Axial Conformers Research Articles

The Conformational Behaviour of Fluorinated Tetrahydrothiopyran.

We present a comprehensive study on the conformational behavior of diversely substituted 4-fluorotetrahydrothiopyran derivatives. Through quantum chemical simulations including DFT as well as NBO and NPA analysis, we elucidate the pivotal role of electrostatic interactions, occasionally complemented by hyperconjugative interactions, in stabilizing axial fluorine conformers. Less polar conformers were occasionally obtained, attributed to the interplay of electrostatic and hyperconjugative interactions. Experimental validation through NMR spectroscopy aligns with the computational analysis, thus providing a coherent understanding of the structural dynamics of these compounds.

Long term follow-up of axial length and orbital dimensions in congenital microphthalmia and anophthalmia.

To evaluate axial length (AL), orbital width (OW) and height (OH) development in congenital microphthalmia and anophthalmia (MICA) using serial ultrasonography measurements. A longitudinal prospective cohort (n = 74) of unilaterally and bilaterally affected MICA patients was followed from 2013 to 2022 at the university hospital in Amsterdam, the Netherlands. Clinical entity, age, severity category based on axial length, conformer treatment and intra-orbital cysts were registered. The main outcome measures were the absolute and relative growth of AL, OW and OH. Surgical and intra-orbital cyst cases were described separately. Absolute microphthalmic eye size increased in 27/49 (55%) unilateral MICA eyes, but growth arrest/decrease in the remaining could shift the case to a more severe category over time. A final affected/unaffected orbital symmetry ≥80% was seen in the large majority of unilateral cases (45/46 for OW, 43/46 for OH). Cases with AL < 10.5 mm had orbital symmetry <80% more often. Most orbital symmetry changes were seen in moderate and severe unilateral cases treated with 3D-printed conformer therapy starting at age <1 year, with 6/10 (60%) symmetry increase, 30% unchanged symmetry and 10% symmetry decrease. All cases older than 6.5 years (n = 6) did not show any change anymore, regardless of treatment. For bilateral and unilateral mild cases, orbital dimensions kept the same proportions during follow-up, with or without conformer treatment. Using severity categories in MICA based on relative AL may aid the decision to start conformer treatment, as most orbital symmetry changes were seen in moderate and severe unilateral cases receiving 3D-printed conformer therapy that started under age 1.

Binding and unbinding of potent melatonin receptor ligands: Mechanistic simulations and experimental evidence.

The labeled ligand commonly employed in competition binding studies for melatonin receptor ligands, 2-[125I]iodomelatonin, showed slow dissociation with different half-lives at the two receptor subtypes. This may affect the operational measures of affinity constants, which at short incubation times could not be obtained in equilibrium conditions, and structure-activity relationships, as the Ki values of tested ligands could depend on either interaction at the binding site or the dissociation path. To address these issues, the kinetic and saturation binding parameters of 2-[125I]iodomelatonin as well as the competition constants for a series of representative ligands were measured at a short (2 h) and a long (20 h) incubation time. Concurrently, we simulated by molecular modeling the dissociation path of 2-iodomelatonin from MT1 and MT2 receptors and investigated the role of interactions at the binding site on the stereoselectivity observed for the enantiomers of the subtype-selective ligand UCM1014. We found that equilibrium conditions for 2-[125I]iodomelatonin binding can be reached only with long incubation times, particularly for the MT2 receptor subtype, for which a time of 20 h approximates this condition. On the other hand, measured Ki values for a set of ligands including agonists, antagonists, nonselective, and subtype-selective compounds were not significantly affected by the length of incubation, suggesting that structure-activity relationships based on data collected at shorter time reflect different interactions at the binding site. Molecular modeling simulations evidenced that the slower dissociation of 2-iodomelatonin from the MT2 receptor can be related to the restricted mobility of a gatekeeper tyrosine along a lipophilic path from the binding site to the membrane bilayer. The enantiomers of the potent, MT2-selective agonist UCM1014 were separately synthesized and tested. Molecular dynamics simulations of the receptor-ligand complexes provided an explanation for their stereoselectivity as due to the preference shown by the eutomer at the binding site for the most abundant axial conformation adopted by the ligand in solution. These results suggest that, despite the slow-binding kinetics occurring for the labeled ligand, affinity measures at shorter incubation times give robust results consistent with known structure-activity relationships and with interactions taken at the receptor binding site.

