Correction to "Structural Landscape of α-Acetamidocinnamic Acid Cocrystals with Bipyridine-Based Coformers: Influence of Crystal Packing on Their Thermal and Photophysical Properties".

[This corrects the article DOI: 10.1021/acs.cgd.3c01374.].

When Unsuspected Crystallinity Ruins Biological Testing in Early Discovery: A Case Study.

The impact of the crystalline or amorphous structure of a solid on the solubility and pharmacokinetic properties of a drug candidate is always considered by the pharmaceutical industry during the development of a new drug; however, it is not so frequently considered during the early drug discovery process by organic and medicinal chemists, particularly those working in academia. We want to share, as an example, the false negative obtained in the biological testing of a solid sample of a tyrosine kinase inhibitor due to its unexpected crystallinity and lower solubility with respect to a solid amorphous batch of the same compound and the experimentation carried out to establish the origin of such a discrepancy.

Structural Landscape of α-Acetamidocinnamic Acid Cocrystals with Bipyridine-Based Coformers: Influence of Crystal Packing on Their Thermal and Photophysical Properties.

Controlling the supramolecular synthon outcome in systems with different functionalities has been a key factor for the design of supramolecular materials, which also affected their physicochemical properties. In this contribution, we have analyzed the structural landscape of α-acetamidocinnamic acid (HACA) aiming to find its synthon outcome from the competitivity between its acidic and amidic groups. We prepared four multicomponent forms including one dihydrate (HACA·2H2O) and three cocrystals bearing different bipyridine coformers with formulas (HACA)2(1,2-bpe) (1), (HACA)2(4,4'-azpy) (2), and (HACA)2(4,4'-bipy)3 (3) (1,2-bpe = 1,2-bis(4-pyridyl)ethylene; 4,4'-azpy = 4,4'-azopyridine; 4,4'-bipy = 4,4'-bipyridine). First, we applied a virtual screening approach to assess the feasibility of cocrystal formation. Then, we synthesized the cocrystals, via liquid-assisted grinding (LAG) (1 and 2) or solvothermal (3) techniques, and single crystals of HACA, and their four multicomponent forms were obtained showing different synthons and crystal packings. Besides, a Cambridge Structural Database (CSD) search of the cocrystals presenting bipyridine-type coformers and molecules with acid and amide functionalities was performed, and the observed synthon occurrences as well as the possibility of synthon modification by tuning the H-donor/H-acceptor propensity of the acidic and amidic groups were shown. Finally, we measured their thermal and photophysical properties, which were correlated with their structural features.

Direct, Stereodivergent, and Catalytic Michael Additions of Thioimides to α,ß-Unsaturated Aldehydes - Total Synthesis of Tapentadol.

Direct and stereodivergent Michael additions of N-acyl 1,3-thiazinane-2-thiones to α,ß-unsaturated aldehydes catalyzed by chiral nickel(II) complexes are reported. The reactions proceed with a remarkable regio-, diastereo-, and enantioselectivity, so access to any of the four potential Michael stereoisomers is granted through the appropriate choice of the chiral ligand of the nickel(II) complex. Simple removal of the heterocyclic scaffold furnishes a wide array of either syn or anti enantiomerically pure derivatives, which can be exploited for the asymmetric synthesis of biologically active compounds, as demonstrated in a new approach to tapentadol. In turn, a mechanism, based on theoretical calculations, is proposed to account for the stereochemical outcome of these transformations.

Slow Magnetic Relaxation in Silver(II) Macrocyclic Systems.

The spin-lattice relaxation time has been studied trough alternating-current susceptometry and ultralow-frequency Raman spectroscopy in a family of silver(II)-derived molecular systems with spin 1/2 and formulas [AgII(m-CTH)(NO3)2] (1) and [AgII(m-CTH)(ClO4)2] (2), where CTH = meso-5,5,7,12,12,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane. The combination of both techniques demonstrates the occurrence of slow spin magnetic relaxation induced by spin-phonon interaction. The magnetic behavior of these silver(II)-derived systems opens the door to a new cation in the scarce family of S = 1/2 systems with slow relaxation of magnetization.

