Strong Hydrogen Bond Donor Research Articles

Unveiling the Mechanism of Phenamacril Resistance in F. graminearum: Computational and Experimental Insights into the C423A Mutation in FgMyoI.

Phenamacril (PHA) is a highly selective fungicide for controlling fusarium head blight (FHB) mainly caused by F. graminearum and F. asiaticum. However, the C423A mutation in myosin I of F. graminearum (FgMyoI) leads to natural resistance to PHA. Here, based on the computational approaches and biochemical validation, we elucidate the atomic-level mechanism behind the natural resistance of F. graminearum to the fungicide PHA due to the C423A mutation in FgMyoI. The mutation leads to a rearrangement of pocket residues, resulting in increased size and flexibility of the binding pocket, which impairs the stable binding of PHA. MST experiments confirm that the mutant protein FgMyoIC423A exhibits significantly reduced affinity for PHA compared to wild-type FgMyoI and the nonresistant C423K mutant. This decreased binding affinity likely underlies the development of PHA resistance in F. graminearum. Conversely, the nonresistant C423K mutant retains sensitivity to PHA due to the introduction of a strong hydrogen bond donor, which facilitates stable binding of PHA in the pocket. These findings shed light on the molecular basis of PHA resistance and provide new directions for the creation of new myosin inhibitors.

Tert‐Butyl as a Functional Group: Non‐Directed Catalytic Hydroxylation of Sterically Congested Primary C−H Bonds

AbstractThe tert‐butyl group is a common aliphatic motif extensively employed to implement steric congestion and conformational rigidity in organic and organometallic molecules. Because of the combination of a high bond dissociation energy (~100 kcal mol−1) and limited accessibility, in the absence of directing groups, neither radical nor organometallic approaches are effective for the chemical modification of tert‐butyl C−H bonds. Herein we overcome these limits by employing a highly electrophilic manganese catalyst, [Mn(CF3bpeb)(OTf)2], that operates in the strong hydrogen bond donor solvent nonafluoro‐tert‐butyl alcohol (NFTBA) and catalytically activates hydrogen peroxide to generate a powerful manganese‐oxo species that effectively oxidizes tert‐butyl C−H bonds. Leveraging on the interplay of steric, electronic, medium and torsional effects, site‐selective and product chemoselective hydroxylation of the tert‐butyl group is accomplished with broad reaction scope, delivering primary alcohols as largely dominant products in preparative yields. Late‐stage hydroxylation at tert‐butyl sites is demonstrated on 6 densely functionalized molecules of pharmaceutical interest. This work uncovers a novel disconnection approach, harnessing tert‐butyl as a potential functional group in strategic synthetic planning for complex molecular architectures.

Tert-Butyl as a Functional Group: Non-Directed Catalytic Hydroxylation of Sterically Congested Primary C-H Bonds.

The tert-butyl group is a common aliphatic motif extensively employed to implement steric congestion and conformational rigidity in organic and organometallic molecules. Because of the combination of a high bond dissociation energy (~ 100 kcal mol-1) and limited accessibility, in the absence of directing groups, neither radical nor organometallic approaches are effective for the chemical modification of tert-butyl C-H bonds. Herein we overcome these limits by employing a highly electrophilic manganese catalyst, [Mn(CF3bpeb)(OTf)2], that operates in the strong hydrogen bond donor solvent nonafluoro-tert-butyl alcohol (NFTBA) and catalytically activates hydrogen peroxide to generate a powerful manganese-oxo species that effectively oxidizes tert-butyl C-H bonds. Leveraging on the interplay of steric, electronic, medium and torsional effects, site-selective and product chemoselective hydroxylation of the tert-butyl group is accomplished with broad reaction scope, delivering primary alcohols as largely dominant products in preparative yields. Late-stage hydroxylation at tert-butyl sites is demonstrated on 6 densely functionalized molecules of pharmaceutical interest. This work uncovers a novel disconnection approach, harnessing tert-butyl as a potential functional group in strategic synthetic planning for complex molecular architectures.

On the solubility of azodicarbonamide in water/DMSO mixtures: an experimental and computational study.

