Spiro Molecules Research Articles

Palladium-Catalyzed Dearomatization of Indoles with Alkynes: Construction of Spirocyclohexaneindolenines.

A palladium-catalyzed dearomatization of indoles with alkynes has been developed, providing an efficient route to access a variety of synthetically useful spirocyclohexaneindolenines in moderate to good yields. The current method features a simple catalytic system, operational simplicity, and good functional group compatibility, which will contribute substantially to the development of dearomatization to access spiro compounds. Besides, the ubiquitous existence of spiro molecules, including spirocyclohexaneindolenines, in drugs and biological active molecules suggests the potential application of this methodology in medicinal chemistry.

Discovery of novel spiro compound as RAF kinase inhibitor with in vitro potency against KRAS mutant cancer

The development of RAF inhibitors targeting cancers with wild type RAF kinase and/or RAS mutation has been challenging due to the paradoxical activation of the RAS-RAF-MEK-ERK cascade following RAF inhibitor treatment. Herein is the discovery and optimization of a series of RAF inhibitors with a novel spiro structure. The most potent spiro molecule 9 showed excellent in vitro potency against b/c RAF enzymes and RAS mutant H358 cancer cells with minimal paradoxical RAF signaling activation. Compound 9 also exhibited good drug-like properties as demonstrated by in vitro cytochrome P450 (CYP), liver microsome stability (LMS) data and moderate oral pharmacokinetics (PK) profiles in rat and mouse.

Cross-conjugated spiro molecules and single-walled carbon nanotubes composite for high-performance organic thermoelectric materials and generators

Organic thermoelectric materials have attracted tremendous attention in virtue of their unique advantages including low thermal conductivity, low cost, easy processability and mechanical flexibility. Herein, a series of novel Spiro molecules are designed to be composited with single-walled carbon nanotubes (SWCNT) as p-type thermoelectric materials. An optimum power factor of 218.6 μW m−1 K−2 is acquired from the SFX-2/SWCNT composite at room temperature. The corresponding flexible thermoelectric generator containing 10p-type legs exhibits an output power of 1.0 μW under a temperature gradient of 60 K. The high thermoelectric performance is attributable to the three dimensional cross-conjugated architecture of the Spiro molecules, which promotes interactions with SWCNT leading to high carrier concentration and moderate carrier mobility in the composite film.

Design of small molecular hole-transporting materials for stable and high-performance perovskite solar cells

Perovskite solar cells represent one of the most exciting developments in photovoltaics in the past decade, with the power conversion efficiencies of over 25% being achieved to date. In high-performance perovskite solar cells, hole-transporting materials are generally employed to extract and transport holes from perovskite. Among them, small molecular hole transporting materials have attracted intense interest due to their tunable energy levels, structural variety, and simple synthesis. The commonly used hole-transporting material is 2,2′,7,7′-tetrakis(N,N-di-p-methoxyphenyl amino)-9,9′-spirobifluorene (spiro-OMeTAD). Considering the high synthetic cost of spiro-OMeTAD and the device stability issue associated with the use of dopants, much research has been focused on the development of alternative high-performance hole-transporting materials. Herein, this review summarizes the recent developments in highly efficient small molecular hole-transporting materials with a power conversion efficiency close to or over 20%. On the basis of their structural features, three categories of small molecules are identified and discussed as highly efficient hole-transporting materials: spiro molecules with new terminal groups or a new spiro skeleton, star-shaped small molecular hole-transporting materials with three or four branches, and linear hole-transporting materials with a D-A, D-π-D, D-A-D, or D-A-π-A-D structure. The relationships of the optoelectronic properties of these hole-transporting materials and the device performance are discussed, with a comparison to those of model compounds in some cases. Finally, an outlook is addressed on the future development of hole-transporting materials for high-performance perovskite solar cells. We hope that this review can provide important guidance for the design and synthesis of new hole-transporting materials and finally help to promote the commercialization of perovskite solar cells.

