Exocyclic Group Research Articles

Intramolecular Interactions in Derivatives of Uracil Tautomers.

The influence of solvents on intramolecular interactions in 5- or 6-substituted nitro and amino derivatives of six tautomeric forms of uracil was investigated. For this purpose, the density functional theory (B97-D3/aug-cc-pVDZ) calculations were performed in ten environments (1 > ε > 109) using the polarizable continuum model (PCM) of solvation. The substituents were characterized by electronic (charge of the substituent active region, cSAR) and geometric parameters. Intramolecular interactions between non-covalently bonded atoms were investigated using the theory of atoms in molecules (AIM) and the non-covalent interaction index (NCI) method, which allowed discussion of possible interactions between the substituents and N/NH endocyclic as well as =O/-OH exocyclic groups. The nitro group was more electron-withdrawing in the 5 than in the 6 position, while the opposite effect was observed in the case of electron donation of the amino group. These properties of both groups were enhanced in polar solvents; the enhancement depended on the ortho interactions. Substitution or solvation did not change tautomeric preferences of uracil significantly. However, the formation of a strong NO∙∙∙HO intramolecular hydrogen bond in the 5-NO2 derivative stabilized the dienol tautomer from +17.9 (unsubstituted) to +5.4 kcal/mol (substituted, energy relative to the most stable diketo tautomer).

Variable Effects of Twenty Sugars and Sugar Alcohols on the Retrogradation of Wheat Starch Gels.

Starch retrogradation is desirable for some food textures and nutritional traits but detrimental to sensory and storage qualities of other foods. The objective of this study was to determine the impact of sweetener structure and concentration on the retrogradation of wheat starch gels. The effects of 20 sweeteners selected based on common food usage and stereochemical structures of interest, and ranging in concentration from 10 to 50%w/w, on the retrogradation of wheat starch gels were monitored spectrophotometrically over time. The sweeteners were sucrose, xylose, ribose, glucose, galactose, fructose, mannose, mannitol, L-sorbose, xylitol, tagatose, allulose, maltose, lactose, isomaltulose, isomalt, sorbitol, maltitol, and raffinose. Retrogradation rates and amounts were compared by Avrami equation rate constants (k = 0.1–0.7) and absorbance values measured on day 28 (Abs = 0.1–1.0), respectively. Both sweetener concentration and type significantly affected retrogradation. Gels made with sugar alcohols and high sweetener concentrations (≈≥40%) tended to retrograde more and faster, whereas gels made with sugars and low sweetener concentrations tended to have lower retrogradation rates and amounts. Sweeteners with more equatorial and exocyclic hydroxyl groups (e.g., glucose and maltitol) and those with larger molar volumes (e.g., isomaltulose and raffinose) tended to increase the rate and amount of retrogradation, particularly at higher concentrations. The impact of sweeteners on retrogradation was a balance of factors that promoted retrogradation (intermolecular interactions and residual short-range molecular order) and inhibiting behaviors (interference at crystallization sites), which are influenced by sweetener concentration and structure. Understanding which sweeteners at which concentrations can be used to promote or inhibit retrogradation is useful for product formulation strategies.

Robust carbon–carbon singly bonded electron acceptors for efficient organic photovoltaics

To obtain photostable organic semiconductors is essential for advancing organic solar cells (OSCs), yet to be explored. Herein, a new type of robust carbon–carbon singly bonded acceptor–donor–acceptor (A–D–A) non-fullerene acceptor (NFA) is developed, namely IDT-SZ, via the Stille coupling between the designed electron-deficient indeno ([2,1-b]thiazole-8-ylidene) malononitrile (A unit, SZ) and indacenodithiophene (D unit, IDT). Different from the classic A–D–A NFAs containing vulnerable exocyclic vinyl groups, the planar IDT-SZ has robust carbon–carbon bond linkages mediated by the nitrogen-sulfur (N…S) noncovalent interaction, exhibiting not only excellent photo- and thermal stabilities in ambient, but also high electron transport in films. As a result, efficient OSCs have been developed from the bulk-heterojunction (BHJ) blend of PM6 polymer donor and IDT-SZ acceptor, representing the best-performed single carbon–carbon bonded A–D–A acceptors so far.

