Phosphonium Research Articles

Mechanistic insights into the base-mediated deuteration of pyridyl phosphonium and ammonium salts.

Pyridines can be deuterated at the remote sites by treatment with KOtBu in DMSO-d 6, although without discrimination between the meta- and para-position. Herein, base-catalyzed deuterations have been studied, computationally and experimentally, using a series of pyridyl phosphonium salts with a temporary electron-withdrawing group to block the para-position while increasing the acidity in the other positions.

From Bio-Based Solvents to a Phosphonium Salt on a Biorefinery Concept: Multiobjective Optimization-Extended Techno-Economic Assessment

From Bio-Based Solvents to a Phosphonium Salt on a Biorefinery Concept: Multiobjective Optimization-Extended Techno-Economic Assessment

Anticancer activity of salinomycin quaternary phosphonium salts.

In recent years salinomycin has emerged as a promising anticancer drug. Many literature reports have proved its remarkable antiproliferative activity. Moreover, chemical modifications of salinomycin lead to analogues with even higher cytotoxicity against cancer cell lines and a better selectivity index for malignant cells than those of the unmodified compound or a standard anticancer drug such as doxorubicin. In this paper we report the synthesis of a series of twelve novel salinomycin conjugates and their characterization by spectroscopic and spectrometric methods. Salinomycin was conjugated with different triphenylphosphonium cations in order to find out whether the conjugation with mitochondrial targeting vectors would have a beneficial impact on biological properties. Salinomycin and its novel conjugates were tested to determine their in vitro antiproliferative and antimicrobial activity. Taking into account the presence of triphenylphosphonium moiety, the impact of the obtained analogues on mitochondria activity was evaluated by MitoTrackers dyes, furthermore their apoptosis effect and cell cycle arrest were assessed. In addition, the changes in the mitochondrial membrane potential were measured and the ability to generate reactive oxygen species was assessed. Finally, we conducted biophysical studies to investigate the impact of the obtained salinomycin analogues on mitochondrial respiration rates and their electrophysiological properties. Results of this study have proved that conjugation of salinomycin with phosphonium cations leads to promising results in the search for promising anticancer agents.

Advances in Pyridine C-H Functionalizations: Beyond C2 Selectivity.

The pyridine core is a crucial component in numerous FDA-approved drugs and Environmental Protection Agency (EPA) regulated agrochemicals. It also plays a significant role in ligands for transition metals, alkaloids, catalysts, and various organic materials with diverse properties, making it one of the most important structural frameworks. However, despite its significance, direct and selective functionalization of pyridine is still relatively underdeveloped due to its electron-deficient nature and the strong coordinating ability of nitrogen. Among the variety of synthetic transformation, direct functionalization of C-H bond is straightforward and atom economical approach and it's advantageous for late-stage functionalization of pyridine containing drugs. In recent years, innovative strategies for regioselective C-H functionalization of pyridines and azines have emerged, offering numerous benefits such as high regioselectivity, mild conditions, and enabling transformations that were challenging with traditional methods. This review emphasizes the latest advancements in meta and para-C-H functionalization of pyridines through various approaches, including pyridine phosphonium salts, photocatalytic methods, temporary de-aromatization, Minisci-type reactions, and transition metal-catalyzed C-H activation techniques. We discuss the advantages and limitations of these current methods and aim to inspire further progress in this significant field.

Modified Microwave-assisted Solid-liquid Halex Reaction using Phosphonium Salt as Efficient and Robust Phase Transfer Catalyst

: A modified solid-liquid halex reaction was developed in the presence of a robust phase transfer catalyst under microwave conditions. A fast, mild, and practical microwave- assisted synthesis of 2,3-difluoro-5-chloropyridine 3 starting from 2,3,5- trichlorpyridine 1 and spray-dried KF in polar aprotic solvent was developed. The addition of Tetrakis (piperidino) phosphonium chloride as phase transfer catalyst A was studied under microwave irritation (450W) and increased the yield and significantly reduced the reaction time in contrast to the conventional heating procedure. The highest reaction rate was observed at 5 wt% phase transfer phosphonium salt catalyst to 2,3,5-trichloropyridine 1.

