Atherton-Todd Reaction Research Articles

Synthesis, Characterization, and Utilization of a Novel Phosphorus/Nitrogen-Containing Flame Retardant

The novel phosphorus/nitrogen-containing flame retardant hexa(phosphaphenanthrene aminophenoxyl)cyclotriphosphazene (HPAPC), which contains phosphaphenanthrene [9,10-dihydro-9-oxa-10-phosphaphenanthrene 10-oxide (DOPO)] and phosphazene (hexachlorocyclotriphosphazene) groups, was synthesized by the classic Atherton–Todd reaction, and its chemical structure was characterized by Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopies. Poly(lactic acid) (PLA) composites containing HPAPC were prepared by melt blending, and their fire performance and thermal behaviors were investigated in terms of limiting oxygen index (LOI), vertical burning (UL-94), cone calorimeter tests, and thermogravimetric analysis (TGA). The LOI value could reach up to 34.7%, and UL-94 could pass V-0 for the PLA composite containing only 5 wt % HPAPC. TGA results showed that the char formation of PLA could be significantly improved by the presence of HPAPC. The evolved gas of the composite was analyzed by FTIR-TGA and pyrolysis–gas chromatography/mass spectrometry (Py–GC/MS). The dispersion of fillers in PLA was observed by back-scattered electron (BSE). The char morphology was characterized by FTIR spectroscopy and scanning electronic microscopy (SEM). It was suggested that the presence of HPAPC could release ammonia gas during combustion, which was beneficial to the formation of an intumescent char structure.

Progress in the Atherton-Todd reaction and its stereochemical mechanism

In this review, we summarize the literatures in the latest decades on the Atherton-Todd reaction of the tetracoordinated and pentacoordinated phosphorus compounds containing P-H bond. Especially, the review focuses on the development of the stereochemical mechanism of the Atherton-Todd reaction. Although the reaction mechanism has been investigated for decades after the discovery of the reaction, the earlier studies mainly concentrated on the reaction intermediate. Up to the past dozen years, the stereochemical mechanism of the Atherton-Todd reaction was studied in detail. However, up to now, there is few review and introduction to the stereochemical mechanism of the Atherton- Todd reaction. We hope this article could compensate for this limitation, and it not only summarizes the general Atherton-Todd reaction, but also introduces the recent research results on the stereochemical mechanism. It is considered that the further investigation on the stereochemical mechanism of the Atherton-Todd reaction will be helpful to design and synthesize the novel tetracoordinated or pentacoordinated compounds with phosphorus chiral centers.

Self-assemblied nanocomplexes based on biomimetic amphiphilic chitosan derivatives for protein delivery.

A bio-inspired nanocarrier was developed for protein delivery based on biodegradable amphiphilic chitosan derivative (DCA-PCCs) with hydrophilic cell membrane mimic phosphorylcholine (PC) and hydrophobic deoxycholic acid (DCA) moieties, which was synthesized via the combination of Atherton-Todd reaction and carbodiimide coupling reaction. Using bovine serum albumin (BSA) as model protein, it was found that DCA-PCCs with suitable degree of substitution of PC and DCA moieties can load proteins by forming nanocomplexes via a solvent evaporation method. The physicochemical characteristics of BSA/DCA-PCCs nanocomplexes were investigated by Zetasizer, atomic force microscopy (AFM) and Fourier-transform infrared (FT-IR) spectroscopy. In vitro biological evaluation revealed BSA/DCA-PCCs nanocomplexes as blank DCA-PCCs nanoparticles had excellent cytocompatibility and hemocompatibility mainly due to the presence of cell membrane mimic phosphorylcholine. BSA release results suggested BSA/DCA-PCCs nanocomplexes showed a sustained release behavior following first order exponential decay kinetics. The results indicated DCA-PCCs provided a promising approach for effectively delivering therapeutic proteins.

