Sulfate‐Selective Recognition by Using Neutral Dipeptide Anion Receptors in Aqueous Solution

The synthesis of six small peptide anion receptors based on thiourea and squaramide recognition moieties is described. These new receptors bind to tetrahedral sulfate anions with remarkable affinity and selectivity in aqueous solution as shown by NMR spectroscopy. Molecular modelling suggests that selectivity is mediated by a hydrogen bond network incorporating the amide backbone protons in a manner similar to that found in the sulfate‐binding protein.     

Synthesis,photophysical and NMR evaluations of thiourea-based anion receptors possessing an acetamide moiety

The synthesis and photophysical evaluation of three diaryl thiourea-based anion receptors (4–6) for comparison with their urea counterparts (1–3) is outlined. These anion receptors posses an acetamide functionality on one of the aryl groups and an electron-withdrawing CF₃ group on the other. By varying the position of the acetamide group, in the o-, m- and p-positions of 4–6, respectively, the anion binding ability was both tuneable and found to be, in some cases, significantly different from that seen for the urea analogues 1–3. The binding affinities of the receptors 4–6, as well as the binding stoichiometries, were evaluated using UV–vis absorption spectroscopy in MeCN. However, these receptors were not sufficiently emissive to quantify the anion recognition using fluorescence. The results confirmed strong binding of these receptors to anions such as fluoride, acetate, phosphate, pyrophosphate and chloride. Nevertheless, the overall results obtained did not conform to the anticipated trends seen for 1–3, which is most likely due to the enhanced binding affinity of the thiourea analogues 4–6. The binding interactions were also investigated by using ¹H NMR which confirmed that these receptors interacted with the anions in a stepwise manner, where the primary anion binding interaction occurred at the thiourea side, which led to an activation of the acetamide moiety towards the second anion binding interaction, an example of an allosteric activation mode.     

N-(二茂铁酰胺基)硫脲类阴离子受体

我们将N-(苯甲酰胺基)硫脲类阴离子识别受体研究拓展至N-(二茂铁酰胺基)硫脲, 设计合成了N-(二茂铁甲酰胺基)-N'-(取代苯基)硫脲(3a～3e, 取代基X＝p-OCH₃, p-CH₃, H, m-Br, m-CF₃), 其中二茂铁基系芳香性的电化学活性基团、“—NH—”为连接臂．研究的目的是进一步理解 “—NH—”连接臂的特性和3a～3e作为阴离子的电化学响应受体的可行性. 我们发现, 3a～3e分子中的N'-苯环取代基不影响其半波电位(0.31V vs. Ag/AgNO₃); 二茂铁环芳香质子和酰胺基—NH质子的核磁化学位移不受取代基的影响, 而N'-苯基芳香质子和硫脲—NH质子的化学位移显著地受制于取代基; 说明受体3分子中酰肼基N—N单键高度扭曲, 阻碍了N'-苯环取代基电子效应传递至二茂铁基. 我们观察到乙腈中3的氧化电位因阴离子如CH₃CO₂^－和F^－的结合负移200 mV, 二茂铁基芳香质子的化学位移向高场移动, 意味着阴离子结合诱导了受体3分子中酰肼基N—N单键构型变化, 使阴离子结合信息得以传递至二茂铁环. 吸收光谱滴定实验表明, 乙腈中3a～3e与阴离子结合时在约315 nm处出现新的吸收峰, 光谱红移达5820 cm^－1, 阴离子如CH₃CO₂^－和F^－的结合常数在10⁶ mol^－1•L, 均远高于传统的二苯基硫脲类受体(1); 我们还发现, 尽管1和3a～3e分子中硫脲—NH质子酸性对取代基的依赖性相近, 3a～3e之阴离子结合常数的取代基效应强于1. 我们认为, 这是由于N—N键的变构作用导致3a～3e的吸收光谱红移、阴离子结合常数和阴离子结合常数的取代基效应远高于传统的N,N'-二苯基硫脲类受体, 因而体现了“—NH—”连接臂的独特性质.     

