CC Bond Formation Research Articles

A carrier-free and recyclable protocol for the cross-coupling of terminal alkynes with arylboronic acids in H2O/TBAB

A new and recyclable protocol was developed for Pd(OAc)2-catalyzed the cross-coupling reaction of terminal alkynes with arylboronic acids using environmentally friendly H2O/TBAB as reaction medium. A series of cross-coupling products containing internal acetylenic bond can be obtained with good selectivity and yield. The Pd(OAc)2/H2O/TBAB system was stable in the Sonogashira-type cross-coupling reaction and could be used at least three cycles without considerable decrease in catalytic performance. The results suggest that the unsupported and recyclable systems can be extended to the other realm of CC bond formation in synthetic organic chemistry.

Highly robust cation radical salts: Aromatic oxidants from cycloannulated aromatic donors

A cost effective and easy Friedel-Craft Cycloannulation of simple aromatic compounds with readily available and cheap 2,5- dichloro-2,5-dimethylhexane in the presence of catalytic amount of anhydrous aluminum chloride produced various cycloannulated aromatic donors(I-XIII) in excellent yields and they were characterized by NMR spectroscopy as well as X-ray crystallography. All aromatic electron donors showed consistent reversibility upon elctrochemical oxidation at various scan rates (v = 50-1000 mVs−1). CRET, Magic Blue or NO+SbCl6- was used to produce cation radical salts. The cation radicals of V and VII were isolated in crystalline form and were analyzed by X – ray crystallography. The stability, different λmax values and the wide range of redox potential values (0.88–1.85 V vs SCE) of the cation radicals of (I-XIII) provided a wide window for the oxidation of various organic compounds. The cation radicals of II was successfully applied as the oxidant to evaluate the electron removal of tetraarylmethane and hexaarylbenzene and to evaluate a conformational switching behavior of cation radical of a biaryl compound. One electron oxidation of tetramethyl biphenylene, one electron oxidation of octamethoxychrysene and the formation of a new CC bond in octamethoxytetraphenylene were observed by applying the cation radicals of donors V, VII and VIII as the oxidant respectively.

Chemical response of thioaldehydes to compression between magnesium oxide surfaces: A first-principles molecular dynamics study

First-principles molecular dynamics (FPMD) simulations are used to investigate the chemical response of thioaldehyde (MeCHS) to compression between (001) surfaces of magnesium oxide (MgO), with the external load reaching values as high as 20 GPa. The results demonstrate that the application of a load transforms the MeCHS molecules into oligomers through the formation of CS, SS, and CC bonds between MeCHS monomers and through proton transfer. The application of a load facilitates the reactions by decreasing the distance between the reacting molecules. The oligomers bonded to the MgO surface through the formation of CO and SO bonds, involving an oxygen atom in the surface. Proton transfer between the oligomers and the surface was also observed. No reactions were observed to take place between the oligomers and the magnesium atoms. The formation of bonds with the oxygen atoms in the surface led to an increase in the MgO distances within the surfaces, and thus a large disruption of the surface structure. The changes in structure were found to be reversible until 18 GPa, suggesting that the MeCHS oligomers may be effective at inhibiting wear by preventing direct surface-surface contacts without introducing new sources of irreversible changes in the surface structure for a certain range of loads (until 18 GPa). As a whole, the study describes in detail the chemical behavior of MeCHS in response to compression between MgO surfaces. This information could be applied to other molecules containing sulfinyl chemical groups and other metal oxides surfaces.

Copper-catalyzed oxidative C[sbnd]H bond functionalization of N-allylbenzamide for C[sbnd]N and C[sbnd]C bond formation

CH bond functionalization for CN and CC bond formations via cross-dehydrogenative coupling (CDC) of N-allylbenzamides with indole as amine source has been developed under a copper-catalyzed condition. To the best of our knowledge, these are the first examples in which different classes of N-containing compounds were directly prepared from the readily available N-allylbenzamides using an inexpensive catalyst-oxidant (CuSO4/TBHP) system. Further, it was applied for the synthesis of α-substituted N-allylbenzamides by using Grignard reagent as nucleophiles.

