We thank Funda&#231;&#227;o de Amparo &#224; Pesquisa do Estado de S&#227;o Paulo (FAPESP, S&#227;o Paulo, Brazil) for financial support (Grant FAPESP 2017/18400-6). This study was financed in part by the Coordena&#231;&#227;o de Aperfei&#231;oamento de Pessoal de N&#237;vel Superior &#8211; Brasil (CAPES) &#8211; Finance Code 001.

CAUTION: Consult Material Safety Data Sheets (MSDS) prior to the use of the chemicals in this procedure. Use appropriate personal protective equipment (PPE), including safety glasses, a lab coat, and nitrile gloves as several reagents and solvents are toxic, corrosive, or flammable. Carry out all reactions in a fume hood. Liquids used in this protocol are micropipette transferred.
1. Benzannulation reaction employing alkynes and &#945;,&#946;-unsaturated compounds
<ol>
	<li>Add 2.0 mL of distilled water to a 15 mL-test tube (1 cm diameter) containing a stir bar. Sequentially, add phenylacetylene (220 &#956;L, 2.00 mmol, 2.0 equiv.), 2-cyclohexen-1-one (96.8 &#956;L, 1.00 mmol, 1.0 equiv.) and ammonium persulfate (1.5 mL of a freshly prepared aqueous solution 1.3 M, 2.00 mmol, 2 equiv.).</li>
	<li>Cap the tube using a rubber septum and insert a needle in it to avoid eventual pressure buildup during the heating.</li>
	<li>Place the tube in an aluminum heating block on a hotplate and heat it at 85 &#176;C under vigorous stirring (1150 rpm) for 8 h.</li>
	<li>To follow the progress of the reaction, take a 50 &#956;L-aliquot of the reaction medium and transfer it to a 1.5 mL-conical vial. Add 50 &#956;L of ethyl acetate to the vial and shake it. Collect the organic top layer with a capillary tube and analyze it by TLC. 
	NOTE: Reaction progress is checked by TLC comparing the disappearance of the &#945;,&#946;-unsaturated compound spot to the appearance of the product under the UV light (254 nm). TLC analysis is performed with silica-coated glass plates and developed with 92:8 hexanes/ethyl acetate. Rf values: phenylacetylene = 0.68; 2-cyclohexen-1-one = 0.23; product 3e = 0.26. 
	CAUTION: Phenylacetylene and 2-cyclohexen-1-one are flammable, acutely toxic and mild irritants. Ammonium persulfate is corrosive and may irritate the mucous membranes.</li>
</ol>
2. Extraction workup and purification
<ol>
	<li>Cool the reaction mixture to room temperature and add ethyl acetate (1 mL) to the test tube. Stir the suspension for ca. 1 min and then centrifuge the suspension at 2,336 &#215; g at room temperature for 1 min. Remove the organic top layer using a Pasteur pipette and transfer it to a round bottom flask. Repeat this step twice. 
	NOTE: The centrifugation step avoids the use of drying agents and readily breaks any eventual emulsion.</li>
	<li>Concentrate the solution under reduced pressure using a rotary evaporator to obtain a crude oil.</li>
	<li>Add 55 mL of a mixture of hexanes/ethyl acetate at the ratio of 92:8 into a Becker containing 7.5 g of SiO2 (pore size 60 &#197;, 35-70 &#956;m particle size, for flash chromatography). Stir the flask to obtain a homogeneous slurry. Transfer the slurry to a column (40 mm internal diameter) and pack the column eluting the solvent. If necessary, elute once again to remove any bubbles from the stationary phase.</li>
	<li>Dissolve the crude oil in a minimal amount of ethyl acetate, and then transfer this solution to the column. Using the same 55 mL of a mixture 92:8 hexanes/ethyl acetate, elute the material, collecting the column effluent in test tubes and following by TLC to obtain the desired pure product.</li>
	<li>Concentrate the solution under reduced pressure on a rotary evaporator and remove the final volatiles under high vacuum for at least 1 h. Analyze a sample of the purified product by 1H and 13C NMR using CDCl3. 
	CAUTION: Ethyl acetate and hexanes are flammable. SiO2 powder is a respiratory irritant.</li>
</ol>

