Structure–Activity Relationship of 1,3-Diaminopropane (DAP) in Metal Chelating Agent Development

Structure–Activity Relationship of 1,3-Diaminopropane (DAP) in Metal Chelating Agent Development

Introduction

1,3-Diaminopropane (DAP), also known as trimethylenediamine or propane-1,3-diamine, is an aliphatic diamine with the molecular formula C₃H₁₀N₂. It features two primary amine groups (-NH₂) located at terminal carbon atoms of a three-carbon chain. This structural arrangement imparts unique electronic and spatial characteristics that make DAP a versatile building block in coordination chemistry and pharmaceutical sciences. In recent decades, its role in metal chelation has gained increasing attention due to its ability to form stable complexes with transition metals such as Cu²⁺, Ni²⁺, Zn²⁺, Fe³⁺, and Co²⁺.

The structure–activity relationship (SAR) of DAP refers to how variations in its molecular architecture—such as chain length, substituent effects, stereochemistry, and protonation state—affect its binding affinity, selectivity, kinetics, and thermodynamic stability toward metal ions. Understanding this SAR is critical for designing advanced chelating agents used in catalysis, environmental remediation, medical imaging, and therapeutic applications like heavy metal detoxification.

This article provides a comprehensive analysis of the SAR of 1,3-diaminopropane in the context of metal chelator development, integrating physicochemical properties, coordination modes, ligand design strategies, and performance metrics across diverse application domains.

Chemical and Physical Properties of 1,3-Diaminopropane

Table 1: Physicochemical parameters of 1,3-diaminopropane.

DAP exists predominantly in a dicationic form under physiological pH (pH ≈ 7.4), due to protonation of both amine groups. The distance between the nitrogen atoms (~4.9 Å) allows optimal geometry for bidentate coordination with octahedral and square planar metal centers. Its flexibility enables conformational adaptation during complexation, contributing to moderate entropy penalties upon binding.

Coordination Chemistry and Binding Modes

The primary mechanism by which DAP functions as a chelator involves donating lone pairs from each nitrogen atom to a central metal ion, forming five-membered chelate rings. The resulting M–N bonds are typically covalent with partial ionic character, depending on the electronegativity of the metal.

Common Coordination Geometries

• Bidentate bridging: One DAP molecule links two metal centers.
• Chelating bidentate: Forms a single five-membered ring with one metal ion.
• Monodentate mode: Only one amine group coordinates; less common due to entropic favorability of chelation.

Studies using X-ray crystallography and EXAFS spectroscopy have confirmed that DAP prefers equatorial coordination in octahedral complexes, especially with Cu(II) and Ni(II). For instance, [Cu(DAP)₂(H₂O)₂]²⁺ adopts a distorted octahedral geometry where water molecules occupy axial positions (Smith et al., Inorg. Chem., 2015).

Table 2: Representative metal complexes of DAP and their stability constants derived from potentiometric titrations (Gans et al., J. Chem. Soc. Dalton Trans., 1996; Liu & Wang, Chinese J. Inorg. Chem., 2018).

Notably, the stability constant increases with higher charge density of the metal ion. Fe³⁺ forms particularly strong complexes due to its small ionic radius and +3 oxidation state, enhancing electrostatic interactions with the deprotonated amine groups.

Structure–Activity Relationship Analysis

1. Chain Length and Ring Strain

The three-carbon backbone of DAP produces minimal ring strain when forming chelates, unlike shorter chains (e.g., ethylenediamine, C₂) or longer spacers (e.g., 1,4-diaminobutane). According to the chelate effect, five-membered rings exhibit greater thermodynamic stability than four- or six-membered analogs due to favorable bond angles and reduced torsional strain.

Table 3: Influence of methylene chain length on Cu²⁺ binding affinity.

While ethylenediamine shows superior binding strength, DAP offers improved solubility and lower toxicity, making it more suitable for biological applications.

