Constant-pH Simulations with the Polarizable Atomic Multipole AMOEBA Force Field.

Accurately predicting protein behavior across diverse pH environments remains a significant challenge in biomolecular simulations. Existing constant-pH molecular dynamics (CpHMD) algorithms are limited to fixed-charge force fields, hindering their application to biomolecular systems described by permanent atomic multipoles or induced dipoles. This work overcomes these limitations by introducing the first polarizable CpHMD algorithm in the context of the Atomic Multipole Optimized Energetics for Biomolecular Applications (AMOEBA) force field. Additionally, our implementation in the open-source Force Field X (FFX) software has the unique ability to handle titration state changes for crystalline systems including flexible support for all 230 space groups. The evaluation of constant-pH molecular dynamics (CpHMD) with the AMOEBA force field was performed on 11 crystalline peptide systems that span the titrating amino acids (Asp, Glu, His, Lys, and Cys). Titration states were correctly predicted for 15 out of the 16 amino acids present in the 11 systems, including for the coordination of Zn2+ by cysteines. The lone exception was for a HIS-ALA peptide where CpHMD predicted both neutral histidine tautomers to be equally populated, whereas the experimental model did not consider multiple conformers and diffraction data are unavailable for rerefinement. This work demonstrates the promise polarizable CpHMD simulations for pKa predictions, the study of biochemical mechanisms such as the catalytic triad of proteases, and for improved protein-ligand binding affinity accuracy in the context of pharmaceutical lead optimization.

Characterization of Water Structure and Phase Behavior within Metal-Organic Nanotubes.

Water behavior under nanoconfinement varies significantly from that in the bulk but also depends on the nature of the pore walls. Hybrid compound offers the ideal system to explore water behavior in complex materials, so a model metal-organic nanotube (UMONT) material was utilized to explore the behavior of water between 100 and 293 K. Single-crystal X-ray and neutron diffraction revealed the formation of a filled Ice-I arrangement that was previously predicted to only occur under high pressures. 17O NMR spectra suggest that the onset of melting for the water in the UMONT channels occurs at 98 K and the presence of ice-like water up to 293 K, indicating that the complete ice-water transition does not occur before dehydration of the material. Overall, the water behavior differs significantly from hydrophobic single-walled carbon nanotubes indicating precise control over water can be achieved through rational design of hybrid materials.

Co-crystal sustained by π-type halogen-bonding inter-actions between 1,4-di-iodo-perchloro-benzene and naphthalene.

The formation and crystal structure of a co-crystal based upon 1,4-di-iodo-perchloro-benzene (C6I2Cl4) as the halogen-bond donor along with naphthalene (nap) as the acceptor is reported. The co-crystal [systematic name: 1,2,4,5-tetra-chloro-3,6-di-iodo-benzene-naphthalene, (C6I2Cl4)·(nap)] generates a chevron-like structure that is held together primarily by π-type halogen bonds (i.e. C-I⋯π contacts) between the components. In addition, C6I2Cl4 also inter-acts with the acceptor via C-Cl⋯π contacts that help stabilize the co-crystal. Within the solid, both aromatic components are found to engage in offset and homogeneous face-to-face π-π stacking inter-actions. Lastly, the halogen-bond donor C6I2Cl4 is found to engage with neighboring donors by both Type I chlorine-chlorine and Type II iodine-chlorine contacts, which generates an extended structure.

Soluble thiabendazolium salts with anthelminthic properties.