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X., Chen, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Base-promoted+direct+synthesis+of+functionalized+N-arylindoles+via+the+cascade+reactions+of+allenic+ketones+with+indoles.">Base-promoted direct synthesis of functionalized N-arylindoles via the cascade reactions of allenic ketones with indoles.</a> Organic and Biomolecular Chemistry. 17, 789-793 (2019).</li><li>Maezono, S. M. B., Poudel, T. N., Lee, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=One-pot+construction+of+sterically+challenging+and+diverse+polyarylphenols+via+transition-metal-free+benzannulation+and+their+potent+in+vitro+antioxidant+activity.">One-pot construction of sterically challenging and diverse polyarylphenols via transition-metal-free benzannulation and their potent in vitro antioxidant activity.</a> Organic and Biomolecular Chemistry. 15, 2052-2062 (2017).</li><li>Shu, W. M., Zheng, K. L., Ma, J. R., Wu, A. X. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Transition-Metal-Free+Multicomponent+Benzannulation+Reactions+for+the+Construction+of+Polysubstituted+Benzene+Derivatives.">Transition-Metal-Free Multicomponent Benzannulation Reactions for the Construction of Polysubstituted Benzene Derivatives.</a> Organic Letters. 17, 5216-5219 (2015).</li><li>Jiang, L., 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=Secondary+amine-catalyzed+[3+benzannulation+to+access+polysubstituted+benzenes+through+iminium+activation.">Secondary amine-catalyzed [3 benzannulation to access polysubstituted benzenes through iminium activation.</a> Synthetic Communications. 48, 336-343 (2018).</li><li>Koening, S. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Scalable Green Chemistry. Case Studies from the Pharmaceutical Industry. , (2013).</li><li>Backvall, J. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Modern Oxidation Methods. , (2004).</li><li>Narayan, S., 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="On+Water":+Unique+Reactivity+of+Organic+Compounds+in+Aqueous+Suspension.">"On Water": Unique Reactivity of Organic Compounds in Aqueous Suspension.</a> Angewandte Chemie International Edition. 44, 3275-3277 (2005).</li><li>de Souza, G. F. P., Salles, A. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Persulfate-Mediated+Synthesis+of+Polyfunctionalized+Benzenes+in+Water+via+Benzannulation+of+Alkynes+and+&#945;,&#946;-Unsaturated+Compounds.">Persulfate-Mediated Synthesis of Polyfunctionalized Benzenes in Water via Benzannulation of Alkynes and &#945;,&#946;-Unsaturated Compounds.</a> Green Chemistry. , (2019).</li><li>Prat, D., Wells, A., Hayler, J., Sneddon, H., McElroy, C. R., Abou-Shehada, S., Dunn, P. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=CHEM21+Selection+Guide+of+Classical-+and+Less+Classical-Solvents.">CHEM21 Selection Guide of Classical- and Less Classical-Solvents.</a> Green Chemistry. 18, 288-296 (2015).</li><li>Sheldon, R. 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The authors have nothing to disclose.

