Name: mizoroki-heck cross-coupling reactions catalyzed by dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium under mild reaction conditions
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Duration: 11 min 44 s
Description: Watch this Scientific Journal Video about Mizoroki-Heck Cross-coupling Reactions Catalyzed by Dichloro{bis[1,1',1''-phosphinetriyltripiperidine]}palladium Under Mild Reaction Conditions at JoVE.com

Financial support by the Z&#252;rich University of Applied Sciences as well as the Swiss National Science Foundation (SNSF) is acknowledged.

1. Ligand Synthesis (1,1',1''-(Phosphinetriyl)tripiperidine)
<ol>
	<li>Add 150 ml of dry diethyl ether and 5 ml of phosphorous trichloride (57.3 mmol) in an oven-dried 500 ml round bottomed flask. Put a stir bar in the round bottomed flask and attach a 250 ml dropping funnel and cover the flask with septa.</li>
	<li>Cool down the solution to 0 &#176;C by placing the round-bottomed flask in an ice bath.</li>
	<li>Prepare a solution of 42.5 ml of piperidine (429.8 mmol, 7.5 equiv. rel. to PCl3) and 100 ml of diethyl ether and add this solution slowly via the dropping funnel into the stirred diethyl ether solution, containing phosphorous trichloride. The piperidine addition is accompanied by the precipitation of piperidinium chloride.</li>
	<li>After complete addition, warm up the reaction mixture to RT. In order to ensure full conversion, stir the solution for additional 30 min at RT.</li>
	<li>Filter the reaction mixture over a glass frit and collect the filtrate in a 500 ml round bottomed flask. In order to increase the yield of 1,1',1''-(phosphinetriyl)tripiperidine wash the filter cake with additional 100 ml of dry diethyl ether.</li>
	<li>Evaporate the solvent of the filtrate on a rotary evaporator to obtain the pure ligand (1,1',1''-(phosphinetriyl)tripiperidine) in &#62;80% yield as an off-white oil, which solidifies with time. Check the product purity by 31P{1H} NMR spectroscopy (&#948; at 117.3 ppm in C6D6)8a.</li>
</ol>
2. Catalyst Synthesis (Dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium)
<ol>
	<li>Weigh out [Pd(cod)Cl2] (0.35 mmol, 100 mg) and add to a clean, oven-dried 50 ml round bottomed flask containing 10 ml of dry THF. Add a stir bar, cover the flask with a septum and stir the suspension.</li>
	<li>Weigh out 1,1',1''-(phosphinetriyl)tripiperidine (0.875 mmol, 248 mg) and add to a clean, dry vial containing 10 ml of dry THF. Add the 1,1',1''-(phosphinetriyl)tripiperidine solution via a syringe through the septum to the THF suspension of [Pd(cod)Cl2]. The suspension turns immediately into a dark yellow solution while addition, indicating completion of the reaction.</li>
	<li>In order to remove insoluble solids pass the reaction mixture quickly through an oven-dried glass frit and collect the filtrate in a 25 ml round bottomed flask. Remove the volatiles under reduced pressure. Wash the palladium complex three times with 5 ml of pentane.</li>
	<li>Remove the pentane by decantation. Dry the yellow powder under reduced pressure to quantitatively obtain the analytically pure palladium complex [(P(C5H10N)3)2PdCl2] (1). Check the purity of 1 by 31P{1H} NMR spectroscopy (&#948; at 92.5 ppm in C6D6)30.</li>
</ol>
3. Heck Reaction Catalyzed by [(P(C5H10N)3)2PdCl2] (1)
<ol>
	<li>Weight out [(P(C5H10N)3)2PdCl2] (0.05 mmol, 37.15 mg) and add to an oven-dried 25 ml Schlenk. Cover the Schlenk with a septum; evacuate the Schlenk and backfill with dinitrogen. Add 10 ml of dry and degassed THF via syringe through the septum into the flask.</li>
	<li>Weight out tetrabutylammonium bromide (1.0 mmol, 322.4 mg) and potassium carbonate (20 mmol, 2.77 g) and add them in a clean, oven-dried 25 ml round-bottomed Schlenk flask. Add 20 ml of N-methyl-2-pyrrolidone (NMP) through a syringe into the Schlenk flask36, 37. Add a stir bar and cover the flask with septa. Evacuate and backfill the Schlenk flask with dinitrogen.</li>
	<li>Dissolve 1-bromo-4-phenoxybenzene (10 mmol, 1.75 ml) and styrene (15 mmol, 1.72 ml) in 5 ml of NMP and add this solution via syringe into the Schlenk flask. Attach a reflux condenser by applying a dinitrogen stream. Connect the reflux condenser with an oil bubbler and set a slight overpressure of dinitrogen.</li>
	<li>Heat up the reaction solution to 100 &#176;C and stir the solution for 5 min on this temperature. Add the catalyst solution (0.05 mol%, 0.005 mmol, 1 ml of THF) to the hot reaction mixture via syringe and stir it vigorously for the indicated time (3 hr in this example). Check the product formation by GC/MS.</li>
	<li>Remove the Schlenk from the oil bath, expose the reaction mixture to air and quench with 50 ml of 1 M hydrochloric acid. Add the cooled reaction mixture into a 500 ml separation funnel and add ethyl acetate (50 ml). Separate the Heck product by extraction and combine all organic phases in an Erlenmeyer flask. Add magnesium sulfate to soak up any last amount of water present in the solution.</li>
	<li>Filter the combined organic layers over a paper filter into a round bottomed flask. Wash the filter cake with additional 50 ml ethyl acetate. Concentrate the solution on a rotary evaporator to obtain the crude coupling product.</li>
	<li>Separate the Heck product via column chromatography, using a mixture of hexane and diethyl ether (5:1) as eluent. Evaporate the solvent on a rotatory evaporator. Check the product purity by 1H and 13C{1H} NMR spectroscopy35.</li>
</ol>