Squaramide-substituted calix[4]pyrrole: Synthesis and ion binding studies

Squaramide-substituted calix[4]pyrrole 2 was synthesized and its anion-binding properties were investigated. On the basis of UV spectroscopy, ¹H NMR spectroscopic and computational DFT model analyses, compared with the parent calix[4]pyrrole 1, compound 2 shows significantly enhanced binding affinities for anions in CH₂Cl₂, and it was concluded that this increase in affinity is ascribed to participation of the squaramide unit in anion binding.     

UV-vis and fluorescence spectroscopic detection of anions by the conformational restriction of 2,2′-binaphthalene derivatives bearing thiourea groups through a methylene spacer

Novel fluorescence receptors, 2 and 3 based on 2,2′-binaphthalene possessing thiourea moieties via a methylene spacer have been synthesized. Hydrogen bonds of NH groups of thiourea moieties with acetate anion were confirmed by ¹H NMR study in MeCN-d₃. These receptors showed characteristic UV-vis spectral changes through isosbestic points on complexation with anions inspite of lacking conjugation between the chromophore and the binding sites in polar organic solvent such as acetonitrile. The UV-vis spectral changes arise from the conformational restriction of the 2,2′-binaphthyl skeleton on the complexation. The receptors exhibit high selectivities for AcO⁻ and F⁻. The fluorescence intensity of the receptors decreases with the increasing amount of the AcO⁻, however, addition of F⁻ induces a different change in its fluorescence spectrum, in which shorter emission of the receptors decreases with the increase in F⁻ concentration, while the longer emission of the receptors increases through an isoemissive point in MeCN. The results suggest that favorable dual-wavelength ratiometric fluorescence measurement can be conducted by the receptors for F⁻.     

Pseudochalkogen-Verbindungen. XVI. IR-spektroskopische Untersuchungen an Cyanamidomonophosphaten, [PO4−n (NCN)n]3−

Pseudochalkogen Compounds. XVI. Infrared-spectroscopic Investigations of Cyanamidomonophosphates, [PO_4?n(NCN)_n]^3? Infrared spectroscopic investigations of trisodium cyanamidomonophosphates of the general type Na₃[PO_4?n(NCN)_n] · aq (n: 1, 2, 3) are reported. The vibrational spectra of the compounds are confirming very clearly the special position of cyanamidophosphates within the group of substituted phosphates: Cyanamidophosphates are characterized by a full participation of pseudochalkogen groups representing NCN substituents into the mesomeric system of the anions and an only slight shortening of the P? O distances in comparision to [PO₄]^3?. Characteristic frequencies between 970 and 1150 cm^?1 are attributed to v(PO_4?nN_n)-stretching frequencies. A partial ¹⁵N labelling of the monocyanamidophosphate anion, [PO₃NCN]^3? leads to some splitting or shifting of frequencies being connected with vibrations of the NCN group; isolated v(P? N) stretching frequencies cannot be found.     

High‐Affinity Anion Binding by Steroidal Squaramide Receptors

Exceptionally powerful anion receptors have been constructed by placing squaramide groups in axial positions on a steroidal framework. The steroid preorganizes the squaramide NH groups such that they can act cooperatively on a bound anion, while maintaining solubility in nonpolar media. The acidic NH groups confer higher affinities than previously‐used ureas or thioureas. Binding constants exceeding 10¹⁴ M ^?1 have been measured for tetraethylammonium salts in chloroform by employing a variation of Cram’s extraction procedure. The receptors have also been studied as transmembrane anion carriers in unilamellar vesicles. Unusually their activities do not correlate with anion affinities, thus suggesting an upper limit for binding strength in the design of anion carriers.     

Tuning CH Hydrogen Bond-Based Receptors toward Picomolar Anion Affinity via the Inductive Effect of Distant Substituents

Inspired by nature, artificial hydrogen bond-based anion receptors have been developed to achieve high anion selectivity; however, their binding affinity is usually low. The potency of these receptors is usually increased by the introduction of aryl substituents, which withdraw electrons from their binding site through the resonance effect. Here, we show that the polarization of the C(sp³)-H binding site of bambusuril receptors, and thus their potency to bind anions, can be modulated by the inductive effect. The presence of electron-withdrawing groups on benzyl substituents of bambusurils significantly increases their binding affinities to halides, resulting in the strongest iodide receptor reported to date with an association constant greater than 10¹³ M⁻¹ in acetonitrile. A Hammett plot showed that while the bambusuril affinity toward halides linearly increases with the electron-withdrawing power of their substituents, their binding selectivity remains essentially unchanged.     