Investigation of excited states of BODIPY derivatives and non-orthogonal dimers from the perspective of singlet fission.

We report state of the art electronic structure calculations RICC2 and XMCQDPT of BODIPY nonorthogonal dimers to understand the photophysical processes from the intramolecular singlet fission (iSF) perspective. We have calculated singlet, triplet and quintet states at the XMCQDPT(8,8)/cc-pVDZ level of theory and diabatic singlet states at the XMCQDPT(4,4)/cc-pVDZ level of theory. In all the systems studied, charge transfer states (1(CA) and 1(AC)) couple strongly with locally excited (1(S1S0)) and multiexcitonic (1(T1T1)) states. The rates of formation of the multiexcitonic state from the locally excited state are very low on account of large activation energy (E(1(T1T1)) - E(1(S1S0))). A relaxed scan along the torsional angle revealed contrasting results for axial and orthogonal conformers. We proposed a probable mechanism for contrasting photophysical properties of dimers B[3,3] and B[2,8]. We also found that substitution of CN, NH2 and BH2 at meso, β and α positions reduces the energy gap (ΔSF = 2E(T1) - E(S1)) significantly, making iSF a competing process in triplet state generation. Intrigued by the success of the CN group at the meso position in reducing the energy gap, we also studied the azaBODIPY monomer and its derivatives using the same methodology. The iSF is slightly endoergic with ΔSF ∼ 0.2 eV in these systems and iSF may play an important role in their photophysical responses.

Anomeric‐Schleyer hyperconjugative interaction as a convenient avenue for aromaticity enhancement of phospholes

AbstractDue to the insufficient interaction of the phosphorus lone pair with the butadiene moiety, the aromaticity of the phosphole ring is lower than that of its counterpart's pyrrole, furan, and thiophene. Considering the high importance of phosphole core in organic chemistry, increasing its stability through reinforcement its aromaticity can be very valuable. In the present work, the aromaticity of the phosphole on the anomeric carbon in both the axial and equatorial conformers of the unsaturated six‐membered heterocycles, using structural, electronic, energetic, and magnetic indices were investigated by the DFT‐B3LYP/6‐311++G(d,p) computational method. Electron pumping through anomeric and then Schleyer hyperconjugative interaction increase the aromaticity of the phosphole ring in axial conformer of compounds 1–11. Based on various types of aromaticity indices, the results showed that the phosphole ring in the axial position has far higher aromaticity than the equatorial position. The phosphole ring containing cyano groups shows an efficient anomeric effect and, as a result, higher aromaticity. Excellent correlations were observed between aromaticity indices with different backgrounds.

Influence of heteroatoms and substituents on structural and spectroscopic parameters of saturated six-member ring heterocycles: experimental and theoretical study of 1-methyl-1-germacyclohexane

The conformational analysis of newly synthesized compound, 1-methyl-1-germacyclohexane, is performed by means of a combined vibrational spectroscopy and theoretical methods. The liquid 1-methyl-1-germacyclohexane at room temperature is investigated using conventional ATR-FTIR, FT-IR (gas phase) and Raman methods. FT-IR spectra of the isolated in low-temperature neon and nitrogen matrices are registered. The further detailed vibrational conformational analysis is performed utilizing density functional theory and perturbation theory based methods. All possible 12 canonical ring conformations considering axial/equatorial CH3 group position are analyzed by utilizing DFT/B3LYP, DFT/M06-2X and MP2 at aug-cc-pVTZ theory level.The most stable conformer with the global energy minimum structure in the chair axial conformation is investigated in detail. Analysis of the potential energy surface reveals transition states (TS) and energy barriers. The conformational path is found to be as follows: chair (1C4)→ envelope/half-chair (TS)→ skew-boat (1S3 - C1 symmetry)→ boat (TS)→ skew-boat (1S5 - C2 symmetry). The energy barrier for 1C4 (chair) to 1S3 (skew-boat) conversion is 4.8 kcal/mol while for the reverse process equals to 0.5 kcal/mol.A similar conformational analysis is performed for different configurations of germacyclohexane, silacyclohexane and cyclohexane with mono- and disubstituents: CH2Cl, CH3, Cl and F. Such approach enables investigation of influence of the heteroatoms and substituents of various size and type on the structural parameters and conformational diversity.