Exploring the unexpected formation of spirobibenzopyrans and benzopyrylium salts and effect of Lewis acids on the Claisen-Schmidt reaction

Unexpected spiro cyclic products were obtained from the popular alkali catalyzed Claisen-Schmidt reaction of ketones with salicylaldehyde apart from the bis-chalcones. However, in the acid catalyzed reaction, we observe their transformation to a benzopyrylium salt. In the present study, we demonstrate this phenomenon for three ketones namely cyclopentanone, cylcohexanone and cylcoheptanone. Each of the corresponding products obained were characterized using UV-Vis, FT-IR, 1H NMR, 13C NMR, and mass spectrometry. In addition, the structure of the spiro molecule synthesized from cylcoheptanone reactant has been determined by X-ray crystallography and further investigated for its thermal properties using TGA/DTA technique. To rationalize this phenomenon, we first studied the effect of solvents on the reaction, and further explored the effect of Lewis acid catalyst and various solvents for the same reaction conditions. Further, we have evaluated in silico, the impact of thermodynamic parameter like entropy. In this regard, we explored the relationship between the bis-chalcone, spiro molecule and the benzopyrylium salt. Consequently, the effect of the ring expansion from cyclopentanone to cycloheptanone was investigated. In conclusion, we have presented the anti-bacterial potential of the synthsized spirobibenzopyrans and the benzopyrylium salts.

Electrooxidative dearomatization of biaryls: synthesis of tri- and difluoromethylated spiro[5.5]trienones.

Radical spirocyclization via dearomatization has emerged as an attractive strategy for the rapid synthesis of structurally diverse spiro molecules. We report the use of electrochemistry to perform an oxidative dearomatization of biaryls leading to tri- and difluoromethylated spiro[5.5]trienones in a user friendly undivided cell set-up and a constant current mode. The catalyst- and chemical oxidant-free dearomatization procedure features ample scope, and employs electricity as the green and sole oxidant.

P(III)‐Mediated Cascade C‐N/C‐S Bond Formation: A Protocol towards the Synthesis of N,S‐Heterocycles and Spiro Compounds

AbstractA P(III)‐mediated entry towards construction of C−N/C−S bond has been devised. The developed heterocyclization method was exercised for the synthesis of a diverse range of N,S‐heterocycles and related spiro molecules. P(NMe2)3 revealed the maximum efficacies under the aerobic reaction conditions and a spectrum of bis‐nucleophiles, and isothiocyanates were tolerated well to serve the access of manifold immense molecules.magnified image

Spiro Heterocyclic Compounds as Potential Anti-Alzheimer Agents (Part 2): Their Metal Chelation Capacity, POM Analyses and DFT Studies.

One of the best methods to treat Alzheimer disease (AD) is through the effective use of cholinesterase inhibitors as vital drugs due to the identification of acetylcholine deficit in the AD patients. The present study aims the investigation of spiro heterocyclic compounds as potential AD agents supported by their metal chelation capacity, POM analyses and DFT studies, respectively. The cholinesterase inhibition and metal chelation ability were performed on ELISA microtiter assay. Whereas, the B3LYP method with 6-31+G(d,p) basis set was implemented to study HOMOLUMO energy calculations. The pharmacokinetic properties of the synthesized molecules were studied through Petra, Osiris and Molinspiration (POM). The six spiro (1-6) skeletons were tested for their inhibitory potential and metal-chelation capacity. Our findings revealed that the tested spiro skeletons exerted none or lower than 50% inhibition against both cholinesterases, while compound 4 proved to be the most active molecule with 57.21±0.89% of inhibition toward BChE. The spiro molecule 3 exhibited the highest metal-chelation capacity (9.12±5.26%). Molecular docking model for the most active molecule exhibited promising bindings with AChE and BChE's active site pertained to hydrophobic hydrogen bonds and positive ionizable interactions. The POM analyses gave the information about the flexibility at the site of coordination of spiro compounds (1-6). The screening of spirocompounds (1-6) against cholinesterases revealed that some of them show considerable potential to inhibit AChE and BChE. Herein, we propose that the spiro molecules after further derivatization could serve interesting AD inhibitor drugs.