This work aims at studying why azodicarbonamide (ADCA), a formally apolar compound with good hydrogen bond (HB) acceptors, is soluble only in polar aprotic solvents like dimethyl sulfoxide (DMSO) but not in water. Solubility measurements, as well as quantum mechanical and classical molecular dynamics simulations, were employed to tackle the problem. We found that in the liquid phase a polar conformer of ADCA (µ = 8.7 D), unreported to date, is favoured under the enthalpic drive provided by a highly polar solvent. At the same time, the very high hydrogen bond propensity of water with itself prevents this solvent from providing an effective hydrogen bond-mediated solvation. Solvents bearing good HB acceptors, while lacking strong HB donors, contribute to further stabilizing solute-solvent adducts through weak and fluxional HBs that involve the amide groups of ADCA. Implications for the solubility of ADCA down to µM concentrations were evaluated, also with the aid of classical simulations of solution nanodroplets.

Anion Binding Interaction Enhances the Robustness of Iodide for High-Performance Perovskite Solar Cells.

Owing to the ionic bond nature of the Pb-I bond, the iodide at the interface of perovskite polycrystalline films was easily lost during the preparation process, resulting in the formation of a large number of iodine vacancy defects. The presence of iodine vacancy defects can cause nonradiative recombination, provide a pathway for iodide migration, and be harmful to the power conversion efficiency (PCE) and stability of organic-inorganic hybrid perovskite solar cells (HPSCs). Here, in order to increase the robustness of iodides at the interface, a strategy to introduce anion binding effects was developed to stabilize the perovskite films. It was demonstrated that the N,N'-diphenylurea (DPU), characterized by high anionic binding constants and a Y-shaped structure, provides a relatively strong hydrogen bond donor site to effectively reduce the iodine loss during film preparation and inhibits iodide migration in the device working condition. As expected, the reduced iodine loss considerably improves the quality of the perovskite films and suppresses nonradiative recombination. The performance of the device after DPU modification was significantly increased, with the PCE rising from 23.65 to 25.01% with huge stability enhancement as well.

More Electropositive is More Electronegative: Atom Size Determines C=X Group Electronegativity.

Opposite to what one might expect, we find that the C=X group can become effectively more, not less, electronegative when the Pauling electronegativity of atom X decreases down Groups 16, 15, and 14 of the Periodic Table. Our quantum-chemical analyses, show that, and why, this phenomenon is a direct consequence of the increasing size of atom X down a group. These findings can be applied to tuning and improving the hydrogen-bond donor strength of amides H2 NC(=X)R by increasingly withdrawing density from the NH2 group. A striking example is that H2 NC(=SiR2 )R is a stronger hydrogen-bond donor than H2 NC(=CR2 )R.

Catalyzing epoxy oxygen migration on the basal surface of graphene oxide using strong hydrogen-bond donors.

High-level double-hybrid DFT simulations reveal that strong hydrogen-bond-donor catalysts (e.g., ethylene glycol, guanidine, and thiourea) significantly accelerate the migration of epoxy oxygen on the surface of graphene oxide, enhancing the reaction rate by 6-12 orders of magnitude. These results shed light on previously puzzling experimental observations.

Unraveling hydrogen bond interactions between ketoconazole and imidazolium-based ionic liquids: An experimental and theoretical study