Novel insight on aromaticity enhancement of pyridone heterocycles using the anomeric effect-Schleyer hyperconjugation aromaticity: A DFT and NBO study

Considering the value of 2-pyridone and 4-pyridone heterocyclic groups in organic chemistry, in this study, the anomeric effect and Schleyer hyperconjugation aromaticity for the first time have been used to increase the aromaticity of these heterocycles. The anomeric effect in tetrahydropyrans containing 2-pyridone or 4-pyridone ring on the anomeric carbon in axial and equatorial conformers has been investigated using the DFT-B3LYP/6–311++G(d,p) calculation method. On the other hand, the aromaticity of 2-pyridone and 4-pyridone in the considered conformers was investigated by nucleus-independent chemical shift indices (NICS) and the harmonic oscillator model of electron delocalization index (HOMED). The results illustrate that placing 2-pyridone and 4-pyridone in the axial position increases their aromaticity through the anomeric effect. Furthermore, connecting the ring from the carbon atom to the anomeric position is better than the nitrogen atom for aromaticity increment. Aromaticity indices show that the anomeric effect-Schleyer hyperconjugation interaction is more robust in the presence of nitrogen atoms than oxygen or sulfur atom.

N-N(+) Bond-Forming Intramolecular Cyclization of O-Tosyloxy β-Aminopropioamidoximes and Ion Exchange Reaction for the Synthesis of 2-Aminospiropyrazolilammonium Chlorides and Hexafluorophosphates.

Our research area is related to the spiropyrazolinium-containingcompounds, which are insufficiently studied compared with pyrazoline-containing compounds. Nitrogen-containing azoniaspiromolecules have also been well studied. In drug design and other areas, they are a priori important structures, since rigid spirocyclic scaffolds with the reduced conformational entropy are able to organize a closely spaced area. Azoniaspirostructures are currently of wide practical interest as ionic liquids, current sources (membranes), structure-directing agents in organocatalysis, and in the synthesis of ordered ceramics. Our goal was the synthesis of 2-aminospiropyrazolilammonium chlorides and hexafluorophosphates. Our methodology is based on the tosylation of β-aminopropioamidoximes with six-membered N-heterocycles (piperidine, morpholine, thiomorpholine, and phenylpiperazine) at the β-position. 2-Aminospiropyrazolilammonium chlorides and hexafluorophosphates were obtained by the reaction of double ion substitution in the reaction of toluenesulfonates of 2-aminospiropyrazolinium compounds with an ethereal solution of HCl in ethanol and with ammonium hexafluorophosphate in ethanol in quantitative yields of 55-97%. The physicochemical characteristics of the synthesized compounds and their IR and NMR spectra are presented. The obtained salts were additionally characterized by the single-crystal XRD analysis. The presence of both axial and equatorial conformations of spirocations in solids was confirmed. 2-Aminospiropyrazolilammonium chlorides and hexafluorophosphates have weak in vitro antimicrobial activity on Gram-positive and Gram-negative bacterial lines.

NMR and FT-IR Investigation Study and Topological Analysis of Various Conformations of 2,5-dimethyl-2,5-dihydroxyl-1,4-dithian using Density Functional Theory Method

Abstract: 1,4-dithian-2,5-dihydroxyl is the major source for the synthesis of sulfur-containing heterocyclic compounds such as thiophene and 1,3-thiazole derivatives, which these compounds are widely used in pharmaceuticals and agricultural industries. Sulfur-containing heterocycles, such as 2-aminothiophene, thiazolidine, oxothiazolidine, and thiazoles, can be comprehensively synthesized from dimerization of the derivatives of 1,4-dithian-2,5- dihydroxyl. FT-IR and NMR spectra of axial and equatorial conformations of 2,5-dimethyl-2,5-dihydroxyl-1,4- dithian compound were investigated by density functional theory (DFT) using B3LYP/6-311++G** and M06- 2X/aug-cc-pVDZ computational methods. The topological properties of the electron charge density were calculated by the quantum theory of atoms in molecules (QTAIM) and non-covalent interactions/reduced electron density gradient (NCI-RDG) theoretical methods. The obtained results of the analyses were also discussed in more detail. The results showed that the steric interactions are more prominent than the van der Waals interactions, and in both conformations, steric interactions are included in the middle of the 1,4-dithian ring and there is hydrogen bonding between hydroxyl groups and 1,4-dithian ring structure heteroatoms in the axial conformation while this interaction is not observed in the case of equatorial conformation. The presence of these interactions was confirmed using NBO analysis.