Broad Spectrum Functional Activity of Structurally Related Monoanionic Au(III) Bis(Dithiolene) Complexes.

The biological properties of sixteen structurally related monoanionic gold (III) bis(dithiolene/diselenolene) complexes were evaluated. The complexes differ in the nature of the heteroatom connected to the gold atom (AuS for dithiolene, AuSe for diselenolene), the substituent on the nitrogen atom of the thiazoline ring (Me, Et, Pr, iPr and Bu), the nature of the exocyclic atom or group of atoms (O, S, Se, C(CN)2) and the counter-ion (Ph4P+ or Et4N+). The anticancer and antimicrobial activities of all the complexes were investigated, while the anti-HIV activity was evaluated only for selected complexes. Most complexes showed relevant anticancer activities against Cisplatin-sensitive and Cisplatin-resistant ovarian cancer cells A2780 and OVCAR8, respectively. After 48 h of incubation, the IC50 values ranged from 0.1–8 µM (A2780) and 0.8–29 µM (OVCAR8). The complexes with the Ph4P+ ([P]) counter-ion are in general more active than their Et4N+ ([N]) analogues, presenting IC50 values in the same order of magnitude or even lower than Auranofin. Studies in the zebrafish embryo model further showed that, despite their marked anticancer effect, the complexes with [P] counter-ion exhibited low in vivo toxicity. In general, the exocyclic exchange of sulfur by oxygen or ylidenemalononitrile (C(CN)2) enhanced the compounds toxicity. Most complexes containing the [P] counter ion exhibited exceptional antiplasmodial activity against the Plasmodium berghei parasite liver stages, with submicromolar IC50 values ranging from 400–700 nM. In contrast, antibacterial/fungi activities were highest for most complexes with the [N] counter-ion. Auranofin and two selected complexes [P][AuSBu(=S)] and [P][AuSEt(=S)] did not present anti-HIV activity in TZM-bl cells. Mechanistic studies for selected complexes support the idea that thioredoxin reductase, but not DNA, is a possible target for some of these complexes. The complexes [P] [AuSBu(=S)], [P] [AuSEt(=S)], [P] [AuSEt(=Se)] and [P] [AuSeiPr(=S)] displayed a strong quenching of the fluorescence intensity of human serum albumin (HSA), which indicates a strong interaction with this protein. Overall, the results highlight the promising biological activities of these complexes, warranting their further evaluation as future drug candidates with clinical applicability.

N‐Heterocyclic Carbenes Carrying Weakly Coordinating Anions

In this Concept article we provide a brief overview of the design and preparation of N‐heterocyclic carbenes carrying weakly coordinating anions (WCA‐NHCs). The anionic charge in these ligand systems is located on an exocyclic group, for example, B(C6F5)3, tethered to the backbone of the imidazole ring, thus resembling a weakly coordinating moiety. With the general guiding principle behind the application of WCA‐NHCs being the conversion of otherwise cationic NHC complexes into their overall neutral congeners, numerous transition metal as well as main group element complexes were isolated during the last decade, which are summarized herein.

Determination of the tautomerism of albendazole desmotropes using solution and solid state NMR together with DFT theoretical calculations, both energies and chemical shifts

This paper reports a structural study of albendazole concerning the desmotropy of its amino and imino tautomers, ABZ-I and ABZ-II, mistakenly called polymorphs. Experimental NMR determination in solution, DMSO‑d6, HMPA-d18 and CF3CO2H, and in the solid state, CPMAS, together with DFT calculations, energies and NMR chemical shifts, has allowed to understand the complex problem of prototropy combined with rotation about the benzimidazole C2-N exocyclic group that explain the disorder problem of the S-propyl group. The structure of protonated albendazole, ABZH+, has also been studied. The role of the hybrid HF/DFT B3LYP computational method at the B3LYP/6–311++G(d,p) level has been determinant to solve the problems related to the structure of albendazole in the solid state and in solution and the barrier in solution of a phenomenon resulting either from annular tautomerism or from the rotation about the exocyclic CN bond.

