Creatininium Cation Research Articles

An endo-functionalized molecular cage for selective potentiometric determination of creatinine.

Potentiometric ion-selective electrodes (ISEs), which rely on selective and lipophilic ionophores, are commonly employed in clinical diagnostics. However, there are very limited specific ionophores for the detection of creatinine, a critical biomarker for renal function assessment. In the present research, we designed and synthesized an endo-functionalized cage, which is able to selectively bind the creatininium cation (K a = 8.6 × 105 M-1) through the formation of multiple C-H⋯O and N-H⋯N hydrogen bonds and cation⋯π interactions. ISEs prepared with this host show a Nernstian response to creatinine and exhibit excellent selectivity and a low detection limit of 0.95 μM. In addition, the creatinine levels in urine or plasma samples determined by our sensor are consistent with those analyzed using enzymatic assay on a Cobas c702. The method is simple, fast and accurate, and amenable to clinical detection of creatinine levels.

Potentiometric detection of creatinine in the presence of nicotine: Molecular recognition, sensing and quantification through multivariate regression

Systematic errors in the calix [4] pyrrole-based potentiometric detection of creatinine have been observed in heavy smokers. This work further characterizes the interactions between the nicotinium cation and the cavitand as well as the resulting interference produced during the potentiometric detection. It is found that the nicotinium cation binds the electronic rich aromatic cavity defined by the pyrrole rings of the receptor's cone conformation with an estimated binding constant higher than 10−4 M−1 in methylene chloride. On the other hand, the creatininium cation is preferentially included in the hydrophobic aromatic cavity of the ionophore by establishing hydrogen bond interactions with the pyrrole NHs groups. Potentiometric calibrations confirmed the detection of the nicotinium cation at neutral and acidic pH, respectively. Due to the lower pka of creatinine, a methodology to quantify creatinine in presence of nicotine by using an array of three sensors at two pH values is proposed. A partial least squares regression was performed and reported recoveries of 103% with a standard deviation of 20%. The improved determination of creatinine was therefore discussed. This approach represents a step forward in the development of effective approaches to improve the measurement of creatinine in decentralized settings.

2-Amino-1-methyl-4-oxo-4,5-dihydro-1H-imidazol-3-ium 3-carboxy-4-hydroxybenzenesulfonate monohydrate

The asymmetric unit of the title molecular salt, C4H7N3O+·C7H5O6S−·H2O, contains a 5-sulfosalicylate anion, a creatininium cation and a water molecule of crystallization. The cation is protonated at the imidazole N atom and the anion is deprotonated at the sulfonic acid group. The creatininium is disordered over two sets of sites with refined site occupancies of 0.771 (3) and 0.229 (3). The benzene ring is approximately orthogonal to the disordered five-membered rings [dihedral angles of 89.7 (2) and 88.3 (8)° for the major and minor occupancy components, respectively]. In the crystal, the ions are connected through pairs of N—H...O hydrogen bonds, generating anR22(8) ring-motif. An intraionic O—H...O hydrogen bond generates anS(6) graph-set motif. Weak C—H...O contacts link the ions and water molecule into a two-dimensional network parallel to (001). The structure was refined as a two-component twin.

Creatininium phosphite

The title salt, C4H8N3O+·H2PO3 −, contains a creatininium cation (2-amino-1-methyl-4-oxo-4,5-dihydro-1H-imidazol-3-ium) and a phosphite anion. The crystal packing shows layers of hydrogen-bonded ions lying parallel to the (-114) and (11-4) planes.

Experimental and computational studies on creatininium 4-nitrobenzoate - An organic proton transfer complex