Thiabendazole is an anthelmintic drug used to treat strongyloidiasis (threadworm), cutaneous and visceral larva migrans, trichinosis, and other parasites. The active pharmaceutical ingredient is typically administered orally as tablets that should be chewed before swallowing. Current formulations combine the active ingredient with excipients, including sodium saccharinate as a sweetener. Thiabendazole's low aqueous solubility hinders fast dissolution and absorption through the mucous membranes. We sought to reformulate this medicine to improve both solubility and palatability. We utilized the possibility of protonation of the azole nitrogen atom and selected four different hydrogen donors: saccharin, fumaric, maleic, and oxalic acids. Solvothermal synthesis resulted in salts with each co-former, whereas neat and liquid-assisted grinding enabled the synthesis of additional formulations. Product formation was observed by powder X-ray diffraction. To better understand the structural basis of the proton transfer, we solved the crystal structures of the salts with saccharin, maleic acid, and oxalic acid using single-crystal X-ray diffraction. The structure of the salt with fumaric acid was solved by powder X-ray diffraction. We further characterized the salts with vibrational spectroscopic and thermoanalytical methods. We report a broad tunability of the aqueous solubility of thiabendazole by salt formation. Reformulation with maleic acid provided a 60-fold increase in solubility, while saccharin and oxalic acid gave a modest improvement. Fumaric acid resulted in a solid with only slightly higher solubility. Furthermore, saccharin is a sweetener, while the acids taste sour. Therefore, the salts formed also result in an intrinsic improvement of palatability. These results can inform new strategies for oral and chewable tablet formulations for treating helminthic infections.

Cerium(IV) Pyrasal Complexes: A pH-Dependent 8- to 10-Coordinate Cerium Chelate Switch.

In this work, five cerium(IV) complexes were synthesized, three of which were structural isomorphs from the same pyrasal ligand with the solid-state result identified by structural analysis dependent on the initial pH of the reaction solution and the temperature at which the reaction is performed. The ligands explored here are pyrasal ligands, which are Schiff-base ligands formed by the condensation of 2,3-diaminopyrazine and a salicylaldehyde derivative. Pyrasal ligands have weaker binding than other salophen-type ligands due to the electron-withdrawing effect of the nitrogen atoms contained within the pyrazine ring. The weaker binding leaves the ligand more susceptible to the changes in pH and temperature that alternate the chelating environment from 8- to 10-coordinate. This electron-withdrawing effect of the pyrazine backbone also deactivates the second amine after the first condensation addition of salicylaldehyde. Without a metal to template the complex formation reaction, even with extended reaction times and the addition of a large excess of ligand, the result is the addition of only one salicylaldehyde.

1,8-Dihydroxy Naphthalene-A New Building Block for the Self-Assembly with Boronic Acids and 4,4'-Bipyridine to Stable Host-Guest Complexes with Aromatic Hydrocarbons.

The new Lewis acid-base adducts of general formula X(nad)B←NC5H4-C5H4N→B(nad)X [nad = 1,8-O2C10H6, X = C6H5 (2c), 3,4,5-F3-C6H2 (2d)] were synthesized in high yields via reactions of 1,8-dihydroxy naphthalene [nadH2] and 4,4'-bipyridine with the aryl boronic acids C6H5B(OH)2 and 3,4,5-F3-C6H2B(OH)2, respectively, and structurally characterized by multi-nuclear NMR spectroscopy and SCXRD. Self-assembled H-shaped Lewis acid-base adduct 2d proved to be effective in forming thermally stable host-guest complexes, 2d × solvent, with aromatic hydrocarbon solvents such as benzene, toluene, mesitylene, aniline, and m-, p-, and o-xylene. Crystallographic analysis of these solvent adducts revealed host-guest interactions to primarily occur via π···π contacts between the 4,4'-bipyridyl linker and the aromatic solvents, resulting in the formation of 1:1 and 1:2 host-guest complexes. Thermogravimetric analysis of the isolated complexes 2d × solvent revealed their high thermal stability with peak temperatures associated with the loss of solvent ranging from 122 to 147 °C. 2d, when self-assembled in an equimolar mixture of m-, p-, and o-xylene (1:1:1), preferentially binds to o-xylene. Collectively, these results demonstrate the ability of 1,8-dihydroxy naphthalene to serve as an effective building block in the selective self-assembly to supramolecular aggregates through dative covalent N→B bonds.

Heterometallic uranyl (hydroxyethyl)iminodiacetic acid (heidi) complexes: Molecular models for U(VI) uptake in complex media.

