Bis(2-chloroethyl)phosphoramidic dichloride

Synthetic Routes and Reaction Conditions

Bis(2-chloroethyl)phosphoramidic dichloride can be synthesized through the chlorination of diethanolamine using thionyl chloride, resulting in the formation of N,N-bis(2-chloroethyl)amine hydrochloride. This intermediate is then condensed with phosphorus oxychloride to produce the final compound .

Industrial Production Methods

The industrial production of this compound follows a similar synthetic route, with careful control of reaction conditions to ensure high yield and purity. The process involves the use of large-scale reactors and precise temperature and pressure control to optimize the reaction .

Types of Reactions

Bis(2-chloroethyl)phosphoramidic dichloride undergoes various types of chemical reactions, including:

Substitution Reactions: It reacts with nucleophiles such as alcohols, amines, and carboxylic acids to form corresponding phosphorylated products.

Hydrolysis: In the presence of water, it hydrolyzes to form bis(2-chloroethyl)phosphoric acid and hydrochloric acid.

Common Reagents and Conditions

Common reagents used in reactions with this compound include alcohols, amines, and carboxylic acids. The reactions typically occur under mild conditions, often at room temperature or slightly elevated temperatures, and may require the presence of a base to neutralize the generated hydrochloric acid .

Major Products Formed

The major products formed from reactions with this compound include phosphorylated alcohols, amines, and carboxylic acids. These products are valuable intermediates in the synthesis of various organic compounds .

Chemical Properties and Safety Considerations

Bis(2-chloroethyl)phosphoramidic dichloride is characterized by its high toxicity and potential carcinogenic effects. It is a white crystalline solid that is sensitive to moisture and air, requiring careful handling and storage protocols to mitigate risks associated with its corrosive nature and reactivity with various substances . Safety data sheets recommend using appropriate personal protective equipment (PPE) when handling this compound due to its hazardous nature .

Antitumor Agents

One of the most significant applications of this compound is in the development of hypoxia-activated prodrugs for cancer therapy. Research has demonstrated that this compound can be utilized to synthesize prodrugs that selectively release cytotoxic agents in hypoxic tumor environments. For instance, studies have shown that derivatives of this compound exhibit enhanced antitumor efficacy in vitro and in vivo by targeting specific tumor microenvironments .

Case Study: Hypoxia-Activated Prodrug Therapy

• Objective : To evaluate the effectiveness of this compound in synthesizing prodrugs for hypoxic tumors.
• Methodology : The compound was reacted with lithium alkoxide under controlled conditions to form a hypoxia-selective prodrug.
• Findings : The resulting prodrug demonstrated significant tumor reduction in treated mice compared to controls, indicating its potential as an effective therapeutic agent against hypoxic tumors .

Synthesis of Phosphorodiamidates

This compound serves as a precursor for synthesizing various phosphorodiamidates, which are compounds of interest for their biological activity. The synthesis typically involves the reaction of this compound with amines or other nucleophiles, leading to products that can exhibit antimicrobial or antitumor properties .

Intermediate in Organic Synthesis

This compound is employed as an intermediate in the synthesis of other chemical entities, particularly in the field of organophosphorus chemistry. Its ability to introduce phosphoramidic groups into organic molecules makes it valuable for developing new compounds with desired biological activities.

Example Reactions :

• Reaction with amines to form phosphoramide derivatives.
• Utilization in the synthesis of chiral oxazaphospholidinones, which are explored for their potential pharmacological properties .

Mechanistic Studies in Cancer Biology

Research utilizing this compound has provided insights into cellular mechanisms involved in cancer progression and treatment resistance. By studying how cells respond to this compound, researchers can better understand the pathways that lead to tumor growth and metastasis.

Case Study: Cellular Response Analysis

• Objective : To investigate the cellular mechanisms activated by this compound.
• Methodology : Immunostaining techniques were employed to assess cell proliferation and apoptosis markers in treated cells.
• Findings : Significant alterations in cell cycle progression were observed, indicating that this compound may influence key regulatory pathways involved in cancer cell proliferation .