Solution and Solid State Studies of Urea Derivatives of DITIPIRAM Acting as Powerful Anion Receptors

Herein, we present the synthesis and anion binding studies of a family of homologous molecular receptors 4–7 based on a DITIPIRAM (8-propyldithieno-[3,2-b:2′,3′-e]-pyridine-3,5-di-amine) platform decorated with various urea para-phenyl substituents (NO₂, F, CF₃, and Me). Solution, X-ray, and DFT studies reveal that the presented host–guest system offers a convergent array of four urea NH hydrogen bond donors to anions allowing the formation of remarkably stable complexes with carboxylates (acetate, benzoate) and chloride anions in solution, even in competitive solvent mixtures such as DMSO-d₆/H₂O 99.5/0.5 (v/v) and DMSO-d₃/MeOH-d₃ 9:1 (v/v). The most effective derivatives among the series turned out to be receptors 5 and 6 containing electron-withdrawing F- and -CF₃ para-substituents, respectively.     

Lower rim amide (1,3) functionalised calix[4]arene amido-thiourea derivatives as dimetallic Zn(II) coordination complexes for anion recognition/sensing

The synthesis of two amido-thiourea based receptors/sensors 1 and 2, formed by functionalisation of the lower rim of a calix[4]arene, and the photophysical analysis of these with Zn(II) and various anions is described. The two structures, differing by the substituent on the thiourea moiety, were found to bind Zn(II) effectively in ethanol (EtOH); the recognition giving rise to significant changes in the UV-vis absorption spectra, which was red-shifted for both chemosensors. The changes in the absorption spectra were further analysed using nonlinear regression analysis programme (using the global analysis software ReactLab? Equilibria), which revealed high binding constants for both systems. The resulting dimetallic complexes (1,2)–Zn₂ were (pre-formed and) then used to coordinate anionic species such as AcO^? , H₂PO₄^?  and Br^?  through electrostatic interactions, showing high affinity towards these anions. In all cases, nonlinear regression analysis showed both 1:1 or 1:2 sensor:anion depending on the anion used. Although the 2-Zn₂ complex showed high affinity for acetate, phosphate and bromide, the 1-Zn₂ complex showed selectivity towards the recognition of phosphate in EtOH.     

Synthesis and Pharmacological Evaluation of Chlorinated N-Alkyl-3- and -5-(2-hydroxyphenyl)pyrazoles as CB1 Cannabinoid Ligands

The syntheses of several new 3- and 5-(4-chloro-2-hydroxyphenyl)-5- and -3-(2,4-dichlorophenyl)-1-alkylpyrazoles are reported. These syntheses started from simple chlorophenols, 2,4-dichlorobenzaldehyde or ethyl 2,4-dichlorobenzoate in order to prepare pyrazoles bearing three and four chloro substituents in certain positions. The affinity of these compounds towards the CB ₁ type cannabinoids receptors was then evaluated in human brain tissues (frontal cortex). The results showed that some of the compounds exhibit affinity towards this kind of receptors in the micromolar range.     

Theoretical study of substituent effects on the acidity of the methyl group: Structure of anions CH2X−

Geometries have been optimized using molecular-orbital calculations (a) with a 4-31G Gaussian basis set for carbanions CH₂X^? where X = H, CH₃, NH₂, OH, F, C?CH, CH?CH₂, CHO, COCH₃, CN, and NO₂; and (b) with an STO -3G basis set for methyl acetate and acetyl deprotonated methyl acetate. All the carbanions containing unsaturated substituents are planar, with a considerable shortening of the C? X bond. Carbanions containing saturated substituents are pyramidal with the out-of-plane angle α increasing with the electronegativity of the substituent. Double-zeta basis set calculations give proton affinities over the range 449 (for CH₃CH₂^?) to 355 kcal/mol (for CH₂NO₂^?), with all unsaturated anions having smaller affinities than saturated anions. The correlation of proton affinities with 1s binding energies, and with charges on both the carbon of the anion and on the acidic proton of the neutral molecule are examined.     