The method reported herein was designed to be a very simple and mild experimental setup for the synthesis of polyfunctionalized benzenes in water15. Under our conditions we could observe excellent yields for the products through the use of ammonium persulfate. A freshly prepared persulfate aqueous solution should be used; however, solid ammonium persulfate can also be employed with no loss in yield. Attention to the temperature of the reaction medium is mandatory. An increase in 10 &#176;C beyond the optimized temperature (85 &#176;C) has a deleterious effect on the yield (Table 1, entry 7)15. Reaction time can be increased without prominently affecting the yield. During the reaction, a needle must be inserted in the septum to relieve eventual pressure in the tube.
We noticed that the reaction involving the electron-rich alkyne 1-ethynyl-4-methoxybenzene was sluggish, thus we decided to use 4 equiv. of ammonium persulfate during 24 h of reaction time to reach an adequate yield (3d, Figure 1).
The workup in this protocol involves a centrifugation step and an extraction step using ethyl acetate. The centrifugation step makes the whole process of isolation much easier since any eventual emulsion formed can be broken promptly. It also avoids the use of drying agents as the separation of the aqueous and organic phases happens more efficiently. We have chosen ethyl acetate for sustainable reasons16; nevertheless, other common solvents for extraction can be used as well.
We observed no challenging purifications for the products; thus, a plug of silica was employed making the whole process more operationally and economically attractive. Most products were purified using 92:8 (hexanes/ethyl acetate). (3d, Figure 1) was purified using 80:20 (hexanes/ethyl acetate) and (3e, Figure 1) was purified using 90:10 (hexanes/ethyl acetate).
This straightforward protocol furnishes an array of functionalized benzene rings in high yields; however, the method is currently limited to terminal alkynes and &#945;,&#946;-unsaturated aliphatic compounds.15 Internal alkynes failed to provide the targeted products. In the reaction employing 4-phenylbut-3-yn-2-ol, a formal reduction of the triple bond occurred during the transformation whereas dimethyl but-2-ynedioate gave a cyclotrimerization product. The aromatic &#945;,&#946;-unsaturated ketone 4-phenylbut-3-en-2-one indeed gave the product but it was not separable employing only a plug of silica. As we were aiming to employ the lowest as possible amount of silica and solvents and consequently reduce the E-factor17, we ranked this substrate as unsuccessful in order to preserve the sustainability of the transformation. Currently, we are investigating modifications in the procedure in order to reach also these substrates.
We then suggested a possible reaction mechanism for the conversion (Figure 4, using phenylacetylene and methyl vinyl ketone as representative substrates). An aqueous solution of (NH4)2S2O8 under heating produces sulfate radical (Figure 4, step I). Such radical is prone to add to phenylacetylene providing radical B and styrene coming from radical B (Step II). Methyl vinyl ketone, radical B and styrene participate in a 3-component reaction to give radical C (Step III). Cyclization of C furnishes radical D (Step IV). Elimination of radical R yields olefin E (Step V) and further aromatization allows the formation of the targeted product (Step VI).
In summary, our protocol is a convenient method to explore the metal-free benzannulation reaction in water fulfilling the demands of sustainable chemistry and advocating in favor of operationally simple experimental setups.

Functionalized benzenes are arguably the most employed precursors in synthetic organic chemistry1,2. They figure in the mainstream of pharmaceuticals, natural products and functional organic materials. Powerful approaches have been reported for the construction of polysubstituted benzene derivatives and among them, well-established methods as aromatic nucleophilic or electrophilic substitution3, cross-coupling reactions4 and directed metalation5 are prevalent approaches. Nevertheless, the widespread application of these strategies may be hampered by limited substrate scope, overreaction and regioselectivity issues.
Tandem cyclization reactions represent a very attractive alternative to classical methods for rapid construction of functionalized benzenes in an atom-economical fashion6,7,8. Within this framework, benzannulation reactions represent a suitable protocol to effectively transform acyclic building blocks into valuable benzene skeletons. This class of reaction is a versatile methodology featuring a variety of chemical feedstocks, mechanisms and experimental conditions9,10,11.
The objective of our study is to develop a simple and practical protocol for a benzannulation reaction to generate unprecedented functionalized benzene rings. Toward this end, we set out to explore a metal-free, persulfate mediated benzannulation in water employing cheap chemical feedstocks (&#945;,&#946;-unsaturated compounds and alkynes).
Several advantages over methods reported in the literature can be pointed out. Metal-free transformations have all necessary attributes to meet the requirement of sustainable development. Just to mention few, there is no need for costly and challenging removal of metal trace amounts from the desired products; the reactions are less sensitive to oxygen and moisture making its manipulation easier and the overall process is normally less expensive12. Persulfate salts are stable, easy to handle and generate only sulphate as the byproduct, thus adding momentum to the green chemistry initiative to minimize waste pollution13. Water is considered a suitable green solvent for organic reactions: it is non-toxic, non-flammable, has a very low odor and is available at a low cost. Even water-insoluble organic compounds can be employed using "on water"14 aqueous suspensions and these straightforward synthetic protocols have been gaining increasing attention during the years.
Our optimized reaction conditions and simple workup/purification procedure provide access to several functionalized benzene rings that offer a wealth of opportunities for further functionalization.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Ammonium persulfate</td>
			<td>Vetec</td>
			<td>276</td>
			<td></td>
		</tr>
		<tr>
			<td>Chloroform-D, (D, 99.8%)</td>
			<td>Sigma Aldrich</td>
			<td>570699-50G</td>
			<td></td>
		</tr>
		<tr>
			<td>2-cyclohexen-1-one &#62;95%</td>
			<td>Sigma Aldrich</td>
			<td>C102814-25ML</td>
			<td></td>
		</tr>
		<tr>
			<td>Ethyl Acetate, 99.9%</td>
			<td>Synth</td>
			<td>01A1010.01.BJ</td>
			<td>ACS</td>
		</tr>
		<tr>
			<td>Hexanes, 98.5%</td>
			<td>Synth</td>
			<td>01H1007.01.BJ</td>
			<td>ACS</td>
		</tr>
		<tr>
			<td>Phenylacetylene 98%</td>
			<td>Sigma Aldrich</td>
			<td>117706-25ML</td>
			<td></td>
		</tr>
		<tr>
			<td>Silica Gel (SiO2)</td>
			<td>Fluka</td>
			<td>60738-5KG</td>
			<td>pore size 60 &#197;, 35-70 &#956;m particle size</td>
		</tr>
		<tr>
			<td>Thin-layer chromatography plates</td>
			<td>Macherey-Nagel</td>
			<td>818333</td>
			<td>0.20 mm silica gel 60 with fluorescent indicator UV254</td>
		</tr>
	</tbody>
</table>