Spiro‐Linked Molecular Hole‐Transport Materials for Highly Efficient Inverted Perovskite Solar Cells

Spiro‐linked compounds have been used as benchmark hole‐transport materials (HTMs) for the construction of efficient normal architecture (n‐i‐p) perovskite solar cells (PSCs). However, the heavy reliance on the use of dopants not only complicates the device fabrication but imposes long‐term stability concern of the devices. Herein, it is reported that solution‐processed dopant‐free spiro molecules can serve as superior HTMs to fabricate efficient inverted (p‐i‐n) PSCs. Rational choice of orthogonal solvent allows us to solution deposit uniform and pinhole‐free perovskite films without compromising the hole‐extraction capability of the spiro‐based interface layers. To illustrate the generality of the strategy, three spiro‐linked molecules are investigated side by side as HTMs in one‐step solution‐processed CH3NH3PbI3 PSCs. Due to the favored energy‐level alignment and high hole mobility, solar cells based on the HTM of spiro‐TTB yield a high efficiency of 18.38% with open‐circuit voltages (VOC) up to 1.09 V. These results suggest that small molecular HTMs commonly developed for normal structure devices can be of great potential to fabricate cost‐effective and highly efficient inverted PSCs.

Synthesis of Pyrrole-Containing Chiral Spiro Molecules and Their Optical and Chiroptical Properties

Abstract The pyrrole-containing chiral spiro π-conjugated compounds were successfully synthesized from 10,10′-spirobi[indeno[1,2-b][1]benzothiophene] 5,5-dioxide and 5,5,5′,5′-tetraoxide via a sequential inter/intramolecular nucleophilic aromatic substitution with arylamines. The enantiopure ones were also prepared from the enantiopure substrates. UV-vis absorption and photoluminescence spectroscopies and theoretical calculations revealed that the replacement of thiophene unit(s) of 10,10′-spirobi[indeno[1,2-b][1]benzothiophene] with pyrrole unit(s) has a great impact on photophysical properties. The pyrrole-containing chiral spiro π-conjugated compounds exhibited circularly polarized luminescence with a relatively large dissymmetry factor.

“On-water” catalyst-free, one-pot synthesis of quaternary centered and spiro-tetrahydrothiophene-barbiturate hybrids

Abstract A green and efficient method have been developed for the synthesis of quaternary centered and spiro-barbiturate-tetrahydrothiophene hybrids via Knoevenagel condensation,1,4-thia-Michael and intramolecular Aldol reactions using “on water” concept under catalyst-free conditions. Systematic studies were carried out to find the role of the water and total reaction concentration (0.086 M) to promote the reaction in two steps (one-pot). The use of water as a reaction medium, catalyst-free conditions, broad substrate scope, one-pot approach for the creation of quaternary centered and spiro molecules are the advantages of this method.

Reducing hole transporter use and increasing perovskite solar cell stability with dual-role polystyrene microgel particles.

Perovskite solar cells (PSCs) are a disruptive technology that continues to attract considerable attention due to their remarkable and sustained power conversion efficiency increase. Improving PSC stability and reducing expensive hole transport material (HTM) usage are two aspects that are gaining increased attention. In a new approach, we investigate the ability of insulating polystyrene microgel particles (MGs) to increase PSC stability and replace the majority of the HTM phase. MGs are sub-micrometre crosslinked polymer particles that swell in a good solvent. The MGs were prepared using a scalable emulsion polymerisation method. Mixed HTM/MG dispersions were subsequently spin-coated onto PSCs and formed composite HTM-MG layers. The HTMs employed were poly(triaryl amine) (PTAA), poly(3-hexylthiophene) (P3HT) and Spiro-MeOTAD (Spiro). The MGs formed mechanically robust composite HTMs with PTAA and P3HT. In contrast, Spiro-MG composites contained micro-cracks due the inability of the relatively small Spiro molecules to interdigitate. The efficiencies for the PSCs containing PTAA-MG and P3HT-MG decreased by only ∼20% compared to control PSCs despite PTAA and P3HT being the minority phases. They occupied only ∼35 vol% of the composite HTMs. An unexpected finding from the study was that the MGs dispersed well within the PTAA matrix. This morphology aided strong quenching of the CH3NH3PbI3-xClx fluorescence. In addition, the open circuit voltages for the PSCs prepared using P3HT-MG increased by ∼170 mV compared to control PSCs. To demonstrate their versatility the MGs were also used to encapsulate P3HT-based PSCs. Solar cell stability data for the latter as well as those for PSCs containing composite HTM-MG were both far superior compared to data measured for a control PSC. Since MGs can reduce conjugated polymer use and increase stability they have good potential as dual-role PSC additives.