Die intermolekulare Wechselwirkung der „Nicht ebenen Deformationsschwingung”︁ in Carbonaten

The intermolecular interactions of the ?non-planar deformation modes”? in arbonates The v₂ coupling constants of some carbonates of the aragonite structure, and of structures with similar configuration of the nearest anion neighbours, are investigated by means of ¹⁴C isotopic substitution. A relationship is found between the coupling constants and the fifth power of the anion distances. This relation shows that short-range repulsion forces and not dipole-dipole interaction governs the v₂ coupling of the carbonates investigated in these studies.     

Synthesis and Pharmacological Evaluation of Chlorinated <Emphasis Type="Italic">N</Emphasis>-Alkyl-3- and -5-(2-hydroxyphenyl)pyrazoles as <Emphasis Type="Italic">CB</Emphasis><Subscript>1</Subscript> Cannabinoid Ligands

Summary. The syntheses of several new 3- and 5-(4-chloro-2-hydroxyphenyl)-5- and -3-(2,4-dichlorophenyl)-1-alkylpyrazoles are reported. These syntheses started from simple chlorophenols, 2,4-dichlorobenzaldehyde or ethyl 2,4-dichlorobenzoate in order to prepare pyrazoles bearing three and four chloro substituents in certain positions. The affinity of these compounds towards the CB ₁ type cannabinoids receptors was then evaluated in human brain tissues (frontal cortex). The results showed that some of the compounds exhibit affinity towards this kind of receptors in the micromolar range.     

The Squaramide versus Urea Contest for Anion Recognition

The interaction of a neutral squaramide‐based receptor, equipped with two 4‐nitrophenyl substituents ( R_sq ), with halides and oxoanions has been studied in MeCN. UV/Vis and ¹H NMR spectroscopy titration experiments clearly indicated the formation of 1:1 hydrogen bonding [ R_sq ???X]⁺ complexes with all the investigated anions. X‐ray diffraction studies on the chloride and bromide complex salts confirmed the 1:1 stoichiometry and indicated the establishment of bifurcated hydrogen‐bond interactions between the squaramide‐based receptor and the halide anion that involved both 1) amide N? H and 2) aryl proximate C? H fragments, for a total of four bonds. Probably due to the contribution of C? H fragments, complexes of R_sq with halides are 1 to 2 orders of magnitude more stable than the corresponding ones with the analogous urea‐based receptor that contains two 4‐nitrophenyl substituents ( R_ur ). In the case of oxoanions, R_sq forms complexes, the stability of which decreases with the decreasing basicity of the anion (H₂PO₄^?>NO₂^?≈HSO₄^?>NO₃^?), and is comparable to that of complexes of the urea‐based receptor R_ur . Such a behaviour is ascribed to the predominance of different contributions: electrostatic interaction for halides, acid‐to‐base ‘frozen’ proton transfer for oxoanions. Finally, with the strongly basic anions F^? and CH₃COO^?, R_sq first gives genuine hydrogen‐bond complexes of 1:1 stoichiometry; then, upon addition of a second anion equivalent, it undergoes deprotonation of one N? H fragment, with the simultaneous formation of the dianion hydrogen‐bond complexes, [HF₂]^? and [CH₃COOH???CH₃COO]^?, respectively. In the case of the urea‐based derivative R_ur , deprotonation takes place with fluoride but not with acetate. The apparently higher Brønsted acidity of R_sq with respect to R_ur reflects the capability of the squaramide receptor to delocalise the negative charge formed on N? H deprotonation over the cyclobutene‐1,2‐dione ring and the entire molecular framework.     