Cyclic Homo- and Heterohalogen Di-λ3-diarylhalonium Structures.

In the context of the ever-growing interest in the cyclic diaryliodonium salts, this work presents synthetic design principles for a new family of structures with two hypervalent halogens in the ring. The smallest bis-phenylene derivative, [(C6H4)2I2]2+, was prepared through oxidative dimerization of a precursor bearing the ortho-disposed iodine and trifluoroborate groups. We also report, for the first time, the formation of cycles containing two different halogen atoms. These present two phenylenes linked by hetero-(I/Br) or -(I/Cl) halogen pairs. This approach was also extended to the cyclic bis-naphthylene derivative [(C10H6)2I2]2+. The structures of these bis-halogen(III) rings were further assessed through X-ray analysis. The simplest cyclic phenylene bis-iodine(III) derivative features the interplanar angle of ∼120°, while a smaller angle of ∼103° was found for the analogous naphthylene-based salt. All dications form dimeric pairs through a combination of π-π and C-H/π interactions. As the largest member of the family, a bis-I(III)-macrocycle was also assembled using the quasi-planar xanthene backbone. Its geometry enables the two iodine(III) centers to be bridged intramolecularly by two bidentate triflate anions. In a preliminary manner, the interaction of the phenylene- and naphthalene-based bis-iodine(III) dications with a new family of rigid bidentate bis-pyridine ligands was studied in solution and the solid state, with an X-ray structure showing the chelating donor bonding to just one of the two iodine centers.

The Formation of a Unique 2D Isonicotinate Polymer Driven by Cu(II) Aerobic Oxidation.

The isolation and structural characterization of a unique Cu(II) isonicotinate (ina) material with 4-acetylpyridine (4-acpy) is provided. The formation of [Cu(ina)2(4-acpy)]n (1) is triggered by the Cu(II) aerobic oxidation of 4-acpy using O2. This gradual formation of ina led to its restrained incorporation and hindered the full displacement of 4-acpy. As a result, 1 is the first example of a 2D layer assembled by an ina ligand capped by a monodentate pyridine ligand. The Cu(II)-mediated aerobic oxidation with O2 was previously demonstrated for aryl methyl ketones, but we extend the applicability of this methodology to heteroaromatic rings, which has not been tested so far. The formation of ina has been identified by 1H NMR, thus demonstrating the feasible but strained formation of ina from 4-acpy in the mild conditions from which 1 was obtained.

Magnetic and optical studies of a new family of multidimensional and multiproperty PO-lanthanide(III) derived systems.

A new family of lanthanide compounds has been synthesized using 1,2-bis(diphenylphosphino)ethane dioxide (dppeO2) as an O-donor ligand through the phosphoryl group to lanthanide(III) cations and structurally, magnetically and optically studied. Depending on the lanthanide, two different topologies appear: the two-dimensional structure [LnIII(dppeO2)1.5(NO3)3(H2O)0.5]n (Ln = Ce (1), Sm (2) and Dy (6)) and the one-dimensional structure [Ln(dppeO2)(NO3)3DMF]n (Ln = Eu (3), Gd (4) and Tb (5)). Some of the Ln-derived complexes have been used as structural probes, while others have been synthesized to use the specific characteristics of each cation to take advantage of their magnetic/luminescence properties. Complex 6 presents slow relaxation of the magnetization while 2, 3 and 5 present emitting properties in the visible range.

Rhodium and ruthenium complexes of methylene-bridged, P-stereogenic, unsymmetrical diphosphanes.