A new organic proton transfer complex of creatininium 4-nitrobenzoate (C4NB) has been synthesized and its single crystals were grown successfully by slow evaporation technique. The grown single crystal was subjected to various characterization techniques like single crystal X-ray diffraction (SCXRD), FTIR, FT-Raman and Kurtz-Perry powder second harmonic generation (SHG). The SCXRD analysis revealed that C4NB was crystallized into orthorhombic crystal system, with noncentrosymmetric (NCS), P212121 space group. The creatininium cation and 4-nitrobenzoate anion were connected through a pair of N__H⋯O hydrogen bonds (N(3)__H(6) ⋯ O(3) (x+1, y, z) and N(2)__H(5) &ctdot O(2) (x-1/2, -y-1/2, -z+2)) and fashioned a R22(8) ring motif. The crystal structure was stabilized by strong N__H⋯O and weak C__H⋯O intermolecular interactions and it was quantitatively analysed by Hirshfeld surface and fingerprint (FP) analysis. FTIR and FT-Raman studies confirmed the vibrational modes of functional groups present in C4NB compound indubitably. SHG efficiency of grown crystal was 4.6 times greater than that of standard potassium dihydrogen phosphate (KDP) material. Moreover, density functional theory (DFT) studies such as Mulliken charge distribution, frontier molecular orbitals (FMOs), molecular electrostatic potential (MEP) map, natural bond orbital analysis (NBO) and first order hyperpolarizability (β0) were calculated to explore the structure-property relationship.

Characterization of a new ionophore-based ion-selective electrode for the potentiometric determination of creatinine in urine

The optimization, analytical characterization and validation of a novel ion-selective electrode for the highly sensitive and selective determination of creatinine in urine is presented. A newly synthesized calix[4]pyrrole-based molecule is used as an ionophore for the enhanced recognition of creatininium cations. The calculation of the complex formation constants in the polymeric membrane with creatininium, potassium and sodium confirms the strong selective interactions between the ionophore and the target. The optimization of the potentiometric sensor presented here yields an outstanding analytical performance, with a linear range that spans from 1µM to 10mM and limit of detection of 10−6.2M. The calculation of the selectivity coefficients against most commonly found interferences also show significant improvements when compared to other sensors already reported. The performance of this novel sensor is tested by measuring creatinine in real urine samples (N=50) and comparing the values against the standard colorimetric approach (Jaffé's reaction). The results show that this sensor allows the fast and accurate determination of creatinine in real samples with minimal sample manipulation.

Crystal structure of creatininium 5-(2,4-di-nitro-phen-yl)-1,3-di-methyl-barbiturate monohydrate: a potential anti-convulsant agent.

In the anion of the title hydrated mol-ecular salt, C4H8N3O(+)·C12H9N4O7 (-)·H2O [systematic name: 2-amino-1-methyl-4-oxo-4,5-di-hydro-1H-imidazol-3-ium 5-(2,4-di-nitro-phen-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetra-hydro-pyrimidin-4-olate monohydrate], the 2,4-di-nitro-phenyl ring is inclined to the mean plane of the pyrimidine ring [r.m.s. deviation = 0.37 Å] by 43.24 (8)°. The five-membered ring of the creatininium cation (2-amino-1-methyl-4-oxo-4,5-di-hydro-1H-imidazol-3-ium) is essentially planar with an r.m.s. deviation of 0.015 Å. In the crystal, the anions and cations are linked via N-H⋯O hydrogen bonds, forming sheets parallel to the ab plane. The sheets are linked via O-H⋯O hydrogen bonds involving the water mol-ecule, forming a three-dimensional framework. Within the framework, there are C-H⋯O hydrogen bonds present. The title mol-ecular salt displays anti-convulsant and hypnotic activities.

Recognition and Sensing of Creatinine

AbstractCurrent methods for creatinine quantification suffer from significant drawbacks when aiming to combine accuracy, simplicity, and affordability. Here, an unprecedented synthetic receptor, an aryl‐substituted calix[4]pyrrole with a monophosphonate bridge, is reported that displays remarkable affinity for creatinine and the creatininium cation. The receptor works by including the guest in its deep and polar aromatic cavity and establishing directional interactions in three dimensions. When incorporated into a suitable polymeric membrane, this molecule acts as an ionophore. A highly sensitive and selective potentiometric sensor suitable for the determination of creatinine levels in biological fluids, such as urine or plasma, in an accurate, fast, simple, and cost‐effective way has thus been developed.

Recognition and Sensing of Creatinine.

Current methods for creatinine quantification suffer from significant drawbacks when aiming to combine accuracy, simplicity, and affordability. Here, an unprecedented synthetic receptor, an aryl-substituted calix[4]pyrrole with a monophosphonate bridge, is reported that displays remarkable affinity for creatinine and the creatininium cation. The receptor works by including the guest in its deep and polar aromatic cavity and establishing directional interactions in three dimensions. When incorporated into a suitable polymeric membrane, this molecule acts as an ionophore. A highly sensitive and selective potentiometric sensor suitable for the determination of creatinine levels in biological fluids, such as urine or plasma, in an accurate, fast, simple, and cost-effective way has thus been developed.