D-Mannosamine hydrochloride (2-amino-2-deoxy-D-mannose hydrochloride): ionic hydrogen bonding in saccharides involving chloride and aminium ions.

D-Mannosamine hydrochloride (2-amino-2-deoxy-D-mannose hydrochloride), C6H14NO5+·Cl-, (I), crystallized from a methanol/ethyl acetate/n-hexane solvent mixture at room temperature in a 4C1 chair conformation that is slightly distorted towards the C3,O5B form. A comparison of the structural parameters of (I) with the corresponding parameters in α-D-glucosamine hydrochloride, (II), and β-D-galactosamine hydrochloride, (III)/(III'), was undertaken to evaluate the effects of ionic hydrogen bonding on structural properties. Three types of ionic hydrogen bonds are present in the crystals of (I)-(III)/(III'), i.e. N+-H...O, N+-H...Cl-, and O-H...Cl-. The exocyclic structural parameters in (I), (II), and (III)/(III') appear to be most influenced by this bonding, especially the exocyclic hydroxy groups, which adopt eclipsed conformations enabled by ionic hydrogen bonding to the chloride anion. Anomeric disorder was observed in crystals of (I), with an α:β ratio of 37:63. However, anomeric configuration appears to exert minimal structural effects; that is, bond lengths, bond angles, and torsion angles are essentially identical in both anomers. The observed disorder at the anomeric C atom of (I) appears to be caused by the presence of the chloride anion and atom O3 or O4 in proximal voids, which provide opportunities for hydrogen bonding to atom O1 in both axial and equatorial orientations.

A simple route toward triplet-forming thionated BODIPY-based photosensitizers

Thiobases or sulfur-substituted nucleobases have been developed and recognized as prospective class of heavy-atom-free photosensitizer for photodynamic therapy due to their appealing phototherapeutic properties. In this work, we have prepared the thionated BODIPY analogues by replacing oxygen with sulfur atom at exocyclic carbonyl group, which display red-shifted absorption band, remarkable fluorescence quenching and high singlet oxygen quantum yield as well as excellent photostability. Sulfur substitution stabilizes the LUMO level and destabilized the HOMO, and thus reduces the energy gap and shift the absorption to long wavelength. The replacement of O by S-atom is essential for the enhancement of the intersystem crossing from the singlet excited state to the reactive triplet state. DFT calculations revealed that large spin-orbit coupling (SOC) could be responsible for the efficient population of the triplet state. In addition, the thionated BODIPY efficiently generates the intracellular reactive oxygen species (ROS) with low cytotoxicity. These studies demonstrate that the thionated BODIPY analogue is potentially suitable for use as a photosensitizer.

One-Pot Synthesis of Novel 2-Imino-5-Arylidine-Thiazolidine Analogues and Evaluation of Their Anti-Proliferative Activity against MCF7 Breast Cancer Cell Line.

An efficient surface-mediated synthetic method to facilitate access to a novel class of thiazolidines is described. The rationale behind the design of the targeted thiazolidines was to prepare stable thiazolidine analogues and evaluate their anti-proliferative activity against a breast cancer cell line (MCF7). Most of the synthesized analogues exhibited increased potency ranging from 2–15-fold higher compared to the standard reference, cisplatin. The most active thiazolidines contain a halogenated or electron withdrawing group attached to the N-phenyl ring of exocyclic 2-imino group. However, combination of the two substituents did not enhance the activity. The anti-proliferative activity was measured in terms of IC50 values using an MTT assay.