Enantiopure P-stereogenic methylphosphane-boranes (SP)-P(BH3)PhArMe (ArMe; Ar = 1-naphthyl (NpMe), and 2-biphenylyl (BiphMe)) have been used to prepare diphosphanes of the type ArPhPCH2PR2 (R = Ph, iPr or tBu; ArR). The ligands have been reacted with [Rh(COD)2]BF4 to furnish the corresponding six monochelated [Rh(COD)(ArR)]BF4 organometallic compounds (RhArR) or, depending on the reaction conditions, the bis(chelated) coordination compound [Rh(BiphiPr)2]BF4 as a mixture of cis and trans isomers. The crystal structure of cis-[Rh(BiphiPr)2]BF4 was obtained. The coordination of the BiphR with [RuCl(µ-Cl)(η6-p-cymene)2]2 under different conditions produced cationic chelated complexes of the type [RuCl(η6-p-cymene)(κ2-BiphR)]PF6 (RuBiphR) and the neutral monocoordinated complex [RuCl2(η6-p-cymene)(κ1-BiphPh)] (RuBiphPh') with the uncoordinated P-stereogenic moiety. The Rh(I) complexes were used in the catalytic hydrogenation of functionalized olefins and the Ru(II) complexes were tested in the transfer hydrogenation of acetophenone. Both precursors displayed good activities with moderate enantioselectivities.

Iron complexes of bridging azo ligands in aqueous solution: changes in the thermal switching mechanism on coordination and oxidation state of metal centres.

Three azobenzenes CN(C6H4)-NN-(C5H4N) (py-iso), CN(C6H4)-NN-(C6H4)CN (cyano-iso) and CN(C6H4)-NN-(C6H4)NC (iso-iso) with good coordinating groups (pyridine, phenylcyano or phenylisocyano) at the ends of the diazenyl unit have been synthesized and fully characterised. These compounds have been used as ligands in the synthesis of water-soluble metallic species by coordination to {FeII(CN)53-} units, either in one or two of the anchoring groups of the derivatives. Both the azo derivatives and their complexes are photochemically active with respect to their trans-to-cis isomerisation process. Their cis-to-trans reverse thermal reaction has been thoroughly studied as a function of the donor groups, solvent, temperature and pressure, in order to gain insight into the rotation or inversion mechanisms involved in the process. A comparison of the isomerisation mechanism between the iron complexes and the corresponding free ligands revealed an interesting fine tuning of the process on coordination of the {FeII(CN)53-} moieties, which may even produce, in some cases, non-photoswitchable species containing typically photoactive units.

Luminescence, CPL and magnetic properties of 1D enantiopure Ln3+ complexes with (S-) and (R-) α-methoxyphenylacetate ligand.

The reaction of Ln(NO3)2·6H2O (Ln = Eu, Tb, Dy and Sm) with (R)-(-)-α-methoxyphenylacetic acid (R-HMPA) and 1,10-phenanthroline (phen) in EtOH/H2O allows the isolation of 1D chiral compounds of formula [Ln(µ-R-MPA)(R-MPA)2(phen)]n in which Ln = Eu (R-Eu), Tb (R-Tb), Dy (R-Dy) and Sm (R-Sm). The same synthesis by using (S)-(+)-α-methoxyphenylacetic acid (S-HMPA) instead of (R)-(-)-α-methoxyphenylacetic acid allows the isolation of the enantiomeric compounds with formula [Ln(µ-S-MPA)(S-MPA)2(phen)]n where Ln = Eu (S-Eu), Tb (S-Tb), Dy (S-Dy) and Sm (S-Sm). Single crystal X-Ray diffraction measurements were performed for compounds R/S-Eu, R/S-Tb, S-Dy and S-Sm. The luminescence and the circular dichroism measured in the solid state are reported. All compounds show sensitized luminescence, notably the Eu3+ and Tb3+ ones, whose emission color can be perceived by the naked eye. For the Eu3+ and Tb3+ derivatives the quantum yield and the circular polarized luminescence have been measured. For the magnetic allowed transition 5D0 → 7F1 of the Eu3+ compound, the anisotropy factor glum is ±0.013 (+for S-Eu). Also, magnetic properties of all compounds were studied with the Dy3+ analogue showing slow relaxation of the magnetization under a direct current magnetic field of 1000 Oe.