Synthesis and Characterization of New Pyrospirophosphoranes Containing a P-O-P Bond by the Atherton-Todd Reaction

The classical Atherton–Todd reaction has been successfully applied to the synthesis of pentacoordinate pyrospirophosphoranes containing a P-O-P bond under mild conditions. The absolute configurations of the products were confirmed by X-ray diffraction analysis and spectroscopic identification. And 31P NMR chemical shifts of the products were correlated with stereochemistry. A possible mechanism for explaining the stereochemistry of the reaction was proposed, and it could well explain the results of the reactions of different pentacoordinate hydrospirophosphoranes.

ChemInform Abstract: Synthesis of Carbohydrate Methyl Phosphoramidates.

A two-step route for introducing methyl phosphoramidate moieties onto carbohydrates is reported. The approach uses methyl pivolyl H-phosphonate as the phosphorylating reagent to produce an isolable carbohydrate H-phosphonate intermediate that is then oxidized by a Todd–Atherton reaction. The stability of the product methyl phosphoramidates was subsequently evaluated using various deprotection strategies.

σ2P,O‐Hybrid Ligands: Synthesis of the First 4‐Hydroxy‐1,3‐benzazaphospholes by ortho‐Lithiation of m‐Amidophenyl Diethyl Phosphates

AbstractThe m‐phosphorylanilides 2 are available from anilides 1 by the Atherton–Todd reaction; the selective ortho‐lithiation of the o′‐methyl‐protected phosphorylpivalanilide 2b with tBuLi proceeded in high yield in the presence of ClSiMe3. The ortho‐lithiation is followed by rapid 1,3‐migration of the PO3Et2 group to yield the phosphonoanilide cis/trans‐3b. This compound mainly reacts with excess LiAlH4 by reductive cyclization to form the 4‐hydroxy‐1H‐1,3‐benzazaphosphole 6. The lithiation of the o′‐unprotected phosphorylpivalanilide 2a with LDA was unselective and led to 3a and 4a in low yields, whereas additional ortho‐lithiation of the benzoyl group occurred for the lithiation of the o′‐protected phosphonobenzanilide 2c with tBuLi/LDA to give 7 in rather low yield. The reduction of crude 7 led to (benzylamino)phenol 8 and the 4‐hydroxy‐1H‐1,3‐benzazaphosphole 9 as a minor product. The properties, NMR spectroscopy data, and crystal structures of 5b, 6, and 8 are reported.

Syntheses and Characterization of Four Phosphaphenanthrene and Phosphazene-based Flame Retardants

GRAPHICAL ABSTRACT

Chemical modification of heptaene macrolide antibiotic Amphotericin B under conditions of the Atherton-Todd reaction

Chemical modification of heptaene macrolide antibiotic Amphotericin B with dialkyl(diaryl)-phosphites has been performed under conditions of the Atherton-Todd reaction. As a result, the corresponding dialkyl(aryl)amidophosphonate derivatives of Amphotericin B have been formed. The prepared derivatives have been characterized by their physicochemical properties, toxicity, and antifungal activity against a set of test cultures of pathogenic fungi and yeast-like fungi of the Candida species.

In vitro drug release and biological evaluation of biomimetic polymeric micelles self-assembled from amphiphilic deoxycholic acid–phosphorylcholine–chitosan conjugate

Novel biomimetic amphiphilic chitosan derivative, deoxycholic acid–phosphorylcholine–chitosan conjugate (DCA–PCCs) was synthesized based on the combination of Atherton–Todd reaction for coupling phosphorylcholine (PC) and carbodiimide coupling reaction for linking deoxycholic acid (DCA) to chitosan. The chemical structure of DCA–PCCs was characterized by 1H and 31P nuclear magnetic resonance (NMR). The self-assembly of DCA–PCCs in water was analyzed by fluorescence measurements, dynamic laser light-scattering (DLS), zeta potential and transmission electron microscopy (TEM) technologies. The results confirmed that the amphiphilic DCA–PCCs can self-assemble to form nanosized spherical micelles with biomimetic PC shell. In vitro biological evaluation revealed that DCA–PCCs micelles had low toxicity against NIH/3T3 mouse embryonic fibroblasts as well as good hemocompatibility. Using quercetin as a hydrophobic model drug, drug loading and release study suggested that biomimetic DCA–PCCs micelles could be used as a promising nanocarrier avoiding unfavorable biological response for hydrophobic drug delivery applications.