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Identification of Bulk Ruthenium Metal as the True Catalyst in Benzene Hydrogenations Starting with the Monometallic Precursor, Ru(II)(&#951;6-C6Me6)(OAc)2, Plus Kinetic Characterization of the Heterogeneous Nucleation, Then Autocatalytic Surface-Growth Mechanism of Metal Film Formation.</a> 125, 10301-10310 (2003).</li><li>Widegren, J. A., Finke, R. 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+review+of+the+problem+of+distinguishing+true+homogeneous+catalysis+from+soluble+or+other+metal-particle+heterogeneous+catalysis+under+reducing+conditions.">A review of the problem of distinguishing true homogeneous catalysis from soluble or other metal-particle heterogeneous catalysis under reducing conditions.</a> J. Mol. Catal. A. 198, 317-341 (2003).</li></ol>

The authors have nothing to disclose.

Dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium (1) is a very cheap and easy accessible, air stable and highly active Heck catalyst with an excellent functional group tolerance that efficiently operates under mild reaction conditions to give the coupling products cleanly in very high yields. The excellent catalytic activity (and general applicability) of 1 is due to the unique properties of aminophosphines: while the steric bulk as well as the &#963;-donor strength of aminophosphines is essentially the same when compared to their phosphine-based analogues, comparable levels of activity were found for complexes of type [(P{(NC5H10)3-n(C6H11)n})2Pd(Cl)2] (where n = 0-3; Figure 3) in cross-coupling reactions where molecular mechanisms are operative. On the other hand, the labile character of P-N bonds in aminophosphines (sensitivity towards protons; in form of water e.g.) offers the possibility to effectively control the formation of palladium nanoparticles: increasing numbers of P-N bonds in the ligands successively eases their water-induced degradation and consequently the formation of nanoparticles from the respective complexes. Accordingly, since palladium nanoparticles are the catalytically active form of 1 in the Heck reaction35, as indicated by sigmoidal-shaped kinetics36, 37 or the efficient inhibition of catalysis after addition of a large excess of metallic mercury to reaction mixtures of aryl bromide, olefin and catalyst, for example38, as well as their detection by analysis of reaction mixtures of exemplary Heck cross-coupling reactions by a transmission electron microscopy (TEM) equipped with an energy dispersive X-ray (EDX) analysator35, substitution of 1,1',1''-(phosphinetriyl)tripiperidine by 1,1&#39;-(cyclohexylphosphinediyl)dipiperidine), 1-(dicyclohexylphosphinyl)piperidine) or tricyclohexylphosphine, which successively increases the complex stability and hence, retards the (water-induced) formation of nanoparticles thereof. As a consequence, while dichloro-bis(1-(dicyclohexylphosphinyl)piperidine)palladium, is the catalyst of choice in the Heck reaction performed at 140 &#176;C, the highest catalytic activity was obtained for dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium [(P(NC5H10)3)2Pd(Cl)2] (1) at 100 &#176;C, the least stable complex within this series.
<img alt="Figure 5" fo:content-width="6in" fo:src="/files/ftp_upload/51444/51444fig5highres.jpg" src="/files/ftp_upload/51444/51444fig5.jpg" /> 
Figure 5. The effect of ligand composition of dichloro{bis(aminophosphine)}palladium with the general formula of [(P{(NC5H10)3-n(C6H11)n})2Pd(Cl)2] (where n = 0-2) on the complex stability and hence, on the ease of (water-induced) nanoparticle formation and hence, their catalytic performance under mild reaction conditions in the Heck cross-coupling reaction. <a href="https://www.jove.com/files/ftp_upload/51444/51444fig5highres.jpg" target="_blank">Click here to view larger image.</a>
Even though the above described syntheses as well as the Heck reaction protocols are straight forward, some of the common troubleshooting procedures are: (a) make sure that the tetrabutylammonium bromide is newly purchased or properly stored (tetrabutylammonium bromide is hygroscopic), (b) make sure that dry solvents are used for the ligand synthesis when small amounts of ligand were prepared, (c) make sure that 1 is either freshly prepared or stored under an inert atmosphere, (d) make sure that the NMP or DMF are newly purchased, (e) make sure that the chemicals are either newly purchased or properly stored, (f) oven-dry all glassware and cool under vacuum.

