Name: [(dpephos)(bcp)cu]pf6: a general and broadly applicable copper-based photoredox catalyst
Uploaded: 2019-05-21T14:45:00
Description: Watch this Scientific Journal Video about [DPEPhosbcpCu]PF6: A General and Broadly Applicable Copper-Based Photoredox Catalyst at JoVE.com

This work was supported by the Universit&#233; libre de Bruxelles (ULB), the F&#233;d&#233;ration Wallonie-Bruxelles (ARC Consolidator 2014-2019), Innoviris (project PhotoCop), and the COST action CM1202. H.B. acknowledges the Fonds pour la formation &#224; la Recherche dans l&#8217;Industrie et dans l&#8217;Agriculture (F.R.I.A.) for graduate fellowship. C.T. acknowledges the Fonds de la Recherche Scientifique (FNRS) for research fellowship.

1. Synthesis of [(DPEPhos)(bcp)Cu]PF6
<ol>
	<li>Add 3.73 g (10.00 mmol) of tetrakisacetonitrile copper(I) hexafluorophosphate and 5.39 g (10.00 mmol) of DPEPhos to a 2 L round bottom flask equipped with a magnetic stir bar.</li>
	<li>Fit the round bottom flask with a three neck vacuum adapter connected to a vacuum line and an argon line.</li>
	<li>Evacuate the flask under vacuum and backfill with argon three times. Replace the three neck vacuum adapter by a rubber septum. 
	NOTE: The reaction can be per...

<ol>
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Synthesis of [(DPEPhos)(bcp)Cu]PF6 
The synthesis of [(DPEPhos)(bcp)Cu]PF6 is typically performed using dry dichloromethane (distilled prior to use) and under argon to ensure the highest yield, purity and good reproducibility. As mentioned in the protocol, the synthesis of [(DPEPhos)(bcp)Cu]PF6 can be performed with regular dichloromethane (99.8%) and/or under air with variable efficiencies. Indeed, while the use of regular dichloromethane under argon afforded the sa...