efficient synthesis of polyfunctionalized benzenes in water via persulfate-promoted benzannulation of &#945;,&#946;-unsaturated compounds and alkynes

Benzannulation reactions represent an effective protocol to transform acyclic building blocks into structurally varied benzene skeletons. Despite classical and recent approaches toward functionalized benzenes, in water metal-free methods remains a challenge and represents an opportunity to expand even more the set of tools used to synthesize polysubstituted benzene compounds. This protocol describes an operationally simple experimental setup to explore the benzannulation of &#945;,&#946;-unsaturated compounds and alkynes to afford unprecedented functionalized benzene rings in high yields. Ammonium persulfate is the reagent of choice and brings notable advantages as stability and easy handling. Moreover, the use of water as a solvent and the absence of metals impart more sustainability to the method. A modified workup procedure that avoids the use of drying agents also adds convenience to the protocol. The purification of the products is performed using only a plug of silica. The substrate scope is currently limited to terminal alkynes and &#945;,&#946;-unsaturated aliphatic compounds.

Polysubstituted benzene (3b, Figure 1) was isolated as a colorless oil (0.2741 g, 0.920 mmol, 92% yield) using our protocol. The structure and purity can be assessed in the 1H and 13C NMR spectra presented in Figure 2 and Figure 3. Peaks for the aromatic protons on the central benzene ring (&#948; 8.37 and &#948; 7.72 ppm) were used as diagnostic signals for the formation of the product.
6,8-diphenyl-3,4-dihydronaphthalen-1(2H)-one (3b). Rf = 0.26 (92:8 hexanes/ethyl acetate); 1H NMR (500 MHz, Chloroform-d): &#948; 8.37 (d, J = 2.26 Hz, 1H), 7.72 (d, J = 2.26 Hz, 1H), 7.67 (dd, J = 8.28, 1.51 Hz, 2H), 7.49-7.37 (m, 8H), 2.89 (t, J = 6.02 Hz, 2H), 2.72 (ap t, J = 6.02 Hz, 2H), 2.09 (quint, J = 6.02 Hz, 2H). 13C NMR (125MHz, Chloroform-d): &#948; 23.19, 28.01, 39.02, 124.86, 127.00, 127.46, 127.64, 128.35, 128.85, 129.19, 133.17, 133.41, 139.13, 139.78, 140.81, 142.51, 198.60. HRMS m/z (ESI): calcd. for C22H19O [M+H]+ 299.1436, found 299.1420.
Several polysubstituted benzene rings were prepared in high yields using our protocol (Figure 1).15 All the products were analyzed by 1H and 13C NMR, as well as high-resolution mass spectrometry (HRMS) in order to fully characterize them.
GC analysis can be used as an alternative method for the detection of the products; although, TLC analysis works efficiently as well. All the products are UV-active and stain in the presence of basic KMnO4 aqueous solution. A plug of silica is adequate for the purification of products.
Optimal yields were obtained when employing a ratio of 2:1 for alkynes and &#945;,&#946;-unsaturated compounds, respectively; 2 equiv. of ammonium persulfate and 85 &#176;C as reaction temperature. In the optimization process, the reaction between phenylacetylene 1a and fumaronitrile 2a was chosen as a model reaction (Table 1). Increasing the amount of the &#945;,&#946;-unsaturated compound led to an inferior result (Table 1, entry 3). Variations of the amount of (NH4)2S2O8 were tested and in every scenario a decrease in the production of 3a was observed (Table 1, entries 4 and 5). Changing the reaction temperature to 25 &#176;C resulted in a complete shutdown of the reactivity (Table 1, entry 6). Increasing the reaction temperature to 95 &#176;C did not enhance the yield (Table 1, entry 7).