Protected syn-Aldol Compounds from Direct, Catalytic, and Enantioselective Reactions of N-Acyl-1,3-oxazinane-2-thiones with Aromatic Acetals.

A direct and asymmetric syn-aldol reaction of N-acyl-1,3-oxazinane-2-thiones with dialkyl acetals from aromatic acetals in the presence of 2-5 mol % [DTBM-SEGPHOS]NiCl2, TMSOTf, and lutidine has been developed. It has been established that the oxazinanethione heterocycle, used for the first time as a scaffold in asymmetric carbon-carbon bond-forming reactions, can be smoothly removed to give access to a variety of enantiomerically pure compounds with high synthetic value.

Occurrence of slow relaxation of the magnetization in a family of copper(II)/manganese(II) quasi-isotropic complexes with different ground spin states.

A family of copper(II)/manganese(II) new clusters with the formulas [CuIINaI(L2)(MeOH)(ClO4)] (1), [CuII2MnII(S,S-L3)2(MeOH)](ClO4)2 (2SS), [{CuIIMnII(L1)(H2O)2(MeOH)}{CuII(L1)}2](ClO4)2 (3), [(µ1,3-N3)2{CuIIMnII(L2)(H2O)}2{CuII(L2)2](ClO4)}2 (4) and [(µ1,1-N3)2{CuIIMnII(L1)(N3)}2{CuIINaI(L1)(MeOH)}2](ClO4)2 (5) with L1 = N,N'-ethylene-bis(3-methoxysalicylaldiimine), L2 = N,N'-ethylene-bis(3-ethoxysalicylaldiimine) and L3 = N,N'-cyclohexane-bis(3-ethoxysalicylaldiimine), has been synthesized, and structurally and magnetically characterized. Reduced magnetization studies demonstrate that the magnetic anisotropy of the systems is very small. However, dynamic magnetic studies and ultra-low-frequency Raman spectroscopy confirm the slow relaxation of these systems despite their quasi-isotropic nature, enlarging the range of non-anisotropic slow relaxing molecules.

Amide-Driven Secondary Building Unit Structural Transformations between Zn(II) Coordination Polymers.

The behavior of coordination polymers (CPs) against external stimuli has witnessed remarkable attention, especially when the resulting CPs present reversible molecular arrays. Accordingly, CPs with these characteristics can lead to differences in their properties owing to these structural differences, being promising for their use as potential molecular switches with diverse applications. Herein, we have synthesized four Zn(II) CPs bearing α-acetamidocinnamic acid (HACA) and 4,4'-bipyridine (4,4'-bipy). The reaction between Zn(OAc)2·2H2O, HACA, and 4,4'-bipy yields {[Zn(ACA)2(4,4'-bipy)]·EtOH} n (1), which was used for the formation of three CPs through dissolution-recrystallization structural transformations (DRSTs): {[Zn(ACA)2(4,4'-bipy)]·2MeOH} n (2), {[Zn2(µ-ACA)2(ACA)2(4,4'-bipy)]·2H2O} n (3), and {[Zn3(µ-ACA)6(4,4'-bipy)]·0.75CHCl3} n (4). The study of the four crystal structures revealed that their secondary building units (SBUs) comprise monomeric, dimeric, and trimeric arrangements linked by 4,4'-bipy ligands. The fundamental role of the utilized solvent and/or temperature, as well as their effect on the orientation of the amide moieties driving the formation of the different SBUs is discussed. Furthermore, the reversibility and interconversion between the four CPs have been assayed. Finally, their solid-state photoluminescence has evinced that the effect of the amide moieties not only predetermine a different SBU but also lead to a different emission in 4 compared with 1-3.

Slow magnetic relaxation for cobalt(II) complexes in axial bipyramidal environment: an S = 1/2 spin case.