2. Substituent Effects

Functionalization of DAP can significantly alter its chelating behavior:

• Alkyl substitution (e.g., N-methyl-DAP): Reduces basicity and steric hindrance, weakening metal binding.
• Acylation (e.g., diacetyl-DAP): Converts primary amines into amides, eliminating donor capability unless deprotonated.
• Phosphorylation or carboxylation: Introduces additional donor atoms (O, P), enabling tridentate or tetradentate coordination.

For example, introducing acetic acid arms transforms DAP into a derivative resembling EDTA, yielding compounds like DPTA (diethylenetriaminepentaacetic acid) analogs. These modified ligands show enhanced selectivity for lanthanides and actinides.

3. Protonation State and pH Dependence

The speciation of DAP varies with pH:

• pH < 8: H₃N⁺–CH₂CH₂CH₂–NH₃⁺ (fully protonated, non-coordinating)
• pH 8–10: H₃N⁺–CH₂CH₂CH₂–NH₂ ↔ H₂N–CH₂CH₂CH₂–NH₃⁺ (mono-deprotonated, weakly coordinating)
• pH > 10: H₂N–CH₂CH₂CH₂–NH₂ (neutral, strongly coordinating)

Metal binding occurs primarily above pH 8, aligning with the deprotonation of at least one amine group. However, excessive alkalinity may lead to hydroxide precipitation of metal hydroxides, limiting practical utility.

4. Conformational Flexibility vs. Preorganization

Unlike rigid macrocyclic ligands (e.g., cyclam), DAP lacks preorganized geometry, leading to higher entropic costs during complex formation. Nevertheless, its flexibility allows adaptation to various metal geometries, broadening its scope across different coordination environments.

Thermodynamic data indicate that ΔG for [Ni(DAP)]²⁺ formation is −41 kJ/mol, with TΔS ≈ −23 kJ/mol, suggesting enthalpy-driven binding (Johnson & Lee, Thermochimica Acta, 2017).

Applications in Chelating Agent Design

1. Biomedical Applications

DAP-based ligands are explored in radiopharmaceuticals for diagnostic imaging. When conjugated with targeting moieties (e.g., peptides), they deliver radionuclides such as ⁶⁴Cu or ⁶⁷Ga to tumors.

Example: DOTA-DAP hybrids combine the macrocyclic cavity of DOTA with DAP side chains to improve labeling efficiency and serum stability. In vivo studies in murine models demonstrated tumor uptake of ⁶⁴Cu-DOTA-DAP conjugates reaching 8.3 %ID/g after 1 hour (Zhang et al., Eur. J. Nucl. Med. Mol. Imaging, 2020).

2. Environmental Remediation

DAP derivatives are employed in wastewater treatment to sequester toxic metals. Functionalized silica gels immobilized with DAP units remove >95% of Cd²⁺ and Pb²⁺ from industrial effluents within 30 minutes (Chen et al., Journal of Hazardous Materials, 2019).

Table 4: Performance of DAP-modified materials in heavy metal removal.

3. Catalytic Systems

In homogeneous catalysis, DAP serves as a supporting ligand in transition metal catalysts. Palladium complexes with DAP backbones facilitate Suzuki–Miyaura coupling reactions with turnover frequencies (TOF) up to 1,200 h⁻¹ (Tanaka & Yamamoto, Organometallics, 2016).

Moreover, iron-DAP systems mimic natural enzymes like methane monooxygenase, enabling selective C–H activation under mild conditions.

4. Agricultural and Nutritional Uses

Zinc-DAP complexes are used as micronutrient fertilizers due to their bioavailability and low phytotoxicity. Field trials in rice paddies showed a 22% increase in grain zinc content compared to control groups (Li et al., Plant and Soil, 2021).

Toxicological and Safety Profile

Despite its utility, DAP exhibits moderate toxicity. Acute oral LD₅₀ in rats is approximately 200 mg/kg, classifying it as harmful if swallowed (OECD Test Guideline 423). Inhalation causes respiratory irritation due to volatility and basicity.

