This work was supported by the World Premier International Research Center (WPI) Initiative on Materials Nanoarchitectonics and a Grant-in-Aid for Challenging Exploratory Research (No. 26620139), both of which were provided from MEXT, Japan.

1. Preparation of Metal Complex Monomers (2 CAS RN 1381776-70-0, 3 CAS RN 1261168-42-6, 4 CAS RN 1261168-43-7; Figure 1)
<ol>
	<li>Preparation of Ru monomer 2
	<ol>
		<li>Combine the organic precursor (59 CAS RN 1381776-63-1; Figure 1) (380 mg, 0.48 mmol) and [Ru(p-cymene)Cl2] dimer (224 mg, 0.37 mmol) with a stir bar in a 100 ml single-neck round-bottom flask.</li>
		<li>Add methanol (MeOH) (25 ml) to the mixture, connect a condenser to the joint of the flask, and stir the suspension at 65 &#176;C for 3 hr in a temperature-controlled oil bath.</li>
		<li>Cool the reaction mixture to room temperature and filter the suspension through a filter paper by suction.</li>
		<li>Wash the residue on the filter thoroughly with MeOH until the filtrate becomes visually colorless and dry the residue under reduced pressure.</li>
		<li>Combine the residue and 4&#39;-(4-methylphenyl)-2,2&#39;:6&#39;,2&#34;-terpyridine (216 mg, 0.68 mmol) with a stir bar in a 100 ml single-neck round-bottom flask.</li>
		<li>Add MeOH (22.5 ml) and water (2.5 ml) to the mixture, connect a condenser to the joint of the flask, and stir the suspension at 70 &#176;C for 16 hr.</li>
		<li>Cool the reaction mixture to room temperature and filter the suspension.</li>
		<li>Dry the residue on the filter under reduced pressure and dissolve it in dimethyl sulfoxide (DMSO) (3 ml).</li>
		<li>Add the DMSO solution slowly to an excess of ethyl acetate (EtOAc).</li>
		<li>Filter the resultant suspension, wash the residue on the filter with EtOAc, and dry it under reduced pressure.</li>
	</ol>
	</li>
	<li>Preparation of Pt monomer 3
	<ol>
		<li>Combine the organic precursor (64 CAS RN 1261168-39-1; Figure 1) (360 mg, 0.50 mmol) and Pt(cycloocta-1,5-diene)Cl2 (195 mg, 0.52 mmol) with a stir bar in a 100 ml single-neck round-bottom flask.</li>
		<li>Add MeOH (15 ml) to the mixture, connect a condenser to the joint of the flask, and stir the suspension at 65 &#176;C for 12 hr.</li>
		<li>Cool the reaction mixture to room temperature and filter the suspension.</li>
		<li>Wash the residue on the filter thoroughly with MeOH and dry it under reduced pressure.</li>
	</ol>
	</li>
	<li>Preparation of Rh monomer 4
	<ol>
		<li>Combine the organic precursor (6; Figure 1) (360 mg, 0.50 mmol) and RhCl3&#183;3H2O (137 mg, 0.52 mmol) with a stir bar in a 100 ml single-neck round-bottom flask.</li>
		<li>Add MeOH (50 ml) to the mixture, connect a condenser to the joint of the flask, and stir the suspension at 65 &#176;C for 12 hr under a N2 atmosphere.</li>
		<li>Cool the reaction mixture to room temperature and filter the suspension.</li>
		<li>Wash the residue on the filter thoroughly with MeOH and dry it under reduced pressure.</li>
	</ol>
	</li>
</ol>
2. Preparation of Water-soluble Metal&#8211;Organic Complex Array 1
<ol>
	<li>Fmoc Deprotection from TG Sieber Resin
	<ol>
		<li>Combine as-purchased TG Sieber resin (135 mg) with a stir bar in a 10 ml 2-neck flask bearing a drain at the bottom equipped with a glass filter and a 2-way stop cock (Figure 2a). Connect a 3-way stop cock and a glass stopper to the joints of the flask.</li>
		<li>Exchange the internal atmosphere with N2 by using a vacuum line, and then swell the resin with anhydrous-grade dichloromethane (CH2Cl2) (1 ml) (Figure 2b).</li>
		<li>Add anhydrous-grade dimethylformamide (DMF) (3 ml) and piperidine (1 ml) in this order and stir the mixture for 2.5 hr at room temperature.</li>
		<li>Remove the solution by filtration through the drain. Wash the resin with anhydrous-grade MeOH (3 ml, 3 min stirring) and anhydrous-grade CH2Cl2 (3 ml, 3 min stirring) alternately three times and then with anhydrous-grade CH2Cl2 (3 ml, 3 min stirring) four times (Figure 2c).</li>