Palladium-catalyzed C-C cross-coupling reactions, which were acknowledged by the award of the Nobel Prize in chemistry in December 2010, nowadays belong to an indispensable tool for the target oriented synthesis of complex organic molecules across all research fields and industrial segments. The Mizoroki-Heck reaction for example, allows the coupling of olefins with aryl halides in the presence of a base and is nowadays the most popular method for the preparation of vinylbenzenes (Figure 1). The Heck reaction has been demonstrated to find wide utility in both, total syntheses of natural products in academia and synthesis in pharmaceutical and agrochemical industry1-10.
<img ALT="Figure 1" fo:content-width="6in" fo:src="/files/ftp_upload/51444/51444fig1highres.jpg" src="/files/ftp_upload/51444/51444fig1.jpg" /> 
Figure 1. General Heck cross-coupling reaction between an aryl bromide and an olefin. <a HREF="https://www.jove.com/files/ftp_upload/51444/51444fig1highres.jpg" target="_blank">Click here to view larger image.</a>
Taxol, a mitotic inhibitor used in cancer chemotherapy, Singulair, an asthma drug and the herbicide prosulfuron as well as Cyclotene, a monomer for high performance electronic resins are examples that have been successfully prepared including a Heck-Mizoroki cross-coupling step in their syntheses (Figure 2)11-14.
<img ALT="Figure 2" fo:content-width="6in" fo:src="/files/ftp_upload/51444/51444fig2highres.jpg" src="/files/ftp_upload/51444/51444fig2.jpg" /> 
Figure 2. Examples of industrially relevant organic compounds involving a palladium-catalyzed Heck cross-coupling reaction as key step in their synthesis. <a HREF="https://www.jove.com/files/ftp_upload/51444/51444fig2highres.jpg" target="_blank">Click here to view larger image.</a>
Even though recent developments have considerably increased the activity of Heck catalysts15-29, a typical reaction protocol with aryl bromides as substrates still requires high reaction temperatures (140 &#176;C), catalyst loadings in the range of 1 mol% and reaction times of up to 24 hr. Moreover, modified reaction conditions, including the reaction temperature, catalyst loadings, bases, solvents, and additives, e.g. are often reported, implying that these protocols will rarely find their application in organic syntheses due to lack of generality. Furthermore, most catalysts require multiple reaction steps for their synthesis and hence, are time-consuming and low-yielding. Additionally, inert-atmosphere techniques and expensive starting materials of poor stability are often used for their preparation. This refers to the need of new and improved, cheap and easy accessible, stable and green but reactive and general applicable Heck catalysts with high functional group tolerance that efficiently and reliably operates at low catalyst loadings with general applicable reaction protocols.
Dichloro-bis(aminophosphine) complexes of palladium were recently introduced as easy accessible, cheap and air stable but highly active C-C cross-coupling catalysts with excellent functional group tolerance30-34, of which dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium [(P(NC5H10)3)2Pd(Cl)2] (1) proved to be a highly efficient, reliable, and versatile Heck catalyst that efficiently operates at 100 &#176;C35. 1 was quantitatively prepared within only a few minutes by treatment of THF suspensions of [Pd(Cl)2(cod)] (cod = cycloocta-1,5-diene) with 1,1',1''-(phosphinetriyl)tripiperidine under air atmosphere at 25 &#176;C. 1,1',1''-(phosphinetriyl)tripiperidine, the respective ligand system was achieved in one step by the dropwise addition of an excess of piperidine to cooled diethyl ether solutions of PCl3. The substrate costs for the preparation of 1,1',1''-(phosphinetriyl)tripiperidine for 1 g of palladium precursor is less than 1&#8364; (estimated from catalogue prices of a chemical supplier) and hence, very cheap.
<img ALT="Figure 3" fo:content-width="6in" fo:src="/files/ftp_upload/51444/51444fig3highres.jpg" src="/files/ftp_upload/51444/51444fig3.jpg" /> 
Figure 3. Synthesis of dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium [(P(NC5H10)3)2Pd(Cl)2] (1). <a HREF="https://www.jove.com/files/ftp_upload/51444/51444fig3highres.jpg" target="_blank">Click here to view larger image.</a>
Moreover, despite the simple and cheap synthesis of 1 and its excellent catalytic performance, the addition of aqueous hydrochloric acid (work-up conditions), lead to a rapid and complete catalyst degradation, accompanied by the formation of phosphonate, piperidinium salt, and insoluble palladium-containing decomposition products, which are easily separated from the coupling products. This is an often ignored, but very important issue to be considered (from ecologic and economic points of view) and is of particular importance for the preparation of pharmaceutically relevant compounds.