The conformational behavior and structure of monosubstituted 1,3,5‐trisilacyclohexanes—Part III: 1‐Methyl‐1,3,5‐trisilacyclohexane

Abstract1‐Methyl‐1,3,5‐trisilacyclohexane was synthesized and its structure and conformational properties have been determined by gas‐phase electron diffraction (GED) and quantum chemical (QC) calculations. The molecule may exist in two forms differing from each other by the substituent's position. QC results show that the equatorial conformer is predicted to be slightly more stable than the axial conformer; note that one method (M06‐2X) with basis set 6‐311G** shows an equal amount of Ax and Eq conformers: ratio (Ax/Eq) = (30–50):(70–50)% (depending on the method and basis set). From the GED data, the molar fractions of the conformers were found to be Ax:Eq = 54(10):46(10) at 280(5) K. A temperature‐dependent Raman experiment resulted in an Ax:Eq ratio of 58(4):42(4). Conformational properties are compared in series of analogous 1‐X‐1‐(hetero)cyclohexanes.

One Scaffold, Two Conformations: The Ring-Flip of the Messenger InsP8 Occurs under Cytosolic Conditions.

Inositol poly- and pyrophosphates (InsPs and PP-InsPs) are central eukaryotic messengers. These very highly phosphorylated molecules can exist in two distinct conformations, a canonical one with five phosphoryl groups in equatorial positions, and a "flipped" conformation with five axial substituents. Using 13C-labeled InsPs/PP-InsPs, the behavior of these molecules was investigated by 2D-NMR under solution conditions reminiscent of a cytosolic environment. Remarkably, the most highly phosphorylated messenger 1,5(PP)2-InsP4 (also termed InsP8) readily adopts both conformations at physiological conditions. Environmental factors-such as pH, metal cation composition, and temperature-strongly influence the conformational equilibrium. Thermodynamic data revealed that the transition of InsP8 from the equatorial to the axial conformation is, in fact, an exothermic process. The speciation of InsPs and PP-InsPs also affects their interaction with protein binding partners; addition of Mg2+ decreased the binding constant Kd of InsP8 to an SPX protein domain. The results illustrate that PP-InsP speciation reacts very sensitively to solution conditions, suggesting it might act as an environment-responsive molecular switch.

Single-atom nanozymes with axial ligand-induced self-adaptive conformation in alkaline medium boost chemiluminescence

Single-atom nanozymes with axial ligand-induced self-adaptive conformation in alkaline medium boost chemiluminescence

The Nicotinic Agonist Cytisine: The Role of the NH···N Interaction.

We report a detailed structural study of cytisine, an alkaloid used to help with smoking cessation, looking forward to unveiling its role as a nicotinic agonist. High-resolution rotational spectroscopy has allowed us to characterize two different conformers exhibiting axial and equatorial arrangements of the piperidinic NH group. Unexpectedly, the axial form has been found as the predominant configuration, in contrast to that observed for related molecules, such as piperidine. This anomalous behavior has been justified in terms of an intramolecular NH···N hydrogen bond. Moreover, this interaction justifies the overstabilization of the axial conformer over the equatorial one and is crucial for the mechanism of action of cytisine over the nicotinic receptor, further rationalizing its behavior as a nicotinic agonist.

Anion‐Directed Conformation Switching and Trigonal Distortion in Hexakis(methylamine)nickel(II) Cations

AbstractThe homoleptic [Ni(NH2CH3)6]2+ cations have dozens of energetically feasible conformational isomers (conformers), and we herein show their conformation is tunable using counter anions. The reaction of Ni(NO3)2 or NiCl2 with aqueous methylamine in dimethylformamide gave [Ni(NH2CH3)6](NO3)2 (1) or [Ni(NH2CH3)6]Cl2 (2) in which methylamine ligands have axial or equatorial orientation with respect to the three‐fold principal axis, respectively. Interestingly, the conformation of methylamine ligands affects geometry around nickel(II) so that the nickel octahedron is trigonally compressed in 1, whereas it is trigonally elongated in 2, causing different visible light absorption properties between 1 and 2. Density functional theory calculations showed that nitrate anions stabilize the axial conformer through two‐point hydrogen bonding interactions with methylamines, whereas spherical chloride anions promote deformation of the axial conformer into the equatorial conformer through formation of three‐point hydrogen bonding interactions.

