Una subvención de puesta en marcha de la Universidad de Ariel y una beca de investigación Individual de ISF (1914/15) a AMS se agradece.

1. preparación de las especies de Enolonium
PRECAUCIÓN: Antes de realizar el protocolo, consulte la MSDS para todos los reactivos y solventes.
Nota: Todos los reactivos fueron utilizados como proveniente de la fuente comercial. Si se ha guardado el eterato de trifluoruro de boro, destilar antes de su uso.
<ol><li>En un lugar seco redondo matraz fondo equipado con un tabique y un imán para agitación magnética, agregar reactivo de Koser (1.5 equiv) y enjuague el matraz con nitrógeno o argón.</li>
	<li>Añadir diclorometano seco para dar una suspensión de concentración formal de 0.234 mol/L.</li>
	<li>Enfríe la suspensión a-78 ° C utilizando un baño de hielo seco/acetona o un baño de acetona/instrumento de dedo frío.</li>
	<li>Añadir aseado BF3OEt2 (1.5 equiv) lentamente.</li>
	<li>Caliente la mezcla heterogénea a temperatura ambiente hasta la formación de la solución amarilla. Por lo general, esto sucede dentro de 5 minutos.</li>
	<li>Enfriar la solución a-78 ° C.</li>
	<li>A la solución enfriada, añadir lo trimetilsilil-enolether (1 equiv, 0,313 mol/L) en diclorometano seco gota a gota sobre el 2-10 minutos (dependiendo de la escala). Después de la adición de éter de enol de sililo es completa, la formación de las especies de enolonium es completa. Nota: La solución de enolonium especies puede dejarse a-78 ° C durante al menos 30 min con ningún deterioro en el rendimiento. La especie enolonium es estable durante este tiempo según lo indicado por divulgado NMR estudios6.</li>
</ol>2. funcionalización de las especies de Enolonium
<ol><li>Cloración con el anión cloruro
	<ol>
<li>Añadir a la solución preparada de especies enolonium, bencil-dimetil-decylammonium cloruro (2.0 equiv, 1,25 mol/L) en diclorometano seco de una manera sabia de gota. Añadir esta solución a un ritmo tal que la temperatura permanezca por debajo de-55 ° C. En el 0.5-2 mmol de escala, además de más de 5 min es satisfactorio.</li>
		<li>Dejar la mezcla de reacción a-78 ° C durante 5 minutos.</li>
		<li>Retirar del baño de enfriamiento y permitir la mezcla de reacción a temperatura ambiente.</li>
		<li>Dejar la reacción a temperatura ambiente durante 20 minutos.</li>
		<li>Añadir agua a la mezcla de reacción (la mitad el volumen de diclorometano que se utiliza en la preparación de las especies de enolonium).</li>
		<li>Extraer tres veces con diclorometano. Normalmente, utilizar 2 - 3 veces el volumen de reacción en cada extracción en 0.5-2 mmol de pequeña escala.</li>
		<li>Lavar las capas orgánicas combinadas dos veces con salmuera. Normalmente, utilizar el mismo volumen de la salmuera como el volumen de reacción combinado.</li>
		<li>Seca con sulfato de sodio anhidro durante 30 minutos.</li>
		<li>Filtro del sulfato de sodio (por ejemplo, a través de un enchufe de Celite).</li>
		<li>Eliminar el solvente en un evaporador rotatorio a presión reducida y a 40 ° C.</li>
		<li>Purifique el producto crudo por cromatografía en columna sobre gel de sílice con eluyentes hexano y acetato de etilo para permitir, después de la eliminación de los solventes, el puro cetona correspondiente de α-azido. Nota: En las escalas de 0.5 mmol a 2 mmol de Trimetilsililo enolate, realizar cromatografía de columna en una columna de vidrio de 2 cm de diámetro con estándar del gel de sílice 60 a una altura (longitud) de 15 cm. El volumen tendrá que variar para otras escalas.</li>
	</ol></li>
	<li>Azidation TMS de azida PRECAUCIÓN: Azidas orgánicas en general son explosivos y debe tenerse cuidado en la manipulación y preparación de los productos. TMS-azida es tóxica. Consulte MSDS antes de usar.<ol>
<li>Añadir a la solución preparada de especies enolonium en-78 ° C, azidotrimethylsilane aseado (2.5 equiv) en forma de gota a gota. Añadir esta solución a un ritmo por lo que la temperatura permanezca por debajo de-55 ° C. En el 0.5-2 mmol de escala, además de sobre 2-3 minutos es satisfactorio.</li>