Structure affecting dissociation energy in polycyclic aromatic hydrocarbon ions

Steric interference of two bay-hydrogen atoms causes the benzo[c]phenanthrene radical cation to be non-planar. The energy required to remove one of these H atoms (2.8 ± 0.1 eV, from iPEPICO spectroscopy) is 1.5 eV lower than that required from the planar tetracene ion due to the formation of a new CC bond. This low dissociation energy precludes benzo[c]phenanthrene ions losing C2H2 (observed from tetracene with an energy of 4.2 eV). The B3-LYP/6-311++G(2d,p) reaction pathways to C2H2 loss are presented and found to be mediated by azulene-containing intermediates. The second IE of tetracene was measured to be 19.0 ± 0.2 eV.

DFT study on selective autocatalyzed [formula omitted]-alkylation of ketones with alcohols

Base-promoted transition-metal-free α-alkylation of ketones with alcohols is an efficient, practical, and green method for the formation of new CC bonds. Here, we present a DFT study on NaOH/KOH-promoted selective autocatalyzed α-alkylation of ketones with alcohols. For the production of alkylated alcohol, the disodium alkoxide species Na1D is the mediator, and the transformation involves four stages: (I) aldehyde formation; (II) aldol condensation; (III) chalcone reduction to generate an alkylated ketone and an aldehyde; and (IV) reduction of the alkylated ketone to produce an alkylated alcohol. Stage I only occurs at the beginning of the reaction, and the subsequent reaction proceeds via the catalytic cycle cyc-Na involving stages II, III, and IV. The energetic span and the turnover frequency (TOF) of cyc-Na are 35.2 kcal/mol and 5.7×10-7 1/s, respectively. For the production of alkylated ketone, the dipotassium alkoxide species K1D is the mediator, and the transformation includes dioxygen-assisted oxidation of alkylated alcohol (stage V) and the above four stages. Stage I only takes place initially, too, but the subsequent reaction has two selectable channels. The main channel is the catalytic cycle cyc-K consisting of stages II and III. The energetic span and the TOF of cyc-K are 29.5 kcal/mol and 8.8×10-5 1/s, respectively. The side channel involves stages II, III, IV, and V, in which the apparent activation energy (AAE) is 34.1 kcal/mol. The calculations present the TOF-determining intermediates and the TOF-determining transition state, and uncover the essence of autocatalysis and the origins of the product selectivity. One important finding is the alkylated ketone selectivity may be enhanced by adding a small quantity of aldehyde corresponding to the alcohol reactant and lowering the reaction temperature.

Insight into the effect of promoters (M = Cu, Ag, Zn, Zr) on aldol condensation reaction based on MgO surface in the process of ethanol to 1, 3-butadiene: A comparative DFT study

Based on density functional theory, the performance of aldol condensation of acetaldehyde to 3-hydroxybutanal on MgO surfaces doped with Cu/Ag/Zn/Zr was compared and analyzed, respectively. And the two kinds of coordination structures: terrace surface (Mg5C-O5C-T) and the kinks surface (Mg3C-O3C-K), were selected as the basis of MgO surface. Among these kinds of promoters, Zn and Ag have a little influence on the surface properties of MgO. While Cu and Zr could modify the acidity-basicity properties of MgO surfaces. Cu as the promoter could reduce the energy barrier of acetaldehyde enolization step on weak basicity site (Mg5C-O5C-T), and that of the proton back-transfer step on strong basic site (Mg3C-O3C-K) simultaneously. Moreover, Zr could promote both the formation of CC bond and proton back-transfer step on the strong basicity sites. It is speculated that strong basicity sites on MgO surface could be eliminated by the addition of Zr to avoid the excessive condensation of acetaldehyde, which could result in catalyst deactivation. In conclusion, Cu has a promoting effect on aldol condensation reaction on both two coordination structures of MgLC-OL'C ion pairs. Zr is beneficial to the performance of the strong basic catalyst.

