3-Methoxypropylamine (MOPA) in Surface Modification of Nanomaterials
1. Introduction
3-Methoxypropylamine (MOPA), chemically designated as OCH₃CH₂CH₂NH₂, is a bifunctional aliphatic amine featuring both a primary amine (–NH₂) group and an ether (–OCH₃) moiety separated by a three-carbon propyl spacer. Its unique molecular architecture—combining nucleophilicity, moderate basicity (pKₐ ≈ 10.2 at 25 °C), hydrophilic-lipophilic balance (HLB ≈ 6.8), and conformational flexibility—endows MOPA with exceptional utility in colloidal stabilization, covalent grafting, and interfacial engineering of nanomaterials. Unlike conventional amines such as ethylenediamine or octadecylamine, MOPA’s methoxy group imparts steric hindrance mitigation, reduced hydrogen-bond-driven aggregation, enhanced solubility in polar aprotic solvents (e.g., THF, DMF, ethanol), and tunable surface dipole orientation—attributes increasingly exploited in next-generation nanocomposites, biosensors, and catalytic nanoreactors.
This article provides a comprehensive, evidence-based analysis of MOPA’s role in nanomaterial surface modification—spanning mechanistic pathways, quantitative performance benchmarks, comparative efficacy versus industry-standard modifiers, and application-specific optimization protocols. Emphasis is placed on experimentally validated parameters, structure–property correlations, and critical evaluation of peer-reviewed findings from leading academic and industrial laboratories worldwide.
2. Chemical and Physical Properties of MOPA
| Property | Value | Measurement Conditions | Reference |
|---|---|---|---|
| Molecular Formula | C₄H₁₁NO | — | Chemical Abstracts Service (CAS No. 2467-09-4) |
| Molecular Weight | 89.14 g/mol | — | Sigma-Aldrich Technical Bulletin MB-123 |
| Boiling Point | 138–140 °C | at 760 mmHg | Merck Index, 15th Ed. |
| Density | 0.852–0.856 g/cm³ | at 20 °C | TCI America SDS (2023) |
| Refractive Index (nD20) | 1.412–1.415 | — | Alfa Aesar Product Sheet |
| Solubility in Water | Miscible (≥500 g/L) | 25 °C | CRC Handbook of Chemistry and Physics, 104th Ed. |
| pKₐ (conjugate acid) | 10.18 ± 0.03 | 25 °C, aqueous solution | J. Phys. Chem. B 2017, 121, 9212–9221 |
| Dielectric Constant (ε) | 9.4 | 25 °C (neat liquid) | J. Chem. Eng. Data 2020, 65, 1789–1797 |
| HLB Value | 6.78 | Griffin method (calculated) | Langmuir 2019, 35, 11205–11216 |
Notably, MOPA exhibits significantly lower volatility than methylamine (bp −6.3 °C) and higher thermal stability than triethanolamine (decomp. >200 °C), rendering it suitable for high-temperature surface grafting (e.g., calcination-assisted silanization). Its log P (octanol/water partition coefficient) of −0.62 (predicted via EPI Suite™ v4.11) confirms amphiphilicity—enabling simultaneous interaction with hydrophobic nanoparticle cores (e.g., graphene, Fe₃O₄) and aqueous biological matrices.
3. Mechanisms of Surface Interaction
MOPA engages nanomaterial surfaces through three dominant, often synergistic, pathways:
3.1 Covalent Grafting onto Oxide Surfaces
On metal oxides (SiO₂, TiO₂, Al₂O₃, ZnO), MOPA reacts via nucleophilic substitution or condensation:
- With surface silanols (≡Si–OH): forms stable Si–O–CH₂CH₂CH₂–NH₂ bonds under mild heating (80–120 °C) or acid-catalyzed reflux.
- With titania hydroxyls (≡Ti–OH): yields Ti–O–CH₂CH₂CH₂–NH₂ linkages, confirmed by XPS (N 1s binding energy shift from 399.6 eV to 400.3 eV; ACS Appl. Mater. Interfaces 2021, 13, 24588–24599).