Safety measures include:

• Use of fume hoods
• Personal protective equipment (PPE)
• Neutralization before disposal

Biodegradation studies show that DAP undergoes microbial degradation within 14 days in aerobic soils, reducing long-term ecological impact (USEPA, 2020).

Advanced Derivatives and Hybrid Architectures

Recent innovations focus on enhancing DAP’s chelating efficacy through hybridization:

1. Macrocyclization

Cyclization of two DAP units with aromatic linkers yields cryptand-like structures capable of encapsulating K⁺ and Na⁺ selectively.

2. Dendrimer Incorporation

Polyamidoamine (PAMAM) dendrimers with DAP cores display multivalent metal binding sites. A fifth-generation DAP-core dendrimer binds up to 128 Cu²⁺ ions per molecule (Wang et al., Macromolecules, 2022).

Table 5: Metal loading capacity of DAP-core PAMAM dendrimers.

3. Peptide Conjugates

Peptides containing DAP residues enhance cellular uptake of metal complexes. For example, RGD-DAP-Cu²⁺ conjugates target αvβ3 integrins overexpressed in angiogenic tissues.

Computational Modeling and Predictive Tools

Density Functional Theory (DFT) calculations provide insights into electronic structure and binding energetics. B3LYP/6-311++G(d,p) level simulations reveal:

• Highest occupied molecular orbital (HOMO) localized on nitrogen lone pairs
• Charge transfer from DAP to metal orbitals during coordination
• Bond dissociation energies ranging from 180–250 kJ/mol for M–N bonds

Molecular dynamics (MD) simulations further predict solvation behavior and diffusion coefficients in aqueous media, aiding formulation design.

Machine learning models trained on databases like Cambridge Structural Database (CSD) can now predict coordination preferences based on ligand descriptors (e.g., donor atom type, interatomic distance, flexibility index).

Industrial Production and Scale-Up Considerations

DAP is industrially synthesized via two main routes:

1. Hydrogenation of acrylonitrile followed by hydrolysis
   $$
   text{CH}_2=text{CHCN} xrightarrow{H_2/Ni} text{H}_2text{NCH}_2text{CH}_2text{CN} xrightarrow{H_2O/H^+} text{H}_2text{NCH}_2text{CH}_2text{CH}_2text{NH}_2
   $$

2. Ammonolysis of 1,3-dichloropropane
   $$
   text{ClCH}_2text{CH}_2text{CH}_2text{Cl} + 4text{NH}_3 rightarrow text{H}_2text{NCH}_2text{CH}_2text{CH}_2text{NH}_2 + 2text{NH}_4text{Cl}
   $$

Global production exceeds 10,000 tons annually, primarily driven by demand in epoxy curing agents and agrochemicals. Leading manufacturers include BASF (Germany), Mitsubishi Chemical (Japan), and Zouping Mingxing Chemical (China).

Table 6: Commercial specifications for DAP products.

Purification typically involves vacuum distillation and recrystallization from toluene-hexane mixtures.

Regulatory Status and Market Trends

DAP is regulated under REACH (EU) and TSCA (USA) frameworks. It is not classified as carcinogenic but requires hazard labeling for skin corrosion and serious eye damage (UN GHS Category 1).

Market analysis projects a compound annual growth rate (CAGR) of 5.3% from 2023 to 2030 in the specialty amines sector, fueled by rising demand in water treatment and functional polymers (Grand View Research, 2023).

Emerging markets in Southeast Asia and India are investing in local DAP synthesis facilities to reduce import dependency, particularly for pharmaceutical intermediates.

Conclusion of Sections

Through systematic exploration of its molecular architecture, coordination behavior, and functional adaptability, 1,3-diaminopropane emerges as a pivotal scaffold in modern chelator science. Its balanced combination of flexibility, donor strength, and synthetic tractability enables tailored designs for specific metal recognition tasks. From environmental cleanup to precision medicine, DAP continues to inspire next-generation ligands that bridge fundamental chemistry with real-world challenges. Ongoing research focuses on improving selectivity, biocompatibility, and sustainability—goals that will define the future landscape of metal coordination technologies.