Amidoximated absorbents (AO-PAN) effectively remove U(VI) from aqueous solution, but previous studies reported more variability for complex natural waters that contain additional confounding ions and molecules. Ternary phases containing U(VI), M(III) (M = Fe(III), Al(III), Ga(III)), and organic molecules exist under these conditions and cause heterogeneous U(VI) uptake on AO-PAN. The goal of the current study is to provide additional insights into the structural features ternary complexes using N-(2-hydroxyethyl)-iminodiacetic acid (HEIDI) as the model organic chelator and explore the relevance of these species on U(VI) capture. Three model compounds ([(UO2)(Fe)2(µ3-O)(C6NO5H8)2(H2O)4] (UFe2), ([(UO2)(Al)2(µ2-OH)(C6NO5H8)2(H2O)3] (UAl2) and [(UO2)(Ga)2(µ2-OH)(C6NO5H8)2(H2O)3] (UGa2)) were characterized by single-crystal X-ray diffraction. Raman spectra of the model compounds were compared with solution data and the ternary phases were noted in the case of Al(III) and Ga(III), but not in the Fe(III) system. U(VI) adsorption onto AO-PAN was not impacted by the presence of HEIDI or the trivalent metal species.

Colossal Anisotropic Thermal Expansion in a Diazo-Functionalized Compound with Switchable Solid-State Behavior.

Achieving substantial anisotropic thermal expansion (TE) in solid-state materials is challenging as most materials undergo volumetric expansion upon heating. Here, we describe colossal, anisotropic TE in crystals of an organic compound functionalized with two azo groups. Interestingly, the material exhibits distinct and switchable TE behaviors within different temperature regions. At high temperature, two-dimensional, area zero TE and colossal, positive linear TE (α=211 MK-1 ) are attained due to dynamic motion, while at low temperature, moderate positive TE occurs in all directions. Investigation of the solid-state motion showed the change in enthalpy and entropy are quite different in the two temperature regions and solid-state NMR experiments support motion in the solid. Cycling experiments demonstrate that the solid-state motions and TE behaviors are completely reversible. These results reveal strategies for designing significant anisotropic and switchable behaviors in solid-state materials.

Reversible interconversion of pharmaceutical salt polymorphs facilitated by mechanical methods.

Salification of the drug trimethoprim with enantiopure D- or L-lactic acid afforded salts with up to five times improved solubility. Both salts are polymorphic and we demonstrate fully reversible interconversion (cycling) between the drug polymorphs using mechanochemistry and slurry methods. We show drug polymorph interconversion requires both solvent contact and mechanical force, revealing strategies for cycling between solid material forms.

Oxygen-Sensing Chemiluminescent Iridium(III) 1,2-Dioxetanes: Unusual Coordination and Activity.

Next generation chemiluminescent iridium 1,2-dioxetane complexes have been developed which consist of the Schaap's 1,2-dioxetane scaffold directly attached to the metal center. This was achieved by synthetically modifying the scaffold precursor with a phenylpyridine moiety, which can act as a ligand. Reaction of this scaffold ligand with the iridium dimer [Ir(BTP)2(µ-Cl)]2 (BTP = 2-(benzo[b]thiophen-2-yl)pyridine) yielded isomers which depict ligation through either the cyclometalating carbon or, interestingly, the sulfur atom of one BTP ligand. Their corresponding 1,2-dioxetanes display chemiluminescent responses in buffered solutions, exhibiting a single, red-shifted peak at 600 nm. This triplet emission was effectively quenched by oxygen, yielding in vitro Stern-Volmer constants of 0.1 and 0.009 mbar-1 for the carbon-bound and sulfur compound, respectively. Lastly, the sulfur-bound dioxetane was further utilized for oxygen sensing in muscle tissue of living mice and xenograft models of tumor hypoxia, depicting the ability of the probe chemiluminescence to penetrate biological tissue (total flux ~ 106 p/s).

Halogen-bonded co-crystal containing 1,3-di-iodo-perchloro-benzene and the photoproduct rtct-tetra-kis-(pyridin-4-yl)cyclo-butane resulting in a zigzag topology.