3.2 Coordination to Metal Nanoparticles & Quantum Dots
The lone pair on nitrogen coordinates to undercoordinated surface metal atoms (e.g., Au, Ag, CdSe). In situ FTIR reveals ν(N–H) red-shift (from 3372 cm⁻¹ to 3298 cm⁻¹) and broadening—indicative of dative bond formation (Nano Res. 2022, 15, 3124–3135). Crucially, the methoxy group suppresses oxidative deamination observed with n-propylamine, enhancing ligand retention over >6 months (Adv. Funct. Mater. 2020, 30, 1908732).
3.3 Electrostatic & Hydrogen-Bond Anchoring on Carbon Allotropes
On oxidized carbon nanotubes (o-CNTs) or graphene oxide (GO), MOPA binds via:
- Proton transfer to carboxylates (–COO⁻⋯⁺H₃N–CH₂CH₂CH₂OCH₃),
- Dual H-bonding: N–H⋯O=C and C–H⋯O–CH₃ (Raman D/G ratio reduction by 32% confirms ordered monolayer formation; Carbon 2023, 202, 412–423).
4. Comparative Performance vs. Common Surface Modifiers
| Modifier | Grafting Density (molecules/nm²) on SiO₂ | Colloidal Stability (t½, h in PBS) | Zeta Potential (mV) on Fe₃O₄ | Toxicity (IC₅₀, HepG2, μM) | Key Limitation |
|---|---|---|---|---|---|
| MOPA | 3.8 ± 0.4 | >240 | +32.1 ± 1.7 | 1280 ± 95 | Moderate volatility above 130 °C |
| APTES | 4.1 ± 0.5 | 48 | +28.5 ± 2.1 | 420 ± 33 | Hydrolytic instability; siloxane cleavage |
| PEI (25 kDa) | 1.2 ± 0.3 | 12 | +41.3 ± 1.9 | 185 ± 12 | Non-specific cytotoxicity; polydispersity |
| Oleic Acid | — | 6 | −24.7 ± 1.5 | >5000 | Poor aqueous dispersibility; no functional handle |
| Cysteamine | 2.6 ± 0.3 | 96 | +19.2 ± 2.4 | 310 ± 28 | Thiol oxidation; disulfide scrambling (Biomaterials 2021, 278, 121165) |
Data compiled from: (i) Zhang et al., J. Mater. Chem. C 2022, 10, 10251–10263; (ii) Wang et al., Colloids Surf. B 2023, 221, 112987; (iii) Liu et al., Nanoscale 2020, 12, 15827–15838.
MOPA achieves optimal balance: higher grafting density than cysteamine (due to lower steric demand), superior biocompatibility than PEI, and greater hydrolytic resilience than APTES—making it ideal for biomedical nanocarriers requiring long-term shelf life and serum stability.
5. Application-Specific Optimization Protocols
5.1 Silica Nanoparticles (15–100 nm)
- Optimal Conditions: 5 mM MOPA in toluene, reflux 6 h, N₂ atmosphere.
- Outcome: Grafting density = 3.8 molecules/nm²; PDI < 0.12 post-modification; zeta potential shifts from −38 mV (unmodified) to +31 mV.
- Validation: Solid-state ¹³C CP/MAS NMR shows peak at δ = 72.3 ppm (–O–CH₂–), confirming ether retention (Chem. Mater. 2018, 30, 8441–8452).
5.2 Iron Oxide Nanocrystals (Fe₃O₄, 8 nm)
- Protocol: Ligand exchange in chloroform at 60 °C, 2 h, [MOPA]/[OA] = 3:1 (OA = oleic acid).
- Result: Saturation magnetization retained at 92% of original; r₂ relaxivity increases from 128 to 196 mM⁻¹s⁻¹ (Theranostics 2022, 12, 2214–2229).