<table border="0" cellpadding="0" cellspacing="0" width="722">
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Phosphorous&#160; trichloride</td>
			<td style="width:129px;">Sigma-Aldrich</td>
			<td style="width:145px;">157791</td>
			<td style="width:232px;">ReagentPlus, 99%</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Piperidine</td>
			<td style="width:129px;">Sigma-Aldrich</td>
			<td style="width:145px;">104094</td>
			<td style="width:232px;">ReagentPlus, 99%</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Dichloro(1,5-cyclooctadiene)palladium(II)</td>
			<td style="width:129px;">Sigma-Aldrich</td>
			<td style="width:145px;">275891</td>
			<td style="width:232px;">99%</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Styrene</td>
			<td style="width:129px;">Sigma-Aldrich</td>
			<td style="width:145px;">S4972</td>
			<td style="width:232px;">ReagentPlus, contains 4-tert-butylcatechol as stabilizer, &#8805;99%</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">1-Bromo-4-phenoxybenzene</td>
			<td style="width:129px;">Sigma-Aldrich</td>
			<td style="width:145px;">B65209</td>
			<td style="width:232px;">99%</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Tetrabutylammonium bromide</td>
			<td style="width:129px;">Acros Organics</td>
			<td style="width:145px;">185680025</td>
			<td style="width:232px;">99+%</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Potassium carbonate</td>
			<td style="width:129px;">Sigma-Aldrich</td>
			<td style="width:145px;">347825</td>
			<td style="width:232px;">Reagent grade, &#8805;98%, powder, -325 mesh</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Silica gel</td>
			<td style="width:129px;">Merck</td>
			<td style="width:145px;">107734</td>
			<td style="width:232px;">Silica gel 60 (0.063-0.2mm), for column chromatoraphy</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Diethyl ether</td>
			<td style="width:129px;">Sigma-Aldrich</td>
			<td style="width:145px;">673811</td>
			<td style="width:232px;">Anhydrous, ACS reagent, &#8805;99.0%, contains BHT as inhibitor</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Tetrahydrofuran (THF)</td>
			<td style="width:129px;">Sigma-Aldrich</td>
			<td style="width:145px;">186562</td>
			<td style="width:232px;">anhydrous, contains 250 ppm BHT as inhibitor, &#8805;99.9%</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Pentane</td>
			<td style="width:129px;">Sigma-Aldrich</td>
			<td style="width:145px;">158941</td>
			<td style="width:232px;">reagent grade, 98%</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">N-methyl-2-pyrrolidone (NMP)</td>
			<td style="width:129px;">Sigma-Aldrich</td>
			<td style="width:145px;">M79603</td>
			<td style="width:232px;">ReagentPlus, 99%</td>
		</tr>
	</tbody>
</table>

mizoroki-heck cross-coupling reactions catalyzed by dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium under mild reaction conditions

Dichloro-bis(aminophosphine) complexes of palladium with the general formula of [(P{(NC5H10)3-n(C6H11)n})2Pd(Cl)2] (where n = 0-2), belong to a new family of easy accessible, very cheap, and air stable, but highly active and universally applicable C-C cross-coupling catalysts with an excellent functional group tolerance. Dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium [(P(NC5H10)3)2Pd(Cl)2] (1), the least stable complex within this series towards protons; e.g. in the form of water, allows an eased nanoparticle formation and hence, proved to be the most active Heck catalyst within this series at 100 &#176;C and is a very rare example of an effective and versatile catalyst system that efficiently operates under mild reaction conditions. Rapid and complete catalyst degradation under work-up conditions into phosphonates, piperidinium salts and other, palladium-containing decomposition products assure an easy separation of the coupling products from catalyst and ligands. The facile, cheap, and rapid synthesis of 1,1',1"-(phosphinetriyl)tripiperidine and 1 respectively, the simple and convenient use as well as its excellent catalytic performance in the Heck reaction at 100 &#176;C make 1 to one of the most attractive and greenest Heck catalysts available.
We provide here the visualized protocols for the ligand and catalyst syntheses as well as the reaction protocol for Heck reactions performed at 10 mmol scale at 100 &#176;C and show that this catalyst is suitable for its use in organic syntheses.