		<li>Revuelva la mezcla de reacción durante 15 min a-78 ° C.</li>
		<li>La mezcla de reacción a-55 ° C y dejar a esta temperatura durante 2 a 3 h.</li>
		<li>Añadir agua a la mezcla de reacción (la mitad el volumen de diclorometano que se utiliza en la preparación de las especies de enolonium).</li>
		<li>Extraer tres veces con diclorometano. Normalmente, utilizar 2 - 3 veces el volumen de reacción en cada extracción en 0.5-2 mmol de pequeña escala.</li>
		<li>Lavar las capas orgánicas combinadas dos veces con salmuera. Normalmente, utilizar el mismo volumen de la salmuera como el volumen de reacción combinado.</li>
		<li>Secar los extractos con sulfato de sodio anhidro durante 30 minutos.</li>
		<li>Filtro del sulfato de sodio.</li>
		<li>Eliminar el solvente en un evaporador rotatorio a presión reducida y a 40 ° C.</li>
		<li>Purifique el producto crudo por cromatografía en columna sobre gel de sílice con eluyentes hexano y acetato de etilo para permitir, después de la eliminación de los solventes, el puro cetona correspondiente de α-azido.</li>
	</ol></li>
	<li>Reacción con azoles
	<ol>
<li>Añadir a la solución preparada de especies enolonium en-78 ° C, azole (4 a 5 equiv, 1 mol/L) disuelto en 5 mL de diclorometano en forma gota a gota. En el 0.5-2 mmol de escala, además de más de 5 min es satisfactorio. Nota: En el caso de azoles poco solubles como tetrazoles, utilizar acetonitrilo en una concentración de 0,5 mol/L en lugar de diclorometano. Añadir esta solución a un ritmo por lo que la temperatura permanezca por debajo de-55 ° C.</li>
		<li>Revuelva la mezcla de reacción durante 15 min a-78 ° C.</li>
		<li>La mezcla de reacción a-55 ° C y dejar a esta temperatura durante 4 a 8 h.</li>
		<li>Añadir agua a la mezcla de reacción (la mitad el volumen de disolventes orgánicos utilizados en la preparación de las especies de enolonium).</li>
		<li>Extraer tres veces con diclorometano. Normalmente, utilizar 2 - 3 veces el volumen de reacción en cada extracción en 0.5-2 mmol de pequeña escala.</li>
		<li>Lavar las capas orgánicas combinadas dos veces con salmuera. Normalmente, utilizar el mismo volumen de la salmuera como el volumen de reacción combinado.</li>
		<li>Secar los extractos con sulfato de sodio anhidro durante 30 minutos.</li>
		<li>Filtro del sulfato de sodio.</li>
		<li>Eliminar el solvente en un evaporador rotatorio a presión reducida y a 40 ° C.</li>
		<li>Purifique el producto crudo por cromatografía en columna sobre gel de sílice con eluyentes hexano y acetato de etilo para permitir, después de la eliminación de los solventes, el puro cetona correspondiente de α-azoles.</li>
	</ol></li>
	<li>Allylation, crotylation, cinnamylation y Prenilación con alílico-silanes
	<ol>
<li>Añadir alílico aseada, crotyl, cinamil-, o prenyl trimetilsilano (2 equiv) lentamente a-78 ° C. Añadir esta solución a un ritmo por lo que la temperatura permanezca por debajo de-55 ° C. En un 0.5-2 mmol de escala, además de sobre 2-3 minutos es satisfactorio.</li>
		<li>Revuelva la mezcla de reacción durante 10 min a-78 ° C.</li>
		<li>Deje que la mezcla de reacción calentar lentamente a temperatura ambiente quitando el baño que se refresca. Dejar la reacción a temperatura ambiente durante 20 minutos.</li>
		<li>Añadir agua a la mezcla de reacción (la mitad el volumen de diclorometano que se utiliza en la preparación de las especies de enolonium).</li>
		<li>Extraer tres veces con diclorometano. Normalmente, utilizar 2 - 3 veces el volumen de reacción en cada extracción en 0.5-2 mmol de pequeña escala.</li>
		<li>Lavar las capas orgánicas combinadas dos veces con salmuera. Normalmente, utilizar el mismo volumen de la salmuera como el volumen de reacción combinado.</li>
		<li>Secar los extractos con sulfato de sodio anhidro durante 30 minutos.</li>
		<li>Filtro del sulfato de sodio.</li>
		<li>Eliminar el solvente en un evaporador rotatorio a presión reducida y a 40 ° C.</li>
