The aryl‐to‐vinyl nickel 1,4‐migration (1,4‐Ni migration) reaction has been reported for the first time. The generated alkenyl Ni species undergo a reductive coupling reaction with unactivated ...brominated alkanes affording a series of trisubstituted olefins. This tandem reaction exhibits mild conditions, a broad substrate scope, high regioselectivity, and excellent Z/E stereoselectivity. A series of controlled experiments have shown that the critical 1,4‐Ni migration process is reversible. In addition, the alkenyl nickel intermediates obtained after migration are highly Z/E stereoselective and do not undergo Z/E isomerization. The obtained trace isomerization products are caused by the instability of the product.
The 1,4‐nickel migration process from aryl to alkenyl groups is now reported for the first time. The alkenyl nickel intermediates generated by this highly stereoselective migration process can be coupled with brominated alkanes to form multisubstituted olefins. The current method provides a new and efficient approach for the synthesis of Z/E olefins with high stereoselectivity.
To investigate the polymorphism in 4-phenylamino-benzoic acids (4-PABAs) in general, and the effect on the polymorphism of these compounds exerted by substitution in particular, a series of 4-PABAs (
...1-8
) varying in the substitution position and pattern were synthesized, and their polymorphic behavior was investigated for the first time. A relatively comprehensive polymorph screening led to the discovery of two forms, one solvent-free and the other solvate, for compounds
1
,
3
and
8
, and one form for the other compounds. The crystal structures were determined by single-crystal XRD. All the 4-PABAs in the crystal structures are highly twisted, and all the solvent-free crystals are based on the conventional acid-acid dimer motif, except for
2
, which has a rarely observed acid-acid catemer motif. Two of the solvates (
1-S
and
8-S
) have pyridine in the lattice while the other (
3-S
) has dichloromethane. The observation indicates that neither conformational flexibility or substitution alone nor the combination of both leads to polymorphism in these compounds, which is in dramatic contrast to the polymorphism of fenamic acids. The thermal properties of each system were investigated by differential scanning calorimetry and desolvation of the solvates was studied by thermogravimetric analysis. Hirshfeld surface analysis and molecular dynamics simulation were performed to study the mechanism of polymorphism and the intermolecular interactions contributing to the formation and stability of each crystal form.
A series of 4-phenylamino-benzoic acids (
1-8
) varying in the substitution position and pattern were synthesized, and their polymorphism was investigated. The rare acid-acid catemer motif was observed for the first time in the crystal structure of one of the compounds.
Substituent size and isomerization play an important role in the polymorphism of 2-(naphthalen-
n
-ylamino)-benzoic acids (
n
= 1, 2; 2-NBAs) as each of the two previously investigated 2-NBAs was ...found to be polymorphic, while their parent compound fenamic acid (FA) has only one form discovered. 2-(Naphthalen-1-ylamino)-nicotinic acid (
1
) and 2-(naphthalen-2-ylamino)-nicotinic acid (
2
) (2-NNA) are isosteric compounds of 2-NBAs, and 2-(2,3-dimethyl-phenylamino)-nicotinic acid (
3
) and 2-(3,4-dimethyl-phenylamino)-nicotinic acid (
4
) are 2-NNA analogues with similar substitution patterns. All four compounds are clonixin analogues. The polymorphism of these four compounds was investigated. One solvent-free form (
1
-A
) and one hydrate (
1
-H
) were discovered for
1
, three forms (
2
-I
,
2
-II
, and
2
-III
) were obtained for
2
, and one form was found for
3
and
4
. The four systems were characterized by single-crystal XRD (SCXRD) and powder XRD (PXRD), and structural properties were compared among the crystals of the four compounds, their isosteres, and other related analogues. The phase behavior of the four systems was studied with differential scanning calorimetry (DSC). Thermogravimetric analysis (TGA) was used to investigate the dehydration of
1
-H
. Computational studies such as stable conformer search, π-π interaction energy calculation, and non-covalent interaction (NCI) analysis were performed to shed light on the rise of polymorphism, and the relative contribution of various intermolecular interactions to the overall stability of the crystals. The study confirmed the effect of substituent size, thus the consequent π-π interactions, on the hydrate formation of compound
1
and polymorphism of compound
2
.
Four analogs (
1-4
) of clonixin were synthesized and their polymorphism was studied. Structural similarity was observed between
1
-A
and CLX-
II
, and
3
and CLX-
I
. π-π stacking played an important role in the hydrate formation of
1
and polymorphism of
2
.
First principles investigation and Hirshfeld surface analysis of 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) crystals have been carried out. The geometrical and electronic structures of TATB ...molecules in the crystal and gas phases were compared. The Hirshfeld surface analysis of the TATB crystal structure shows that the intermolecular H O interactions make important contributions in stabilizing the TATB crystal, while other intermolecular H N and H C interactions, O O, N O, C O, and C N close contacts also make contributions. QTAIM analyses of the intermolecular interactions in the molecular pairs confirm the presence of these intermolecular interactions based on Hirshfeld surface analyses, indicating that these intermolecular interactions play important roles in the crystal. The reason why the TATB crystal adopts a high energy conformer in which the NO
2
and NH
2
groups are coplanar with the benzene ring is elaborated. The cooperativity between hydrogen bonding and π π interactions in the TATB crystal is verified and illustrated.
The N-H O hydrogen bonding between neighboring TATB molecules within a planar layer cooperates with π π interaction between two adjacent molecules from two adjacent layers in the TATB crystal.