Implementation of phosphonium salt for high-performance supercapacitors from room to ultra-low temperature conditions

Conventional supercapacitors encounter limitations in operating voltage and performance at low temperatures due to poor ionic conductivity and diminished interfacial dynamics in electrolytes. In this study, we synthesized the phosphonium salt 5-phosphinaspiro[4.4] nonane tetrafluoroborate (PSNBF4) for the first time. We extensively characterized the physical and electrochemical properties of PSNBF4 in acetonitrile (AN) and propionitrile (PN) as electrolytes, assessing their performance in supercapacitors at room temperature and − 40 °C. The results demonstrate PSNBF4 electrolytes exhibit high solubility, outstanding ionic conductivity (1 M PSNBF4/AN: 49.8 mS cm−1; 1 M PSNBF4/PN: 27.5 mS cm−1), and high electrochemical stability, contributing to good capacitance retention after 500 h of floating tests at 25 °C. Supercapacitors using PSNBF4/AN retained 78 % of their capacitance at 3.1 V, whereas those with PSNBF4/PN maintained 68 % at 3.2 V. Impressively, these supercapacitors performed exceptionally well at −40 °C, displaying excellent cycle stability and high capacitance retention at elevated voltages. Supercapacitors with PSNBF4/AN retain 96.6 % of their capacitance at 3.2 V, while PSNBF4/PN retained 93.4 % of their capacitance at 3.4 V after floating for 500 h. These results demonstrate PSNBF4-based supercapacitors can operate effectively at high voltages in both room and extremely low temperatures, addressing a significant challenge in commercial supercapacitor applications.

Introduction of Cyclic Structures into Phosphonium Salts As Potential Guest Substances for Ionic Clathrate Hydrates

Ionic clathrate hydrates (ICHs) are complex compounds formed from multiple water molecule cages and ionic guest substances. The guest substances are quaternary ammonium and phosphonium salts, among which ICHs with tetra-n-butylammonium bromide (N4444-Br) and tetra-n-butylphosphonium bromide (P4444-Br) are well known. The quaternary onium cations are encapsulated in a water network. Since ICHs also exhibit dissociation temperatures higher than 273 K and large dissociation enthalpies at atmospheric pressure, ICHs have recently been applied to phase change materials (PCMs) [1]. We have introduced various substituents into the quaternary phosphonium cations, examining the thermodynamic properties of the ICHs [2]. The substituents with appropriate branched chains were suggested to increase both the structural stability and dissociation enthalpy of ICHs. We also have investigated the ICHs with quaternary phosphonium salts having isopentyl and cyclobutylmethyl groups; however, guest substances having the other alicyclic and aromatic substituents have not been well investigated. In this paper, we discuss comparatively the thermodynamic properties of tri-n-butyl(cyclohexylmethyl)phosphonium bromide (P444(1c6)-Br) ICH and tri-n-butyl(benzyl)phosphonium chloride (P444(Bzl)-Cl) ICH (Fig 1).The guest substances were synthesized by Menschutkin reaction of tri-n-butylphosphine with alkyl halides such as (bromomethyl)cyclohexane and benzyl chloride under a nitrogen atmosphere at a maximum temperature of 363 K. The crude products were washed with hexane, and then were dried in vacuo to obtain the target products. The purified products were confirmed by 1H, 13C, 31P-NMRs. We prepared 5-50 wt% aqueous solutions of the phosphonium salts. The ICH was formed by freezing each sample at 253 K overnight. The temperature at which the ICHs completely dissociated was defined as the phase equilibrium temperature. The sample temperatures were increased at rate of 0.1 K for a minimum of 5 hours.The solid-liquid equilibria for P444(Bzl)-Cl ICH and P444(1c6)-Br ICH were examined. The highest equilibrium temperature of the P444(1c6)-Br ICH and P444(Bzl)-Cl ICH was 276.2 and 274.4 K, respectively. These ICHs showed phase equilibrium temperatures lower than that with unsubstituted P4444-Br ICH. Both cyclohexylmethyl and benzyl groups are longer than the n-butyl group, so that the guest cations are physically closer to the water molecules in the hydrate cage, resulting in the instability of the ICHs. The equilibrium temperature of the P444(Bzl)-Cl ICH was lower than of P444(1c6)-Br ICH, despite that both cyclohexylmethyl and benzyl groups have the same number of carbon atoms. This result suggests that the thermodynamic stability of P444(Bzl)-Cl ICH is lower than that of P444(1c6)-Br ICH. The influence of the ring size and steric conformation of the guest cations will be discussed.[1] T. Suginaka, et al., Fluid Phase Equilibria, 317, 25-27 (2012).[2] J. Shimada, et al., Chem. Eng. Sci., 236, 116514 (2021).[3] S. Azuma, et al., New J. Chem., 47, 231-237 (2023). Figure 1