A new family of magnetically mononuclear cobalt(II) complexes with formula [{NiII(L)CoII(H2O)2(MeOH)}{NiII(L)}2](ClO4)2 where H2L1 = bis(N,N'-bis(3-methoxysalicylidene)ethylene-1,2-diamine) (1), H2L2 = bis(N,N'-bis(3-methoxysalicylidene)propane-1,2-diamine) (2) and [{CuII(L4)}2CoII](ClO4)2 (3) where H2L4 = bis(N,N'-bis(3-ethoxysalicylidene)cyclohexane-1,2-diamine) have been obtained employing non chiral or enantiomerically pure Schiff bases. The structural studies have been carried out by single crystal X-ray and powder diffraction. Dynamic magnetic studies indicate that some members of this family present field induced slow relaxation of the magnetization and its response has been compared with the magnetically diluted [Zn0.9Co0.1] complex 1D. Ultra-low frequency Raman spectroscopy has been used to relate the slow relaxation with lattice vibrations.

Direct and Asymmetric Aldol Reactions of N-Azidoacetyl-1,3-thiazolidine-2-thione Catalyzed by Chiral Nickel(II) Complexes. A New Approach to the Synthesis of ß-Hydroxy-α-Amino Acids.

A direct and asymmetric triisopropylsilyltrifluoromethanesulfonate (TIPSOTf) mediated aldol reaction of N-azidoacetyl-1,3-thiazolidine-2-thione with aromatic aldehydes catalyzed by a chiral nickel(II)-Tol-BINAP complex has been developed (BINAP=2,2'-bis(diphenylphosphino)-1,1'-binaphthyl). The catalytic protocol gives the corresponding anti α-azido-ß-silyloxy adducts with outstanding stereocontrol and in high yields. Theoretical calculations account for the stereochemical outcome of the reaction and lay the foundations for a mechanistic model. In turn, the easy removal of the thiazolidinethione yields a wide array of enantiomerically pure derivatives in a straightforward and efficient manner. Such a noteworthy character of the heterocyclic scaffold together with the appropriate manipulation of the azido group open a new route to the synthesis of di- and tripeptide blocks containing a ß-aryl-ß-hydroxy-α-amino acid.

Controlling the Formation of Two Concomitant Polymorphs in Hg(II) Coordination Polymers.

Controlling the formation of the desired product in the appropriate crystalline form is the fundamental breakthrough of crystal engineering. On that basis, the preferential formation between polymorphic forms, which are referred to as different assemblies achieved by changing the disposition or arrangement of the forming units within the crystalline structure, is one of the most challenging topics still to be understood. Herein, we have observed the formation of two concomitant polymorphs with general formula {[Hg(Pip)2(4,4'-bipy)]·DMF}n (P1A, P1B; Pip = piperonylic acid; 4,4'-bipy = 4,4'-bipyridine). Besides, [Hg(Pip)2(4,4'-bipy)]n (2) has been achieved during the attempts to isolate these polymorphs. The selective synthesis of P1A and P1B has been successfully achieved by changing the synthetic conditions. The formation of each polymorphic form has been ensured by unit cell measurements and decomposition temperature. The elucidation of their crystal structure revealed P1A and P1B as polymorphs, which originates from the Hg(II) cores and intermolecular associations, especially pinpointed by Hg···π and π···π interactions. Density functional theory (DFT) calculations suggest that P1B, which shows Hg(II) geometries that are further from ideality, is more stable than P1A by 13 kJ·mol-1 per [Hg(Pip)2(4,4'-bipy)]·DMF formula unit, and this larger stability of P1B arises mainly from metal···π and π···π interactions between chains. As a result, these structural modifications lead to significant variations of their solid-state photoluminescence.

Tuning Photophysical Properties by p-Functional Groups in Zn(II) and Cd(II) Complexes with Piperonylic Acid.