Electrochemical, Photophysical, Morphological and DFT Study of Polymorphic Sn(IV)-Porphyrins Containing Fluorinated Axial Ligand.

In this study, we report the polymorphism of six coordinated Sn(IV)- tetrabromophenyl porphyrins axially armed with fluorine-substituted phenolate ligands (structural formula [Sn(TBrPP)2+ (A- )2 ], where A is the axial ligand=3,5-difluoro phenol, compound 1). One form stabilizes in triclinic system (namely, 1α), and the other stabilizes in monoclinic system (namely, 1β). The two 1α and 1β polymorphs display distinct photophysical and morphological properties in the solid state. X-ray diffraction study reveals that these polymorphs 1α and 1β significantly differ in their supramolecular architecture, different axial phenolate conformations, and noncovalent interactions, which are responsible for their distinct solid-state properties. The crystal packing of these polymorphs dominates by intermolecular C-H⋅⋅⋅F, C-H⋅⋅⋅π and C-Br⋅⋅⋅F interhalogen interactions. Furthermore, the solid-state emission spectra of 1α showed red-shifted emission bands with respect to 1β, in addition the redox behavior of 1α is slightly different in comparison to 1β. Complementary theoretical studies with Hirshfeld surface analysis show the definite role of Br⋅⋅⋅F interhalogen interactions in the overall stability. Mapping the electrostatic potential isosurfaces with the aid of density functional theory in compound 1 clearly shows the presence of σ-hole, a requisite feature to show halogen interactions in the crystalline state. In addition, lattice energy and single point energy calculation shows that 1α was found to be energetically more favorable and thermodynamically more stable compare to 1β.

Solvent effects on the vibrational modes of (R)-3-methylcyclohexanone conformers

• DFT calculations of IR spectra are reported for ( R )-3-methylcyclohexanone ( R 3MCH) conformers in 11 solvents. • Solvent effects on IR spectra of R 3MCH conformers are investigated. • DFT calculations of the dipole moment components and magnitude of R 3MCH conformers were performed in 11 solvents. • A weak linear correlation was observed between the EQ and AX enthalpy difference as a function of solvent polarity. Quantum chemical calculations of the IR spectra, dipole moments, and enthalpies for the optimized geometries of dominant Equatorial (EQ) and Axial (AX) conformers of R-(+)-3-methylcyclohexanone (R3MCH) were performed in 11 common solvents of different polarity and nature, in the framework of polarizable continuum model (PCM). Density Functional Theory (DFT) involving exchange–correlation functional B3LYP and aug-cc-pVTZ basis set were used. The IR calculations of the individual conformers of R3MCH in CCl 4 yielded two distinct vibrational modes at 1086.13 cm −1 and 1030.86 cm −1 that were identified as unique markers of the EQ and AX conformers, respectively. By monitoring the calculated peaks of these two markers in 11 different solvents, a linear correlation between the EQ and AX markers’ intensities and frequencies with solvent polarity was observed. This correlation was directly related to the dipole moment orientation of each conformer. Upon increasing solvent polarity, the mode frequency of the EQ and AX markers experienced hypsochromic (blue) and bathochromic (red) shifts, respectively. A weak linear correlation was observed between the EQ and AX enthalpy difference as a function of solvent polarity.

The 130–360 GHz rotational spectrum of isocyanocyclobutane (C4H7NC) and cyanocyclobutane (C4H7CN)