Stereocontrolled Formation of a [4.4]Heterospiro Ring System with Unexpected Inversion of Configuration at the Spirocenter.

Stereoselective construction of the 1,3-diazaspiro[4.4]nonane core skeleton of massadine and related dimeric pyrrole-imidazole alkaloids is a synthetic challenge. We describe herein the synthesis of all C13/14 diastereomers of this spiro molecule through controlled oxidation and epimerization of the C13 spirocenter under mild acidic conditions.

Photo-Physical Behavior and Fluorescence of Thermo Switchable Nanocomposite Based on Methyl Methacrylate -Spirobenzopyran.

Nanocomposites with thermo and photo-switchable fluorescent properties were synthesized via mini-emulsion polymerization based on spiropyran and methyl methacrylate monomer. The photophysical behavior of fluorescence nanocomposites was investigated by fluorescence spectrophotometry in different temperature, UV-light and time of exposure. It was found that methyl methacrylate polymer is capable of acting as a protective layer and play a critical role in improving the photostability of colorants. The nanocomposites exhibited excellent fluorescent thermo-switching action with respect to the free spiro molecule. Graphical Abstract ᅟ.

Green Synthesis and Urease Inhibitory Activity of Spiro-Pyrimidinethiones/Spiro-Pyrimidinones-Barbituric Acid Derivatives.

Sulfonic acid functionalized SBA-15 (SBA-Pr-SO3H) with pore size 6 nm as an efficient heterogeneous nanoporous solid acid catalyst exhibited good catalytic activity in the Biginelli-like reaction in the synthesis of spiroheterobicyclic rings with good yield and good recyclability. Spiro-pyrimidinethiones/spiro-pyrimidinones-barbituric acid derivatives were synthesized in a simple and efficient method using the one-pot three-component reaction of a cyclic 1,3- dicarbonyl compounds (barbituric acid), an aromatic aldehyde and urea or thiourea in the presence of nanoporous silica SBA-Pr-SO3H under solvent free conditions. Urease inhibitory activity of spiro compounds were tested against Jack bean urease using Berthelot alkaline phenol-hypochlorite method. Five of 13 compounds were inhibitor and two of them were enzyme activators. Analysis of the docking results showed that, in most of the spiro molecules, one of the carbonyl groups is coordinated with both nickel atoms, while the other one is involved in the formation of hydrogen bonds with important active-site residues. The effect of inserting two methyl groups on N atoms of barbiturate ring, S substituted, ortho, meta and para substituted compounds were investigated too.

Infrared and Raman spectra, theoretical calculations, conformations, and two-dimensional potential energy surface of 2-cyclopenten-1-one ethylene ketal.

The infrared and Raman spectra of the bicyclic spiro molecule 2-cyclopenten-1-one ethylene ketal (CEK) have been recorded. Density functional theory (DFT) calculations were used to compute the theoretical spectra, and these agree well with the experimental spectra. The structures and conformational energies for the two pairs of conformational minima, which can be defined in terms of ring-bending (x) and ring-twisting (τ) vibrational coordinates, have also been calculated. Utilizing the results from ab initio MP2/cc-PVTZ computations, a two-dimensional potential energy surface (PES) was calculated. The energy levels and wave functions for this PES were then calculated, and the characteristics of these were analyzed. At lower energies, all of the quantum states are doubly degenerate and correspond to either the lower-energy conformation L or to conformation H, which is 154 cm(-1) higher in energy. At energies above the barrier to interconversion of 264 cm(-1), the wave functions show that the quantum levels have significant probabilities for both conformations.