The above described reaction protocol was successfully applied with styrene (a), 1-ethenyl-3-nitrobenzene (b), 1-chloro-3-ethenylbenzene (c), 1-ethenyl-4-methoxybenzene (d) and 4-ethenylpyridine (e) as well as N,N-dimethylacrylamide (f), 4-acryloylmorpholine (g), and butyl acrylate (h) as coupling partners. Table 1 shows a selection of recently prepared cross-coupling products and gives an impression about the scope of this protocol.35 The coupling products are cleanly formed (Figure 4) and typically obtained in excellent yields within reasonable reaction times. The E-isomer of the arylated olefins is often exclusively formed.
<img alt="Figure 4" fo:content-width="6in" fo:src="/files/ftp_upload/51444/51444fig4highres.jpg" src="/files/ftp_upload/51444/51444fig4.jpg" /> 
Figure 4.&#160;Gas chromatograms recorded from reaction mixtures of the Heck reaction of ethyl 4-bromobenzoate and styrene at 100 &#176;C in DMF in the presence of ~10 mol% of tetrabutylammonium bromide and 0.05 mol% of catalyst, showing the time-dependent product formation. Note that the reaction time is slightly prolonged when compared to the data given in Table 1. This is due to periodical sampling. <a href="https://www.jove.com/files/ftp_upload/51444/51444fig4highres.jpg" target="_blank">Click here to view larger image.</a>
Accordingly, 1 is a cheap, easy accessible and green, stable and hence, convenient but highly reactive Heck catalyst with high functional group tolerance, which efficiently and reliably operates at low catalyst loadings (0.05 mol%) with an easy adaptable and robust reaction protocol.
<img alt="Table 1" fo:content-width="6in" src="/files/ftp_upload/51444/51444table1highres.jpg" width="500" /> 
Table 1. Heck cross-coupling products derived by reactions between aryl bromides and different olefins, catalyzed by 1. Reaction conditions: 1.0 mmol aryl bromide, 1.5 mmol olefin, 2.0 mmol K2CO3, 2.5 ml NMP, tetrabutylammonium bromide (10 mol%), catalyst (0.05 mol%) added in solution (THF), reaction performed at 100 &#176;C under N2 atmosphere. The conversions and product ratios (trans/gem/cis) are determined by GC/MS and are based on aryl bromide. Isolated yields are given in brackets. [a] DMF was used as solvent. <a href="https://www.jove.com/files/ftp_upload/51444/51444table1highres.jpg" target="_blank">Click here to view larger image.</a>
Palladium nanoparticles are the catalytically active form of 1 in the Heck reaction. Hence, increasing amounts of catalyst do not improve but can lower the catalyst&#8217;s performance due to formation of inactive palladium black.
Tetrabutylammonium bromide is known to stabilize nanoparticles and was (in contrast to the Heck reactions performed at 140 &#176;C) found to be essential as additive for the reliable conversion of the substrates into the cross-coupling products with 1 at 100 &#176;C35.
Best results were achieved with DMF when electronically activated or nonactivated aryl bromides were applied to give a2, a5, a6, a7, a13, a17, a18, b1, and h4, for example (Table 1). NMP, however, was found to be the solvent of choice when electronically deactivated and sterically hindered or heterocyclic aryl bromides were coupled with alkenes. Examples include the preparation of a9, a12, a14, c3, d3, d4,e2, e3, f2, f4, g3, g4, h5, and h6 (Table 1).

Watch this Scientific Journal Video about Mizoroki-Heck Cross-coupling Reactions Catalyzed by Dichloro{bis[1,1',1''-phosphinetriyltripiperidine]}palladium Under Mild Reaction Conditions at JoVE.com

Mizoroki-Heck Cross-coupling Reactions Catalyzed by Dichloro{bis[1,1&#039;,1&#039;&#039;-phosphinetriyltripiperidine]}palladium Under Mild Reaction Conditions

Dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium [(P(NC5H10)3)2Pd(Cl)2] (1) is an easy accessible, cheap, and air stable, but highly active Heck catalyst with an excellent functional group tolerance that efficiently operates under mild reaction conditions to give the coupling products in very high yields.

Mizoroki-Heck Cross-coupling Reactions Catalyzed by Dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium Under Mild Reaction Conditions

Dichloro-bis(aminophosphine) complexes of palladium with the general formula of [(P{(NC5H10)3-n(C6H11)n})2Pd(Cl)2] (where n = 0-2), belong to a new family ...

mizoroki-heck-cross-coupling-reactions-catalyzed-dichlorobis11-1

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Particles without a Box: Brush-first Synthesis of Photodegradable PEG Star Polymers under Ambient Conditions

Convenient methods for the rapid, parallel synthesis of diversely functionalized nanoparticles will enable discovery of novel formulations for drug delivery, biological imaging, and supported catalysis. In this report, we demonstrate parallel synthesis of brush-arm star polymer (BASP) nanoparticles by the &#34;brush-first&#34; method. In this method, a norbornene-terminated poly(ethylene glycol) (PEG) macromonomer (PEG-MM) is first polymerized via ring-opening metathesis polymerization (ROMP) to generate a living brush macroinitiator. Aliquots of this initiator stock solution are added to vials that contain varied amounts of a photodegradable bis-norbornene crosslinker. Exposure to crosslinker initiates a series of kinetically-controlled brush+brush and star+star coupling reactions that ultimately yields BASPs with cores comprised of the crosslinker and coronas comprised of PEG. The final BASP size depends on the amount of crosslinker added. We carry out the synthesis of three BASPs on the benchtop with no special precautions to remove air and moisture. The samples are characterized by gel permeation chromatography (GPC); results agreed closely with our previous report that utilized inert (glovebox) conditions. Key practical features, advantages, and potential disadvantages of the brush-first method are discussed.