Vibrational frequencies and force constants of N2O4 in complexes with molecules of different solvents determined by Raman spectra andAb initio calculation

The Raman spectra of N₂O₄ solutions in organic solvents have been recorded. The frequencies ofv ₁,v ₂, andv ₃ bands of N₂O₄ increase with increasing solvent electron-donor properties. Especially large changes ofv ₃ N-N stretching band have been observed (254.5 cm^–1 in n-hexane, 276.5 cm^–1 in 1,4-dioxane). The ab initio calculations have shown that the interaction between N₂O₄ and electron-donor molecules causes an increase of N-N and N-O stretching and O-N-O bending force constants of N₂O₄ in agreement with the results of Raman study.     

Control of Chromophore Symmetry by Positional Isomerism of Peripheral Substituents

The first example of the control of porphyrinoid chromophore symmetry based on the positional isomerism of peripheral substituents has been achieved by preparing tetraazaporphyrins (TAPs) with C_4h, D_2h, C_2v, and C_s symmetry due to the relative arrangement of peripheral tert‐butylamino and cyano groups as push and pull substituents, respectively. The four structural isomers were successfully isolated and characterized by ¹H NMR spectroscopy and X‐ray crystallography. The band morphology in the Q‐band region varies depending on the molecular symmetry due to the significant perturbation introduced into the chromophore by the push and pull substituents. The C_4h and C_2v isomers exhibit a single Q band, whereas the Q bands of the D_2h and C_s isomers show a marked splitting. The magnetic circular dichroism spectra indicate that the push–pull TAPs retain the properties of the 16‐membered 18π‐electron perimeter generally observed for porphyrinoids. Theoretical calculations have demonstrated that the perturbation introduced by the substituents lowers the D_4h symmetry of the parent TAP π‐conjugated system, and this results in significant spectral changes. A novel approach to the fine‐tuning of the spectral properties of porphyrinoids based on changes in the chromophore symmetry is described.     

A linear free-energy correlation in the low-energy tandem mass spectra of protonated tripeptides Gly–Gly–Xxx

The backbone cleavages of protonated tripeptide ions of the series Gly—Gly—Xxx, where Xxx ? Gly, Ala, Val, d-Leu, l-Leu, Ile, Phe, Tyr, Trp, Pro, Met and Glu, were studied in a hybrid tandem mass spectrometer. C-Terminal y-type ions and N-terminal a- and b-type ions were noted. A linear relationship between log (y₁/b₂) and the proton affinity of the C-terminal amino acid substituents was found: as the proton affinity of the C-terminal residue increases, the fraction of y₁ ion formation increases. When the C-terminal substituent was more basic than Trp, the b₂ ion was not observed. It is likely that the site of protonation changes from peptide bond to side-chain for just these residues, Lys, His and Arg.     

The Coordination Chemistry of the N-Donor-Substituted Phosphazanes

Phosph(III)azanes, featuring the heterocyclobutane P₂N₂ ring, have now been established as building blocks in main-group coordination and supramolecular compounds. Previous studies have largely involved their use as neutral P-donor ligands or as anionic N-donor ligands, derived from deprotonation of amido-phosphazanes [RNHP(μ-NR)]₂. The use of neutral amido-phosphazanes themselves as chelating, H-bond donors in anion receptors has also been an area of recent interest because of the ease by which the proton acidity and anion binding constants can be modulated, by the incorporation of electron-withdrawing exo- and endo-cyclic groups (R) and by the coordination of transition metals to the ring P atoms. We observed recently that the effect of P,N-chelation of metal atoms to the P atoms of cis-[(2-py)NHP(μ-N^tBu)]₂ (2-py=2-pyridyl) not only pre-organises the N−H functionality for optimum H-bonding to anions but also results in a large increase in anion binding constants, well above those for traditional organic receptors like squaramides and ureas. Here, we report a broader investigation of ligand chemistry of [(2-py)NHP(μ-^tNBu)]₂ (and of the new quinolyl derivative [(8-Qu)NHP(μ-N^tBu)]₂ (8-Qu=8-quinolyl). The additional N-donor functionality of the heterocyclic substituents and its position has a marked effect on the anion and metal coordination chemistry of both species, leading to novel structural behaviour and reactivity compared to unfunctionalized counterparts.