Dependence of Carboxylate Anions on Physicochemical Properties of Tributyloctylphosphonium-Based Ionic Liquids

Ionic liquids, i.e. organic molten salts composed of cations and anions with melting points below 100°C, have unique properties such as high ionic conductivity, high thermal stability, low vapor pressure, low flammability, and so on. Among the numerous ionic liquids, considerable ionic liquids based on carboxylate anions have been reported1). On the other hand, several published papers reported ionic liquids based on quaternary phosphonium cations, demonstrating relatively high transport properties and thermal stability2,3). Our research group has preliminarily attempted to design and synthesize several carboxylate-based ionic liquids based on quaternary phosphonium cations. This paper discusses the dependence of carboxylate anions on physicochemical properties of room-temperature ionic liquids based on tributyloctylphophonium (P4448) cation in combination with various carboxylate anions (Fig. 1).The precursor hydroxides were synthesized from the corresponding phosphonium bromides by using an anion exchange resin (Amberlite IRN78 OH). Carboxylate-based phosphonium salts were obtained by adding equimolar amounts of carboxylic acids (formic, acetic, propionic, butyric, octanoic and lactic acids) into the hydroxide solution. The products were isolated by evaporation and then were dried under high vacuum at 50°C. The physicochemical properties of carboxylate-based ionic liquids, e.g. melting point, density, viscosity, conductivity and thermal decomposition temperature, were measured under argon atmosphere.Table 1 shows the melting points, glass transition temperature, thermal decomposition temperature and physicochemical properties of the carboxylate-based phosphonium ionic liquids at 25°C. All P4448-based ionic liquids became viscous liquids at room temperature, showing considerably low-melting behavior. It is noted that the density of P4448-Lac was higher than P4448-EtCO2. This result seems likely to be attributed to hydrogen bonding of the hydroxyl group in the lactate anion. The viscosity was decreased with increasing the carbon numbers in the alkyl chains of lower carboxylate anions. Although the details of this relationship between measured viscosity and the carbon numbers of the alkyl chains in carboxylate anions still remain unclear at present, the charge distribution of the anions is thought to be one of the factors. The acetate-, propionate-, butyrate-, and octanoate-based ionic liquids showed thermal decomposition temperatures around 280°C; however, lactate-based ionic liquids exhibited relatively high thermal decomposition temperature above 310°C. This may be due to the delocalization of the charge distribution in the lactate anion, resulting in the high thermal stability.References1) M. T. Clough, et al, Phys. Chem. Chem. Phys., 15, 20480 (2013).2) K. Tsunashima, et al, Electrochem. Commun., 9, 2353 (2007).3) K. Tsunashima, et al, Electrochemistry, 75, 734 (2007). Figure 1

Combating Bacterial Resistance by Polymers and Antibiotic Composites.

(1) Background: Since the discovery of antibiotics in the first half of the 20th century, humans have abused this privilege, giving rise to antibiotic-resistant pathogens. Recent research has brought to light the use of antimicrobial peptides in polymers, hydrogels, and nanoparticles (NPs) as a newer and safer alternative to traditional antibiotics. (2) Methods: This review article is a synthesis of the scientific works published in the last 15 years, focusing on the synthesis of polymers with proven antimicrobial properties. (3) Results: After a critical review of the literature was made, information and data about the synthesis and antimicrobial activity of antibacterial polymers and NPs functionalized with antibiotics were extracted. Fluorinated surfactants such as the Quaterfluo® series presented significant antimicrobial effects and could be modulated to contain thioesters to boost this characteristic. Biopolymers like chitosan and starch were also doped with iodine and used as iodophors to deliver iodine atoms directly to pathogens, as well as being antimicrobial on their own. Quaternary phosphonium salts are known for their increased antimicrobial activity compared to ammonium-containing polymers and are more thermally stable. (4) Conclusions: In summary, polymers and polymeric NPs seem like future alternatives to traditional antibiotics. Future research is needed to determine functional doses for clinical use and their toxicity.