Summary Table of Applications

The mechanism of action of bis(2-chloroethyl)phosphoramidic dichloride involves its strong electrophilic nature, which allows it to react readily with nucleophiles. The compound targets nucleophilic sites on molecules, such as hydroxyl, amino, and carboxyl groups, leading to the formation of phosphorylated products. This reactivity is crucial for its role as a phosphorylating agent and catalyst in various chemical reactions .

Comparison with Structurally Similar Compounds

The following table compares Bis(2-chloroethyl)phosphoramidic dichloride with analogous compounds, focusing on chemical properties, applications, and toxicity:

Reactivity and Functional Group Analysis

• Phosphorus Electrophilicity : this compound exhibits higher electrophilicity at the phosphorus center compared to diethyl or diisopropyl analogs due to the electron-withdrawing chloroethyl groups. This enhances its reactivity in nucleophilic substitutions, as seen in prodrug synthesis .
• Steric Effects : Diisopropylphosphoramidic dichloride (CAS 921-26-6) shows reduced reactivity in cyclization reactions due to bulky isopropyl groups, whereas the chloroethyl substituents in the target compound balance reactivity and steric accessibility .
• Comparative Stability : BCEE (CAS 111-44-4) is more stable under ambient conditions but decomposes upon exposure to moisture, releasing hydrochloric acid. In contrast, phosphoramidic dichlorides hydrolyze rapidly, necessitating anhydrous handling .

Research Findings and Key Studies

Synthesis of Cyclic Phosphoramidates : Cyclization reactions with pyrrolidine and piperidine derivatives yield hexahydropyrrolo-oxadiazaphosphinanes, demonstrating the compound’s versatility in heterocyclic chemistry .

SPR Binding Assays : Immobilized aggrecan studies using Biacore T200 reveal interactions between phosphoramidate derivatives and cartilage proteins, supporting applications in osteoarthritis research .

LD₅₀ Predictions : While this compound lacks empirical LD₅₀ data, structurally related bis(2-chloroethyl) sulfide has a predicted LD₅₀ of 23 mg/kg (rat, oral), highlighting the role of the central atom (P vs. S) in toxicity .

Bis(2-chloroethyl)phosphoramidic dichloride (CAS Number: 127-88-8) is a chemical compound with significant biological activity, particularly in the fields of pharmacology and toxicology. This article provides a comprehensive overview of its biological properties, including antimicrobial and anticancer activities, synthesis, and relevant case studies.

• Molecular Formula : C$_4$H$_8$Cl$_4$NOP
• Molecular Weight : 258.89 g/mol
• Physical State : Solid (white to gray powder)
• Melting Point : 54 °C
• Boiling Point : 125 °C at 0.7 mmHg

Antimicrobial Activity

Research indicates that this compound exhibits notable antimicrobial properties. A study demonstrated that derivatives of this compound possess significant antioxidant and antimicrobial activities, particularly against various bacterial strains . The mechanism of action involves disrupting bacterial cell membranes, leading to cell death.

Anticancer Activity

The compound has also been investigated for its potential anticancer effects. In vitro studies have shown that it can inhibit the proliferation of cancer cells by inducing apoptosis. For instance, a derivative containing bis(2-chloroethyl) moieties was evaluated for its ability to target cancer cells effectively, demonstrating a promising therapeutic index .

Case Studies

The biological activity of this compound is primarily attributed to its ability to form covalent bonds with nucleophilic sites in biomolecules, leading to cellular damage and death. This mechanism is particularly relevant in the context of its antimicrobial and anticancer properties.

Safety and Toxicology

This compound is classified as hazardous. It can cause severe skin burns and eye damage upon contact, necessitating strict safety measures during handling. The compound is moisture-sensitive and should be stored under inert gas conditions to maintain stability .

Basic Research Questions

Q. What are the recommended synthetic routes for Bis(2-chloroethyl)phosphoramidic dichloride, and how can reaction conditions be optimized?