Aggregation between discrete molecules is an essential factor to prevent aggregation-caused quenching (ACQ). Indeed, functional groups capable of generating strong hydrogen bonds are likely to assemble and cause ACQ and photoinduced electron transfer processes. Thus, it is possible to compare absorption and emission properties by incorporating two ligands with a different bias toward intra- and intermolecular interactions that can induce a specific structural arrangement. In parallel, the π electron-donor or electron-withdrawing character of the functional groups could modify the Highest Ocuppied Molecular Orbital (HOMO)-Lowest Unocuppied Molecular Orbital (LUMO) energy gap. Reactions of M(OAc)2·2H2O (M = Zn(II) and Cd(II); OAc = acetate) with 1,3-benzodioxole-5-carboxylic acid (Piperonylic acid, HPip) and 4-acetylpyridine (4-Acpy) or isonicotinamide (Isn) resulted in the formation of four complexes. The elucidation of their crystal structure showed the formation of one paddle-wheel [Zn(µ-Pip)2(4-Acpy)]2 (1); a mixture of one dimer and two monomers [Zn(µ-Pip)(Pip)(Isn)2]2·2[Zn(Pip)2(HPip)(Isn)]·2MeOH (2); and two dimers [Cd(µ-Pip)(Pip)(4-Acpy)2]2 (3) and [Cd(µ-Pip)(Pip)(Isn)2]2·MeOH (4). They exhibit bridged (1, µ2-η1:η1), bridged, chelated and monodentated (2, µ2-η1:η1, µ1-η1:η1 and µ1-η1), or simultaneously bridged and chelated (3 and 4, µ2-η2:η1) coordination modes. Zn(II) centers accommodate coordination numbers 5 and 6, whereas Cd(II) presents coordination number 7. We have related their photophysical properties and fluorescence quantum yields with their geometric variations and interactions supported by TD-DFT calculations.

Magnetic and Luminescence Properties of 8-Coordinate Holmium(III) Complexes Containing 4,4,4-Trifluoro-1-Phenyl- and 1-(Naphthalen-2-yl)-1,3-Butanedionates.

A new series of mononuclear Ho3+ complexes derived from the ß-diketonate anions: 4,4,4-trifluoro-1-phenyl-1,3-butanedioneate (btfa-) and 4,4,4-trifuoro-1-(naphthalen-2-yl)-1,3-butanedionate (ntfa-) have been synthesized, [Ho(btfa)3(H2O)2] (1a), [Ho(ntfa)3(MeOH)2] (1b), (1), [Ho(btfa)3(phen)] (2), [Ho(btfa)3(bipy)] (3), [Ho(btfa)3(di-tbubipy)] (4), [Ho(ntfa)3(Me2bipy)] (5), and [Ho(ntfa)3(bipy)] (6), where phen is 1,10-phenantroline, bipy is 2,2'-bipyridyl, di-tbubipy is 4,4'-di-tert-butyl-2,2'-bipyridyl, and Me2bipy is 4,4'-dimethyl-2,2'-bipyridyl. These compounds have been characterized by elemental microanalysis and infrared spectroscopy as well as single-crystal X-ray difraction for 2-6. The central Ho3+ ions in these compounds display coordination number 8. The luminescence-emission properties of the pyridyl adducts 2-6 display a strong characteristic band in the visible region at 661 nm and a series of bands in the NIR region (excitation wavelengths (λex) of 367 nm for 2-4 and 380 nm for 5 and 6). The magnetic properties of the complexes revealed magnetically uncoupled Ho3+ compounds with no field-induced, single-molecule magnet (SMMs).

Polymorphism in the 1/1 Pterostilbene/Picolinic Acid Cocrystal.

The crystal structures of two new polymorphs of the 1/1 pterostilbene/picolinic acid cocrystal have been analyzed by single-crystal X-ray diffraction and studied by means of DFT calculations and a set of computational tools (QTAIM, NCIplot, MEP). The observation of a new R2 2(10) synthon in each of the two polymorphs has been analyzed energetically, characterized using the topology of the electron density, and rationalized using the MEP surfaces. The exceptional bioavailability of the cocrystal is explained on the basis of BFDH morphology calculations, and the study is complemented by a deep analysis of the supramolecular synthons formed by both neutral and zwitterionic forms of picolinic acid, a versatile coformer for crystal engineering.