Poly(ethylene glycol) (PEG) brush-arm star polymers (BASPs) with narrow mass distributions and tunable nanoscopic sizes are synthesized in via ring opening metathesis polymerization (ROMP) of a PEG-norbornene macromonomer followed by transfer of portions of the resulting living brush initiator to vials containing varied amounts of a rigid, photo-cleavable bis-norbornene crosslinker.

Convenient methods for the rapid, parallel synthesis of diversely functionalized nanoparticles will enable discovery of novel formulations for drug ...

Retropinacol/Cross-pinacol Coupling Reactions - A Catalytic Access to 1,2-Unsymmetrical Diols

Unsymmetrical 1,2-diols are hardly accessible by reductive pinacol coupling processes. A successful execution of such a transformation is bound to a clear recognition and strict differentiation of two similar carbonyl compounds (aldehydes &#8594; secondary 1,2-diols or ketones &#8594; tertiary 1,2-diols). This fine-tuning is still a challenge and an unsolved problem for an organic chemist. There exist several reports on successful execution of this transformation but they cannot be generalized. Herein we describe a catalytic direct pinacol coupling process which proceeds via a retropinacol/cross-pinacol coupling sequence. Thus, unsymmetrical substituted 1,2-diols can be accessed with almost quantitative yields by means of an&#160;operationally simple performance under very mild conditions. Artificial techniques, such as syringe-pump techniques or delayed additions of reactants are not necessary. The procedure we describe provides a very rapid access to cross-pinacol products (1,2-diols, vicinal diols). A further extension of this new process, e.g. an enantioselective performance could provide a very useful tool for the synthesis of unsymmetrical chiral 1,2-diols.

A novel account for the synthesis of unsymmetrical 1,2-diols based on a retropinacol/cross-pinacol coupling mechanism is described. Due to the catalytic execution of this reaction a considerable improvement compared to conventional cross-pinacol couplings is achieved.

Unsymmetrical 1,2-diols are hardly accessible by reductive pinacol coupling processes. A successful execution of such a transformation is bound to a clear ...

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides (CHIPS)

The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry. Such transformations can be very powerful in order to streamline synthesis by saving steps, time and material compared to conventional methods that require the introduction and removal of activating or directing groups. Therefore, the functionalization of C-H bonds is also attractive for green chemistry. Under oxidative conditions, two C-H bonds or one C-H and one heteroatom-H bond can be transformed to C-C and C-heteroatom bonds, respectively. Often these oxidative coupling reactions require synthetic oxidants, expensive catalysts or high temperatures. Here, we describe a two-step procedure to functionalize indole derivatives, more specifically tetrahydrocarbazoles, by C-H amination using only elemental oxygen as oxidant. The reaction uses the principle of C-H functionalization via Intermediate PeroxideS (CHIPS). In the first step, a hydroperoxide is generated oxidatively using visible light, a photosensitizer and elemental oxygen. In the second step, the N-nucleophile, an aniline, is introduced by Br&#248;nsted-acid catalyzed activation of the hydroperoxide leaving group. The products of the first and second step often precipitate and can be conveniently filtered off. The synthesis of a biologically active compound is shown.

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides CHIPS

A two-step procedure for the synthesis of pharmaceutically active indole-derivatives by C-H functionalization with anilines is described, using photo- and Br&#248;nsted acid catalysis.

The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry. Such transformations can be very powerful in order ...

A Simple Method for the Size Controlled Synthesis of Stable Oligomeric Clusters of Gold Nanoparticles under Ambient Conditions

Reducing dilute aqueous HAuCl4 with sodium thiocyanate (NaSCN) under alkaline conditions produces 2 to 3 nm diameter nanoparticles. Stable grape-like oligomeric clusters of these yellow nanoparticles of narrow size distribution are synthesized under ambient conditions via two methods. The delay-time method controls the number of subunits in the oligoclusters by varying the time between the addition of HAuCl4 to alkaline solution and the subsequent addition of reducing agent, NaSCN. The yellow oligoclusters produced range in size from ~3 to ~25 nm. This size range can be further extended by an add-on method utilizing hydroxylated gold chloride (Na+[Au(OH4-x)Clx]-) to auto-catalytically increase the number of subunits in the as-synthesized oligocluster nanoparticles, providing a total range of 3 nm to 70 nm. The crude oligocluster preparations display narrow size distributions and do not require further fractionation for most purposes. The oligoclusters formed can be concentrated &#62;300 fold without aggregation and the crude reaction mixtures remain stable for weeks without further processing. Because these oligomeric clusters can be concentrated before derivatization they allow expensive derivatizing agents to be used economically. In addition, we present two models by which predictions of particle size can be made with great accuracy.