Tautomeric equilibrium of creatinine and creatininium cation in aqueous solutions explored by Raman spectroscopy and density functional theory calculations

The Raman spectral studies of creatinine with pH dependence were performed to explore the effects of pH values on the Raman spectroscopy of creatinine. Firstly, we calculated vibrational spectra by DFT to derive the equilibrium geometries and protonated form of creatinine. Comparing simulated and observed Raman spectra of creatinine in aqueous solution at pH 2, it is found the theoretical predicted spectra agree well with those of the experiment while seven water molecules are aggregated around the creatinine. Additionally, the tautomeric equilibrium of creatinine in aqueous solutions was studied and two tautomers are found to coexist by comparing its experimental and calculated Raman spectra. A water dimer being used to solvate creatinine would make the thermodynamic energy favor convert from the imino tautomer to the amino tautomer. Besides, the molecular electrostatic potential (MEP) analysis of the creatinine further confirms their discrepancies of typical experimental Raman spectra at different pH values.

Bis(creatininium) tetra-chlorido-cadmate(II).

In the title compound, (C4H8N3O)2[CdCl4], the asymmetric unit comprises two creatininium cations and one tetra­chloridocadmate anion. Cd⋯O secondary bonding links one of the two imidazole rings and the anion into ion pairs. The free and bound cations form layers between which the [CdCl4]2− anions are sandwiched. The CdII atom adopts a distorted trigonal-bipyramidal geometry in which the Cd⋯O bond is axial. Inter­molecular N—H⋯Cl hydrogen bonds form a two-dimensional network parallel to (001) which ensures the junction between creatininium cations and [CdCl4]2− anions.

Hydroxonium creatininium bis(pyridine-2,6-dicarboxylato-κ3O2,N,O6)cobaltate(II) trihydrate

The title compound, (C4H8N3O)(H3O)[Co(C7H3NO4)2]·3H2O, contains a protonated creatininium cation, a hydrox­onium (H3O)+ cation, a [Co(pydc)2]2− (pydcH2 = pyridine-2,6-dicarboxylic acid) complex anion, and three uncoordinated water mol­ecules. The CoII atom is coordinated by four O and two N atoms from two pydc ligands in a distorted octa­hedral environment. The structure also contains three uncoordinated water mol­ecules. Extensive inter­molecular O—H⋯O, N—H⋯O and C—H⋯O hydrogen bonds, π–π stacking inter­actions [centroid–centroid distances = 3.565 (14) and 3.425 (14) Å] and O⋯π inter­actions [O⋯centroid distance = 3.480 (2) Å] connect the various components in the crystal structure.

Creatinium perchlorate.

The title compound, C4H8N3O+·ClO4 −, is built up from creatininium cations and perchlorate anions. Crystal cohesion and perchlorate stability are ensured by N—H⋯O hydrogen bonds that together with weak C—H⋯O inter­actions build up a three-dimensional network.

Assessment of density functionals, semiempirical methods, and SCC-DFTB for protonated creatinine geometries

Creatinine concentrations in blood and urine can be used to detect renal insufficiencies and muscle diseases, but current chemical sensors cannot measure creatinine with sufficient selectivity and robustness because they lack a receptor that binds protonated creatinine (creatininium) selectively enough. As a first step toward identifying potential receptors for creatininium, we examine the accuracy of density functional theory (DFT) and wave function theory (WFT) calculations for creatininium cation geometries, evaluated against reference parameters from experiment. We tested twenty-one local and nonlocal density functionals, Hartree-Fock theory, four semiempirical molecular orbital (SEMO) methods of the neglect of differential overlap (NDO) type, and one self-consistent-field nonorthogonal tight-binding method (SCC-DFTB) as implemented in two closely related software packages. DFT and HF calculations were carried out with the MG3S augmented polarized triple-zeta basis set. We find that DFT significantly outperforms SEMO methods for our dataset, and both SCC-DFTB releases we tested (which gave almost identical results) were less accurate than 81% of the density functionals evaluated. The top five functionals for the creatininium structures we examined were MPW1B95, PBEh, mPW1PW, SVWN5, and B97-2, with MMUEs in bond length of 0.0126, 0.0129, 0.0133, 0.0142, and 0.0144 Å respectively, which indicates that all five functionals are similarly suitable for creatininium. The popular B3LYP functional has a MMUE of 0.0178 Å, which ranks it 16th overall. B3LYP also performs less favorably than the best local functional (SVWN5), which is less expensive.