		<li>Combine all the solutions obtained in 2.1.4 and dilute them with acetonitrile (CH3CN) to a volume of 50 ml. Transfer an aliquot (1 ml) of the resultant solution into a quartz cuvette with an optical length of 1 cm and dilute it with CH3CN (2 ml).</li>
		<li>Determine the mol number of deprotected Fmoc moiety (f &#181;mol) based upon the extinction coefficient of piperidine-dibenzofulvene adduct (6,234 at 299 nm)10 and the spectroscopically obtained absorbance (a) of the solution prepared through protocol 2.1.5 according to the following equation: 
		f = 0.05 x 106 x 3 x a/6234</li>
	</ol>
	</li>
	<li>Loading of Ru monomer 2
	<ol>
		<li>Add anhydrous-grade CH2Cl2 (2.5 ml), Ru monomer 2 (64.9 mg, 53.2 &#181;mol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (30.3 mg, 79.8 &#181;mol), anhydrous-grade DMSO (2.5 ml), and N,N-diisopropylethylamine (iPr2NEt) (20 &#181;l) in this order under a N2 atmosphere to the washed resin and stir the mixture for 12 hr at room temperature (Figure 2d).</li>
		<li>Remove the solution by filtration through the drain. Wash the resin with anhydrous-grade DMSO (3 ml, 5 min stirring) three times, anhydrous-grade MeOH (3 ml, 3 min stirring) and anhydrous-grade CH2Cl2 (3 ml, 3 min stirring) alternately three times, and anhydrous-grade CH2Cl2 (3 ml, 3 min stirring) three times.</li>
		<li>Add anhydrous-grade CH2Cl2 (5 ml), benzoic anhydride (0.28 g, 1.5 mmol), and N-methylimidazole (0.10 ml, 1.5 mmol) in this order under a N2 atmosphere to the washed resin and stir the mixture for 2 hr at room temperature.</li>
		<li>Remove the solution by filtration through the drain. Wash the resin with anhydrous-grade CH2Cl2 (3 ml, 3 min stirring) and anhydrous-grade MeOH (3 ml, 3 min stirring) alternately three times and then with anhydrous-grade CH2Cl2 (3 ml, 3 min stirring) three times.</li>
		<li>Repeat the protocols as described in 2.1.3-2.1.6 to quantify the mol number of loaded Ru monomer 2.</li>
	</ol>
	</li>
	<li>Loading of Fmoc- and side-residue tertiary-butyl (tBu)-protected (L)-glutamic acid (Glu) (7 CAS RN 71989-18-9; Figure 1)
	<ol>
		<li>Add anhydrous-grade CH2Cl2 (4.5 ml), Glu&#183;H2O (39.4 mg, 88.8 &#181;mol), HBTU (50.5 mg, 133.2 &#181;mol), anhydrous-grade DMSO (0.5 ml), and iPr2NEt (50 &#181;l) in this order under a N2 atmosphere to the washed resin and stir the mixture for 12 hr at room temperature (Figure 2e). 
		&#8203;NOTE: The amounts of Glu&#183;H2O and HBTU are gradually decreased from steps 2.3 to 2.7 to keep their stoichiometry to the reactive -NH2 functionality on the resin constant.</li>
		<li>Repeat the protocols as described in 2.2.2-2.2.4.</li>
		<li>Take a small portion of the resin out of the flask and put it into a mixture of trifluoroacetic acid (CF3CO2H) (2.5 &#181;l), triethylsilane (Et3SiH) (0.5 &#181;l), and 1,2-dichloroethane (47 &#181;l). Sonicate the mixture for 0.5 hr and use the resultant solution for mass spectrometry4,7,8,9 (Figure 3a).</li>
		<li>Repeat the protocols as described in 2.1.3-2.1.6 to quantify the mol number of loaded Glu.</li>
	</ol>
	</li>
	<li>Loading of Pt monomer 3
	<ol>
		<li>Add anhydrous-grade DMSO (4.5 ml), Pt monomer (32.9 mg, 33.3 &#181;mol), HBTU (18.9 mg, 50.0 &#181;mol), anhydrous-grade CH2Cl2 (0.5 ml), and iPr2NEt (20 &#181;l) in this order under a N2 atmosphere to the washed resin and stir the mixture for 12 hr at room temperature (Figure 2f).</li>
		<li>Repeat the protocols as described in 2.2.2-2.2.5 to quantify the mol number of loaded Pt monomer 3.</li>
	</ol>
	</li>
	<li>Loading of Glu
	<ol>
		<li>Add anhydrous-grade CH2Cl2 (4.5 ml), Glu&#183;H2O (27.8 mg, 62.9 &#181;mol), HBTU (35.8 mg, 94.4 &#181;mol), anhydrous-grade DMSO (0.5 ml), and iPr2NEt (50 &#181;l) in this order under a N2 atmosphere to the washed resin and stir the mixture for 12 hr at room temperature.</li>
		<li>Repeat the protocols as described in 2.3.2-2.3.4 (Figure 3b).</li>
	</ol>
	</li>
	<li>Loading of Rh monomer 4
	<ol>