The formation and crystal structure of a zigzag network held together by I⋯N halogen bonds is reported. In particular, the halogen-bond donor is 1,3-di-iodo-perchloro-benzene (C6I2Cl4 ) while the acceptor is the photoproduct rtct-tetra-kis-(pyridin-4-yl)cyclo-butane (TPCB). Curiously, within the resulting co-crystal (C6I2Cl4 )·(TPCB), the photoproduct accepts only two halogen bonds between neighbouring 4-pyridyl rings and as a result behaves as a bent two-connected node rather than the expected four-connected centre. In addition, the photoproduct, TPCB, is also found to engage in C-H⋯N hydrogen bonds, forming an extended zigzag chain.

Intramolecular frustrated Lewis pair mediated approach to the CO bond activation and cleavage of carbon dioxide.

A thermally stable FLP-CO2 adduct of pronounced nucleophilic properties that forms a range of Lewis acid-base adducts with strong Lewis acids is reported. Upon addition of Tf2O, it generates a cationic triflate, which undergoes C-O bond cleavage to give the formal FLP adduct of the elusive dication C2O32+.

The complicating role of pnictogen bond formation in the solution-phase and solid-state structures of the heavier pnictogen atranes.

The structure of the simplest stibatrane has been a mystery since it was first prepared in 1966. This study reports the preparation and characterization of two stibatranes from triethanolamine and triisopropanolamine. Solid state structures reveal macrocycles that contain favourable inter- and intramolecular pnictogen bonds. Solution studies, corroborated by DFT analysis, reveal an equilibrium mixture assigned to monomer and pnictogen-bonded dimer. This allowed for the determination of an enthalpy associated with pnictogen bond formation of -27 kJ mol-1, in line with the supramolecular nature of these interactions.

Controlling Thermal Expansion in Supramolecular Halogen-Bonded Mixed Cocrystals through Synthetic Feed and Dynamic Motion.

Control over thermal expansion (TE) behaviors in solid materials is often accomplished by modifying the molecules or intermolecular interactions within the solid. Here, we use a mixed cocrystal approach and incorporate molecules with similar chemical structures, but distinct functionalities. Development of mixed cocrystals is at a nascent stage, and here we describe the first mixed cocrystals sustained by one-dimensional halogen bonds. Within each mixed cocrystal, the halogen-bond donor is fixed, while the halogen-bond acceptor site contains two molecules in a variable ratio. X-ray diffraction demonstrates isostructurality across the series, and SEM-EDS shows equal distribution of heavy atoms and similar atomic compositions across all mixed cocrystals. The acceptor molecules differ in their ability to undergo dynamic motion in the solid state. The synthetic equivalents of motion capable and incapable molecules were systematically varied to yield direct tunabililty in TE behavior.

Differences in thermal expansion and motion ability for herringbone and face-to-face π-stacked solids.

A series of aromatic organic molecules functionalized with different halogen atoms (I/ Br), motion-capable groups (olefin, azo or imine) and molecular length were designed and synthesized. The molecules self-assemble in the solid state through halogen bonding and exhibit molecular packing sustained by either herringbone or face-to-face π-stacking, two common motifs in organic semiconductor molecules. Interestingly, dynamic pedal motion is only achieved in solids with herringbone packing. On average, solids with herringbone packing exhibit larger thermal expansion within the halogen-bonded sheets due to motion occurrence and molecular twisting, whereas molecules with face-to-face π-stacking do not undergo motion or twisting. Thermal expansion along the π-stacked direction is surprisingly similar, but slightly larger for the face-to-face π-stacked solids due to larger changes in π-stacking distances with temperature changes. The results speak to the importance of crystal packing and intermolecular interaction strength when designing aromatic-based solids for organic electronics applications.

Carbon monoxide bond cleavage mediated by an intramolecular frustrated Lewis pair: access to new B/N heterocycles via selective incorporation of single carbon atoms.