Neuropathic pain is a type of chronic pain induced by either central or peripheral nerve injury. MicroRNAs have been recently linked to many diseases, including neuropathic pain. However, the role of ...miR-7a in neuropathic pain still remains elusive. Thus, we aim to investigate the effects of miR-7a on neuropathic pain based on the spinal nerve ligation rat model. After establishment of spinal nerve ligation rat models, rats were infected with adeno-associated virus-neurofilament light polypeptide, adeno-associated virus-miR-7a or treated with metformin. The paw withdrawal threshold and paw withdrawal latency were assessed afterward, and the expression of miR-7a and neurofilament light polypeptide as well as their interaction was determined. Subsequently, miR-7a was overexpressed or silenced in dorsal root ganglion cells to investigate the role of miR-7a in neuropathic pain. Furthermore, the regulatory effect of neurofilament light polypeptide on neuropathic pain was detected using plasmid overexpressing neurofilament light polypeptide. Spinal nerve ligation rat model exhibited upregulation of neurofilament light polypeptide but downregulation of miR-7a. In addition, neurofilament light polypeptide accumulation or miR-7a inhibition decreased paw withdrawal threshold and paw withdrawal latency. Then, neurofilament light polypeptide accumulation or miR-7a inhibition was observed to increase the phosphorylation level of signal transducer and activator of transcription. miR-7a was found to directly target neurofilament light polypeptide and downregulate neurofilament light polypeptide. In addition, inhibiting the signal transducer and activator of transcription signaling pathway was also revealed to increase paw withdrawal threshold and paw withdrawal latency. Collectively, our study demonstrated that miR-7a ameliorated neuropathic pain via blocking the signal transducer and activator of transcription signaling pathway by repressing neurofilament light polypeptide. These findings, if taken further, can be of important clinical significance in treating patients with neuropathic pain.
•The mechanisms for organocatalytic synthesis of chiral allene by racemic propargylic alcohol and 3-phenylindole were proposed.•Eight possible reaction pathways were found after the dehydration ...process.•The intermolecular interactions including HBs and π-π interactions play crucial roles in determining the enantioselectivity.
Organocatalytic synthesis of chiral allene can be successfully achieved through the reaction between propargylic alcohol and 3-phenylindole catalyzed by chiral phosphoric acid with high yield and high enantioselectivity. The detailed reaction mechanism and origin of enantioselectivity were uncovered by quantum mechanical calculations. The results indicate that the reactions undergo the dehydration process, the C–C bonding reaction, the hydrogen abstraction and the regeneration of catalyst. Eight possible pathways were found and the most favorable reaction paths leading to the major and minor products were evaluated which were consistent with the experimental results. The distortion/interaction analyses of the transition states in enantioselectivity-determining steps confirm the most favorable pathway in leading the major product. QTAIM and IGM analyses are used to illustrate the role of intermolecular interactions. EDA analysis is also employed to understand the origin of selectivity. This work would provide insightful viewpoints on the asymmetric organocatalytic reaction by chiral phosphoric acid.
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The amination reaction between azonaphthalene and carbazole to achieve the C–H amination of an arene can be effectively accomplished by the usage of a chiral phosphoric acid catalyst, which can ...generate the important N-arylcarbazole framework compound with high yield and excellent enantioselectivity. To figure out the reaction mechanism, origin and influencing factors of enantioselectivity, quantum mechanical calculations were carried out. The results indicate that two pathways lead to the experimental desired major product while other two pathways lead to the enantiomeric minor product. The theoretical ee value is 90% which is in agreement with the experimental 96% ee value. Quantum theory of atoms in molecules was employed to illustrate the roles of weak intermolecular interactions in the reaction process. A detailed analysis of the types of chiral phosphoric acids was performed to elaborate on what factors affect the enantioselectivity and how they cause the effect, and a statistical analysis of the performances of different types of chiral phosphoric acids in the C–N and C–C bond formation reactions was conducted. It is expected that the present work would be insightful for understanding the chiral phosphoric acid catalyzed C–N cross-coupling reaction and thus can guide the selection of chiral phosphoric acids for the asymmetry reaction.
A series of phenylalkylamino-nicotinic acids (1–4) were synthesized by varying the length of the linker between the pyridine and benzene rings, and their polymorphism was investigated. Under the same ...crystallization conditions, one crystal form was found for compounds 1 and 2, three forms were obtained for compound 3, and two forms were harvested for compound 4. A detailed conformational analysis was performed, and the polymorphism of 3 and 4 was found to be caused by the anti and/or gauche conformation of specific sigma bonds within them. However, there appears to be no correlation between the number of polymorphs and sigma bonds, and the rotation of which sigma bond(s) is responsible for the polymorphism could not be predicted. Phase behavior studies by differential scanning calorimetry (DSC) revealed a phase transition from 4-I with a small asymmetric unit (Z′ = 1) to 4-II with a larger asymmetric unit (Z′ = 2). Computational studies including Hirshfeld surface analysis and independent gradient model (IGM) analyses were performed to highlight the most significant intermolecular interactions in the crystals.
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•Mechanism of DABCO mediated-4+4 domino annulation reaction were theoretically investigated.•The reactivity tendency of possible reaction sites in the reactants was evaluated.•The ...role of DABCO in the hydrogen abstraction reaction was illustrated.
As natural products with important biological activities, eight-membered cyclic ethers can be achieved in good yields by the 4 + 4 domino annulation reactions of ynones and α-cyano-α,β-unsaturated ketones mediated by DABCO under mild conditions. To figure out the detailed reaction mechanism, quantum mechanical calculations were carried out. The global and local reactivity indexes were employed to evaluate the nucleophilic or electrophilic property and reactivity tendency of possible reaction sites in the reactants. Quantum theory of atoms in molecules were used to illustrate the intermolecular interactions formed in the complexes and transition states. The results indicate that two possible pathways exist for the 4 + 4 domino annulation reaction, and they were compared to figure out which one is more feasible and favorable. The important role of DABCO in the reaction was illustrated.
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