Radical transformations have been known for decades to provide remarkably efficient pathways in synthetic chemistry which are often complementary to transformations based on cationic, anionic or pericyclic processes1. While particularly promising for various types of transformations, radical-based chemistry has however long been underexploited, mainly because of the need for highly toxic reagents which considerably limits its attractiveness. Moreover, radical processes have long been considered as transformations associated with poor levels of control in terms of regio- and/or stereoselectivity, or leading to extensive dimerization and/or polymerization issues.
Alternative strategies have recently been developed in order to facilitate the generation and better control the reactivity of radical species. Among them, photoredox catalysis has become one of the most powerful methods as it allows the convenient generation of radical species using a light-responsive compound, namely the photoredox catalyst, and visible light irradiation2,3. Visible light itself is indeed able to promote population of the excited state of the photoredox catalyst which becomes, consequently, both a stronger reductant and oxidant than in its corresponding ground state. These enhanced redox properties make single-electron transfer processes, not feasible in the ground state, possible under mild conditions from the excited state. Over the past decade, visible light photoredox catalysis has become an attractive and powerful technique in organic synthesis and has allowed the development of numerous remarkably efficient and selective transformations based on radical intermediates generated under sustainable, mild and user-friendly conditions.
While most photoredox processes reported to date are dominated by the use of iridium- and ruthenium-based photoredox catalysts, as well as by some organic dyes such as pyrylium and acridinium derivatives4, cheaper alternatives are still highly demanded for the development of complementary processes of interest for industrial applications. In this regard, the use of copper-based photoredox catalysts appears particularly appealing as they are not only cheaper but also provide opportunities to activate a broader and/or different range of substrates, which therefore opens new perspectives in photoredox catalysis5,6,7,8. Despite some promising early works reported by the Kutal9, Mitani10&#160;and Sauvage11&#160;groups, photoactivatable copper complexes have, however, only been scarcely used in photoredox catalysis, most probably because of their short-lived excited states compared to their ruthenium- and iridium-based congeners. More recently, recent remarkable contributions by Peters and Fu12,13,14,15, Reiser16,17,18,19,20&#160;and other groups21,22,23,24,25&#160;have clearly brought attention back to copper-based photoredox catalysts and demonstrated their unique potential.
As part of our recent interest in copper-catalyzed radical processes26,27, we recently reported a general and broadly applicable copper-based photoredox catalyst, [(DPEPhos)(bcp)Cu]PF6 (DPEPhos: bis[(2-diphenylphosphino)phenyl] ether; bcp: bathocuproine), which turned out to be particularly efficient for the activation of organic halides under visible light irradiation (Figure 1A)28,29,30. Upon irradiation with visible light and in the presence of an amine as sacrificial reductant, a wide range of unactivated aryl and alkyl halides was shown to be easily activated by catalytic amounts of [(DPEPhos)(bcp)Cu]PF6 and therefore to participate in various radical transformations including reductions, cyclizations and direct arylation of several electron-rich (hetero)arenes. Furthermore, [(DPEPhos)(bcp)Cu]PF6 has also proven successful at promoting photoinduced radical domino cyclizations of ynamides and cyanamides, providing an efficient and straightforward access to complex tri-, tetra- and pentacyclic nitrogen heterocycles at the core structures of various natural products. This strategy permitted the efficient synthesis of rosettacin, luotonin A, and deoxyvasicinone, natural products that exhibit anticancer, antimicrobial, anti-inflammatory and antidepressant activities. These transformations are illustrated in Figure 1C. From a mechanistic standpoint, the photoinduced activation of organic halides with [(DPEPhos)(bcp)Cu]PF6 proceeds through a rare Cu(I)/Cu(I)*/Cu(0) catalytic cycle, which has been confirmed by extensive mechanistic and photophysical studies. In particular, excitation of the ground state [(DPEPhos)(bcp)Cu]PF6 [Cu(I)] upon irradiation by visible light leads to the formation of the corresponding excited complex [(DPEPhos)(bcp)Cu]PF6* [Cu(I)*] which is then reduced by the sacrificial amine to generate the corresponding [(DPEPhos)(bcp)Cu]PF6 [Cu(0)] species. This Cu(0) intermediate is reductive&#160;enough to reduce the carbon&#8211;halogen bond of various organic halides to generate the corresponding radicals, which can then participate in the aforementioned transformations, together with regeneration of the starting catalyst (Figure 1B).
In the following section, we first describe the protocol to synthesize the photoactivatable [(DPEPhos)(bcp)Cu]PF6 (whose NMR and spectroscopic characterizations are presented in the representative results section). The synthesis is straightforward and particularly convenient, and simply requires addition of 1 equivalent of DPEPhos and 1 equivalent of bcp to a solution of tetrakisacetonitrile copper(I) hexafluorophosphate in dichloromethane. The desired [(DPEPhos)(bcp)Cu]PF6 is then isolated by precipitation from diethyl ether and can be easily obtained on a multigram scale (Figure 2A). Importantly, the isolated copper complex is not particularly sensitive to oxygen and moisture and can therefore be conveniently handled with no specific precautions other than being stored away from light.
Secondly, we describe the protocols to activate organic halides using [(DPEPhos)(bcp)Cu]PF6 under visible light irradiation by focusing on two different transformations. The first reaction is the direct arylation of N-methylpyrrole with 4-iodobenzonitrile using catalytic amounts of [(DPEPhos)(bcp)Cu]PF6 as photoredox catalyst, dicyclohexylisobutylamine as the sacrificial reductant and potassium carbonate as the base under irradiation at 420 nm (Figure 2B). The second reaction is the radical cyclization of N-benzoyl-N-[(2-iodoquinolin-3-yl)methyl]cyanamide, using the same catalyst and sacrificial reductant, whose cyclization directly leads to luotonin A, a natural product displaying interesting anticancer activities (Figure 2C). Detailed protocols are provided for both transformations.