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/60767/60767fig01.jpg" /> 
Figure 1: General scheme and scope of the transformation. General conditions: 2 mL of water, 1 (2.0 mmol), 2 (1.0 mmol), (NH4)S2O8 (2.0 mmol, aqueous solution 1.3 M), 85 &#176;C, 8 h. Yields of the isolated products. aUsing 4.0 mmol of (NH4)S2O8, 24 h reaction time. This figure has been modified from de Souza et al.15 <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/60767/60767fig1alarge.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/60767/60767fig02.jpg" /> 
Figure 2: 1H NMR of 3b. Spectrum obtained in CDCl3 at 400 MHz. This figure has been modified from de Souza et al.15. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/60767/60767fig2alarge.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/60767/60767fig03.jpg" /> 
Figure 3: 13C NMR of 3b. Spectrum obtained in CDCl3 at 400 MHz. This figure has been modified from de Souza et al.15. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/60767/60767fig3alarge.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/60767/60767fig04.jpg" /> 
Figure 4: Proposed reaction mechanism. This figure has been modified from de Souza et al.15. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/60767/60767fig4alarge.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td colspan="5"><img src="/files/ftp_upload/60767/60767table1.jpg" /></td>
		</tr>
		<tr>
			<td rowspan="2">Entrya</td>
			<td rowspan="2">Ratio 1a:2a</td>
			<td>NH4S2O8</td>
			<td>Temperature</td>
			<td rowspan="2">Yield (%)b</td>
		</tr>
		<tr>
			<td>(Equiv)</td>
			<td>(T, &#176;C)</td>
		</tr>
		<tr>
			<td>1</td>
			<td>1:1</td>
			<td>2.0</td>
			<td>85</td>
			<td>69</td>
		</tr>
		<tr>
			<td>2</td>
			<td>2:1</td>
			<td>2.0</td>
			<td>85</td>
			<td>90</td>
		</tr>
		<tr>
			<td>3</td>
			<td>1:2</td>
			<td>2.0</td>
			<td>85</td>
			<td>65</td>
		</tr>
		<tr>
			<td>4</td>
			<td>2:1</td>
			<td>1.0</td>
			<td>85</td>
			<td>56</td>
		</tr>
		<tr>
			<td>5</td>
			<td>2:1</td>
			<td>3.0</td>
			<td>85</td>
			<td>72</td>
		</tr>
		<tr>
			<td>6</td>
			<td>2:1</td>
			<td>2.0</td>
			<td>25</td>
			<td>0</td>
		</tr>
		<tr>
			<td>7</td>
			<td>2:1</td>
			<td>2.0</td>
			<td>95</td>
			<td>88</td>
		</tr>
		<tr>
			<td colspan="5">aGeneral conditions for the optimization: In the sequence, 1.0 mL of water, 1a (0.5 or 1.0 mmol), 2a (0.5 or 1.0 mmol), (NH4)2S2O8, 8 h. bYield of the isolated product.</td>
		</tr>
	</tbody>
</table>
Table 1. Optimization of the reaction conditions. This table has been modified from de Souza et al.15

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Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of &#945;,&#946;-Unsaturated Compounds and Alkynes

A persulfate-promoted metal-free benzannulation of &#945;,&#946;-unsaturated compounds and alkynes in water toward the synthesis of unprecedented polyfunctionalized benzenes is reported.

Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of &#945;,&#946;-Unsaturated Compounds and Alkynes

Benzannulation reactions represent an effective protocol to transform acyclic building blocks into structurally varied benzene skeletons. Despite ...