A Synthetic Approach to Singlet Phospholo[3,4‐c]thiophene Biradicals via the Conversion from Phosphole to Thiophene

This paper proposes a molecular design for open‐shell singlet biradicals through a synthetic study of phospholo[3,4‐c]thiophenes in which the phosphole ring is fused with thiophene. The sulfur‐bridged diyne was converted into the titanacycle intermediate, and the subsequent treatment with chlorodiphenylphosphine provided the corresponding phosphole via the [2+2+1] cycloaddition process. The ‐CH2SCH2‐bridged phosphole oxide could be isomerized to the corresponding thiophene structure probably because of the larger aromaticity of thiophene rather than phosphole. The 4,6‐dihydrophospholo[3,4‐c]thiophene 5‐oxide derivative was triflated to give the thiophene‐fused cyclic phosphonium salt, which could generate the desired singlet biradical by treatment with potassium hydride. In addition, pai‐extension of the 4,6‐dihydrophospholo[3,4‐c]thiophene 5‐oxide unit using the Pd‐catalyzed cross‐coupling reaction with arylstannanes was accomplished, and the resultant isolable 5,6‐dihydro‐4H‐phospholo[3,4‐c]thiophene derivatives showed potent characters as precursors of singlet biradical. The generation of biradical phospholo[3,4‐c]thiophenes was supported by the [4+2] trapping reaction and the 1,2‐migration leading to a cyclic phosphaalkene.

Heteroarylation of Organophosphonium Salts with Indoles in Water: Synthesis of Symmetrical and Unsymmetrical 3,3′‐Bisindolylmethane Derivatives.

AbstractA method for the synthesis of symmetrical and unsymmetrical 3,3′‐bis(indolyl)methanes (3,3′‐BIMs) has been developed through the direct heteroarylation of indolyl‐containing di(hetero)aryl phosphonium salts with indole derivatives in aqueous media. This metal‐free reaction proceeds smoothly under mild conditions, eliminating the need for hazardous solvents and expensive additives/catalysts typically used in conventional synthesis routes, thereby highlighting the synthetic practicality and efficiency of the process. The success of this approach is largely attributed to the role of water as a promoter, facilitating the C−P bond functionalization of the phosphonium salts. Furthermore, the reaction demonstrates a broad substrate scope, good functional group tolerance, and excellent scalability. Moreover, the protocol can also be extended to the synthesis of triindolylmethane compound and diarylmethylated indole.

Olefination of Activated Alkyl Halides with Phosphonium Salts

Olefination of Activated Alkyl Halides with Phosphonium Salts

Coordination chemistry of a weakly coordinating carbanion

Carbanions are typically highly reactive species but can be efficiently stabilized to even function as stable weakly coordinating anions (WCA). We now report on the coordination chemistry of the recently introduced allyl anion 1, stabilized by ArF (ArF = 3,5-bis(trifluoromethyl)phenyl), triflyl substituents, with various s-block metals. A systematic crystallographic study on the s-block metal salts (Li-Cs, Ca) showed that the alkali metals have minimal impact on the anion, as indicated by the similar structural properties compared to the phosphonium salt of 1. In contrast, the calcium complex showed a slightly more pronounced distortion of the allyl symmetry due to stronger Ca–O interactions with the triflyl group. Additionally, the significance of the allyl moiety in stabilizing the carbanionic charge in 1 was demonstrated by comparing the structural parameters and charge distribution with those of an analogous C1-anion. Overall, these studies confirm the enhanced stability of 1 and its weak coordination tendency.