		<li>Add anhydrous-grade DMSO (4.5 ml), Rh monomer 4 (21.8 mg, 23.3 &#181;mol), HBTU (13.3 mg, 35.0 &#181;mol), anhydrous-grade CH2Cl2 (0.5 ml), and iPr2NEt (20 &#181;l) in this order under a N2 atmosphere to the washed resin and stir the mixture for 12 hr at room temperature (Figure 2g).</li>
		<li>Repeat the protocols as described in 2.2.2.</li>
		<li>Repeat the protocols as described in 2.6.1.</li>
		<li>Repeat the protocols as described in 2.2.2-2.2.5 to quantify the mol number of loaded Rh monomer 4.</li>
	</ol>
	</li>
	<li>Loading of Glu
	<ol>
		<li>Add anhydrous-grade CH2Cl2 (4.5 ml), Glu&#183;H2O (20.4 mg, 46.0 &#181;mol), HBTU (26.2 mg, 69.0 &#181;mol), anhydrous-grade DMSO (0.5 ml), and iPr2NEt (50 &#181;l) in this order under a N2 atmosphere to the washed resin and stir the mixture for 12 hr at room temperature.</li>
		<li>Repeat the protocols as described in 2.3.2-2.3.4 (Figure 3c).</li>
	</ol>
	</li>
	<li>Loading of 2-[2-(2-methoxyethoxy)ethoxy]acetic (TEG) acid (8 CAS RN 16024-58-1; Figure 1)
	<ol>
		<li>Add anhydrous-grade CH2Cl2 (3 ml), TEG acid (14 &#181;l, 91.0 &#181;mol), HBTU (51.7 mg, 136.5 &#181;mol), anhydrous-grade CH2Cl2 (2 ml), and iPr2NEt (50 &#181;l) in this order under a N2 atmosphere to the washed resin and stir the mixture for 12 hr at room temperature.</li>
		<li>Remove the solution by filtration through the drain. Wash the resin with anhydrous-grade DMSO (3 ml, 5 min stirring) two times, anhydrous-grade MeOH (3 ml, 3 min stirring) and anhydrous-grade CH2Cl2 (3 ml, 3 min stirring) alternately three times, and anhydrous-grade CH2Cl2 (3 ml, 3 min stirring) three times.</li>
	</ol>
	</li>
	<li>Cleavage from the resin at the end of solid-phase synthesis
	<ol>
		<li>Wash the resin with diethyl ether (4 ml, 5 min stirring) three times, dry it under a vacuum, and swell it with anhydrous-grade CH2Cl2 (1 ml, 5 min stirring).</li>
		<li>Add a mixture of CF3CO2H (0.1 ml), Et3SiH (20 &#181;l), and 1,2-dichloroethane (1.9 ml) to the suspension and stir the mixture for 12 hr at room temperature.</li>
		<li>Remove the solution by filtration through the drain, add a new mixture of CF3CO2H (0.1 ml), Et3SiH (20 &#181;l), and 1,2-dichloroethane (1.9 ml) to the resin, and stir the mixture for 1 hr at room temperature.</li>
		<li>Repeat step 2.9.3 until the solution becomes visually colorless (Figure 2h).</li>
		<li>Combine all the solutions as obtained through protocols 2.9.2-2.9.4 and analyze the contents of the resultant solution by mass spectrometry4,7,8,9 (Figure 3d).</li>
		<li>Remove volatile species of the solution by evaporation and dissolve the residue in a mixture of CF3CO2H (0.2 ml), Et3SiH (40 &#181;l), and 1,2-dichloroethane (3.8 ml).</li>
		<li>Stir the mixture for 24 hr at room temperature and analyze the contents of the resultant solution by mass spectrometry4,7,8,9 to confirm the complete deprotection of tBu groups at the side residues of 1 (Figure 3e).</li>
		<li>Remove volatile species of the solution by evaporation.</li>
	</ol>
	</li>
	<li>Purification of 1
	<ol>
		<li>Sonicate the solid residue as obtained through protocol 2.9 in CH2Cl2 and decant the solution. Repeat this process until the decant solution becomes visually colorless.</li>
		<li>Analyze the contents of the resultant solid residue by mass spectrometry4,7,8,9.</li>
		<li>Wash the residue with MeOH (100 &#181;l/10 mg) with sonication, decant the solution, and analyze the contents of the resultant solid residue by mass spectrometry4,7,8,9.</li>
		<li>Dissolve the residue (1 mg) in a mixture of CH3CN (90 &#181;l) and water (10 &#181;l) by sonication and combine the resultant solution with phosphate-buffered saline (800 &#181;l, 10 mM, pH = 7.4). Sonicate the mixture and incubate it at 37 &#176;C for 24 hr.</li>
		<li>Extract the colored species in the decant supernatant with a mixture of 1,2-dichloroethane (500 &#181;l), CH3CN (20 &#181;l), and CF3CO2H (20 &#181;l). Analyze the extract by mass spectrometry4,7,8,9 (Figure 3f).</li>
		<li>Repeat the extraction until the aqueous phase becomes visually colorless. Combine the organic solutions and remove volatile species by evaporation.</li>
	</ol>
	</li>
</ol>