The 130–360 GHz rotational spectrum of isocyanocyclobutane is reported herein for the first time. Over 2200 transitions were measured, assigned, and least-squares fit to a partial-octic distorted-rotor Hamiltonian with small deviation (σfit < 50 kHz) for the equatorial conformer. The axial conformer has so far remained elusive. For cyanocyclobutane, we measured the rotational spectra of both equatorial and axial conformers in the same frequency region to allow a direct comparison between the isomers. Transition frequencies for each conformational isomer of cyanocyclobutane were similarly fit to partial octic distorted-rotor Hamiltonians with small deviation. The experimental spectroscopic constants are in very good agreement with the predicted values (B3LYP) for all three species and with those reported in an earlier microwave study of cyanocyclobutane. Measurement of the relative transition intensities provides an updated energy difference of 0.69 (7) kcal/mol between the two conformers, with the equatorial conformation being the more stable one. Analysis of the axial conformation of cyanocyclobutane reveals coupling of its ground state to the vibrationally excited states of the equatorial conformation. Our observations of the vibrationally excited states of the equatorial conformer suggest that there are many Coriolis interactions between these states that were not described previously. Combined with literature values of nuclear quadrupole coupling constants, these spectroscopic constants and reported transition frequencies provide the basis for future astronomical searches for isocyanocyclobutane and cyanocyclobutane.

Photoelectron Circular Dichroism as a Signature of Subtle Conformational Changes: The Case of Ring Inversion in 1-Indanol.

Chirality plays a fundamental role in the molecular recognition processes. Molecular flexibility is also crucial in molecular recognition, allowing the interacting molecules to adjust their structures and hence optimize the interaction. Methods probing simultaneously chirality and molecular conformation are therefore crucially needed. Taking advantage of a possible control in the gas phase of the conformational distribution between the equatorial and axial conformers resulting from a ring inversion in jet-cooled 1-indanol, we demonstrate here the sensitivity of valence-shell photoelectron circular dichroism (PECD) to both chirality and subtle conformational changes, in a case where the photoelectron spectra of the two conformers are identical. For the highest occupied orbital, we observe a dramatic inversion of the PECD-induced photoelectron asymmetries, while the photoionization cross-section and usual anisotropy (β) parameter are completely insensitive to conformational isomerism. Such a sensitivity is a major asset for the ongoing developments of PECD-based techniques as a sensitive chiral (bio)chemical analytical tool in the gas phase.

Reversible Self-Assembly of an N-Heterocyclic Carbene on Metal Surfaces.

Self-assembly of cyclohexyl cyclic (alkyl)(amino)carbenes (cyCAAC) can be realized and reversibly switched from a close-packed trimer phase to a chainlike dimer phase, enabled by the ring-flip of the cyclohexyl wingtip. Multiple methods including scanning tunneling microscopy (STM), X-ray photoelectron spectroscopy (XPS) and density functional theory (DFT) calculations identified a distinct isomer (axial or equatorial chair conformer) in each phase, and consequently support the conclusion regarding the determination of molecular surface geometry on the self-assembly of cyCAAC. Moreover, various substrates such as Ag (111) and Cu (111) are tested to elucidate the importance of cyCAAC-surface interactions on cyCAAC based nanopatterns. These investigations of patterned surfaces prompted a deep understanding of cyCAAC binding mode, surface geometry and reversible self-assembly, which are of paramount significance in the areas of catalysis, biosensor design and surface functionalization.

Reversible Selbstorganisation eines N‐heterocyclischen Carbens auf Metalloberflächen

AbstractCyclohexyl(alkyl)(amino)carbene (cyCAAC) bilden selbstorganisierende Monolagen, die durch den Ring‐Flip der Cyclohexyl‐Seitengruppe reversibel von einer dicht gepackten Trimer‐Phase in eine kettenartige Dimer‐Phase umgeschaltet werden können. Mehrere Methoden, darunter Rastertunnelmikroskopie (STM), Röntgen‐Photoelektronenspektroskopie (XPS) und Dichtefunktionaltheorie (DFT)‐Berechnungen, identifizierten ein eindeutiges Isomer (axiales oder äquatoriales Sesselkonformer) in jeder Phase und stützen somit die Schlussfolgerung hinsichtlich des Einflusses der molekularen Oberflächengeometrie auf die Selbstorganisation von cyCAAC. Darüber hinaus wurden verschiedene Substrate wie Ag(111) und Cu(111) getestet, um die Bedeutung der Wechselwirkungen zwischen cyCAAC und der Oberfläche für die auf cyCAAC basierenden Nanomuster aufzuklären. Die Untersuchungen von gemusterten Oberflächen führten zu einem tieferen Verständnis der cyCAAC‐Bindungsweise, der Oberflächengeometrie und der reversiblen Selbstorganisation, die in den Bereichen Katalyse, Biosensor‐Design und Oberflächenfunktionalisierung von herausragender Bedeutung sind.