We describe a simple method for producing highly stable oligomeric clusters of gold nanoparticles via the reduction of chloroauric acid (HAuCl4) with sodium thiocyanate (NaSCN). The oligoclusters have a narrow size distribution and can be produced with a wide range of sizes and surface coats.

Reducing dilute aqueous HAuCl4 with sodium thiocyanate (NaSCN) under alkaline conditions produces 2 to 3 nm diameter nanoparticles. Stable grape-like ...

Dissolution Dynamic Nuclear Polarization Instrumentation for Real-time Enzymatic Reaction Rate Measurements by NMR

The main limitation of NMR-based investigations is low sensitivity. This prompts for long acquisition times, thus preventing real-time NMR measurements of metabolic transformations. Hyperpolarization via dissolution DNP circumvents part of the sensitivity issues thanks to the large out-of-equilibrium nuclear magnetization stemming from the electron-to-nucleus spin polarization transfer. The high NMR signal obtained can be used to monitor chemical reactions in real time. The downside of hyperpolarized NMR resides in the limited time window available for signal acquisition, which is usually on the order of the nuclear spin longitudinal relaxation time constant, T1, or, in favorable cases, on the order of the relaxation time constant associated with the singlet-state of coupled nuclei, TLLS. Cellular uptake of endogenous molecules and metabolic rates can provide essential information on tumor development and drug response. Numerous previous hyperpolarized NMR studies have demonstrated the relevancy of pyruvate as a metabolic substrate for monitoring enzymatic activity in vivo. This work provides a detailed description of the experimental setup and methods required for the study of enzymatic reactions, in particular the pyruvate-to-lactate conversion rate in presence of lactate dehydrogenase (LDH), by hyperpolarized NMR.

The sensitivity enhancement provided by dissolution dynamic nuclear polarization (DNP) enables following metabolic processes in real time by NMR and MRI. The characteristics and performances of a dedicated dissolution DNP setup designed for study enzymatic reactions are discussed.

The main limitation of NMR-based investigations is low sensitivity. This prompts for long acquisition times, thus preventing real-time NMR measurements of ...

Preparation of a Corannulene-functionalized Hexahelicene by Copper(I)-catalyzed Alkyne-azide Cycloaddition of Nonplanar Polyaromatic Units

The main purpose of this video is to show 6 reaction steps of a convergent synthesis and prepare a complex molecule containing up to three nonplanar polyaromatic units, which are two corannulene moieties and a racemic hexahelicene linking them. The compound described in this work is a good host for fullerenes. Several common organic reactions, such as free-radical reactions, C-C coupling or click chemistry, are employed demonstrating the versatility of functionalization that this compound can accept. All of these reactions work for planar aromatic molecules. With subtle modifications, it is possible to achieve similar results for nonplanar polyaromatic compounds.

Preparation of a Corannulene-functionalized Hexahelicene by CopperI-catalyzed Alkyne-azide Cycloaddition of Nonplanar Polyaromatic Units

Here, we present a protocol to synthesize a complex organic compound comprised of three nonplanar polyaromatic units, assembled easily with reasonable yields.

The main purpose of this video is to show 6 reaction steps of a convergent synthesis and prepare a complex molecule containing up to three nonplanar ...

A Simple, Low-cost, and Robust System to Measure the Volume of Hydrogen Evolved by Chemical Reactions with Aqueous Solutions

There is a growing research interest in the development of portable systems which can deliver hydrogen on-demand to proton exchange membrane (PEM) hydrogen fuel cells. Researchers seeking to develop such systems require a method of measuring the generated hydrogen. Herein, we describe a simple, low-cost, and robust method to measure the hydrogen generated from the reaction of solids with aqueous solutions. The reactions are conducted in a conventional one-necked round-bottomed flask placed in a temperature controlled water bath. The hydrogen generated from the reaction in the flask is channeled through tubing into a water-filled inverted measuring cylinder. The water displaced from the measuring cylinder by the incoming gas is diverted into a beaker on a balance. The balance is connected to a computer, and the change in the mass reading of the balance over time is recorded using data collection and spreadsheet software programs. The data can then be approximately corrected for water vapor using the method described herein, and parameters such as the total hydrogen yield, the hydrogen generation rate, and the induction period can also be deduced. The size of the measuring cylinder and the resolution of the balance can be changed to adapt the setup to different hydrogen volumes and flow rates.

