For most nanoparticle applications, understanding the "strength" of anchoring events at the surface is necessary to design effective ligand exchange processes. The present report demonstrates the ability to direct the ordering of phosphonic acid, catechol, and carboxylic acid as anchoring groups for iron oxide nanoparticles, enabled by a stepwise phase-transfer strategy. A key feature was the use of a cyclohexane-based thermomorphic system that provided a unique homogeneous field for ligand-exchange processes, where hydrophobic nanoparticles and a hydrophilic ligand, or hydrophilic nanoparticles and a hydrophobic ligand, effectively mixed together within a moderate temperature range.Iron oxide nanoparticles are powerful platforms capable of producing novel functional materials, and can impart useful magnetic responses to molecules anchored onto their surface. [1] These responses can be exploited to develop contrast agents for magnetic resonance imaging (MRI), probes for in vitro diagnostics, and devices to induce hyperthermia. The low toxicity and low cost of iron oxide nanoparticles have resulted in the development of numerous creative applications, especially in biomedicine as magnetic carriers. Although a one-step process to produce iron oxide nanoparticles capped with organic molecules is possible, [2] biomolecules should be designed and pre-synthesized prior to anchoring onto the surface of the nanoparticles because nanoparticle production conditions generally are too harsh for biomolecules and can damage them. Therefore, the iron oxide nanoparticles and biomolecules should be prepared separately and attached during the final step. Separate preparation of the biomolecules is also important for their characterization, because one-dimensional solution 1 H nuclear magnetic resonance (NMR) spectroscopy, a fundamental organic analytical technique, is much less effective after anchoring due to the magnetic response.To obtain stable colloidal iron oxide nanoparticles, the surface must be capped with suitable ligands to prevent nanoparticle aggregation. In general, the ligands are designed with an anchoring group of specific organic chain(s) selected for affinity toward the solvent. Oleic acid (1) is a standard ligand and one of the most useful for iron oxide nanoparticles because it promotes nanoparticle stability in low-polarity solvents. [3] A carboxylic acid is used as an anchoring group for various oxide surfaces, [4] because it forms relatively weak reversible bonds with the surface. This weak and reversible bonding is important for ligand exchange processes, [5] through which biomolecules equipped with another anchoring group can be loaded onto the oxide surface. The driving force for these ligand exchange processes is based on equilibrium; the ligand anchored onto the surface can be exchanged by the addition of a large excess of another ligand. In addition, anchoring reversibility is key to understanding the driving force for the ligand exchange processes. A ligand forming a reversible bond, such as a c...

Chemically stable hydrophobic magnetic nanoparticles were prepared by using an isocyanate as an anchoring group and were applied to the soluble tag‐assisted liquid‐phase peptide synthesis of the peptide elastin. Couplings and deprotections were effectively performed in the presence of the nanoparticles, and the desired product was rapidly collected as a “magnetic” precipitate, enabling a one‐pot procedure. Sonication of the nanoparticles significantly suppressed gelation of the reaction mixture, which allowed the highly aggregating elastin peptide to be synthesized in one pot without difficulty.

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