The solubility and solvation mechanism of the Biopharmaceutical Classification System class II insoluble drug, ketoconazole (KCZ), were investigated in eight different types of imidazolium-based ionic liquids (ILs). An in vitro cytotoxicity test was conducted on Human immortalized keratinocytes cells to evaluate the potential toxicity of these ILs. The results showed no cytotoxicity for any of the imidazolium-based ILs tested. The solubility of KCZ was then examined in the eight imidazolium-based ILs at temperatures ranging from 298.15 K to 338.15 K. The findings revealed that the solubility of KCZ followed a specific order among the imidazolium-based ILs tested. The imidazolium-based IL [BMIM][Tf2N] exhibited the highest solubility of KCZ, followed by [HMIM][PF6], [EMIM][Tf2N], [BMIM][TfO], [BMIM][PF6], [EMIM][TfO], [BMIM][BF4], and [EMIM][BF4] in decreasing order. To understand the interaction mechanism between the imidazolium-based ILs and KCZ, the cations, anions and KCZ were analyzed using σ-profiles computed from both the COSMO-RS model and quantum chemical calculations. The results indicated that KCZ had strong hydrogen bond (HB) acceptors, particularly the oxygen atom of the carbonyl group and the nitrogen atom of the imidazole ring. These HB acceptors contributed to the formation of stronger HBs with the hydrogen atoms of cations compared to the oxygen atoms of the anions. The trend of HB strength followed [Emim]+ > [Bmim]+ > [Hmim]+ > [Tf2N]− > [TfO]− > [PF6]− > [BF4]−. Based on these findings, it can be concluded that [BMIM][Tf2N], which has a strong HB donor cation and a strong HB acceptor anion, displayed the most effective dissolution of KCZ.

COSMO-RS guided screening of ionic liquids for the separation of fluorinated greenhouse gases R-410A: Delving into anion, cation effects, and hydrogen bond dynamics

Reclamation of high-GWP near-azeotropic refrigerant R-410A (50 wt% R-32 (difluoromethane) + 50 wt% R-125 (pentafluoroethane)) can be an effective way to mitigate the greenhouse effect and achieve a circular economy. Efficient ionic liquids (ILs) as extractants needed to be found for the extractive distillation (ED) separation process of R-410A. Given the numerous combinations of cations and anions in ILs, the discovery of an efficient IL via experimental methods proves to be an exceedingly complex task. In this work, the solubilities of R-32, and R-125 in 840 conventional ILs (comprised of 20 cations and 42 anions) were analyzed based on infinite dilution activity coefficient. The absorption mechanisms of R-32 and R-125 in ILs were elucidated by analyzing excess enthalpy (HE), excess Gibbs free energy (GE)) and surface charge density distribution through COSMO-RS (Conductor-like Screening Model for Real Solvents). Results revealed that HE and GE of the mixture formed by R-125 and most ILs surpassed those of R-32, resulting in higher solubility of R-32 in most ILs compared to R-125. Structural changes of anions and cations had a greater effect on the solubility of R-125 in ILs. It is found for the first time that the existence of a strong hydrogen bond donor region in cations/anions generated intense repulsion with the hydrogen atom in R-125. Furthermore, a large area of weak polarity on the surface of cations/anions was difficult to form an effective charge shield with fluorine atoms in R-125, thus inhibiting the dissolution of R-125. Finally based on the identified interaction sites, combined with melting point and viscosity, some novel functional ILs with high selectivity for R-32 + R-125 were designed and determined for actual separation process. These findings significantly enrich the understanding of the solubility mechanism and provide theoretical guidance for designing new ILs for R-410A reclamation.

Solid-State [4+4] Cycloaddition and Cycloreversion with Use of Unpaired Hydrogen-Bond Donors to Achieve Solvatomorphism and Stabilization.

The crystal structure of a commercially available anthracene derivative, anthracene-9-thiocarboxamide, is reported here for the first time. The compound undergoes a [4+4] cycloaddition in the solid state to afford facile synthesis of the cycloadduct (CA). The cycloaddition is also reversible in the solid state using heat or mechanical force. Due to the presence of unpaired, strong hydrogen-bond donor atoms on the CA, significant solvatomorphism is achieved, and components of the solvatomorphs self-assemble into four different classes of supramolecular structures. The CA readily crystallizes with a variety of structurally-diverse solvents including those containing oxygen-, nitrogen-, or pi-acceptors. Some of the solvents the CA crystallized with include thiophene, benzene, and the three xylene isomers; thus, the CA was employed in industrially-relevant solvent separation. However, in competition studies, the CA did not exhibit selectivity. Lastly, it is demonstrated that the CA crystallizes with vinyl-containing monomers and is currently the only compound that crystallizes with both widely used monomers 4-vinylpyridine and styrene. Solid-state complexation of the CA with the monomers affords over a 50 °C increase in the monomer's thermal stabilities. The strategy of designing molecules with unused donors can be applied to achieve separations or volatile liquid stabilization.