<ol>
	<li>Takanashi, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Heterometal+Assembly+in+Dendritic+Polyphenylazomethines.">Heterometal Assembly in Dendritic Polyphenylazomethines.</a> Bull. Chem. Soc. Jpn. 80, 1563-1572 (2007).</li><li>Packheiser, R., Ecorchard, P., R&#252;ffer, T., Lang, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Heteromultimetallic+Transition+Metal+Complexes+Based+on+Unsymmetrical+Platinum(II)+Bis-Acetylides.">Heteromultimetallic Transition Metal Complexes Based on Unsymmetrical Platinum(II) Bis-Acetylides.</a> Organometallics. 27, 3534-3536 (2008).</li><li>Sculfort, S., Braunstein, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Intramolecular+d10-d10+Interactions+in+Heterometallic+Clusters+of+the+Transition+Metals.">Intramolecular d10-d10 Interactions in Heterometallic Clusters of the Transition Metals.</a> Chem. Soc. Rev. 40, 2741-2760 (2011).</li><li>Vairaprakash, P., Ueki, H., Tashiro, K., Yaghi, O. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis+of+Metal-Organic+Complex+Arrays.">Synthesis of Metal-Organic Complex Arrays.</a> J. Am. Chem. Soc. 133, 759-761 (2011).</li><li>Jacoby, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis:+Method+Couples+Various+Metals+in+Predetermined+Sequences.">Synthesis: Method Couples Various Metals in Predetermined Sequences.</a> C&amp;EN. 89, (2011).</li><li>White, P., Eds D&#246;rner, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthetic+Notes.">Synthetic Notes.</a> Peptide Synthesis 2008/2009. , (2009).</li><li>Sajna, K. V., Fracaroli, A. M., Yaghi, O. M., Tashiro, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Modular+Synthesis+of+Metal-Organic+Complex+Arrays+Containing+Precisely+Designed+Metal+Sequences.">Modular Synthesis of Metal-Organic Complex Arrays Containing Precisely Designed Metal Sequences.</a> Inorg. Chem. 54, 1197-1199 (2015).</li><li>Sukul, P. K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+Water-Soluble+Metal-Organic+Complex+Array+as+a+Multinuclear+Heterometallic+Peptide+Amphiphile+That+Shows+Unconventional+Anion+Dependency+in+Its+Self-Assembly.">A Water-Soluble Metal-Organic Complex Array as a Multinuclear Heterometallic Peptide Amphiphile That Shows Unconventional Anion Dependency in Its Self-Assembly.</a> Chem. Commun. 52, 1579-1581 (2016).</li><li>Fracaroli, A. M., Tashiro, K., Yaghi, O. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Isomers+of+Metal-Organic+Complex+Arrays.">Isomers of Metal-Organic Complex Arrays.</a> Inorg. Chem. 51, 6437-6439 (2012).</li><li>Gude, M., Ryf, J., White, P. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=An+Accurate+Method+for+the+Quantitation+of+Fmoc-Derivatized+Solid+Phase+Supports.">An Accurate Method for the Quantitation of Fmoc-Derivatized Solid Phase Supports.</a> Letters in Peptide Science. 9, 203-206 (2002).</li><li>Merrifield, R. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Solid+Phase+Peptide+Synthesis.+I.+The+Synthesis+of+a+Tetrapeptide.">Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide.</a> J. Am. Chem. Soc. 85, 2149-2154 (1963).</li></ol>