Synthesis of the Sex Pheromones of the Pine Caterpillar, Dendrolimus punctatus (Walker)

The pine caterpillar, Dendrolimus punctatus (Walker), is a notorious forest pest. An efficient and convenient synthesis of the sex pheromones of this pest has been achieved. In our synthetic approach, a Wittig coupling of an aldehyde with an ester-bearing phosphonium salt was used to construct the Z-alkene, whereas the E-alkene was prepared via a stereoselective reduction of an alkyne with LiAlH4. The synthetic sex pheromones would be useful for integrated pest management of the pine caterpillar.

Novel antibacterial pullulan derivatives modified with quaternary phosphonium salts for infected wound treatments

The development of novel antibacterial agents is urgently needed to tackle bacterial infection, the major global issue menacing human health. Among them, polymeric quaternary phosphonium salts are worth noticing owing to their strong antibacterial activities and other merits including low bacterial drug resistance. Herein, pullulan modified with quaternary phosphonium salts (PQP) was synthesized using esterification reactions of pullulan and (5-carboxypentyl)triphenylphosphonium bromide (CPTPPB) mediated by N,N′‑carbonyldiimidazole (CDI), and was evaluated as novel antibacterial agents for treating wound infection for the first time. The chemical structures, chemical bonding, elemental compositions, crystalline properties and thermostability of PQP were systematically investigated. PQP exhibited in vitro antibacterial activities against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli), which were unveiled by the spread plate method and possibly resulted from the damage of bacterial cell walls/membranes mediated by electrostatic and hydrophobic interactions according to preliminary mechanism studies. Weak cytotoxicity and excellent hemocompatibility of PQP at the effective bactericidal concentration were observed. Moreover, in the infected wound model of mice, PQP was capable of disinfecting the wound and accelerating the healing. We opine PQP in this work is promising for antibacterial applications and will inspire the synthesis of novel antibacterial agents derived from natural polymers.

High-Energy Ball Milling Enables an Ultra-Fast Wittig Olefination Under Ambient and Solvent-free Conditions.

30 Seconds to success!-The Wittig reaction, a fundamental and extensively utilized reaction in organic chemistry, enables the efficient conversion of carbonyl compounds to olefins using phosphonium salts. Traditionally, meticulous reaction setup, including the pre-formation of a reactive ylide species via deprotonation of a phosphonium salt, is crucial for achieving high-yielding reactions under classical solution-based conditions. In this report, we present an unprecedented protocol for an ultra-fast mechanically induced Wittig reaction under solvent-free and ambient conditions, often eliminating the need for tedious ylide pre-formation under strict air and moisture exclusion. A range of aldehydes and ketones were reacted with diverse phosphonium salts under high-energy ball milling conditions, frequently giving access to the respective olefins in only 30 seconds.

Synthesis, Structures, and Properties for PIII-Doped Hetero-Buckybowls and Their Phosphonium Salts.

Doping polycyclic aromatic hydrocarbons with heteroatoms enables manipulation of their electronic structures. Herein, the structures and properties of phosphorus (P) doped heterosumanenes (HSEs) are regulated by varying the valence states of P-dopant. The phosphine sulfide (PV) and chalcogens (S, Se, Te) co-doped HSEs (1-3) are reduced to trivalent phosphorus (PIII) doped analogues 4-6. Then, the PIII-dopants on 4-6 are converted to phosphonium salts (R4P+), giving 7-9. The valence states of P-dopant show great influence on molecular geometries and electronic structures. Taking P and S co-doped HSEs as example, bowl-depths increase in the order of 1 (PV)<7 (R4P+)<4 (PIII), and the HOMO energy levels and HOMO-LUMO gaps increase to be 7<1<4. Consistent with the theoretical calculation, the first oxidation potentials decrease and the absorption/emission bands show blue shift from 7 to 1 to 4. The transformation of PV to PIII leads to large variations on the coordination with Ag+, owing to the alteration of coordination site from P=S to PIII. The phosphonium salts show ring-opening of phosphole rings under electrochemical reduction. It is found that chalcogen atoms play pivotal roles on coordination patterns of coordination complexes and the conversion rates of ring-opening reactions.