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7.7K Views.  University of Campinas. A persulfate-promoted metal-free benzannulation of α,β-unsaturated compounds and alkynes in water toward the synthesis of unprecedented polyfunctionalized benzenes is reported.

Video: Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of α,β-Unsaturated Compounds and Alkynes

Facile and Efficient Preparation of Tri-component Fluorescent Glycopolymers via RAFT-controlled Polymerization

Synthetic glycopolymers are instrumental and versatile tools used in various biochemical and biomedical research fields. An example of a facile and efficient synthesis of well-controlled fluorescent statistical glycopolymers using reversible addition-fragmentation chain-transfer (RAFT)-based polymerization is demonstrated. The synthesis starts with the preparation of &#946;-galactose-containing glycomonomer 2-lactobionamidoethyl methacrylamide obtained by reaction of lactobionolactone and N-(2-aminoethyl) methacrylamide (AEMA). 2-Gluconamidoethyl methacrylamide (GAEMA) is used as a structural analog lacking a terminal &#946;-galactoside. The following RAFT-mediated copolymerization reaction involves three different monomers: N-(2-hydroxyethyl) acrylamide as spacer, AEMA as target for further fluorescence labeling, and the glycomonomers. Tolerant of aqueous systems, the RAFT agent used in the reaction is (4-cyanopentanoic acid)-4-dithiobenzoate. Low dispersities (&#8804;1.32), predictable copolymer compositions, and high reproducibility of the polymerizations were observed among the products. Fluorescent polymers are obtained by modifying the glycopolymers with carboxyfluorescein succinimidyl ester targeting the primary amine functional groups on AEMA. Lectin-binding specificities of the resulting glycopolymers are verified by testing with corresponding agarose beads coated with specific glycoepitope recognizing lectins. Because of the ease of the synthesis, the tight control of the product compositions and the good reproducibility of the reaction, this protocol can be translated towards preparation of other RAFT-based glycopolymers with specific structures and compositions, as desired.

An efficient, three-step synthesis of RAFT-based fluorescent glycopolymers, consisting of glycomonomer preparation, copolymerization, and post-modification, is demonstrated. This protocol can be used to prepare RAFT-based statistical glycopolymers with desired structures.

Synthetic glycopolymers are instrumental and versatile tools used in various biochemical and biomedical research fields. An example of a facile and ...

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 ...

Synthesis of Protein Bioconjugates via Cysteine-maleimide Chemistry

The chemical linking or bioconjugation of proteins to fluorescent dyes, drugs, polymers and other proteins has a broad range of applications, such as the development of antibody drug conjugates (ADCs) and nanomedicine, fluorescent microscopy and systems chemistry. For many of these applications, specificity of the bioconjugation method used is of prime concern. The Michael addition of maleimides with cysteine(s) on the target proteins is highly selective and proceeds rapidly under mild conditions, making it one of the most popular methods for protein bioconjugation.
We demonstrate here the modification of the only surface-accessible cysteine residue on yeast cytochrome c with a ruthenium(II) bisterpyridine maleimide. The protein bioconjugation is verified by gel electrophoresis and purified by aqueous-based fast protein liquid chromatography in 27% yield of isolated protein material. Structural characterization with MALDI-TOF MS and UV-Vis is then used to verify that the bioconjugation is successful. The protocol shown here is easily applicable to other cysteine - maleimide coupling of proteins to other proteins, dyes, drugs or polymers.

Synthesis of Protein Bioconjugates via Cysteine-maleimide Chemistry

This protocol details the important steps required for the bioconjugation of a cysteine containing protein to a maleimide, including reagent purification, reaction conditions, bioconjugate purification and bioconjugate characterization.

The chemical linking or bioconjugation of proteins to fluorescent dyes, drugs, polymers and other proteins has a broad range of applications, such as the ...

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.