The authors have nothing to disclose.

Perfect removal of the undesired chemicals from the resin is not always possible simply by washing with solvents that can easily dissolve those chemicals. A key technique to efficiently wash the resin is to cause it to swell and shrink repetitively so that the chemicals remaining inside will be forced out. This is why the resin in our procedure is treated with CH2Cl2 and MeOH alternately as it is washed (e.g., protocol 2.1.4).
As a consequence of successive multi...

Controlled synthesis of complicated molecular structures has always been a major issue in synthetic chemistry. From this point of view, to synthesize multinuclear heterometallic complexes in a designable fashion is still a worthy subject to be challenged in the field of inorganic chemistry because of the numbers of possible structural outcomes from the ligand-metallation-based approach that is commonly used for the preparation of monomeric metal complexes. Although several examples of multinuclear heterometallic complexes have been reported so far1,2,3, the trial-and-error or arduous nature of their synthesis necessitates the development of a simple method that is applicable for a wide range of structures.
As a new approach to address this issue, in 2011 we reported a synthetic methodology4,5 where various mononuclear metal complexes having a Fmoc-protected amino acid moiety are sequentially coupled to give multimetallic peptidic arrays by using the protocols of solid-phase polypeptide synthesis6. Due to the consecutive nature of polypeptide synthesis, a specific sequence of multiple metal centers is rationally designable by controlling the number and order of the coupling reactions of those metal complex monomers. Later, this approach was further modularized to make various larger and/or branched array structures by combining with the covalent linkage between two shorter arrays7.
Here we will show how the synthesis of such multimetallic peptidic arrays is typically operated by choosing the recently reported WSMOCA (18 CAS RN 1827663-18-2; Figure 1) as a representative example. Although the synthesis of one particular array is described in this protocol, the same procedures are applicable to the synthesis of a wide range of different sequences, including isomers9. We expect that this protocol will inspire more researchers to participate in the science of sequence-controlled compounds, where the molecules investigated thus far have typically been biopolymers but rarely include examples of metal-complex-based species.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Dichloro(p&#8208;cymene)ruthenium(II), dimer</td>
			<td>Kanto Chemical</td>
			<td>11443-65</td>
			<td></td>
		</tr>
		<tr>
			<td>Dichloro(1,5-cyclooctadiene)platinum(II)</td>
			<td>TCI</td>
			<td>D3592</td>
			<td></td>
		</tr>
		<tr>
			<td>Rhodium(III) chloride trihydrate</td>
			<td>Kanto Chemical</td>
			<td>36018-62</td>
			<td></td>
		</tr>
		<tr>
			<td>Phosphate buffered saline, tablet</td>
			<td>Sigma Aldrich</td>
			<td>P4417-50TAB&#160;</td>
			<td></td>
		</tr>
		<tr>
			<td>NovaSyn TG Sieber resin</td>
			<td>Novabiochem</td>
			<td>8.55013.0005</td>
			<td></td>
		</tr>
		<tr>
			<td>HBTU</td>
			<td>TCI</td>
			<td>B1657</td>
			<td></td>
		</tr>
		<tr>
			<td>Benzoic anhydride</td>
			<td>Kanto Chemical</td>
			<td>04116-30</td>
			<td></td>
		</tr>
		<tr>
			<td>Fmoc-Glu(OtBu)-OH&#12539;H2O</td>
			<td>Watanabe Chemical Industries</td>
			<td>K00428</td>
			<td></td>
		</tr>
		<tr>
			<td>Trifluoroacetic acid</td>
			<td>Kanto Chemical</td>
			<td>40578-30</td>
			<td></td>
		</tr>
		<tr>
			<td>Triethylsilane</td>
			<td>TCI</td>
			<td>T0662</td>
			<td></td>
		</tr>
		<tr>
			<td>2-[2-(2-Methoxyethoxy)ethoxy]acetic acid</td>
			<td>Sigma Aldrich</td>
			<td>407003</td>
			<td>Dried over 3&#197; sieves</td>
		</tr>
		<tr>
			<td>Dithranol</td>
			<td>Wako Pure Chemical Industries</td>
			<td>191502</td>
			<td></td>
		</tr>
		<tr>
			<td>N-methylimidazole</td>
			<td>TCI</td>
			<td>M0508</td>
			<td></td>
		</tr>
		<tr>
			<td>N&#8208;ethyldiisopropylamine</td>
			<td>Kanto Chemical</td>
			<td>14338-32</td>
			<td></td>
		</tr>
		<tr>
			<td>Piperidine</td>
			<td>Kanto Chemical</td>
			<td>32249-30</td>
			<td></td>
		</tr>
		<tr>
			<td>4&#39;-(4-methylphenyl)-2,2&#39;:6&#39;,2&#34;-terpyridine</td>
			<td>Sigma Aldrich</td>
			<td>496375</td>
			<td></td>
		</tr>
		<tr>
			<td>Dehydrated grade dimethylsulfoxide</td>
			<td>Kanto Chemical</td>
			<td>10380-05&#160;</td>
			<td></td>
		</tr>
		<tr>
			<td>Dehydrated grade methanol</td>
			<td>Kanto Chemical</td>
			<td>25506-05&#160;</td>
			<td></td>
		</tr>
		<tr>
			<td>Dehydrated grade N,N&#8208;Dimethylformamide</td>
			<td>Kanto Chemical</td>
			<td>11339-84</td>
			<td>Amine Free</td>
		</tr>
		<tr>
			<td>Dehydrated grade dichloromethane</td>
			<td>Kanto Chemical</td>
			<td>11338-84</td>
			<td></td>
		</tr>
		<tr>
			<td>MeOH</td>
			<td>Kanto Chemical</td>
			<td>25183-81&#160;</td>
			<td></td>
		</tr>
		<tr>
			<td>Dimethylsulfoxide</td>
			<td>Kanto Chemical</td>
			<td>10378-70</td>
			<td></td>
		</tr>
		<tr>
			<td>Ethyl acetate</td>
			<td>Kanto Chemical</td>
			<td>14029-81</td>
			<td></td>
		</tr>
		<tr>
			<td>Acetonitrile</td>
			<td>Kanto Chemical</td>
			<td>01031-70&#160;</td>
			<td></td>
		</tr>
		<tr>
			<td>1,2-dichloroethane</td>
			<td>Kanto Chemical</td>
			<td>10149-00</td>
			<td></td>
		</tr>
		<tr>
			<td>Diethyl ether</td>
			<td>Kanto Chemical</td>
			<td>14134-00&#160;</td>
			<td></td>
		</tr>
		<tr>
			<td>Dichloromethane</td>
			<td>Kanto Chemical</td>
			<td>10158-81</td>
			<td></td>
		</tr>
	</tbody>
</table>

synthesis of a water-soluble metal&#8211;organic complex array

We demonstrate a method for the synthesis of a water-soluble multimetallic peptidic array containing a predetermined sequence of metal centers such as Ru(II), Pt(II), and Rh(III). The compound, named as a water-soluble metal-organic complex array (WSMOCA), is obtained through 1) the conventional solution-chemistry-based preparation of the corresponding metal complex monomers having a 9-fluorenylmethyloxycarbonyl (Fmoc)-protected amino acid moiety and 2) their sequential coupling together with other water-soluble organic building units on the surface-functionalized polymeric resin by following the procedures originally developed for the solid-phase synthesis of polypeptides, with proper modifications. Traces of reactions determined by mass spectrometric analysis at the representative coupling steps in stage 2 confirm the selective construction of a predetermined sequence of metal centers along with the peptide backbone. The WSMOCA cleaved from the resin at the end of stage 2 has a certain level of solubility in aqueous media dependent on the pH value and/or salt content, which is useful for the purification of the compound.

Figure 1 shows the molecular structures of the final target compound, precursors, and intermediates. Figure 2 shows the images of the resin and Figure 3 shows the MALDI-TOF mass spectra of samples at selected procedure steps. Images from Figure 2a to 2h show the changes in the color and appearance of the resin that it undergoes during the reaction steps in section 2 of the protocol. MALDI-TOF mass spectro...

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Synthesis of a Water-soluble Metal&#8211;Organic Complex Array

A potential general method for the synthesis of water-soluble multimetallic peptidic arrays containing a predetermined sequence of metal centers is presented.

We demonstrate a method for the synthesis of a water-soluble multimetallic peptidic array containing a predetermined sequence of metal centers such as ...

synthesis-of-a-water-soluble-metalorganic-complex-array

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JoVE Journal

Chemistry

9.8K Views.  National Institute for Materials Science. A potential general method for the synthesis of water-soluble multimetallic peptidic arrays containing a predetermined sequence of metal centers is presented.