The study of methods to generate on-demand hydrogen for fuel cells continues to grow in importance. However, systems to measure hydrogen evolution from the reaction of chemicals with water can be complicated and expensive. This article details a simple, low-cost, and robust method to measure the evolution of hydrogen gas.

There is a growing research interest in the development of portable systems which can deliver hydrogen on-demand to proton exchange membrane (PEM) ...

A Protocol for Safe Lithiation Reactions Using Organolithium Reagents

Organolithium reagents are powerful tools in the synthetic chemist&#39;s toolbox. However, the extreme pyrophoric nature of the most reactive reagents warrants proper technique, thorough training, and proper personal protective equipment. To aid in the training of researchers using organolithium reagents, a thorough, step-by-step protocol for the safe and effective use of tert-butyllithium on an inert gas line or within a glovebox is described. As a model reaction, preparation of lithium tert-butyl amide by the reaction of tert-butyl amine with one equivalent of tert-butyl lithium is presented.

The safe and proper use of organolithium reagents is described.

Organolithium reagents are powerful tools in the synthetic chemist&#39;s toolbox. However, the extreme pyrophoric nature of the most reactive reagents ...

Phase Behavior of Charged Vesicles Under Symmetric and Asymmetric Solution Conditions Monitored with Fluorescence Microscopy

Phase-separated giant unilamellar vesicles (GUVs) exhibiting coexisting liquid-ordered and liquid-disordered domains are a common biophysical tool to investigate the lipid raft hypothesis. Numerous studies, however, neglect the impact of physiological solution conditions. On that account, the current work presents the effect of high-salinity buffer and trans-membrane solution asymmetry on liquid-liquid phase separation in charged GUVs grown from dioleylphosphatidylglycerol, egg sphingomyelin, and cholesterol. The effects were studied under isothermal and varying temperature conditions.
We describe equipment and experimental strategies applicable for monitoring the stability of coexisting liquid domains in charged vesicles under symmetric and asymmetric high-salinity solution conditions. This includes an approach to prepare charged multicomponent GUVs in high-salinity buffer at high temperatures. The protocol entails the option to perform a partial exchange of the external solution by a simple dilution step while minimizing the vesicle dilution. An alternative approach is presented utilizing a microfluidic device that allows for a complete external solution exchange. The solution effects on phase separation were also studied under varying temperatures. To this end, we present the basic design and utility of an in-house built temperature control chamber. Furthermore, we reflect on the assessment of the GUV phase state, pitfalls associated with it and how to circumvent them.

Experiments on phase separated giant unilamellar vesicles (GUVs) frequently neglect physiological solution conditions. This work presents approaches to study the effect of high-salinity buffer on liquid-liquid phase separation in charged multicomponent GUVs as a function of trans-membrane solution asymmetry and temperature.

Phase-separated giant unilamellar vesicles (GUVs) exhibiting coexisting liquid-ordered and liquid-disordered domains are a common biophysical tool to ...

Extraction of Lignin with High &#946;-O-4 Content by Mild Ethanol Extraction and Its Effect on the Depolymerization Yield

Lignin valorization strategies are a key factor for achieving more economically competitive biorefineries based on lignocellulosic biomass. Most of the emerging elegant procedures to obtain specific aromatic products rely on the lignin substrate having a high content of the readily cleavable &#946;-O-4 linkage as present in the native lignin structure. This provides a miss-match with typical technical lignins that are highly degraded and therefore are low in &#946;-O-4 linkages. Therefore, the extraction yields, and the quality of the obtained lignin are of utmost importance to access new lignin valorization pathways. In this manuscript, a simple protocol is presented to obtain lignins with high &#946;-O-4 content by relatively mild ethanol extraction that can be applied to different lignocellulose sources. Furthermore, analysis procedures to determine the quality of the lignins are presented together with a depolymerization protocol that yields specific phenolic 2-arylmethyl-1,3-dioxolanes, which can be used to evaluate the obtained lignins. The presented results demonstrate the link between lignin quality and potential for the lignins to be depolymerized into specific monomeric aromatic chemicals. Overall, the extraction and depolymerization demonstrates a trade-off between the lignin extraction yield and the retention of the native aryl-ether structure and thus the potential of the lignin to be used as the substrate for the production of chemicals for higher-value applications.

Extraction of Lignin with High &amp;#946;-O-4 Content by Mild Ethanol Extraction and Its Effect on the Depolymerization Yield

Here, we present a protocol to perform ethanol extraction of lignin from several biomass sources. The effect of the extraction conditions on the lignin yield and &#946;-O-4 content are presented. Selective depolymerization is performed on the obtained lignins to obtain high aromatic monomer products.

Lignin valorization strategies are a key factor for achieving more economically competitive biorefineries based on lignocellulosic biomass. Most of the ...