between the regio-isomeric adducts allows reversible inversion of the directionality of the system. Thanks to this directional control, the regioselective mono-carbamoylation of the unsymmetrical triamine guest was successfully achieved on a preparative scale. This case study shows that a funnel-like receptor can be used as a supramolecular protecting tool allowing a transformation which would be impracticable with conventional covalent chemistry.

Influence of the Arene Ligand, the Number and Type of Metal Centers, and the Leaving Group on thein VitroAntitumor Activity of Polynuclear Organometallic Compounds

Dinuclear ruthenium complexes were shown to exhibit strong antiproliferative properties in human tumor cell lines. In order to extend the structure−activity relationships (SARs), a series of new RuII(arene)X complexes (X = Cl, Br, I) linked by pyridinone-based spacers were synthesized and assayed for their in vitro antineoplastic effect. The SARs were established in terms of the arene ligand, the leaving group (the halide ligand), and the nature and number of the metal centers. It was demonstrated that, besides the previously shown effect of the spacer length, the nature of the metal center has the biggest influence on the in vitro anticancer activity. The halide ligand had no effect on the cytotoxicity, due to rapid formation of the same aquation product for all evaluated compounds. Furthermore, nearly identical activity was observed when varying the arene ligand from p-cymene to biphenyl. However, the number of metal centers was found to be important, with the dinuclear compound being more active than the analogous mono- and trinuclear species.

Facile Synthesis of Bismuth(III) and Antimony(III) Complexes Supported by Silylated Calix[5]arenes.

A series of bismuth(III) and antimony(III) complexes supported by silicon-containing calix[5]arene ligands were synthesized and fully characterized by NMR, X-ray, IR, mp, UV/vis, and elemental analysis. Reaction of the para-tert-butylcalix[5]arene [(t)BuC5(H)(5)] disodium salt, Na(2) x (t)BuC5(H)(3), with 1 equiv of R(2)SiCl(2) (R = Me, (i)Pr, Ph, CH=CH(2)) or treatment of the (t)BuC5(H)(5) lower rim monobenzyl ether [(t)BuC5(Bn)(H)(4)] in a 1:1 ratio with Me(2)Si(NMe(2))(2) yields the (t)BuC5(SiRR')(H)(3) (1-5) and (t)BuC5(Bn)(SiMe(2))(H)(2) (6) ligands, respectively. The (1)H NMR spectra of the (t)BuC5(SiRR')(H)(3) (1-5) ligands show three pairs of doublets and three singlets for the (t)Bu peaks, consistent with a C(s) symmetry. In the case of the (t)BuC5(Bn)(SiMe(2))(H)(2) (6) ligand, the presence of the monobenzyl group changes the (1)H NMR patterns to indicate a C(1) symmetry. Treatment of (t)BuC5(SiRR')(H)(3) (1-5) or (t)BuC5(Bn)(SiMe(2))(H)(2) (6) with 1 equiv of M(O(t)Bu)(3) (M = Bi, Sb) or Sb(NMe(2))(2) readily yields metalated products of the type [M{(t)BuC5(SiRR')}] (7-16) and [MX{(t)BuC5(Bn)(SiMe(2))}] (X = O(t)Bu, (NMe(2))(2)) (17-19), respectively. All monometallic complexes [M{(t)BuC5(SiRR')}] (7-19) display excellent solubility in organic solvents including pentane and hexane. The (1)H NMR patterns for complexes 7-16 are consistent with a 1,2- or 1,3-alternate conformation while complexes [MX{(t)BuC5(Bn)(SiMe(2))}] (17-19) display patterns for a C(1) symmetry. All crystals show monomeric structures. Ligand (t)BuC5(SiPh(2))(H)(3) (3) displays a distorted cone conformation while the presence of the monobenzyl ether in (t)BuC5(Bn)(SiMe(2))(H)(2) (6) forces a partial cone conformation. Complexes 7-19 all display a distorted 1,2-alternate conformation with the metal centers displaying coordination numbers of three, four or five. No Si...M interactions were observed.

Tuning the Efficacy of Ruthenium(II)-Arene (RAPTA) Antitumor Compounds with Fluorinated Arene Ligands

A series of compounds of general formula [Ru(η6-fluoroarene)(pta)Cl2] (fluoroarene = C6H5F, C6H5CF3, and 1,4-C6H4CH3F; pta = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane) have been prepared and characterized spectroscopically. Additionally, X-ray diffraction was employed to characterize two of the complexes and the corresponding precursors, i.e., [Ru(acac)2(η4-cod)] and Ru(η6-fluoroarene)(η4-cod)] (cod = cycloocta-1,5-diene). The solubility, pKa’s, and the stability toward hydrolysis of the [Ru(η6-fluoroarene)(pta)Cl2] complexes were studied, and DFT calculations were performed to assist in rationalizing the observed properties at a molecular level. The cytotoxicities of the pta-based compounds were evaluated in A2780 ovarian cancer cells, and the observed activities were correlated to the above-mentioned properties. The rate of hydrolysis of the Ru−Cl bonds in the C6H5CF3 derivative was found to increase significantly at low pH, which represents a possible method of tumor targeting based on the reduced ...