Chain and ring motifs in bis(creatininium) sulfate

The title compound, 2C4H8N3O+·SO4 2−, crystallizes with two creatininium cations and one sulfate anion in the asymmetric unit. Cations and anions dimerize through N—H...O hydrogen bonds forming R 2 2(8) ring motifs. Furthermore, these rings are connected via N—H...O hydrogen bonds, leading to C 2 2(6) and C 2 2(8) chain motifs. These interactions lead to a parallel set of hydrogen-bonded lamellar aggregations propagating along the c axis of the unit cell. Another cation is situated above these sheets, leading to a grid-like structure.

Creatininium benzoate

In the title compound, C4H8N3O+·C7H5O2−, the asymmetric unit comprises one creatininium cation and one benzoate anion. Inter­molecular N—H⋯O hydrogen bonds link the cations and anions into ion pairs, which are further linked into zigzag chains by other N—H⋯O hydrogen bonds. The crystal packing also exhibits weak inter­molecular C—H⋯O hydrogen bonds and dipole–dipole inter­actions.

Hydrogen bonding in creatininium nitrate

In the title compound, C4H8N3O+·NO3−, creatininium cations and nitrate anions are linked to each other through strong hydrogen bonds, formed by all H atoms covalently bonded to the N atoms. Short contacts are also observed between the anions. This complex three-dimensional network of hydrogen bonds ensures the cohesion of the ionic structure.

Creatinine and creatininium cation in DMSO-d6 solution. Structure and restricted internal rotation of NH2 group.

Investigation of 15N NMR spectra of isotopically enriched creatinine has unequivocally shown that in DMSO-d6 solution it exists as amino tautomer (2-amino-1-methylimidazoline-4-one), which in the presence of acid is protonated at N-3. Free energies of activation of the amino group rotation in creatinine and its cation have been determined to be 56 kJ/mol and 60 kJ/mol, respectively, at 298 K, by performing the simultaneous analysis of the lineshapes of -NH2 proton signals in the whole set of 1H NMR spectra recorded at various temperatures and magnetic fields. These results have been theoretically reproduced by the calculations of molecular structures and energies of creatinine and creatininium cation in their ground states and transition states of the amino group rotation, using DFT (B3LYP) method, involving the influence of the solvent.

Analytical Study of New Creatininium and Tetramethyl-ammonium Cation Selective Membrane Electrodes

Abstract Two new liquid membrane electrodes which respond to creatininium and tetramethylammonium cations are described. The creatininium cation electrode exhibits rapid and near Nernstian response to creatininium cation activity, at pH 3, in the 10−3−10−1 mol/L range. The useful concentration range extends to 10−4 mol/L. The tetramethyl-ammonium cation electrode exhibits rapid and near Nernstian response to tetramethylammonium cation activity, at pH 2–11.5, in the 2x10−5− 10−1 mol/L range. Major interferences for the creatininium electrode are Na+, K+, NH+ 4 and creatine. The pKa of the creatininium cation was calculated. A method is described for the potentiometric precipitation titration of tetramethylammonium cation with sodium tetraphenylboron. Amounts of tetramethylammonium in the range 20–200 μol have been determined using Gran's plots, with an average error of about 0.6%.

Crystal and molecular structure of creatininium tetrachlorocuprate(II)

Preparation, crystal and molecular structure of creatininium tetrachlorocuprate(II) is described. The structure was solved by X-ray diffraction studies and was refined by least-squares methods to R = 0.041 for 1344 reflections. The compound is monoclinic, space group, P2 1/c. The unit cell parameters are a = 8.080(3), b = 7.831(2), c = 13.922(3) Å, β = 113.77(2)°, V = 806.2 Å 3, d c = 1.786, d m = 1.77(1) g cm −3, Z = 2. The [CuCl 4] 2− ion is centrosymmetric and the copper atom is surrounded by four Cl atoms (CuCl1 2.233(1), CuCl2 2.268(1)) in a square planar arrangement. The creatininium cation is almost planar and each cation is linked to [CuCl 4] 2− units through hydrogen bonding involving the amino and imino nitrogen atoms.