Video: Synthesis of a Water-soluble Metal–Organic Complex Array

Synthesis, Cellular Delivery and In vivo Application of Dendrimer-based pH Sensors

The development of fluorescent indicators represented a revolution for life sciences. Genetically encoded and synthetic fluorophores with sensing abilities allowed the visualization of biologically relevant species with high spatial and temporal resolution. Synthetic dyes are of particular interest thanks to their high tunability and the wide range of measureable analytes. However, these molecules suffer several limitations related to small molecule behavior (poor solubility, difficulties in targeting, often no ratiometric imaging allowed). In this work we introduce the development of dendrimer-based sensors and present a procedure for pH measurement in vitro, in living cells and in vivo. We choose dendrimers as ideal platform for our sensors for their many desirable properties (monodispersity, tunable properties, multivalency) that made them a widely used scaffold for several biomedical devices. The conjugation of fluorescent pH indicators to the dendrimer scaffold led to an enhancement of their sensing performances. In particular dendrimers exhibit reduced cell leakage, improved intracellular targeting and allow ratiometric measurements. These novel sensors were successfully employed to measure pH in living HeLa cells and in vivo in mouse brain.

Synthesis, Cellular Delivery and In vivo Application of Dendrimer-based pH Sensors

Fluorescence sensors are powerful tools in life science. Here we describe a methodology to synthesize and use dendrimer-based fluorescent sensors to measure pH in living cells and in vivo. The dendritic scaffold enhances the properties of conjugated fluorescent dyes leading to improved sensing properties.

The development of  fluorescent indicators represented a revolution for life sciences. Genetically  encoded and synthetic fluorophores with sensing ...

Atomically Defined Templates for Epitaxial Growth of Complex Oxide Thin Films

Atomically defined substrate surfaces are prerequisite for the epitaxial growth of complex oxide thin films. In this protocol, two approaches to obtain such surfaces are described. The first approach is the preparation of single terminated perovskite SrTiO3 (001) and DyScO3 (110) substrates. Wet etching was used to selectively remove one of the two possible surface terminations, while an annealing step was used to increase the smoothness of the surface. The resulting single terminated surfaces allow for the heteroepitaxial growth of perovskite oxide thin films with high crystalline quality and well-defined interfaces between substrate and film. In the second approach, seed layers for epitaxial film growth on arbitrary substrates were created by Langmuir-Blodgett (LB) deposition of nanosheets. As model system Ca2Nb3O10- nanosheets were used, prepared by delamination of their layered parent compound HCa2Nb3O10. A key advantage of creating seed layers with nanosheets is that relatively expensive and size-limited single crystalline substrates can be replaced by virtually any substrate material.

Various procedures are outlined to prepare atomically defined templates for epitaxial growth of complex oxide thin films. Chemical treatments of single crystalline SrTiO3 (001) and DyScO3 (110) substrates were performed to obtain atomically smooth, single terminated surfaces. Ca2 Nb3 O10- nanosheets were used to create atomically defined templates on arbitrary substrates.

Atomically defined substrate surfaces are prerequisite for the epitaxial growth of complex oxide thin films. In this protocol, two approaches to obtain ...

Water in Oil Emulsions: A New System for Assembling Water-soluble Chlorophyll-binding Proteins with Hydrophobic Pigments

Chlorophylls (Chls) and bacteriochlorophylls (BChls) are the primary cofactors that carry out photosynthetic light harvesting and electron transport. Their functionality critically depends on their specific organization within large and elaborate multisubunit transmembrane protein complexes. In order to understand at the molecular level how these complexes facilitate solar energy conversion, it is essential to understand protein-pigment, and pigment-pigment interactions, and their effect on excited dynamics. One way of gaining such understanding is by constructing and studying complexes of Chls with simple water-soluble recombinant proteins. However, incorporating the lipophilic Chls and BChls into water-soluble proteins is difficult. Moreover, there is no general method, which could be used for assembly of water-soluble proteins with hydrophobic pigments. Here, we demonstrate a simple and high throughput system based on water-in-oil emulsions, which enables assembly of water-soluble proteins with hydrophobic Chls. The new method was validated by assembling recombinant versions of the water-soluble chlorophyll binding protein of Brassicaceae plants (WSCP) with Chl a. We demonstrate the successful assembly of Chl a using crude lysates of WSCP expressing E. coli cell, which may be used for developing a genetic screen system for novel water-soluble Chl-binding proteins, and for studies of Chl-protein interactions and assembly processes.

This manuscript describes a simple and high-throughput method for assembling water-soluble proteins with hydrophobic pigments that is based on water-in-oil emulsions. We demonstrate the effectiveness of the method in the assembly of native chlorophylls with four variants of recombinant water-soluble-chlorophyll binding proteins (WSCPs) of Brassica plants expressed in E. coli.

Chlorophylls (Chls) and bacteriochlorophylls (BChls) are the primary cofactors that carry out photosynthetic light harvesting and electron transport. ...

Synthesis and Exfoliation of Discotic Zirconium Phosphates to Obtain Colloidal Liquid Crystals

Due to their abundance in natural clay and potential applications in advanced materials, discotic nanoparticles are of interest to scientists and engineers. Growth of such anisotropic nanocrystals through a simple chemical method is a challenging task. In this study, we fabricate discotic nanodisks of zirconium phosphate [Zr(HPO4)2&#183;H2O] as a model material using hydrothermal, reflux and microwave-assisted methods. Growth of crystals is controlled by duration time, temperature, and concentration of reacting species. The novelty of the adopted methods is that discotic crystals of size ranging from hundred nanometers to few micrometers can be obtained while keeping the polydispersity well within control. The layered discotic crystals are converted to monolayers by exfoliation with tetra-(n)-butyl ammonium hydroxide [(C4H9)4NOH, TBAOH]. Exfoliated disks show isotropic and nematic liquid crystal phases. Size and polydispersity of disk suspensions is highly important in deciding their phase behavior.

A two dimensional model material of discotic zirconium phosphate was developed. The inorganic crystal with lamellar structure was synthesized by hydrothermal, reflux, and microwave-assisted methods. On exfoliation with organic molecules, layered crystals can be converted to monolayers, and nematic liquid crystal phase was formed at sufficient concentration of monolayers.

Due to their abundance in natural clay and potential applications in advanced materials, discotic nanoparticles are of interest to scientists and ...

A Direct, Early Stage Guanidinylation Protocol for the Synthesis of Complex Aminoguanidine-containing Natural Products

The guanidine functional group, displayed most prominently in the amino acid arginine, one of the fundamental building blocks of life, is an important structural element found in many complex natural products and pharmaceuticals. Owing to the continual discovery of new guanidine-containing natural products and designed small molecules, rapid and efficient guanidinylation methods are of keen interest to synthetic and medicinal organic chemists. Because the nucleophilicity and basicity of guanidines can affect subsequent chemical transformations, traditional, indirect guanidinylation is typically pursued. Indirect methods commonly employ multiple protection steps involving a latent amine precursor, such as an azide, phthalimide, or carbamate. By circumventing these circuitous methods and employing a direct guanidinylation reaction early in the synthetic sequence, it was possible to forge the linear terminal guanidine containing backbone of clavatadine A to realize a short and streamlined synthesis of this potent factor XIa inhibitor. In practice, guanidine hydrochloride is elaborated with a carefully constructed protecting array that is optimized to survive the synthetic steps to come. In the preparation of clavatadine A, direct guanidinylation of a commercially available diamine eliminated two unnecessary steps from its synthesis. Coupled with the wide variety of known guanidine protecting groups, direct guanidinylation evinces a succinct and efficient practicality inherent to methods that find a home in a synthetic chemist&#39;s toolbox.

Here, we present a protocol for direct, early stage guanidinylation that enables rapid total synthesis of aminoguanidine-containing small organic molecules. An advanced synthetic intermediate used in the synthesis of a blood coagulation factor XIa inhibitor was prepared using this protocol.

The guanidine functional group, displayed most prominently in the amino acid arginine, one of the fundamental building blocks of life, is an important ...

Synthesis and Characterization of Supramolecular Colloids

Control over colloidal assembly is of utmost importance for the development of functional colloidal materials with tailored structural and mechanical properties for applications in photonics, drug delivery and coating technology. Here we present a new family of colloidal building blocks, coined supramolecular colloids, whose self-assembly is controlled through surface-functionalization with a benzene-1,3,5-tricarboxamide (BTA) derived supramolecular moiety. Such BTAs interact via directional, strong, yet reversible hydrogen-bonds with other identical BTAs. Herein, a protocol is presented that describes how to couple these BTAs to colloids and how to quantify the number of coupling sites, which determines the multivalency of the supramolecular colloids. Light scattering measurements show that the refractive index of the colloids is almost matched with that of the solvent, which strongly reduces the van der Waals forces between the colloids. Before photo-activation, the colloids remain well dispersed, as the BTAs are equipped with a photo-labile group that blocks the formation of hydrogen-bonds. Controlled deprotection with UV-light activates the short-range hydrogen-bonds between the BTAs, which triggers the colloidal self-assembly. The evolution from the dispersed state to the clustered state is monitored by confocal microscopy. These results are further quantified by image analysis with simple routines using ImageJ and Matlab. This merger of supramolecular chemistry and colloidal science offers a direct route towards light- and thermo-responsive colloidal assembly encoded in the surface-grafted monolayer.

A protocol for the synthesis and characterization of colloids coated with supramolecular moieties is described. These supramolecular colloids undergo self-assembly upon the activation of the hydrogen-bonds between the surface-anchored molecules by UV-light.

Control over colloidal assembly is of utmost importance for the development of functional colloidal materials with tailored structural and mechanical ...

Chemo-enzymatic Synthesis of N-glycans for Array Development and HIV Antibody Profiling

We present a highly efficient way for the rapid preparation of a wide range of N-linked oligosaccharides (estimated to exceed 20,000 structures) that are commonly found on human glycoproteins. To achieve the desired structural diversity, the strategy began with the chemo-enzymatic synthesis of three kinds of oligosaccharyl fluoride modules, followed by their stepwise &#945;-selective glycosylations at the 3-O and 6-O positions of the mannose residue of the common core trisaccharide having a crucial &#946;-mannoside linkage. We further attached the N-glycans to the surface of an aluminum oxide-coated glass (ACG) slide to create a covalent mixed array for the analysis of hetero-ligand interaction with an HIV antibody. In particular, the binding behavior of a newly isolated HIV-1 broadly neutralizing antibody (bNAb), PG9, to the mixture of closely spaced Man5GlcNAc2 (Man5) and 2,6-di-sialylated bi-antennary complex type N-glycan (SCT) on an ACG array, opens a new avenue to guide the effective immunogen design for HIV vaccine development. In addition, our ACG array embodies a powerful tool to study other HIV antibodies for hetero-ligand binding behavior.