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		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Bathocuproine (bcp)</td>
			<td style="width:71px;">Acros</td>
			<td style="width:119px;">161340010</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Acetonitrile, 99.9+</td>
			<td style="width:71px;">Acros</td>
			<td style="width:119px;">326811000</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Celite 545</td>
			<td style="width:71px;">Acros</td>
			<td style="width:119px;">349670025</td>
			<td></td>
		</tr>
		<tr height="63">
			<td height="63" style="height:63px;width:216px;">Bis[(2-diphenylphosphino)phenyl] ether (DPEphos)</td>
			<td style="width:71px;">Acros</td>
			<td style="width:119px;">383370050</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Calcium hydride</td>
			<td style="width:71px;">Acros</td>
			<td style="width:119px;">C/1620/48</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Dichloromethane, 99.8%</td>
			<td style="width:71px;">Fisher Chemical</td>
			<td style="width:119px;">D/1852/25</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Dietyl ether, &#62;= 99%</td>
			<td style="width:71px;">Fisher Chemical</td>
			<td style="width:119px;">D/2400/MS21</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Ethyl acetate</td>
			<td style="width:71px;">Fisher Chemical</td>
			<td style="width:119px;">E/0900/25</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">N-Methylpyrrole, 99%</td>
			<td style="width:71px;">Sigma Aldrich</td>
			<td style="width:119px;">M78801</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">4-Iodobenzonitrile, 98%</td>
			<td style="width:71px;">Combi-Blocks</td>
			<td style="width:119px;">OR-3151</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Petroleum ether (40-60 &#176;)</td>
			<td style="width:71px;">Fisher Chemical</td>
			<td style="width:119px;">P/1760/25</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Potassium carbonate, anhydrous</td>
			<td style="width:71px;">Fisher Chemical</td>
			<td style="width:119px;">P/4120/60</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Tetrakisacetonitrile copper(I) hexafluorophosphate, 97%</td>
			<td style="width:71px;">Sigma Aldrich</td>
			<td style="width:119px;">346276</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Equipment</td>
			<td style="width:71px;"></td>
			<td style="width:119px;"></td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">1H and 13C NMR spectrometer</td>
			<td style="width:71px;">Bruker</td>
			<td style="width:119px;">Avance 300 Spectrometer</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">1H and 13C NMR spectrometer</td>
			<td style="width:71px;">Varian</td>
			<td style="width:119px;">VNMRS 400 Spectrometer</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">420 nm light tubes</td>
			<td style="width:71px;">Luzchem</td>
			<td style="width:119px;">LZC-420</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Blue LEDs lamp</td>
			<td style="width:71px;">Kessil</td>
			<td style="width:119px;">H150-Blue</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Blue LEDs strips</td>
			<td style="width:71px;">Eglo</td>
			<td style="width:119px;">92065</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Photochemistry Device PhotoRedOx Box</td>
			<td style="width:71px;">Hepatochem</td>
			<td style="width:119px;">HCK1006-01-016</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Photoreactor</td>
			<td style="width:71px;">Luzchem</td>
			<td style="width:119px;">CCP-4V</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Spectrofluorimeter</td>
			<td style="width:71px;">Shimadzu</td>
			<td style="width:119px;">RF-5301PC</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">UV/Vis spectrometer</td>
			<td style="width:71px;">Perkin Elmer</td>
			<td style="width:119px;">Lambda 40</td>
			<td></td>
		</tr>
	</tbody>
</table>

[(dpephos)(bcp)cu]pf6: a general and broadly applicable copper-based photoredox catalyst

