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Heating of polycrystalline cis aquabis(L-valinato)copper(II) at 90 °C resulted in a dehydrated powder. Recrystallization from aqueous solution of the obtained product yielded anhydrous trans bis(L-valinato)copper(II). The X-ray crystal and molecular structures of trans bis(L-valinato)copper(II) and cis aquabis(L-valinato)copper(II) are presented. Molecular modeling calculations were attempted to resolve factors that influenced the isomerization and crystallization of either the aqua cis- or the anhydrous trans-isomer. Conformational analyses of trans- and cis-isomers were completed in vacuo and in crystal by molecular mechanics, and in aqueous solution by molecular dynamics (MD) simulations using the same force field. Although the conformers with trans-configuration are the most stable in vacuo, those with cis-configuration form more favorable intermolecular interactions. Consequently, both cis- and trans-isomers are predicted to be present in aqueous solution. According to the crystal structure simulations and predictions, cis-isomer requires water molecules to form energetically more stable crystal packings than trans-isomer. The MD modeling of the self-assembly of 16 bis(L-valinato)copper(II) complexes in aqueous solution for the first time predicted the crystallization nucleus formation to proceed from monomers to oligomers by Cu-to-O(carboxylato) and/or N-H···O(carboxylato) weak bonds; these oligomers then bind together via water molecules until they acquire the right positions for noncovalent bonding like in the experimental crystal structures. Fifty-nanosecond MD simulations accomplished for a system consisting of equal numbers of complexes and water molecules at 298 and 370 K suggested complete cis-to-trans transformation at the higher temperature. Prevalence of either cis- or trans-conformers in water upon dissolvation may explain the crystallization results.

The X-ray crystal and molecular structure of a new polymorph of cis-aquabis(l-isoleucinato)copper(II), obtained by recrystallization from an acetic acid–water mixture and determined at 120 and 295 K, revealed triple dynamic disorder over one isoleucinato ligand at both temperatures. The complicated multipart disorder was resolved with the help of extensive computational crystal structure simulations, which were undertaken for the first time to interpret disorder in a crystal of bioinorganic compound. The new polymorph (space group C2) is conformationally polymorphic with the already known P212121 crystal form. To discover the conformers that can participate in self-associations in solution, and to rationalize an interplay of intramolecular and intermolecular interactions in the crystallization of different conformers, conformational analyses of cis and trans isomers were performed using the same force field in vacuo, in aqueous solution, and for selected conformers in P212121 and C2 crystals. Three conformers identified in the disorder were estimated to form the most favorable intermolecular interactions in the solid state, and one of them (the most populated conformer in the disorder) also in aqueous solution. The crystal structure reproduction of all possible arrangements of the three conformers in C2 unit cell helped to find the most plausible crystal packing motif.

The solid‐state 13C and 2H NMR spectra of paramagnetic anhydrous trans‐bis(L‐valinato)copper(II) and cis‐aquabis(L‐valinato)copper(II) complexes have been obtained. Under the very fast MAS conditions, both the 13C and 2H MAS spectra were well enough resolved to allow the easy distinction between the trans and cis stereoisomers. The conformational disorder observed previously in the X‐ray structure of the cis isomer was also reflected in the 13C and 2H MAS spectra. Variable‐temperature 2H MAS spectra of differently deuterated ligand species, that is, the copper(II) complexes with L‐[D2]valine, L‐[D8]valine, and L‐[D10]valine, suggested the dynamic nature of this disorder in the aqua cis isomer and confirmed static ND2 deuterons in the anhydrous trans isomer. Quantum chemical DFT/B3LYP calculations of the 13C hyperfine (Fermi contact) shifts of the paramagnetic term were useful as assignment aids in the interpretation of the 13C MAS spectra.

Reactions of copper­(II) sulfate with 1,10-phenanthroline, l-serine, and a base were investigated under different solution-based and mechanochemical synthetic procedures. Six complexes with serine were obtained: [Cu­(l-ser)­(H2O)­(phen)]2SO4­·xH2O (x = 4, 6, or 10; 1·4H 2 O, 1·6H 2 O, and 1·10H 2 O), [Cu­(l-ser)­(H2O)­(phen)]­[Cu­(l-ser)­(CH3OH)­(phen)]­SO4·3H2O­·CH3OH (1·2·3H 2 O­·CH 3 OH), [Cu­(l-ser)­(CH3OH)­(phen)]2SO4­·xCH3OH (x = 2 or 2.5; 2·2CH 3 OH and 2·2.5CH 3 OH), and two without serine: [Cu­(SO4)­(phen)2]­·xH2O (x = 4.5 or 6.75; 3·4.5H 2 O and 3·6.75H 2 O) (phen = 1,10-phenanthroline, l-ser = l-serinato). The X-ray crystal structure analysis of serine-containing complexes revealed extensive hydrogen bonding and π-interactions that link complex cations, sulfate anions, and solvent molecules into three-dimensional architectures. Most of the water/methanol solvent molecules in these porous compounds are found in channels, some in pockets connected to channels, and can be exchanged in vapors of the other solvent. Along with the solvent exchange, the solvent molecule apically coordinated to copper­(II) is also exchanged in some transformations. By neat grinding, all serine-containing complexes transform into 1·6H 2 O. Quantum chemical calculations were done for compounds 1·4H 2 O and 1·6H 2 O in the gas phase and an aqueous (or methanol) surrounding. 1·6H 2 O and 3·4.5H 2 O showed pronounced antiproliferative activity toward human breast and lung tumor cell lines.

Reliable density functional theory (DFT) calculations can be performed in conjuction with spectroscopic measurements to elucidate the structural properties of physiologically important bis(amino acidato)copper(II) compounds in solutions. They can provide insight into the influence of intermolecular interactions on the molecular geometry in the crystal lattice or solution when compared with a DFT gas-phase minimum. Our previous paper [Marković et al. (2014) Eur J Inorg Chem 198] reported the DFT-determined geometries and Raman spectra for different conformers of physiological bis(L-histidinato)copper(II) with 20 explicit water molecules, as calculated using the B3LYP functional. The present study examined the reliability of those B3LYP results by applying the M06 functional instead, as it should better account for noncovalent interactions. The water molecules were positioned more compactly around the complex by M06 than by B3LYP. The accuracies of the two functionals when compared to relevant experimental data showed that M06 was better at reproducing in-plane Cu-N bond lengths but B3LYP gave more accurate axial Cu-O distances. Both functionals reproduced the experimental Raman spectrum at pH 8 to similar levels of accuracy and provided precise information on the Cu(II) coordination mode and conformation in aqueous solution. Additionally, we assessed several DFT and DFT-D functionals (BP86, B3LYP, B3LYP-D, M06, M06 L, wB97XD, mPW2PLYPD) by using them to model the geometries of experimental bis(L-histidinato)copper(II) crystalline conformations as isolated systems, and then benchmarking the results against those from high-level second-order pertubation Møller-Plesset (MP2) calculations. Although this assessment resulted in an equivocal conclusion because the MP2 results for the isolated complex were inconsistent with the corresponding DFT outcomes, it does provide new information on future benchmark options.

In bis(L‐histidinato)copper(II), the amino acid L‐histidine can bind to copper(II) in glycine‐like (G), histamine‐like (H), and imidazole–propionic acid like (I) coordination modes. This complex is known as the predominant copper(II)–amino acid complex in human blood serum. Numerous experimental studies of this physiological complex reported several coordination modes to coexist in aqueous solutions, but without providing complete structures. This paper is the first to investigate the relative stability of all possible copper(II) coordination modes and conformations of isolated bis(L‐histidinato)copper(II), and several conformers surrounded with up to 22 water molecules by DFT/B3LYP calculations. The vibration wavenumbers of four bis(L‐histidinato)copper(II)·20H2O structures were calculated and assigned for IR and Raman spectra. Among 83 isolated conformers obtained, 37 are in trans configuration, 45 in cis configuration, and one exhibits a trigonal‐bipyramidal structure. The most stable isolated conformer has a trans‐GG coordination. A comparison between the known X‐ray crystal and B3LYP vacuum molecular structures of bis(L‐histidinato)copper(II) dihydrate showed that the X‐ray cis‐HG mode with an intramolecular apical Cu–Ocarboxylato bond is unstable under vacuum and thus is greatly affected by crystal‐lattice effects. In the systems with 20 water molecules, the lowest energy was estimated for the conformer with a cis‐HH coordination and two axial Cu–Ocarboxylato bonds. This structural finding complements previous experimental studies, which reported an HH coordination mode as the prevailing in aqueous solutions under physiological conditions. The axial Cu–Ocarboxylato bond, unformed in any of the 83 isolated conformers, is stabilized by intermolecular interactions. The arrangement of water molecules around the complex might affect the coordination mode formation and stability.

Detailed structural properties of physiological bis(amino acidato)copper(II) complexes are generally unknown in solutions. This paper examines how stereochemical differences between the essential amino acid l-threonine and its diastereomer l-allo-threonine, which is rarely present in nature, may affect relative stabilities of bis(l-threoninato)copper(II) and bis(l-allo-threoninato)copper(II) in the gas phase and aqueous solution. These amino acids can bind to Cu(II) via the nitrogen and carboxylato oxygen atoms, the nitrogen and hydroxyl oxygen atoms, and the carboxylato and hydroxyl oxygen atoms. We term these coordination modes G, No, and Oo, respectively. The density functional theory (DFT) calculations with the B3LYP functional of the conformational landscapes for all possible coordination modes of both complexes revealed their very similar stability in the gas phase and in aqueous solution. The conformational analyses resulted in 196 and 267 conformers of isolated copper(II) chelates with l-threonine and l-allo-threonine, respectively. The G-G coordination mode is the most stable, both in the gas phase and aqueous solution. Very similar energy values of the lowest-energy solvated cis and trans G-G conformers in implicitly accounted water medium are in accord with the experimental results that these isomers are present in aqueous solution at physiological pH values. The transition-state structures, activation Gibbs free energies, and reaction rates calculated using DFT/B3LYP and MP2 for the transformations from the most stable cis G-G and trans Oo-G conformers to trans G-G ones for the first time reveal several alternate coordination-mode transformation mechanisms in the copper(II) complexes with amino acids other than glycine. The trans Oo-G conformers are kinetically more stable than cis G-G ones in the gas phase. The only significant difference found between the two complexes is a more suitable position of the hydroxyl group in physiological bis(l-threoninato)copper(II) to form intramolecular hydrogen bonds, which may restrain its conformational space.