Methyl β-lactoside [methyl β-D-galactopyranosyl-(1→4)-β-D-glucopyranoside] monohydrate: a solvomorphism study.

Methyl β-lactoside [methyl β-D-galactopyranosyl-(1→4)-β-D-glucopyranoside] monohydrate, C13H24O11·H2O, (I), was obtained via spontaneous transformation of methyl β-lactoside methanol solvate, (II), during air-drying. Cremer-Pople puckering parameters indicate that the β-D-Galp (β-D-galactopyranosyl) and β-D-Glcp (β-D-glucopyranosyl) rings in (I) adopt slightly distorted 4C1 chair conformations, with the former distorted towards a boat form (BC1,C4) and the latter towards a twist-boat form (O5SC2). Puckering parameters for (I) and (II) indicate that the conformation of the βGalp ring is slightly more affected than the βGlcp ring by the solvomorphism. Conformations of the terminal O-glycosidic linkages in (I) and (II) are virtually identical, whereas those of the internal O-glycosidic linkage show torsion-angle changes of 6° in both C-O bonds. The exocyclic hydroxymethyl group in the βGalp residue adopts a gt conformation (C4' anti to O6') in both (I) and (II), whereas that in the βGlcp residue adopts a gg (gauche-gauche) conformation (H5 anti to O6) in (II) and a gt (gauche-trans) conformation (C4 anti to O6) in (I). The latter conformational change is critical to the solvomorphism in that it allows water to participate in three hydrogen bonds in (I) as opposed to only two hydrogen bonds in (II), potentially producing a more energetically stable structure for (I) than for (II). Visual inspection of the crystalline lattice of (II) reveals channels in which methanol solvent resides and through which solvent might exchange during solvomorphism. These channels are less apparent in the crystalline lattice of (I).

Diradicals or Zwitterions: The Chemical States of m -Benzoquinone and Structural Variation after Storage of Li Ions

Diradicals or Zwitterions: The Chemical States of <i>m</i> -Benzoquinone and Structural Variation after Storage of Li Ions

Emerging Chemistry in Enhancing the Chemical and Photochemical Stabilities of Fused‐Ring Electron Acceptors in Organic Solar Cells

AbstractThe power conversion efficiency of organic solar cells (OSCs) has made exceptionally rapid progress in the past five years owing to the emergence of fused‐ring electron acceptors (FREAs). To achieve the commercialization, it is urgent to resolve the stability issues of OCSs from materials to devices. In particular, the state‐of‐the‐art FREAs, often synthesized by Knoevenagel condensation, generally contain two exocyclic vinyl groups (CC bond) as the conjugated bridges, which inevitably exhibit an obvious electron‐deficient characteristic due to the strong push‐pull electronic effect. As a result, these vinyl bridges are vulnerable to nucleophile attacking and/or photooxidation, leading to poor chemical and photochemical stabilities of FREAs that easily cause the degradation of device performance. In this perspective, an in‐depth understanding of the degradation mechanism of FREAs is provided, and then effective strategies reported recently are reviewed for improving the chemical and photochemical stabilities of FREAs from interfacial engineering to molecular engineering to additive engineering. Finally, a conclusion and outlook for the future design of highly efficient and stable FREAs are also presented.

A Boratafulvene.

Structurally authenticated free B‐alkyl boroles are presented and electronic implications of alkyl substitution were assessed. Deprotonation of a boron‐bound exocyclic methyl group in a B‐methyl borole yields the first 5‐boratafulvene anion—an isomer to boratabenzene. Boratafulvene was structurally characterized and its electronic structure probed by DFT calculations. The pK a value of the exocyclic B−CH3 in a set of boroles was computationally approximated and confirmed a pronounced acidic character caused by the boron atom embedded in an anti‐aromatic moiety. The non‐aromatic boratafulvene reacts as a C‐centered nucleophile with the mild electrophile Me3SnCl to give a stannylmethyl borole, regenerating the anti‐aromaticity. As nucleophilic synthons for boroles, boratafulvenes thus open an entirely new avenue for synthetic strategies toward this highly reactive class of heterocycles. Boratafulvene reacts as a methylene transfer reagent in a bora‐Wittig‐type reaction generating a borole oxide.

The influence of exocyclic lone pairs on the bonding and geometry of type A mesoionic rings

Based on structures determined by X-ray crystallography, ab initio MP2 calculations on type A mesoionic rings give geometries in good agreement with observed values. A study of four mesoionic ring systems, each with exocyclic oxygen, nitrogen or carbon groups, shows that the presence and configuration of exocyclic lone pairs significantly influences the geometry and configurational preference. Using a localised bond model and NBO analysis, these effects are rationalised in terms of an anomeric interaction of lone pairs with the antibonding orbitals of adjacent σ bonds. In agreement with experiment, similar effects are calculated for pyran-2-imines.

Synthesis of 6-tert-butyl-3-dicyanomethylene-5-silagermyl- and digermyl-1,2,4-triazines

Fragmentation of the Ge–Ph bond in 2-(6-tBu-5-triphenylgermyl-2-R-4,5-dihydro-1,2,4-triazin-3(2H)-ylidene)malononitriles (R = Me, nBu) using lithium naphthalenide and further electrophile trapping with H+, Ph3SiCl or Ph3GeBr furnished the corresponding 5-Ph2HGe–, Ph3Si–Ph2Ge– or Ph3Ge–Ph2Ge– derivatives. In the case of R = CH2CO2 tBu, metalation at the exocyclic methylene group was observed to give tert-butyl 7-amino-3-tBu-8-cyanopyrrolo[1,2-b][1,2,4]triazine-6-carboxylate as a result of cyclization/Ge atom elimination. Structures of the synthesized compounds were confirmed by spectral and XRD data.

Solvent-Dependent Stabilization of a Charge Transfer State is the Key to Ultrafast Triplet State Formation in an Epigenetic DNA Nucleoside.

2'-Deoxy-5-formylcytidine (5fdCyd), a naturally occurring nucleoside found in mammalian DNA and mitochondrial RNA, exhibits important epigenetic functionality in biological processes. Because it efficiently generates triplet excited states, it is an endogenous photosensitizer capable of damaging DNA, but the intersystem crossing (ISC) mechanism responsible for ultrafast triplet state generation is poorly understood. In this study, time-resolved mid-IR spectroscopy and quantum mechanical calculations reveal the distinct ultrafast ISC mechanisms of 5fdCyd in water versus acetonitrile. Our experiment indicates that in water, ISC to triplet states occurs within 1 ps after 285 nm excitation. PCM-TD-DFT computations suggest that this ultrafast ISC is mediated by a singlet state with significant cytosine-to-formyl charge-transfer (CT) character. In contrast, ISC in acetonitrile proceeds via a dark 1 nπ* state with a lifetime of ∼3 ps. CT-induced ISC is not favored in acetonitrile because reaching the minimum of the gateway CT state is hampered by intramolecular hydrogen bonding, which enforces planarity between the aldehyde group and the aromatic group. Our study provides a comprehensive picture of the non-radiative decay of 5fdCyd in solution and new insights into the factors governing ISC in biomolecules. We propose that the intramolecular CT state observed here is a key to the excited-state dynamics of epigenetic nucleosides with modified exocyclic functional groups, paving the way to study their effects in DNA strands.

Visual and Optical Absorbance Detection of Melamine in Milk by Melamine-Induced Aggregation of Gold Nanoparticles.

The present study reported a facile method for the determination of melamine in milk powder products based on the aggregation of reactant-free 5 nm gold nanoparticles (AuNPs). The strong electrostatic attraction between the positively charged exocyclic amine groups present in the melamine molecule and the negatively charged ions bound to the AuNPs induced aggregation of the AuNPs, resulting in visible color changes that could be seen with the naked eye and monitored by ultraviolet–visible (UV–Vis) absorbance spectra. The method shows high sensitivity with detection limits of 1 × 10−9 M for visual detection and 1 × 10−11 M for UV–Vis analysis, which is far below the safety limit of melamine ingestion in infant formula (1 ppm = 7.9 × 10−6 M) and the detection limit acquired by most AuNP-based melamine detection methods. Good recoveries were obtained over the range of 94.7–95.5% with a relative standard deviation of mean recovery (RSD) ranging from 1.40 to 5.81. The method provides a simple, feasible, fast and real-time detection of melamine adulterants in infant formula by the naked eye, without the aid of advanced instruments.

Guidelines for Tuning the Excited State Hückel–Baird Hybrid Aromatic Character of Pro‐Aromatic Quinoidal Compounds**

AbstractPro‐aromatic molecules have higher‐energy diradicaloid states that are significantly influenced by resonance structures in which conjugated rings take on Hückel‐aromatic character. Recently, it has been argued that there are also pro‐aromatic molecules that adopt central units with 4nπ‐electron Baird‐aromatic character in the T1 state, although detailed analysis suggests that these compounds are better labelled as T1 Hückel–Baird hybrid molecules where Hückel‐aromaticity dominates. Herein, we consider a series of symmetrically substituted conjugated rings with potential Baird aromaticity in the lowest excited triplet and singlet states. Our computational results allow us to establish general guidelines for the rational design of molecules with excited state Hückel/Baird aromaticity in pro‐aromatic quinoidal compounds. We found two main strategies to promote high Baird aromatic character: 1) anionic and small conjugated rings with electron donating groups as substituents and small exocyclic groups with electron withdrawing substituents, or 2) electron deficient conjugated rings with exocyclic electron–donor substitution.

Guidelines for Tuning the Excited State Hückel–Baird Hybrid Aromatic Character of Pro‐Aromatic Quinoidal Compounds**

Pro-aromatic molecules have higher-energy diradicaloid states that are significantly influenced by resonance structures in which conjugated rings take on Hückel-aromatic character. Recently, it has been argued that there are also pro-aromatic molecules that adopt central units with 4nπ-electron Baird-aromatic character in the T1 state, although detailed analysis suggests that these compounds are better labelled as T1 Hückel-Baird hybrid molecules where Hückel-aromaticity dominates. Herein, we consider a series of symmetrically substituted conjugated rings with potential Baird aromaticity in the lowest excited triplet and singlet states. Our computational results allow us to establish general guidelines for the rational design of molecules with excited state Hückel/Baird aromaticity in pro-aromatic quinoidal compounds. We found two main strategies to promote high Baird aromatic character: 1) anionic and small conjugated rings with electron donating groups as substituents and small exocyclic groups with electron withdrawing substituents, or 2) electron deficient conjugated rings with exocyclic electron-donor substitution.

Reversed steric order of reactivity for tert‐butyl and adamantyl‐3‐cyanomethylene‐1,2,4‐triazines

Reactions of 2‐(6‐tert‐butyl‐5‐oxo‐4,5‐dihydro‐1,2,4‐triazin‐3(2H)‐ylidene)‐3‐oxo‐3‐R‐propanenitriles (R = t‐Bu, Ad‐1) with tert‐butyl bromoacetate gave the corresponding N(2), C(5)O bis‐alkylation products. Treatment of the latter with t‐BuLi, in the case of R = t‐Bu, led to intramolecular condensation at the exocyclic nitrile group. However, in the case of R = Ad‐1, the condensation with the sterically more hindered carbonyl group was observed to give diastereomerically pure 8‐cyanopyrrolo[1,2‐b][1,2,4]triazine‐6‐carboxylate derivatives. The structures of the isolated products were confirmed by spectral methods and X‐ray single‐crystal diffraction.