5.3 Perovskite Quantum Dots (CsPbBr₃)
- Critical Innovation: MOPA passivates Br vacancies while suppressing ion migration.
- Performance: PLQY increases from 45% → 89%; operational half-life (under UV/air) extends from 4 min to 128 min (Nature Photon. 2023, 17, 456–465).
6. Advanced Functionalization Architectures Enabled by MOPA
MOPA’s terminal –NH₂ serves as a versatile handle for secondary conjugation:
| Architecture | Conjugation Chemistry | Application Example | Key Metric Improvement |
|---|---|---|---|
| MOPA–PEG–NHS | NHS-ester coupling | Stealth liposomal nanocarriers | Blood circulation t₁/₂ extended from 1.8 h → 14.3 h (J. Control. Release 2021, 338, 456–467) |
| MOPA–biotin | Amidation (EDC/NHS) | Multiplexed biosensing platforms | LOD for PSA reduced to 0.17 pg/mL (Anal. Chem. 2022, 94, 10221–10230) |
| MOPA–DTPA | Carbodiimide coupling | Radiolabeled theranostics (⁶⁴Cu) | Chelation efficiency >98.5% at pH 5.5 (Eur. J. Nucl. Med. Mol. Imaging 2023, 50, 1129–1141) |
| MOPA–peptide | Solid-phase synthesis | Targeted tumor penetration | 3.7× higher tumor accumulation vs. untargeted control (ACS Nano 2020, 14, 14713–14727) |
The methoxy group further enables orthogonal reactivity: selective demethylation (BBr₃, −78 °C) yields 3-hydroxypropylamine for subsequent esterification—a strategy recently deployed in stimuli-responsive hydrogel-nanoparticle hybrids (Adv. Healthcare Mater. 2023, 12, e2202841).
7. Industrial Scalability and Regulatory Status
MOPA is manufactured globally at multi-ton scale (e.g., Jiangsu Yabang Corp., China; BASF SE, Germany). Key regulatory milestones include:
- REACH registered (ECHA No. 01-2119448125-45-0003);
- FDA GRAS status for indirect food contact (21 CFR 175.300);
- ICH Q3C Class 3 solvent (low toxicological concern).
Process economics favor MOPA: raw material cost ≈ USD 28/kg (bulk, FOB Shanghai), compared to USD 112/kg for APTES and USD 390/kg for custom PEGylated amines. Pilot-scale surface modification (10 kg SiO₂ batch) demonstrates <5% mass loss and consistent coating uniformity (verified by TEM-EDS line scans; Org. Process Res. Dev. 2022, 26, 2155–2164).
8. Emerging Frontiers and Unresolved Challenges
Recent work explores MOPA in:
- Electrocatalysis: MOPA-functionalized NiFe-LDH nanosheets exhibit overpotential η₁₀ = 198 mV for OER—outperforming NH₃-treated analogues by 42 mV (Energy Environ. Sci. 2023, 16, 2341–2354);
- Neuromodulation: MOPA-coated MoS₂ flakes show voltage-gated ion channel modulation in hippocampal neurons (Sci. Adv. 2022, 8, eabq7933);
- Antifouling Membranes: MOPA-grafted PVDF membranes reduce protein adsorption by 89% vs. pristine (J. Membr. Sci. 2023, 675, 121489).
Persistent challenges include:
- Quantitative mapping of MOPA orientation (upright vs. tilted) on curved nanostructures;
- Long-term fate of the methoxy group under enzymatic hydrolysis (e.g., esterases in lysosomes);
- Standardization of grafting yield assays across labs (XPS vs. TGA vs. acid-base titration discrepancies up to ±22%).
Ongoing efforts by the National Center for Nanoscience and Technology (NCNST, Beijing) and the Max Planck Institute for Colloids and Interfaces (Potsdam) aim to resolve these through operando SFG spectroscopy and machine-learning-guided molecular dynamics simulations.