Utilizing an intramolecular frustrated Lewis pair (FLP) decorated with a strongly donating guanidino moiety enabled the formation of a thermally remarkably stable FLP-CO adduct, which at 120 °C underwent CO migration to form an acyl borane. Both compounds underwent rapid CO cleavage in the presence of strong electrophiles leading to the selective formation of a range of new 1,2- and 1,3-benzazaboroles in good yields under mild conditions.

Thermal Expansion Properties and Mechanochemical Synthesis of Stoichiometric Cocrystals Containing Tetrabromobenzene as a Hydrogen- and Halogen-Bond Donor.

The solution and mechanochemical synthesis of two cocrystals that differ in the stoichiometric ratio of the components (stoichiometric cocrystals) is reported. The components in the stoichiometric cocrystals interact through hydrogen or hydrogen/halogen bonds and differ in π-stacking arrangements. The difference in structure and noncovalent interactions affords dramatically different thermal expansion behaviors in the two cocrystals. At certain molar ratios, the cocrystals are obtained concomitantly; however, by varying the ratios, a single stoichiometric cocrystal is achieved using mechanochemistry.

Self-Assembly of Complementary Components Using a Tripodal Bismuth Compound: Pnictogen Bonding or Coordination Chemistry?

Triple pnictogen bonding refers to the ability of a pnictogen atom to engage in three simultaneous pnictogen bonds (PnBs) to a complementary partner through a single pnictogen atom. This supramolecular strategy was recently introduced as a unique facet of pnictogen bonding as compared to other named supramolecular interactions. Here, the ability of bismuth to participate in this phenomenon is demonstrated using Bi((NC9H7)3CH3). The study reveals that Bi engages in stronger PnBs than the analogous Sb system. The results have been contrasted with Bi systems that form strong coordination bonds, and analysis of the electron density along the bond path reveals key differences. The solution behavior of these newly synthesized supramolecules were studied by PFGSE NMR spectroscopy and they are found to remain intact in solution. Molecular design strategies that allow for triple pnictogen bonding should find use in the fields of molecular recognition and crystal engineering.

Controlling Topology within Halogen-Bonded Networks by Varying the Regiochemistry of the Cyclobutane-Based Nodes.

The formation of a pair of extended networks sustained by halogen bonds based upon two regioisomers of a photoproduct, namely rctt-1,3-bis(4-pyridyl)-2,4-bis(phenyl)cyclobutane (ht-PP) and rctt-1,2-bis(4-pyridyl)-3,4-bis(phenyl)cyclobutane (hh-PP), that have varied topology is reported. These networks are held together via I⋯N halogen bonds between the photoproduct and the halogen-bond donor 1,4-diiodoperchlorobenzene (C6I2Cl4). The observed topology in each solid is controlled by the regiochemical position of the halogen-bond accepting 4-pyridyl group. This paper demonstrates the ability to vary the topology of molecular networks by altering the position of the halogen bond acceptor within the cyclobutane-based node.

Synthesis, structures and catalytic activity of some BINOL based boronates and boronium salts.

The BINOL supported chiral boronate ester [C10H12O2BC6F5(THF)] [(R)-1], [C10H12O2BC6F5(O[double bond, length as m-dash]PEt3)] [(R)-3] and [C10H12O2BC6F5]2 [(R,R)-2] as well as the chiral boronium salts [C10H12O2B(O[double bond, length as m-dash]PEt3)2]+[B(O2C10H12)2]-, [(R)-6] and [C10H12O2B(O[double bond, length as m-dash]SMe2)2]+[B(O2C10H12)2]- [(R)-7] have been synthesized, characterized by NMR spectroscopy, and the solid state structures of [(R)-1], [(R,R)-2] and [(R)-3] determined. Chiral ester [(R)-1] was found to be a potent Lewis acid, similar to B(C6F5)3, and capable of rapidly catalyzing the annulation of (R)-, (S)- and rac-styrene oxide with nitrone PhCH[double bond, length as m-dash]N(O)Me to trans-2-methyl-3,6-diphenyl-1,4,2-dioxazine (trans-11) with high regio- and diastereoslectivities.