The role of halogen bonding in the interaction landscape directing the crystal packing in a homologous series of halogenated coumarin derivatives

The role of halogen bonding as a supramolecular directing interaction was investigated in a series of ten 3-halogenocoumarin derivatives using X-ray diffraction analysis. Halogen bonds might not be as strong as classical hydrogen bonds in molecules such as substituted coumarins but are nevertheless expected to play a certain role in the supramolecular assemblies. Hirshfeld surface analysis, full interaction maps and quantum calculations are used to identify halogen interactions such as X···O, X···π or interhalogen contacts of type I and II, where X is a halogen atom. The halogen interactions in this series appear to be in competition with other supramolecular interactions which leads to a larger structural diversity than expected. This might be due to the steric shielding by the ortho substituents of the halogen atom in the 3-position on the lactone ring of the coumarin motif which are themselves strong hydrogen bond acceptors or donors, but also to the relatively abundant presence of π- π interactions between the aromatic coumarin moieties.

Peracid Oxidation of Unactivated sp3 C-H Bonds: An Important Solvent Effect.

The peracid oxidation of hydrocarbons in chlorinated solvents is a low yielding and poorly selective process. Through a combination of DFT calculations, spectroscopic studies, and kinetic measurement it is shown that the origin of this is electronic in nature and can be influenced through the addition of hydrogen bond donors (HBD) and hydrogen bond acceptors (HBA). Performing the reaction of a cycloalkane with mCPBA in a fluorinated alcohol solvent such as nonafluoro-tert-butanol (NFTB) or hexafluoroisopropanol (HFIP), which act as strong HBD and poor HBA, leads to significantly higher yields and selectivities being observed for the alcohol product. Application of the optimised reaction conditions allows for the selective oxidation of both cyclic and linear alkane substrates delivering the corresponding alcohol in up to 86 % yield. The transformation shows selectivity for tertiary centres over secondary centres and the oxidation of secondary centres is strongly influenced by stereoelectronic effects. Primary centres are not oxidised by this method. A simple computational model developed to understand this transformation provides a powerful tool to reliably predict the influence of substitution and functionality on reaction outcome.

Hydrogen Bonding-Assisted and Nonheme Manganese-Catalyzed Remote Hydroxylation of C-H Bonds in Nitrogen-Containing Molecules.

The development of catalytic systems capable of oxygenating unactivated C-H bonds with excellent site-selectivity and functional group tolerance under mild conditions remains a challenge. Inspired by the secondary coordination sphere (SCS) hydrogen bonding in metallooxygenases, reported herein is an SCS solvent hydrogen bonding strategy that employs 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as a strong hydrogen bond donor solvent to enable remote C-H hydroxylation in the presence of basic aza-heteroaromatic rings with a low loading of a readily available and inexpensive manganese complex as a catalyst and hydrogen peroxide as a terminal oxidant. We demonstrate that this strategy represents a promising compliment to the current state-of-the-art protection approaches that rely on precomplexation with strong Lewis and/or Brønsted acids. Mechanistic studies with experimental and theoretical approaches reveal the existence of a strong hydrogen bonding between the nitrogen-containing substrate and HFIP, which prevents the catalyst deactivation by nitrogen binding and deactivates the basic nitrogen atom toward oxygen atom transfer and the α-C-H bonds adjacent to the nitrogen center toward H-atom abstraction. Moreover, the hydrogen bonding exerted by HFIP has also been demonstrated not only to facilitate the O-O bond heterolytic cleavage of a putative MnIII-OOH precursor to generate MnV(O)(OC(O)CH2Br) as an active oxidant but also to affect the stability and the activity of MnV(O)(OC(O)CH2Br).