Tissue-Compatible and Lubricated Hydrogel Catheter with Promising Activity Against Polymicrobial Infections for Ventilator-Associated Pneumonia Prevention.

Endotracheal intubation is a vital means of saving critically ill patients. However, the inserted catheter often causes tissue damage and the formation of tenacious biofilms containing drug-resistant bacteria and fungi, leading to severe ventilator-associated pneumonia (VAP). Currently, the resolution of VAP is usually based on antibiotic treatment and lacks targeted prophylaxis. Here, a quaternary phosphonium salts functionalized hydrogel catheter that enhances tissue compatibility yet inhibits complex and tenacious pathogens in the catheter, thus preventing VAP is reported. By copolymerizing the quaternary phosphonium electrolyte and acrylic acid monomers, the hydrogel catheter demonstrates good shape-supporting ability, and its strength and modulus can be adjusted over a wide range to meet the needs of different ages. Moreover, it possesses good tissue compatibility, antifouling properties, stable lubrication capability, and superior hydrophilicity, which may mitigate tissue damage caused by contact. Importantly, the hydrogel catheter demonstrates potent broad-spectrum intrinsic antimicrobial activity, eradicating nearly 99% of multi-drug resistant bacteria and 80% of fungi. To validate its role in preventing VAP, the real VAP pathogenesis process is mimicked, establishing a polymicrobial infections model considering time effects. The results prove that the hydrogel catheter effectively inhibits the invasion of various drug-resistant pathogens and prevents biofilm formation.

Design, synthesis and antitumor effects of lupeol quaternary phosphonium salt derivatives

Lupeol is a natural pentacyclic triterpenoid with a wide range of biological activities. To improve the water solubility and targeting of lupeol, in the following study, we synthesized 27 lupeol derivatives in the first series by introducing lipophilic cations with lupeol as the lead compound. Through the screening of different cancer cells, we found that some of the derivatives showed better activity than cisplatin against human non-small cell lung cancer A549 cells, among which compound 6c was found to have an IC50 value of 1.83 μM and a selectivity index of 21.02 (IC50MRC-5/IC50A549) against A549 cells. To further improve the antiproliferative activity of the compounds, we replaced the ester linkage of the linker with a carbamate linkage and synthesized a second series of five lupeol derivatives which were screened for activity, among which compound 14f was found to have an IC50 value of 1.36 μM and a selectivity index of 15.60 (IC50MRC-5/IC50A549) against A549 cells. We further evaluated the bioactivity of compounds 6c and 14f and found that both compounds induced apoptosis in A549 cells, promoted an increase in intracellular reactive oxygen species and decrease in mitochondrial membrane potential, and inhibited the cell cycle in the S phase. Of the compounds, compound 14f showed stronger bioactivity than compound 6c. We then selected compound 14f for molecular-level Western blot evaluation and in vivo evaluation in the zebrafish xenograft A549 tumor cell model. Compound 14f was found to significantly downregulate Bcl-2 protein expression and upregulate Bax, Cyt C, cleaved caspase-9, and cleaved caspase-3 protein expression, and 14f was found to be able to inhibit the proliferation of A549 cells in the zebrafish xenograft model. The above results suggest that compound 14f has great potential in the development of antitumor drugs targeting mitochondria.

Cooperative Noncovalent Interactions Controlling Amine-Catalyzed Aldol Reaction Pathways Catalyzed by the Bifunctional Amino Quaternary Phosphonium Ion.

Members of a new class of bifunctional amino quaternary phosphonium salts have been synthesized and utilized as catalysts in aldol condensation reactions, as demonstrated herein. These secondary amines feature a phosphonium ion connected by a carbon chain, enabling the quaternary phosphonium ion to engage in distinct cooperative noncovalent interactions. These interactions work in tandem to stabilize different transition state complexes, exclusively controlling competing amine-catalyzed aldol pathways via the Mannich mechanism. Comprehensive mechanistic investigations were conducted through theoretical calculations. This study uncovers a proximity-driven catalytic mechanism in which the distance between the N and the P+ of the bifunctional catalyst emerges as a critical factor determining catalytic efficacy. The method has been demonstrated through its application to the total synthesis of several bioactive natural products.