Our group recently reported the use of [(DPEPhos)(bcp)Cu]PF6 as a general copper-based photoredox catalyst which proved efficient to promote the activation of a broad variety of organic halides, including unactivated ones. These can then participate in various radical transformations such as reduction and cyclization reactions, as well as in the direct arylation of several (hetero)arenes. These transformations provide a straightforward access to a range of small molecules of interest in synthetic chemistry, as well as to biologically active natural products. Altogether, [(DPEPhos)(bcp)Cu]PF6 acts as a convenient photoredox catalyst which appears to be an attractive, cheap and complementary alternative to the state-of-the-art iridium- and ruthenium-based photoredox catalysts. Here, we report a detailed protocol for the synthesis of [(DPEPhos)(bcp)Cu]PF6, as well as NMR and spectroscopic characterizations, and we illustrate its use in synthetic chemistry for the direct arylation of (hetero)arenes and radical cyclization of organic halides. In particular, the direct arylation of N-methylpyrrole with 4-iodobenzonitrile to afford&#160;4-(1-methyl-1H-pyrrol-2-yl)benzonitrile and the radical cyclization of N-benzoyl-N-[(2-iodoquinolin-3-yl)methyl]cyanamide to afford natural product luotonin A are detailed. The scope and limitations of this copper-based photoredox catalyst are also briefly discussed.

Synthesis of [(DPEPhos)(bcp)Cu]PF6 
As shown by the protocol described in the above section, the synthesis of [(DPEPhos)(bcp)Cu]PF6 is particularly convenient and can be easily performed on a multigram scale. The 1H and 13C NMR spectra indicate formation of the pure complex (Figure 4A,B). The spectroscopic data correspond to those previously reported31.
...

Watch this Scientific Journal Video about [DPEPhosbcpCu]PF6: A General and Broadly Applicable Copper-Based Photoredox Catalyst at JoVE.com

[DPEPhosbcpCu]PF6: A General and Broadly Applicable Copper-Based Photoredox Catalyst

Detailed and general protocols are presented for the synthesis of [(DPEPhos)(bcp)Cu]PF6, a general copper-based photoredox catalyst, and for its use in synthetic chemistry for the direct arylation of C-H bonds in (hetero)arenes and radical cyclization of organic halides.

[(DPEPhos)(bcp)Cu]PF6: A General and Broadly Applicable Copper-Based Photoredox Catalyst

Our group recently reported the use of [(DPEPhos)(bcp)Cu]PF6 as a general copper-based photoredox catalyst which proved efficient to promote the ...