Influence mechanism of different organic solvents on API solvation behaviors: Molecular dynamics simulations

Solubilities of active pharmaceutical ingredients (APIs) in different solvents are important fundamental properties and are of particular interest in purification (e.g. crystallization) of APIs in industry. Therefore, the objective of this work is to investigate the solvation mechanisms of the poorly soluble API ibuprofen in various organic solvents, by using molecular dynamics (MD) simulations. It was found that the solvation performance of ibuprofen in protic solvents mainly depend on van der Waals interaction, while that in aprotic solvents mainly depend on the ability of forming hydrogen bond (H-bond) of the solvents. Wherein, the strength of H-bond between ibuprofen and protic solvents mainly depends on the hydrogen bond donor (HBD) of the solvent, while hydrogen bond acceptor (HBA) ability of solvents directly determines the strength of H-bond between ibuprofen and aprotic solvents. This difference nature in solvation mechanism was due to the structural properties of protic solvents and aprotic solvents. Among them, protic solvents containing hydroxyl group have strong HBD and HBA characteristics, whereas aprotic solvents only show the characteristics of HBA, because it does not contain active hydrogen protons. In general, the MD simulation results revealed that the better solvation performance of ibuprofen in organic solvents corresponds to the higher polarizability of protic solvents or the stronger HBA ability of aprotic solvents. This work is expected to provide theoretical guidance for choosing appropriate solvents during API preparation and development.

Lewis Acid-Catalyzed [3 + 2]-Cyclization of Iodonium Ylides with Azadienes: Access to Spiro[benzofuran-2,2'-furan]-3-ones.

A highly regioselective synthesis of spiro[benzofuran-2,2'-furan]-3-ones has been explored via Lewis acid-catalyzed [3 + 2] cyclization of iodonium ylides with azadienes. The acidity of the Lewis acid was significantly strengthened with strong hydrogen bond donors, thereby promoting the enolization isomerization of iodonium ylides for the subsequent cycloaddition. This reaction was compatible with a broad range of substrates under the mild reaction conditions, and efficiently delivered spiro-heterocycles with excellent stereoselectivity.

Direct regio- and stereoselective mono- and polyoxyfunctionalization of estrone derivatives at C(sp3)-H bonds

Late-stage catalytic selective oxidative C-H functionalization at B and C rings of estrone 3-acetate, 17α- and 17β-estradiol 3-acetates with H2O2 in the presence of bioinspired nonheme Mn complexes with N4-donor ligands has been developed. Depending on the ligand architecture and absolute chirality, products of α-hydroxylation or ketonization at C6, or α-hydroxylation at C9, or 9,11-desaturation/C12α-hydroxylation can be obtained in synthetically useful yields; the resulting monooxygenated derivatives can be involved in further selective oxidative transformations to yield polyoxygenated metabolites. The aromatic A ring remains intact under the conditions, and ketonization of the hydroxo groups at C17 is effectively prevented by using hexafluoroisopropanol as strong hydrogen bond donor reaction solvent.

Squaramide-Tethered Sulfonamides and Coumarins: Synthesis, Inhibition of Tumor-Associated CAs IX and XII and Docking Simulations.

(1) Background: carbonic anhydrases (CAs) are attractive targets for the development of new anticancer therapies; in particular, CAs IX and XII isoforms are overexpressed in numerous tumors. (2) Methods: following the tail approach, we have appended a hydrophobic aromatic tail to a pharmacophore responsible for the CA inhibition (aryl sulfonamide, coumarin). As a linker, we have used squaramides, featured with strong hydrogen bond acceptor and donor capacities. (3) Results: Starting from easily accessible dimethyl squarate, the title compounds were successfully obtained as crystalline solids, avoiding the use of chromatographic purifications. Interesting and valuable SARs could be obtained upon modification of the length of the hydrocarbon chain, position of the sulfonamido moiety, distance of the aryl sulfonamide scaffold to the squaramide, stereoelectronic effects on the aromatic ring, as well as the number and type of substituents on C-3 and C-4 positions of the coumarin. (4) Conclusions: For sulfonamides, the best profile was achieved for the m-substituted derivative 11 (Ki = 29.4, 9.15 nM, CA IX and XII, respectively), with improved selectivity compared to acetazolamide, a standard drug. Coumarin derivatives afforded an outstanding selectivity (Ki > 10,000 nM for CA I, II); the lead compound (16c) was a strong CA IX and XII inhibitor (Ki = 19.2, 7.23 nM, respectively). Docking simulations revealed the key ligand-enzyme interactions.