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 Substrate-Bound Au Nanowires Via an Active Surface Growth Mechanism

Advancing synthetic capabilities is important for the development of nanoscience and nanotechnology. The synthesis of nanowires has always been a challenge, as it requires asymmetric growth of symmetric crystals. Here, we report a distinctive synthesis of substrate-bound Au nanowires. This template-free synthesis employs thiolated ligands and substrate adsorption to achieve the continuous asymmetric deposition of Au in solution at ambient conditions. The thiolated ligand prevented the Au deposition on the exposed surface of the seeds, so the Au deposition only occurs at the interface between the Au seeds and the substrate. The side of the newly deposited Au nanowires is immediately covered with the thiolated ligand, while the bottom facing the substrate remains ligand-free and active for the next round of Au deposition. We further demonstrate that this Au nanowire growth can be induced on various substrates, and different thiolated ligands can be used to regulate the surface chemistry of the nanowires. The diameter of the nanowires can also be controlled with mixed ligands, in which another &#34;bad&#34; ligand could turn on the lateral growth. With the understanding of the mechanism, Au nanowire-based nanostructures can be designed and synthesized.

We report a solution-based method to synthesize substrate-bound Au nanowires. By tuning the molecular ligands used during the synthesis, the Au nanowires can be grown from various substrates with different surface properties. Au nanowire-based nanostructures can also be synthesized by adjusting the reaction parameters.

Advancing synthetic capabilities is important for the development of nanoscience and nanotechnology. The synthesis of nanowires has always been a ...

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 ...

Synthesis of Esters Via a Greener Steglich Esterification in Acetonitrile

The Steglich esterification is a widely-used reaction for the synthesis of esters from carboxylic acids and alcohols. While efficient and mild, the reaction is commonly performed using chlorinated or amide solvent systems, which are hazardous to human health and the environment. Our methodology utilizes acetonitrile as a greener and less hazardous solvent system. This protocol exhibits rates and yields that are comparable to traditional solvent systems and employs an extraction and wash sequence that eliminates the need for the purification of the ester product via column chromatography. This general method can be used to couple a variety of carboxylic acids with 1&#176; and 2&#176; aliphatic alcohols, benzylic and allylic alcohols, and phenols to obtain pure esters in high yields. The goal of the protocol detailed here is to provide a greener alternative to a common esterification reaction, which could serve useful for ester synthesis in both academic and industrial applications.

A modified Steglich esterification reaction was used to synthesize a small library of ester derivatives with primary and secondary alcohols. The methodology uses a non-halogenated and greener solvent, acetonitrile, and enables product isolation in high yields without the need for chromatographic purification.

The Steglich esterification is a widely-used reaction for the synthesis of esters from carboxylic acids and alcohols. While efficient and mild, the ...

Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of &#945;-Imino &#947;-Lactones and Alkylidene Pyrazolones

Bispirocyclic scaffolds are one of the important structural subunits in many natural products that exhibit diverse and attractive biological activities. Recently, we have developed an efficient organocatalytic strategy, which provides facile access to a variety of enantiomerically enriched bispiro[&#947;-butyrolactone-pyrrolidin-4,4&#39;-pyrazolone] skeletons. In this paper, we demonstrate a detailed protocol for the asymmetric synthesis of drug-like bispirocyclic compounds with two spirocyclic carbon centers via an organocatyltic 1,3-dipolar cycloaddition reaction. Spirocyclization synthons &#945;-imino &#947;-lactones and alkylidene pyrazolones are prepared first, which are then subjected to a cycloaddition reaction in the presence of a bifunctional squaramide organocatalyst to afford the desired bispirocycles in high yields and excellent stereoselectivities. Chiral high-performance liquid chromatography (HPLC) is carried out to determine the enantiomeric purity of the products, and the d.r. value is examined by proton nuclear magnetic resonance (1H NMR). The absolute configuration of the product is assigned according to an X-ray crystallographic analysis. This synthetic strategy allows scientists to prepare a diversity of bispirocyclic scaffolds in high yields and excellent diastereo- and enantioselectivities.

Enantiomerically enriched bispiro[&#947;-butyrolactone-pyrrolidin-4,4&#39;-pyrazolone] skeletons are asymmetrically synthesized through a simple organocatalytic 1,3-dipolar cycloaddition reaction.

Bispirocyclic scaffolds are one of the important structural subunits in many natural products that exhibit diverse and attractive biological activities. ...