Atherton-Todd reaction: mechanism, scope and applications.

Initially, the Atherton–Todd (AT) reaction was applied for the synthesis of phosphoramidates by reacting dialkyl phosphite with a primary amine in the presence of carbon tetrachloride. These reaction conditions were subsequently modified with the aim to optimize them and the reaction was extended to different nucleophiles. The mechanism of this reaction led to controversial reports over the past years and is adequately discussed. We also present the scope of the AT reaction. Finally, we investigate the AT reaction by means of exemplary applications, which mainly concern three topics. First, we discuss the activation of a phenol group as a phosphate which allows for subsequent transformations such as cross coupling and reduction. Next, we examine the AT reaction applied to produce fire retardant compounds. In the last section, we investigate the use of the AT reaction for the production of compounds employed for biological applications. The selected examples to illustrate the applications of the Atherton–Todd reaction mainly cover the past 15 years.

Synthesis of carbohydrate methyl phosphoramidates.

A two-step route for introducing methyl phosphoramidate moieties onto carbohydrates is reported. The approach uses methyl pivolyl H-phosphonate as the phosphorylating reagent to produce an isolable carbohydrate H-phosphonate intermediate that is then oxidized by a Todd-Atherton reaction. The stability of the product methyl phosphoramidates was subsequently evaluated using various deprotection strategies.

ChemInform Abstract: Systematic Study for the Stereochemistry of the Atherton—Todd Reaction.

AbstractThe stereochemistry of H‐phosphinates with different nucleophiles (amines, alcohols, phenols, and mercaptanes) under Atherton—Todd reaction conditions is investigated.

Study on the Atherton–Todd reaction mechanism

A new mechanism of the Atherton–Todd reaction is discussed. The first step of the reaction between diesters of H-phosphonic acid and carbon tetrachloride in the presence of a base is a salt formation between carbon tetrachloride and the base [amine·Cl]+CCl3−. The trichloromethanide anion [CCl3−] deprotonates dialkyl H-phosphonate to form chloroform and dialkyl phosphonate anion [(RO)2P(O)]−. The latter anion reacts with the chlorine cation to furnish dialkyl chlorophosphate.

Systematic study for the stereochemistry of the Atherton–Todd reaction

Under the Atherton–Todd reaction conditions, the stereochemistry on the reaction of H-phosphinates with different nucleophiles (e.g., amines, alcohols, phenols) was investigated. All reactions took place stereospecifically with inversion of configurations at the phosphorus centers. The reaction might proceed via a phosphoryl chloride intermediate with retention of configuration at phosphorus, followed by the attack of nucleophiles from the backside of Cl to give the substitution products with inversion of configuration at the phosphorus center. A plausible mechanism was proposed for these reactions.

A polyphosphoester conjugate of melphalan as antitumoral agent

The low molecular weight of many chemotherapeutics causes their untargeted distribution in the body and fast renal clearance, which leads to a loss of therapeutic activity and to unspecific toxic side effects. Therefore, there is a growing interest in conjugating anticancer drugs to water soluble polymers and thus, take advantage of the ‘enhanced permeability and retention’ (EPR) effect in tumors. In this study, water soluble polyphosphoesters were used as polymer carriers of melphalan hydrochloride (hydrochloride of p-bis(2-chloroethyl)amino-l-phenylalanine), which is a multifunctional alkylating agent. Melphalan was chemically immobilized by covalent bonding to poly(oxyethylene H-phosphonate) under Atherton-Todd reaction conditions. Novel polymer-melphalan complexes with ionic and hydrogen bonds were designed as controls, basing on two other biodegradable polyphosphoesters: poly(hydroxyoxyethylene phosphate) and poly(methyloxyethylene phosphate). The structure of the formed products was elucidated by 1H, 13C, 31P NMR and FT-IR spectroscopy. The cytotoxic effect of the melphalan formulations was evaluated on different tumor cell lines. The novel polymer formulations showed a concentration dependent antitumoral activity, comparable to the effect of unmodified melphalan. The polymer-melphalan conjugate was also evaluated in vivo in the human hepatocellular carcinoma HuH7 xenograft mouse model. It improved the therapeutic efficacy of pure melphalan without causing side effects.