Intra- and Intermolecular Hydrogen Bonding in Miscible Blends of CO2/Epoxy Cyclohexene Copolymer with Poly(Vinyl Phenol).

In this study, we synthesized a poly(cyclohexene carbonate) (PCHC) through alternative ring-opening copolymerization of CO2 with cyclohexene oxide (CHO) mediated by a binary LZn2OAc2 catalyst at a mild temperature. A two-dimensional Fourier transform infrared (2D FTIR) spectroscopy indicated that strong intramolecular [C–H···O=C] hydrogen bonding (H-bonding) occurred in the PCHC copolymer, thereby weakening its intermolecular interactions and making it difficult to form miscible blends with other polymers. Nevertheless, blends of PCHC with poly(vinyl phenol) (PVPh), a strong hydrogen bond donor, were miscible because intermolecular H-bonding formed between the PCHC C=O units and the PVPh OH units, as evidenced through solid state NMR and one-dimensional and 2D FTIR spectroscopic analyses. Because the intermolecular H-bonding in the PCHC/PVPh binary blends were relatively weak, a negative deviation from linearity occurred in the glass transition temperatures (Tg). We measured a single proton spin-lattice relaxation time from solid state NMR spectra recorded in the rotating frame [T1ρ(H)], indicating full miscibility on the order of 2–3 nm; nevertheless, the relaxation time exhibited a positive deviation from linearity, indicating that the hydrogen bonding interactions were weak, and that the flexibility of the main chain was possibly responsible for the negative deviation in the values of Tg.

Influence of Multiple Binding Sites on the Supramolecular Assembly of N-[(3-pyridinylamino) Thioxomethyl] Carbamates.

In this study, we investigated how the presence of multiple intermolecular interaction sites influences the heteromeric supramolecular assembly of N-[(3-pyridinylamino) thioxomethyl] carbamates with fluoroiodobenzenes. Three targets—R-N-[(3-pyridinylamino) thioxomethyl] carbamate (R = methyl, ethyl, and isobutyl)—were selected and crystallized, resulting in three parent structures, five co-crystals, and one co-crystal solvate. Three hydrogen-bonded parent crystal structures were stabilized by N-H···N hydrogen bonding and assembled into layers that stacked on top of one another. Molecular electrostatic potential surfaces were employed to rank binding sites (Npyr > C=S > C=O) in order to predict the dominant interactions. The N-H⋯H hydrogen bond was replaced by I⋯Npyr in 3/6 cases, I⋯C=S in 4/6 cases, and I⋯O=C in 1 case. Interestingly, the I⋯C=S halogen bond coexisted twice with I⋯Npyr and I⋯O=C. Overall, the MEPs were fairly reliable for predicting co-crystallization outcomes; however, it is crucial to also consider factors such as molecular flexibility. Finally, halogen-bond donors are capable of competing for acceptor sites, even in the presence of strong hydrogen-bond donors.

Theoretical search of crystal polymorphs of temozolomide

Possible polymorphic forms of the chemotherapy drug, temozolomide were predicted from the ab initio and DFT methods. The lattice minimization via distributed multipole analysis was carried out for the hypothetical generated structures. A crystal with unit cell parameters close to the real one and of same space group was retrieved, with partly similar packing and interactions. The analysis of inter molecular interaction (through Hirshfeld surface) and electrostatic potential reveals the complementary sites in the molecule. The 26 predicted structures were analyzed with respect to two computed lattice energies and hydrogen-bond propensity. The lattice energy of the real crystal [EXP] packing ranked number 6 compared on the basis of DMACRYS software and number 3 on the basis of the total lattice energy issued from the Crystalexplorer17 software at the B3LYP/6-31G∗∗ level of theory. The molecule has two strong hydrogen bond donors and five strong acceptors. The predicted packings are stabilized by one or two strong N–H…O/N–H…N as well as weak C–H…O/C–H…N and H…π hydrogen bonds. While the real structure with Z’ = 1, EXP, forms only one strong H-bond (N–H…O=C), several of the predicted packings form two strong H-bonds. Two predicted crystal packings have unit cell parameters close to the real structure, one of them shares several common intermolecular interactions.