Synthesis of Monodisperse Cylindrical Nanoparticles via Crystallization-driven Self-assembly of Biodegradable Block Copolymers

The production of monodisperse cylindrical micelles is a significant challenge in polymer chemistry. Most cylindrical constructs formed from diblock copolymers are produced by one of three techniques: thin film rehydration, solvent switching or polymerization-induced self-assembly, and produce only flexible, polydisperse cylinders. Crystallization-driven self-assembly (CDSA) is a method which can produce cylinders with these properties, by stabilizing structures of a lower curvature due to the formation of a crystalline core. However, the living polymerization techniques by which most core-forming blocks are formed are not trivial processes and the CDSA process may yield unsatisfactory results if carried out incorrectly. Here, the synthesis of cylindrical nanoparticles from simple reagents is shown. The drying and purification of reagents prior to a ring-opening polymerization of &#949;-caprolactone catalyzed by diphenyl phosphate is described. This polymer is then chain extended by methyl methacrylate (MMA) followed by N,N-dimethyl acrylamide (DMA) using reversible addition&#8722;fragmentation chain-transfer (RAFT) polymerization, affording a triblock copolymer that can undergo CDSA in ethanol. The living CDSA process is outlined, the results of which yield cylindrical nanoparticles up to 500 nm in length and a length dispersity as low as 1.05. It is anticipated that these protocols will allow others to produce cylindrical nanostructures and elevate the field of CDSA in the future.

Crystallization-driven self-assembly (CDSA) displays the unique ability to fabricate cylindrical nanostructures of narrow length distributions. The organocatalyzed ring-opening polymerization of &#949;-caprolactone and subsequent chain extensions of methyl methacrylate and N,N-dimethyl acrylamide are demonstrated. A living CDSA protocol that produces monodisperse cylinders up to 500 nm in length is outlined.

The production of monodisperse cylindrical micelles is a significant challenge in polymer chemistry. Most cylindrical constructs formed from diblock ...

Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the preparation of all-carbon quaternary centers. Though conjugate additions of organometallic reagents are typically performed utilizing highly reactive organolithium or Grignard reagents, organozinc reagents have garnered attention for their enhanced chemoselectivity and mild reactivity. Despite numerous recent advances with more reactive diorganozinc and mixed diorganozinc reagents, the generation of all-carbon quaternary centers via the conjugate addition of functionalized monoorganozinc reagents remains a challenge. This protocol details a convenient and mild &#8220;one-pot&#8221; preparation and copper mediated conjugate addition of functionalized monoorganozinc bromides to cyclic &#945;,&#946;-unsaturated carbonyls to afford a broad scope of all-carbon quaternary centers in generally excellent yield and diastereoselectivity. Key to the development of this technology is the utilization of DMA as a reaction solvent with TMSCl as a Lewis acid. Notable advantages to this methodology include the operational simplicity of the organozinc reagent preparation afforded by the utilization of DMA as a solvent, as well as an efficient conjugate addition mediated by various Cu(I) and Cu(II) salts. Moreover, an intermediate silyl enol ether can be isolated utilizing a modified workup procedure. The substrate scope is limited to cyclic unsaturated ketones, and the conjugate addition is impeded by stabilized (e.g., allyl, enolate, homoenolate) and sterically encumbered (e.g., neopentyl, o-aryl) monoorganozinc reagents. Conjugate additions to five- and seven-membered rings were effective, albeit in lower yields compared with six-membered ring substrates.

A simple and practical protocol for the efficient conjugate addition of functionalized monoorganozinc bromides to cyclic &#945;,&#946;-unsaturated carbonyls to furnish all-carbon quaternary centers was developed.

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the ...

Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of α,β-Unsaturated Compounds and Alkynes

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Chapters in this video

Facile and Efficient Preparation of Tri-component Fluorescent Glycopolymers via RAFT-controlled Polymerization

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

Synthesis of Protein Bioconjugates via Cysteine-maleimide Chemistry

Synthesis of a Water-soluble Metal–Organic Complex Array

Synthesis of Substrate-Bound Au Nanowires Via an Active Surface Growth Mechanism

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

Synthesis of Esters Via a Greener Steglich Esterification in Acetonitrile

Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of α-Imino γ-Lactones and Alkylidene Pyrazolones

Synthesis of Monodisperse Cylindrical Nanoparticles via Crystallization-driven Self-assembly of Biodegradable Block Copolymers

Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides