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Crystallization and multicomponent crystal formation of active pharmaceutical ingredients Baclofen and Phenibut with dicarboxylic acid co-formers are discussed. The crystallization process of several crystalline entities is elucidated via single crystal—as well as powder X-ray—diffraction, followed by thermal analysis and phase stability studies over time. Both APIs form increasingly complex crystalline phases with co-formers malic and tartaric acid, where phase purity of a desired compound is not necessarily a given. Therefore, the influence of different solution and milling environments during crystallization on the outcome is studied. Emphasis is laid on how molecular influences such as the chirality, propensity to form hydrates as well as low solubility of Baclofen and Phenibut impede attempts to gather high-quality single crystals. The results highlight that targeted crystallization of these compounds with dicarboxylic acids can be difficult and unreliable. [ABSTRACT FROM AUTHOR]

The Schiff-base ligand N-2-(pyridyl)salicylaldimine (HL) reacts with zinc(ii) acetate or nitrate to obtain the enantiomorphous chiral-at-metal compound Δ/Λ-bis[N-2-(pyridyl)salicylaldiminato-κ2N,O]zinc(ii), [Zn(L)2] (1), which crystallizes as a racemic conglomerate via spontaneous resolution. Two deprotonated N,O-chelate ligands form a pseudo-tetrahedral N2O2-coordination sphere with a Δ/Λ-configured zinc atom. The Δ- and Λ-configured molecular complexes in 1 assemble in P (right)- and M (left)-handed 41- and 43-helical chains in the chiral space groups P41212 and P43212, respectively, through weak C–H…O hydrogen bonding between neighbouring molecules along the chain axis. Only molecules of the same Δ- or Λ-configuration combine into a helical chain and only chains of the same P- or M-handedness combine to form homochiral crystals. According to the analyses of intermolecular interactions with the Hirshfeld surface, the supramolecular packing features C–H…O bonding as the most apparent significant contribution. This is a rare example of solely weak C–H…O hydrogen bonding interaction leading to spontaneous resolution to a racemic conglomerate. This case also supports the notion of less repulsive packing interactions between homochiral molecules because of spin polarization. Optimized structures and excited state properties by DFT/TD-DFT calculations are comparable to experimental results. [ABSTRACT FROM AUTHOR]

Enantiopure bis[{(R or S)-N-1-(Ar)ethyl-2-oxo-1-naphthaldiminato-κ2N,O}]nickel(ii) complexes {Ar = C6H5 (1R or 1S), p-OMeC6H4 (2R or 2S), and p-BrC6H4 (3R or 3S)} are synthesized from the reactions between (R or S)-N-1-(Ar)ethyl-2-oxo-1-naphthaldimine and nickel(ii) acetate. Circular-dichroism spectra and their density-functional theoretical simulation reveal the expected mirror image relationship between the enantiomeric pairs 1R/1S and 3R/3S in solution. CD spectra are dominated by the metal-centered Λ- or Δ-chirality of non-planar four-coordinated nickel, this latter being in turn dictated by the ligand chirality. Single crystal structure determination for 1R and 1S shows that there are two symmetry-independent molecules (A and B) in each asymmetric unit that give a Z′ = 2 structure. Two asymmetric and chiral bidentate N^O-chelate Schiff base ligands coordinate to the nickel atom in a distorted square planar N2O2-coordination sphere. The conformational difference between the symmetry-independent molecules arises from the “up-or-down” folding of the naphthaldiminato ligand with respect to the coordination plane, which creates right- (P) or left-handed (M) helical conformations. Overall, the combination of ligand chirality, chirality at the metal and ligand folding gives rise to discrete metal helicates of preferred helicity in a selective way. Cyclic voltammograms (CV) show an oxidation wave at ca. 1.30 V for the [Ni(L)2]/[Ni(L)2]+ couple, and a reduction wave at ca.−0.35 V for the [Ni(L)2]/[Ni(L)2]− couple in acetonitrile. [ABSTRACT FROM AUTHOR]

Bidentate enantiopure Schiff base ligands, (R or S)-N-1-(Ar)ethyl-2-oxo-1-naphthaldiminato-κ2N,O, diastereoselectively yield Δ/Λ-chiral four-coordinated, non-planar Cu(N⋀O)2 complexes [Ar = C6H5 R/S-L1, m-C6H4OMe R-L2, p-C6H4OMe R/S-L3, and p-C6H4Br R/S-L4]. Two N,O-chelate ligands coordinate to the copper(II) atom in distorted square-planar mode, and induce metal-centered Δ/Λ-chirality at the copper atom in the C2-symmetric complexes. In the solid state, the R-L1 (or R-L4) ligand chirality diastereoselectively induces a Λ-Cu configuration in Λ-Cu-R-L1 (or Λ-Cu-R-L4), the S-L1 ligand a Δ-Cu configuration in Δ-Cu-S-L1, forming enantiopure crystals upon crystallization. Conversely, the R-L2 ligand combines both Λ/Δ-Cu-R-L2 as a diastereomeric pair in the crystals. In solution, electronic circular dichroism (CD) spectra show full or partial diastereoselectivity towards Λ-Cu for R ligands and towards Δ-Cu for S ligands. The electronic CD spectra measured on all complexes obtained from R ligands (or S ligands), e.g. Cu-R-L1, Cu-R-L2, Cu-R-L3, and Cu-R-L4 (or Cu-S-L1, Cu-S-L3, and Cu-S-L4), show consistent spectral features. TDDFT calculations of the electronic CD spectra for the diastereomers Λ-Cu-RL1 and Δ-Cu-R-L1 suggest that the CD spectra are largely dominated by the configuration at the metal center (Λ vs. Δ). The experimental CD spectrum of Cu-R-L1 agrees well with the one calculated for the Λ-Cu-R-L1 configuration. Cyclic voltammetry of Cu-R-L1 reveals a quasi-reversible redox wave corresponding to one-electron transfer for the [CuIIL2]0/[CuIL2]-1 couple in acetonitrile. DSC analyses for the complexes show an exothermic peak between 377 and 478 K (ΔH = -12 to -43 kJ mol-1), corresponding to a phase transformation from distorted square-planar/tetrahedral to regular tetrahedral geometry on heating. [ABSTRACT FROM AUTHOR]

Highlights: [•] Diastereoselection of S or R-HL1 with Zn(II) gives major diastereomer Δ or Λ-Zn-S or R-L1. [•] CD pattern corresponds to Δ-Zn-S-L1 and Λ-Zn-R-L1 as the major diastereomer. [•] Racemic R/S-HL2 gives major diastereomers of enantiomeric pair Λ-Zn-S-L2, Δ-Zn-R-L2. [•] The enantiomeric pair crystallizes in non-centrosymmetric polar space group Iba2. [•] Diastereomerization of Λ/Δ-Zn-S/R-L2 to Δ/Λ-Zn-S/R-L2 shows a ratio of 54:46 over 36h. [Copyright &y& Elsevier]