Photoredox catalysis has emerged over the past decade as one of the most efficient methods to promote radical processes. It is indeed especially easy to implement, user-friendly, highly sustainable, and also it does not rely on the use of toxic or hazardous reagents that are usually used in radical chemistry. The main principle of photoredox catalysis is very simple, since, as you can tell by the name, it is based on the use of light-responsive compound called the photoredox catalyst that can be easily activated by irradiation with visible light in order to initiate the catalytic cycle.Among all photoredox catalysts that have been reported and utilized to date, most of them are actually based on ruthenium and iridium complexes which pose a rather strong limitation due to the high prices. As a consequence, the development of alternative photoredox catalysts that are based on cheaper and non-noble metals such as copper is therefore highly important not only for the development of less expensive systems but also for new applications. This was a main motivation when we started the synthesis and the development of this new copper-based photoredox catalyst whose synthesis is presented in this video together with synthetic applications.In addition to the role for chemical syntheis, copper-based catalysts could also play a role in photocatalysis, for instance, in a water reduction or carbon dioxide reduction which is very important for clean energy production and storage and also for the pollution. The procedures will be demonstrated by two PhD students from my lab, Ms.Hajar Baguia and Mr.Jerome Beaudelot. To begin, add 10 millimoles of tetrakisacetonitrile copper(I)hexafluorophosphate and 10 millimoles of DPEPhos to a two liter round bottom flask equipped with a magnetic stir bar.Fit the round bottom flask with a three neck vacuum adapter connected to a vacuum line and a balloon filled with argon. Turn the adapter to evacuate the flask for one minute and then turn it again to backfill the flask with argon. Repeat this cycle two times.Replace the three neck vacuum adapter by a rubber septum with a balloon of argon. Through a needle, add 800 milliliters of distilled dichloromethane and wrap the flask with aluminum foil to block light. Place the flask on a magnetic stirrer and stir the reaction mixture for two hours at approximately 23 to 25 degrees Celsius under the argon atmosphere.After that, add 10 millimoles of bcp to a 500 milliliter round bottom flask equipped with a magnetic stir bar. Fit the round bottom flask with a three neck vacuum adapter connected to a vacuum line and a balloon filled with argon. Evacuate the flask under vacuum and backfill with argon three times.Replace the three neck vacuum adapter by a rubber septum with a balloon of argon. Through a needle, add 200 milliliters of distilled dichloromethane and gently stir the suspension until complete dissolution of the bcp. Equip a cannula to the two rubber septa on the two liter and 500 milliliter flasks with the end of the canula submerged in the solution in the 500 milliliter flask.Remove the balloon of argon from the two liter flask to transfer the whole content of the smaller flask to the bigger flask. Then, put the balloon of argon back on the two liter flask. Stir for an additional hour in the dark at approximately 23 to 25 degrees Celsius under an argon atmosphere.Next, place a pad of celite in a fritted funnel on top of a flask and filter the mixture. Wash with approximately 100 milliliters of distilled dichloromethane. Then, place the flask on a rotary evaporator to concentrate the filtrate to a volume between 50 to 100 milliliters under reduced pressure.Use an addition funnel to add the concentrate drop-wise to one liter of diethyl ether on a magnetic stirrer with vigorous stirring to induce precipitation of the desired complex. Now, collect the precipitate by filtration through a fritted funnel with a pore size of three micrometers on top of a Buchner flask and wash the precipitate with approximately 100 milliliters of diethyl ether. Dry the bright yellow precipitate under vacuum at room temperature for five hours to recover 10.1 grams equaling 91%yield of the copper complex.First, in an oven-dried 10 milliliter vial, add 0.05 millimoles of the synthesized catalyst, 0.25 millimoles of dicyclohexyl isobutylamine, one millimole of potassium carbonate, and 0.5 millimoles of 4-iodobenzonitrile. Place a magnetic stir bar. Seal the vial with rubber septum.Connect the vial to a rubber line connecting to vacuum, evacuate the vial under vacuum for 30 seconds, and backfill with argon three times. Then, through the septum, add five milliliters of freshly distilled and degassed acetonitrile and 890 microliters of n-methylpyrrole to the vial. Replace the rubber septum by a screw cap.Place the vial in a photoreactor under 420-nanometer-wavelength irradiation and stir the reaction mixture for three days at approximately 23 to 25 degrees Celsius. Blue LED strips or a blue LED lamp at 440 nanometers and 34 watts can be used instead. After three days, filter the reaction mixture through a pad of celite.Wash with approximately five milliliters of diethyl ether and concentrate the filtrate under reduced pressure on a rotary evaporator. Next, dissolve the concentrate with the minimum amount of solvent and place it on top of a column chromatography to start purifying the crude residue over silica gel. After that, place the content of all tubes containing the pure product in a flask and concentrate on a rotary evaporator.Place the flask on a vacuum line to dry the pure compound at room temperature for three hours in order to recover 65 milligrams equaling 72%healed of the desired C2 arylated pyrrole. In this protocol, the synthesis of DPEPhos bcp copper(I)hexafluorophosphate is particularly convenient and can be easily performed on a multigram scale. The proton and carbon-13 NMR spectra indicate formation of the pure complex.The UV and visible light absorption spectrum displays two main absorption bands with two maxima at 385 nanometers and 485 nanometers. The emission spectrum obtained by excitation at 445 nanometers displays maximum at 535 nanometers. As for the characterization of the C2 arylated pyrrole, the proton and carbon-13 NMR spectra indicate formation of the pure compound.The photocatalyst can be used for the synthesis of other molecules as exemplified with the total synthesis of the anti-cancer agent, luotonin A, which demonstrated a good purity shown by its proton and carbon-13 NMR spectra. One of the most important things to remember is that molecular oxygen can be activated by the photocatalyst and induce side reaction. As a consequence, all reactions should therefore be performed under argon and with strict exclusion of oxygen.Copper-based photoredox catalyst can be utilized in other areas of photocatalysis and other copper complexes are being developed and studied right now. The photoreactor emits strong light and care should therefore be taken to turn it on only after closing the door. And to avoid any further exposure, UV-filtering goggles should be worn in addition.

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