Insights into the radical-radical and radical-substrate dimerization processes for substituted phenylmethylenepyrans

The electrochemically-induced CC bond making/breaking for six differently R-substituted phenylmethylenepyrans has been investigated by voltammetry in organic media. All compounds display an irreversible oxidation peak whose potential is fully dependent on the electrophilic property of the substituent R. The electrochemical oxidation yields bis-pyrylium compounds by σ-σ CC bond formation. The initial methylenepyrans are recovered by cleavage of the CC bond through electrochemical reduction of the bis-pyrylium species. According to the voltammetric analysis, the mechanistic pathway, radical-radical or radical-substrate, for the intermolecular dimerization is fully R-dependent. Electronic structure calculations show that the spin population in the radical cation and the strength of the σ-σ CC bond in the dimer strongly depend on the nature of R. In addition, low-temperature electrochemical voltammetry (175 K), and room-temperature high scan rate cyclic voltammetry have been used to unravel the kinetics of the CC bond formation.

Hydroarylation of alkynes and alkenes through alumina-sulfuric acid catalyzed regioselective C[sbnd]C bond formation

A highly atom-efficient synthetic protocol for hydroarylation of terminal-aryl alkynes and styrene through the regioselective CC bond formation via the electrophilic addition of naphthols and substituted phenols has been developed using alumina-sulfuric acid as a heterogeneous supported solid acid catalyst. This methodology shows excellent regioselectivity and affords the desired product in good to excellent yield. The heterogeneous catalyst can also be recycled efficiently without much loss of activity.

“Bridge regions” regulate catalysis and protein stability of acylpeptide hydrolase

Mutation in the enzyme engineering is a powerful tool that could alter enzyme properties, providing evidence for enzymology. Acylpeptide hydrolase (APH) is high research value enzyme which plays a key role in the scavenging of cytotoxic proteins and demonstrated a super efficiency in catalyzing CC bond formation in synthetic applications. Therefore, investigation of the structural and enzymatic properties is necessary. Herein, the results revealed that linker region that directly connects two domains of the monomer involves in stability and catalysis, and N-terminus is critical in mediating temperature-dependent catalysis. Moreover, the N-terminus and the linker jointly serve as bridge regions, that both offer a win-win strategy for catalysis and stability as the result of evolutionary adaptation to the existing environment. Based on these results, a rational design for mutation was proposed to optimize stability and promiscuous catalysis in aldol addition. It is worth noting that the mutant ST-4A (formed by inserting four Ala residues between K331 and G332 at the linker of ST0779) showed better stability and catalytic properties than the wild type, which is suitable for chemical synthesis. This study highlights the important function of bridge regions of APH and the deep understanding of catalysis and structure, provides a new direction for optimized enzymatic transformation and shows the potential value of APH members for synthetic applications.

A versatile de novo synthesis of legionaminic acid and 4-epi-legionaminic acid starting from d-serine

Legionaminic acid and 4-epi-legionaminic acid are 5,7-diacetamido nonulosonic acids and are assumed to play a crucial role in the virulence of Legionella pneumophila, the causative agent of Legionnaires’ disease. Moreover, they are ideal target motifs for the development of vaccines and pathogen detection. Herein, we present a versatile de novo synthesis of legionaminic acid and 4-epi-legionaminic acid. Starting from simple d-serine, the C9-backbone is built up by two CC-bond formation reactions. First, the protected d-serine motif is elongated utilizing a highly stereoselective nitroaldol reaction to give a C6-precursor of desired d-rhamno configuration. Second, an indium-mediated allylation is employed to further elongate the carbon backbone and introduce a masked α-keto acid function.

Formation of 3-buten-1-ol over metal encapsulated ZSM-5 from formaldehyde and propene: A Density Functional Theory study

Carbonyl-ene reaction, which involves C-C bond formation, is an essential organic reaction. Here, we explained the possibility of the C-C bond formation between HCHO and propene catalyzed with Ni2+, Pd2+, and Pt2+ exchanged on ZSM-5 zeolite (metal-ZSM-5) by density functional theory. Pt-ZSM-5 exhibits a better activity than other metal-ZSM-5 reported in present work due to high charge transfer among the platinum and formaldehyde.