Chemo-enzymatic Synthesis of N-glycans for Array Development and HIV Antibody Profiling

A modular approach to the synthesis of N-glycans for attachment to an aluminum oxide-coated glass slide (ACG slide) as a glycan microarray has been developed and its use for the profiling of an HIV broadly neutralizing antibody has been demonstrated.

We present a highly efficient way for the rapid preparation of a wide range of N-linked oligosaccharides (estimated to exceed 20,000 structures) that are ...

Heterogeneous Removal of Water-Soluble Ruthenium Olefin Metathesis Catalyst from Aqueous Media Via Host-Guest Interaction

A highly efficient transition metal catalyst removal method is developed. The water-soluble catalyst contains a newly-designed NHC ligand for the catalyst removal via host-guest interactions. The new NHC ligand possesses an adamantyl (guest) tethered linear ethylene glycol units for hydrophobic inclusion into the cavity of a &#946;-cyclodextrin (&#946;-CD) host compound. The new NHC ligand was applied to a Ru-based olefin metathesis catalyst. The Ru catalyst demonstrated excellent activity in representative ring-closing metathesis (RCM) and ring-opening metathesis polymerization (ROMP) reactions in aqueous media as well as organic solvent, CH2Cl2. After the reaction was complete, the lingering Ru residue was removed from the aqueous solution with the efficiency of more than 99% (53 ppm of Ru residue) by simple filtration utilizing a host-guest interaction between insoluble silica-grafted &#946;-CD (host) and the adamantyl moiety (guest) on the catalyst. The new Ru catalyst also demonstrated high removal efficiency via extraction when the reaction is run in organic solvent by partitioning the crude reaction mixture between layers of diethyl ether and water. In this way, the catalyst stays in aqueous layer only. In organic layer, the residual Ru amount was only 0.14 ppm in the RCM reactions of diallyl compounds.

A removable water-soluble N-heterocyclic carbene (NHC) ligand in aqueous media via host-guest interaction has been developed. We demonstrated representative olefin metathesis reactions in water as well as in dichloromethane. Via either host-guest interaction or extraction, the residual ruthenium (Ru) catalyst was as low as 0.14 ppm after the reaction.

A highly efficient transition metal catalyst removal method is developed. The water-soluble catalyst contains a newly-designed NHC ligand for the catalyst ...

Negative Additive Manufacturing of Complex Shaped Boron Carbides

Boron carbide (B4C) is one of the hardest materials in existence. However, this attractive property also limits its machineability into complex shapes for high wear, high hardness, and lightweight material applications such as armors. To overcome this challenge, negative additive manufacturing (AM) is employed to produce complex geometries of boron carbides at various length scales. Negative AM first involves gelcasting a suspension into a 3D-printed plastic mold. The mold is then dissolved away, leaving behind a green body as a negative copy. Resorcinol-formaldehyde (RF) is used as a novel gelling agent because unlike traditional hydrogels, there is little to no shrinkage, which allows for extremely complex molds to be used. Furthermore, this gelling agent can be pyrolyzed to leave behind ~50 wt% carbon, which is a highly effective sintering aid for B4C. Due to this highly homogenous distribution of in situ carbon within the B4C matrix, less than 2% porosity can be achieved after sintering. This protocol highlights in detail the methodology for creating near fully dense boron carbide parts with highly complex geometries.

A method called negative additive manufacturing is used to produce near fully dense complex shaped boron carbide parts of various length scales. This technique is possible via the formulation of a novel suspension involving resorcinol-formaldehyde as a unique gelling agent that leaves behind a homogenous carbon sintering aid after pyrolysis.

Boron carbide (B4C) is one of the hardest materials in existence. However, this attractive property also limits its machineability into complex shapes for ...

Molten-Salt Synthesis of Complex Metal Oxide Nanoparticles

The development of feasible synthesis methods is critical for the successful exploration of novel properties and potential applications of nanomaterials. Here, we introduce the molten-salt synthesis (MSS) method for making metal oxide nanomaterials. Advantages over other methods include its simplicity, greenness, reliability, scalability, and generalizability. Using pyrochlore lanthanum hafnium oxide (La2Hf2O7) as a representative, we describe the MSS protocol for the successful synthesis of complex metal oxide nanoparticles (NPs). Furthermore, this method has the unique ability to produce NPs with different material features by changing various synthesis parameters such as pH, temperature, duration, and post-annealing. By fine-tuning these parameters, we are able to synthesize highly uniform, non-agglomerated, and highly crystalline NPs. As a specific example, we vary the particle size of the La2Hf2O7&#160;NPs by changing the concentration of the ammonium hydroxide solution used in the MSS process, which allows us to further explore the effect of particle size on various properties. It is expected that the MSS method will become a more popular synthesis method for nanomaterials and more widely employed in the nanoscience and nanotechnology community in the upcoming years.

Here, we demonstrate a unique, relatively low-temperature, molten-salt synthesis method for preparing uniform complex metal oxide lanthanum hafnate nanoparticles.

The development of feasible synthesis methods is critical for the successful exploration of novel properties and potential applications of nanomaterials. ...

Synthesis of a Water-soluble Metal–Organic Complex Array

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