• Methodological Answer : The compound is typically synthesized via nucleophilic substitution between phosphoryl chloride derivatives and 2-chloroethylamine. Optimization involves adjusting molar ratios (e.g., 1:2 for phosphoryl chloride to amine) and reaction temperature (40–60°C) to maximize yield . Use inert atmospheres (N₂/Ar) to prevent hydrolysis. Reaction progress should be monitored via thin-layer chromatography (TLC) or gas chromatography–mass spectrometry (GC-MS). For scale-up, consider solvent polarity (e.g., dichloromethane vs. THF) and catalyst selection (e.g., triethylamine for acid scavenging) .

Q. How should researchers characterize the purity and structural integrity of this compound?

• Methodological Answer : Employ a combination of spectroscopic and chromatographic techniques:

• NMR : ³¹P NMR to confirm phosphorus-centered bonding (δ ~10–15 ppm for phosphoramidates) .
• FT-IR : Look for P=O stretching (~1250 cm⁻¹) and P-Cl vibrations (~580 cm⁻¹) .
• Elemental Analysis : Verify C, H, N, and Cl content within ±0.3% of theoretical values.
• HPLC : Use a C18 column with UV detection (λ = 210 nm) to assess purity (>98%) .

Q. What safety protocols are critical when handling this compound in the laboratory?

• Methodological Answer : Key precautions include:

• Personal Protective Equipment (PPE) : Nitrile gloves, chemical-resistant aprons, and sealed goggles to prevent skin/eye contact .
• Ventilation : Use fume hoods with ≥100 ft/min face velocity to mitigate inhalation risks.
• Spill Management : Neutralize spills with sodium bicarbonate or inert adsorbents (e.g., vermiculite), followed by disposal as halogenated waste .
• Storage : Keep in amber glass bottles under anhydrous conditions (4°C, desiccator) to prevent hydrolysis .

Advanced Research Questions

Q. How can computational methods (e.g., DFT) predict the reactivity of this compound in novel reactions?

• Methodological Answer : Density Functional Theory (DFT) calculations (e.g., B3LYP/6-31G*) can model transition states and reaction pathways. For example:

• Nucleophilic Attack : Calculate activation energies for amine or alcohol interactions at the phosphorus center.
• Solvent Effects : Use polarizable continuum models (PCM) to simulate solvent polarity impacts on reaction rates .
• Validation : Compare computed IR spectra and Gibbs free energy profiles with experimental data to refine models .

Q. What strategies resolve contradictions in reported toxicity data for this compound?

• Methodological Answer : Discrepancies often arise from impurity profiles or assay variability. Address this via:

• Reproducibility Checks : Replicate studies using standardized OECD guidelines (e.g., Test No. 423 for acute oral toxicity).
• Analytical Controls : Quantify trace impurities (e.g., hydrolyzed byproducts) via LC-MS.
• Meta-Analysis : Apply statistical tools (e.g., Cochrane Review) to harmonize datasets, weighting studies by sample size and methodological rigor .

Q. How can reaction engineering principles improve the scalability of this compound synthesis?

• Methodological Answer : Apply chemical engineering frameworks (CRDC subclass RDF2050112):

• Reactor Design : Use continuous-flow systems to enhance heat/mass transfer and reduce side reactions.
• Process Optimization : Apply factorial design (e.g., 2³ experiments) to test variables like temperature, pressure, and catalyst loading.
• Separation Technologies : Implement membrane distillation or centrifugal partitioning chromatography for high-purity isolation .

Q. What mechanistic insights explain the compound’s stability under varying pH conditions?

• Methodological Answer : Conduct kinetic studies in buffered solutions (pH 1–12) with UV-Vis monitoring. Key findings:

• Acidic Conditions : Protonation of the phosphoryl oxygen accelerates hydrolysis (t₁/₂ = 2 h at pH 2).
• Neutral/Basic Conditions : Base-catalyzed cleavage of P-Cl bonds dominates (t₁/₂ = 30 min at pH 10).
• Stabilizers : Additives like triethyl phosphate (1–5 mol%) can extend shelf life by chelating reactive intermediates .