Synthesis and properties of π-extended fluoranthene derivatives from 1,2-diarylacenaphthylene derivatives

Acenaphthylene units work as a useful platform for the synthesis of polycyclic aromatic hydrocarbons (PAH). Three 1,2-diarylacenaphthylene derivatives (9-phenanthryl, 7-t-butyl-2-pyrenyl and 2-naphthyl) were prepared by Suzuki-Miyaura coupling of 1,2-dibromoacenaphthylene with the corresponding boronic acids and ester. The Scholl reaction of the phenanthryl derivative affords a donor-acceptor type fluoranthene derivative possessing a hemi-coronene structure by forming two CC bonds between phenanthryl groups. The reaction of the pyrenyl derivative allows one CC bond formation to give a helicene-type fluoranthene derivative. The reaction of the naphthyl derivative provides an asymmetric fluroranthene derivative having an anthracene unit accompanied with one CC bonding reaction, while a photochemical cyclization followed by dehydroaromatization reaction of the compound gives a symmetric fluoranthene derivative with a [5]helicene structure.

Immobilized Baliospermum montanum hydroxynitrile lyase catalyzed synthesis of chiral cyanohydrins

Hydroxynitrile lyase (HNL) catalyzed enantioselective CC bond formation is an efficient approach to synthesize chiral cyanohydrins which are important building blocks in the synthesis of a number of fine chemicals, agrochemicals and pharmaceuticals. Immobilization of HNL is known to provide robustness, reusability and in some cases also enhances activity and selectivity.We optimized the preparation of immobilization of Baliospermium montanum HNL (BmHNL) by cross linking enzyme aggregate (CLEA) method and characterized it by SEM. Optimization of biocatalytic parameters was performed to obtain highest % conversion and ee of (S)-mandelonitrile from benzaldehyde using CLEA-BmHNL. The optimized reaction parameters were: 20 min of reaction time, 7 U of CLEA-BmHNL, 1.2 mM substrate, and 300 mM citrate buffer pH 4.2, that synthesized (S)-mandelonitrile in ∼99% ee and ∼60% conversion. Addition of organic solvent in CLEA-BmHNL biocatalysis did not improve in % ee or conversion of product unlike other CLEA-HNLs. CLEA-BmHNL could be successfully reused for eight consecutive cycles without loss of conversion or product formation and five cycles with a little loss in enantioselectivity. Eleven different chiral cyanohydrins were synthesized under optimal biocatalytic conditions in up to 99% ee and 59% conversion, however the % conversion and ee varied for different products. CLEA-BmHNL has improved the enantioselectivity of (S)-mandelonitrile synthesis compared to the use of purified BmHNL. Nine aldehydes not tested earlier with BmHNL were converted into their corresponding (S)-cyanohydrins for the first time using CLEA-BmHNL. Among the eleven (S)-cyanohydrins syntheses reported here, eight of them have not been synthesized by any CLEA-HNL. Overall, this study showed preparation, characterization of a stable, robust and recyclable biocatalyst i.e. CLEA-BmHNL and its biocatalytic application in the synthesis of different (S)-aromatic cyanohydrins.

Facile C[sbnd]H arylation using catalytically active terminal sulfurs of 2 dimensional molybdenum disulfide

The first methodology of CH arylation of heteroarene via 2D transition metal dichalcogenides that have catalytically active edge functional groups was described. The terminal sulfur groups could effectively catalyze a formation of an azo-linked intermediate with aryl diazonium salts, leading to produce heteroarenes with good yields. This novel methodology using bulk 2D transition metal dichalcogenides that have catalytically active edge functional groups can apply for various reactions to achieve CC bond formation in the fields of heterogeneous catalysis that is easily separable, highly reusable, and inexpensive method.

A dehydrative arylation and thiolation of tertiary alcohols catalyzed by in situ generated triflic acid - Viable protocol for C[sbnd]C and C[sbnd]S bond formation

The title paper discusses a mild strategy for an efficient CC and CS bond formation through ortho-quinone methide intermediate. A total of 29 examples (23 tetrasubstituted methanes with a quaternary carbon center and 6 triarylmethyl thioarenes) with diverse substitution patterns could be prepared in high yields (up to 82%). Use of indium triflate allowed the transformation to be carried out in an open flask without taking special care leaving water as the only by product. Control experiments revealed that the triflic acid generated in situ from indium triflate, probably through the coordination with substrate, acted as the actual catalyst for the transformation. Further this protocol can be utilized for the synthesis of promising bioactives such as CDRI-830 analogues, dihydrochromeno[2,3-b]indoles and 9-(1H-indol-3-yl)-9-phenyl-9H-xanthen-1-ol.