Phosphorylation of ethyl acetoacetate and acetylacetone in the conditions of Todd-Atherton reaction

Phosphorylation of ethyl acetoacetate and acetylacetone in the conditions of Todd-Atherton reaction

Synthesis and self-assembly of biomimetic phosphorylcholine-bound chitosan derivatives

Biomimetic N-phosphorylcholine (PC)-chitosan derivatives (PCCs) with a phosphoramide linkage between glucosamine and PC in various degree of substitution (DS) were synthesized through Atherton–Todd reaction and subsequently hydrolysis under the mild conditions, and structurally characterized by 1H NMR, 31P NMR, FT-IR and GPC. The incorporation of zwitterionic PC groups modified the hydrophilic/hydrophobic balance of chitosan derivatives to induce the formation of nanosized micelles by self-assembly in neutral aqueous solution. Fluorescence measurements revealed that the critical aggregation concentration (CAC) of PCCs solutions increased with increasing the DS of PC. The physicochemical properties of PCCs aggregates in neutral aqueous solutions were investigated by AFM and dynamic light scattering (DLS). The results confirmed that the amphiphilic PCCs copolymers can self-assemble to form nanosized spherical micelles with zeta potential between 0 and 4mV, suggesting that the PCCs nano-aggregates were mostly covered with electrically neutral zwitterionic PC groups. Furthermore, all the PCCs samples showed low toxicity against NIH/3T3 cells after incubated for 4h or 24h, indicating their safety for biomedical application.

Spectral Assignment of Phenanthrene Derivatives Based on 6H-Dibenzo[C,E][1,2] Oxaphosphinine 6-Oxide by NMR and Quantum Chemical Calculations

Organophosphorus compounds such as 6H-dibenzo[c,e][1,2]oxaphosphinine 6-oxide (DOPO, 1) and its derivatives are important and versatile compounds for a broad field of applications. However, a thorough spectral assignment is often subordinate to its chemical properties. This article presents and unambiguously attributes the 1H and 13C NMR spectra of DOPO (1), selected products yielded from the Atherton–Todd reaction (2–4), DOPO-HQ (5) as well as sulfur derivatives (6–7) via a set of 1D- and 2D-NMR experiments. The complex P-C and P-H coupling patterns are discussed and compared with the derivatives possessing different chemical environments around the phosphorus atom. In addition, we compared our results with density functional theory calculations. Even though the prediction of NMR data of organophosphorus compounds via molecular modeling is limited, this study presents a method that yields good results for this class of heterocycles. This knowledge should help to quickly assign NMR spectroscopic data of other DOPO (1) derivatives and can be extrapolated to organophosphorus compounds in general. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental resource: NMR Spectra of Compounds 1-7 (Figures S1 - S15).

Highly Regioselective Synthesis of Novel 4-O-Phosphorylated Paeonol Analogs

4-O-phosphorylated paeonol derivatives were conveniently prepared by a facile method. Resacetophenone was prepared by the Friedel–Crafts acylation reaction of acetic acid with resorcinol. It was then phosphorylated regioselectively at the 4-O position using the Atherton–Todd reaction. An efficient, highly regioselective method to synthesize 4-O-phosphorylated paeonol derivatives is provided, and the approach has the merits of mild reaction conditions. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Phosphoramidates: Features of the formation mechanism and the relationship structure-bioaction

Mechanism of the synthesis of phosphoramidates by Todd-Atherton reaction is based on the primary interaction of a polyhaloalkane with the highly basic amine to form a 1:1 associate. The subsequent attack by the associate on the hydrophosphoryl compound of “symmetric” structure leads to the formation of the target compounds in high yields. The test of the effect of dialkyl hexamethylene- and dialkyl(pyridin-2-yl)-phosphoramidates in vitro against the strains of a number of the producents of pathogenic bacteria and mycotoxins showed that the high level of biological activity of the target compounds is correlated well with the physicochemical parameters characterizing their structure.