Synthesis and Characterization of Accessible Metal Surfaces in Calixarene-Bound Gold Nanoparticles

Use of organic ligands to partially passivate nanoparticles against sintering yet retain a degree of small molecule accessibility to the metal surface has been a lofty goal in functional materials synthesis, which in principle also enables the design of preferred electronic and steric environments on a nanoparticle surface. Catalysis using gold in particular requires donor ligands that facilitate an electron-rich metal surface and generalizable strategies for dealing with deactivation due to sintering. Here, synthesis and characterization of gold nanoparticles postsynthetically modified with the chelating ligand cone-5,11,17,23,29,35-hexa(tert-butyl)-37,39,41-tris(diphenylphosphinomethoxy)-38,40,42-trimethoxycalix[6]arene (1) is reported. In solution as well as when supported on the surface of TiO2, nanoparticles modified with tripodal calix[6]arene phosphine ligand 1 demonstrate enhanced protection against sintering relative to unmodified, tetraoctylammonium bromide-surfactant-stabilized gold nanoparticles. In between adsorbed calixarene ligands, there is accessible gold surface area in these nanoparticles, and this is measured quantitatively for the first time for a calixarene-modified nanoparticle, using a newly developed fluorescence methodology involving 2-naphthalenethiol as a relevant chemisorption probe molecule. Ligand steric bulk critically influences amount of accessible surface on the metal nanoparticle since the use of a smaller calix[4]arene ligand (MBC) results in a 7-fold lower accessible surface area relative to using 1 under otherwise similar conditions. In addition, surface coverage of 1 controls accessible surface area in an unintuitive fashion: a 4-fold increase in accessible metal surface area is observed upon increasing the surface coverage of 1 to be 1.5-fold higher than the minimum required for surface saturation. This is presumably the result of a more open ligand packing of 1 at higher surface coverages, which allows greater accessibility to 2-napthalenethiol.

Calix[4]arene-based conical-shaped ligands for voltage-dependent potassium channels

Potassium channels are among the core functional elements of life because they underpin essential cellular functions including excitability, homeostasis, and secretion. We present here a series of multivalent calix[4]arene ligands that bind to the surface of voltage-dependent potassium channels (K(v)1.x) in a reversible manner. Molecular modeling correctly predicts the best candidates with a conical C(4) symmetry for optimal binding, and the effects on channel function are assessed electrophysiologically. Reversible inhibition was observed, without noticeable damage of the oocytes, for tetraacylguanidinium or tetraarginine members of the series with small lower rim O-substituents. Apparent binding constants were in the low micromolar range and had Hill coefficients of 1, consistent with a single site of binding. Suppression of current amplitude was accompanied by a positive shift in the voltage dependence of gating and slowing of both voltage sensor motion and channel opening. These effects are in keeping with expectations for docking in the central pore and interaction with the pore domain "turret."

Arene Control over Thiolate to Sulfinate Oxidation in Albumin by Organometallic Ruthenium Anticancer Complexes

Interactions of organometallic ruthenium anticancer complexes [Ru(eta6-arene)Cl(en)][PF6] (arene=p-cymene (1) or biphenyl (2), en=ethylenediamine) with human serum albumin were investigated by means of mass spectrometry combined with trypsin digestion, specific sidechain modifications and computational modelling. Both complexes were shown to bind to surface histidine (His128, His247, His510) and methionine (Met298) residues in human albumin, but only the p-cymene complex can gain entry to the crevice containing the free cysteine thiolate (Cys34) and induce oxidation to sulfinate. The two complexes exhibit a similar coordination preference for histidine and methionine residues on the protein surface. His128 binding is favoured both kinetically and thermodynamically. At 310 K, six days of incubation of recombinant human albumin (rHA) with complex 1 (rHA:Ru 50:250 microM) led to about 18 % ruthenation of His128 in the protein. However, the extent of ruthenation of albumin by complex 2 was less than that by 1, due to the steric hindrance from the biphenyl ligand. These results imply that the arene ligand in the organometallic ruthenium anticancer complexes plays a crucial role in interactions with proteins.

Organometallic Osmium(II) and Ruthenium(II) Biphenyl Sandwich Complexes: X‐ray Crystal Structures and 187Os NMR Spectroscopic Studies in Solution

AbstractWe report the synthesis of the ruthenium(II) and osmium(II) organometallic sandwich complexes [Ru(η6‐bip)2](OTf)2 (1) and [Os(η6‐bip)2](OTf)2 (2) containing biphenyl (bip) as the arene ligand, and the X‐ray crystal structures of 1·MeOH and 2. The unit cell of the osmium complex contains molecules in which the unbound phenyl ring of the biphenyl ligands exists in both staggered and eclipsed configurations, whereas for the ruthenium complex the rings are only eclipsed. Both crystal structures possess CH/π and π–π stacking interactions. 187Os (nuclear spin 1/2, natural abundance of 1.64 %) has a very low gyromagnetic ratio and is one of the most insensitive nuclei in the periodic table. We show that inverse NMR spectroscopic detection by the use of 1H/187Os heteronuclear multiple bond correlation (HMBC) spectroscopy allows the ready observation of the 187Os resonance of complex 2 via couplings to arene ring protons. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)