EOMCC, MRPT, and TDDFT Studies of Charge Transfer Processes in Mixed-Valence Compounds: Application to the Spiro Molecule†

The proper description of electron transfer (ET) processes in mixed-valence compounds poses a significant challenge for commonly used theoretical approaches. In this paper we analyze the 1(2)A(2) and 2(2)A(2) potential energy surfaces of the Spiro cation (5,5'(4H,4H')-spirobi[cyclopenta[c]pyrrole]2,2',6,6'-tetrahydro cation) which is a frequently used model to study ET processes. We compare and contrast the results obtained with three different methods: multireference perturbation theory, equation-of-motion coupled cluster theory, time-dependent density functional theory. We demonstrate that the proper inclusion of dynamical correlation effects plays a crucial role in the description of an avoided crossing between potential energy surfaces. We also find that proper balancing of the ground- and excited-state correlation effects is especially challenging in the vicinity of the 1(2)A(2) and 2(2)A(2) avoided crossing region.

Modulation of Unconventional Fluorescence of Novel Photochromic Perimidine Spirodimers

Fluorescence modulation by a class of photochromic perimidine spirodimers, which exhibit a characteristic fluorescence associated with their photochromic reactions, has been described. Upon irradiation using 365 nm light, these non-fluorescent spiro molecules undergo a thermally-reversible ring opening at their spiro junction resulting in the generation of strong fluorescence. The fluorescing species is distinctly different from both the stable ring-closed and the ring-opened compounds, though it appears to have been formed from and remains in equilibrium with the photochemically generated ring-opened form. While the fluorescing species possesses a narrow absorption band with its maximum centered at 500 nm, the ring-opened form exhibits a broad absorption across the visible region with two maxima centered at 410 and 650 nm, respectively. After initiating the photochromic reactions in these molecules using 365 nm light, purely photochemically-controlled fluorescence modulation can be carried out using two wavelengths in the visible region, that is, 500 and 700 nm, while the equilibrium concentration of the ring-opened form and the fluorescing species is controlled. Fluorescence modulation is attained also by controlling the ratio of the ring-closed and ring-opened forms by photochemical ring-opening and thermal ring-closing reactions. The study on the effect of substitution of these molecules suggests that by extending the conjugation of the perimidine core in the ring-opened form the molecule is rendered non-fluorescent and hence it can be assumed that the perimidine core forms the fluorescing entity of the molecule.

Synthesis of Novel Photochromic Spiro Compounds based on Thieno[3,2-b]Pyrroles

ABSTRACT Two routes to thieno[3,2-b]pyrrolenines are developed and new spiropyranes and spirooxazines based on thienopyrrole are synthesized. Benzene ring in the chromene part of the spiro molecule is also replaced with thiophene one to give new merocyanines.

Electronic structure and optical properties of electroluminescent spiro-type molecules

The electronic structure and optical properties of the propeller-shaped spiro molecules, 2,2′-bis(5-(4-tert-butylphenyl)-1,3,4-oxadiazol-2-yl)-9,9′-spirobifluorene, and 2,2′,7,7′-tetrakis (biphenyl-4-yl)-9,9-spirobifluorene, have been studied by photoelectron spectroscopy, Raman spectroscopy, and spectroscopic ellipsometry. The experimental spectra are analyzed with the help of results from quantum-chemical calculations. The excellent agreement between experiment and theory allows for a detailed characterization of the frontier electronic structure and lowest-energy optical transitions in these novel compounds. It follows that most of the electronic and optical properties of the these spiro-molecules can be deduced by consideration of a single branch; in this case a sexi-phenyl and PBD branch. In particular, although the branches in the spiro molecules are perpendicular to each other, there is considerable interaction at the spiro-center between the π-electron systems of the two branches, indicating, among other things, that chemistry involving either branch is dependent on the other branch.