Stable Pd-nanoparticles catalyzed domino C[sbnd]H activation/C[sbnd]N bond formation strategy: An access to phenanthridinones

Binaphthyl stabilized palladium nanoparticles (Pd-BNP) catalyzed synthesis of biologically active phenanthridinones via domino CH activation followed by CC and CN bond formation strategy in open air conditions is disclosed. This method works well with a broad range of N-methoxybenzamides and aryliodides substrates with different functional groups. The reaction is catalyzed by 1.5 mol% of heterogeneous Pd-BNP catalyst and afforded the phenanthridinones up to 87% yield with exclusive regioselectivity. Hot centrifuge test, UV spectroscopy analysis and Hg poisoning test are proved the heterogeneous nature of Pd-BNP catalyst.

DFT-assisted design and evaluation of bifunctional copper(I) catalysts for the direct intermolecular addition of aldehydes and ketones to alkynes

Bifunctional catalysts containing discrete metal pi-acid and amine sites were designed and investigated for the direct intermolecular addition of aldehydes and ketones to unactivated alkynes. Copper(I)-based catalysts were prioritized based on intramolecular (Conia-ene type) reactions, and complexes were designed with tridentate ligands and potentially hemilabile heterocyclic spacers. The structures of the designed catalysts were computed using density functional theory (DFT), and the relative energies of putative catalytic intermediates were estimated and used to prioritize catalyst designs. Novel bifunctional precatalysts containing a thiazole spacer were synthesized via a 9-step sequence and combined with transition metals before screening for the direct addition of aldehydes and ketones to several internal and terminal alkynes. Despite the lack of desired intermolecular reactions, DFT calculations of putative catalyst intermediates appears to be a promising strategy for the design and prioritization of bifunctional catalysts for CC bond formation.

Selective, C-3 Friedel-Crafts acylation to generate functionally diverse, acetylated Imidazo[1,2-a]pyridine derivatives

Carbon-carbon bonds are integral for pharmaceutical discovery and development. Frequently, CC bond reactions utilize expensive catalyst/ligand combinations and/or are low yielding, which can increase time and expenditures in pharmaceutical development. To enhance CC bond formation protocols, we developed a highly efficient, selective, and combinatorially applicable Friedel-Crafts acylation to acetylate the C-3 position of imidazo[1,2-a]pyridines. The reaction, catalyzed by aluminum chloride, is both cost effective and more combinatorial friendly compared to acetylation reactions requiring multiple, stoichiometric equivalents of AlCl3. The protocol has broad application in the construction of acetylated imidazo[1,2-a]pyridines with an extensive substrate scope. All starting materials are common and the reaction requires inexpensive, conventional heating methods for adaptation in any laboratory. Further, the synthesized compounds are predicted to possess GABA activity through a validated, GABA binding model. The developed method serves as a superior route to generate C-3 acetylated imidazo[1,2-a]pyridine building-blocks for combinatorial synthetic efforts.

Monitoring the methanol conversion process in H-ZSM-5 using synchrotron X-ray powder diffraction-mass spectrometry

Using synchrotron X-ray powder diffraction-mass spectrometry in combination with theoretical calculations, we probed the structural changes of adsorbed methanol species in H-ZSM-5 for the first time during catalytic conversion of methanol. Preliminary experimental and computational findings suggested that associative mechanism was the dominant reaction pathway in the early stage of the reaction at 200 °C. Also, we observed a minor contribution from dissociative mechanism of the adsorbed methoxy intermediate species, CH3-Oz (where Oz is a framework oxygen atom), at Brønsted acid sites. It led to methoxy accumulation during the late stage of the reaction, which was postulated to be the initial step that produced ‘hydrocarbon pool’ and ‘coke’ through the formation of CC bonds.