		<li>Purifique el producto crudo por cromatografía en columna sobre gel de sílice con eluyentes hexano y acetato de etilo para permitir, después de la eliminación de los solventes, el puro producto de α-alílico correspondiente.</li>
	</ol></li>
	<li>Arilación Nota: Para cetonas, utilice 3 equivalentes de BF3OEt2 durante la preparación de las especies de enolonium para evitar tosylation de las especies de enolonium como una reacción del lado mayor. En general, se necesita solamente 1.6 equivalente del sustrato aromático. Sin embargo, si el sustrato aromático es un pyrane tiofeno y pirrol, los mejores resultados se consiguen utilizando 5 equivalentes del sustrato aromático.<ol>
<li>A la solución de enolonium preparado especies agregar una solución de sustrato aromático en diclorometano seco (1.6 equiv, 0,5 mol/L) en forma de gota a gota. Añadir esta solución a un ritmo por lo que la temperatura permanezca por debajo de-55 ° C. En el 0.5-2 escala mmol, durante 5-10 min es satisfactoria.</li>
		<li>Una vez finalizada la adición del sustrato aromático, aumentar la temperatura de la mezcla a-55 ° C y dejar la mezcla a esta temperatura durante 20 minutos.</li>
		<li>Añadir agua a la mezcla de reacción (la mitad el volumen de diclorometano que se utiliza en la preparación de las especies de enolonium).</li>
		<li>Extraer tres veces con diclorometano. Normalmente, utilizar 2 - 3 veces el volumen de reacción en cada extracción en 0.5-2 mmol de pequeña escala.</li>
		<li>Lavar las capas orgánicas combinadas dos veces con salmuera. Normalmente, utilizar el mismo volumen de la salmuera como el volumen de reacción combinado.</li>
		<li>Secar los extractos con sulfato de sodio anhidro durante 30 minutos.</li>
		<li>Filtro del sulfato de sodio.</li>
		<li>Eliminar el solvente en un evaporador rotatorio a presión reducida y a 40 ° C.</li>
		<li>Purifique el producto crudo por cromatografía en columna sobre gel de sílice con eluyentes hexano y acetato de etilo para permitir, después de la eliminación de los solventes, el puro cetona de α-arylated correspondiente.</li>
	</ol></li>
</ol>

<ol>
	<li>Mizar, P., Wirth, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Flexible+stereoselective+functionalizations+of+ketones+through+umpolung+with+hypervalent+iodine+reagents.">Flexible stereoselective functionalizations of ketones through umpolung with hypervalent iodine reagents.</a> Angewandte Chemie International Edition. 53 (23), 5993-5997 (2014).</li><li>Yoshimura, A., Zhdankin, V. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Advances+in+synthetic+applications+of+hypervalent+iodine+compounds.">Advances in synthetic applications of hypervalent iodine compounds.</a> Chemical Reviews. 116 (5), 3328-3435 (2016).</li><li>Zhdankin, V. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Hypervalent Iodine Chemistry: Preparation, Structure, and Synthetic Applications of Polyvalent Iodine Compounds. , (2013).</li><li>Wirth, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Topics in Current Chemistry. 373, (2016).</li><li>Merritt, E. A., Olofsson, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=&#945;-functionalization+of+carbonyl+compounds+using+hypervalent+iodine+reagents.">&#945;-functionalization of carbonyl compounds using hypervalent iodine reagents.</a> Synthesis. 4 (4), 517-538 (2011).</li><li>Arava, 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=Enolonium+Species-Umpoled+Enolates.">Enolonium Species-Umpoled Enolates.</a> Angewandte Chemie International Edition. 56 (10), 2599-2603 (2017).</li><li>Parida, K. N., Maksymenko, S., Pathe, G. K., Szpilman, A. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cross-Coupling+of+Dissimilar+Ketone+Enolates+via+Enolonium+Species+to+afford+Nonsymmetrical+1,4-Diketones.">Cross-Coupling of Dissimilar Ketone Enolates via Enolonium Species to afford Nonsymmetrical 1,4-Diketones.</a> Beilstein Journal of Organic Chemistry. 14, 992-997 (2018).</li><li>Zhdankin, V. V., 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=Carbon-carbon+bond+formation+in+reactions+of+PhIO&#183;HBF4-silyl+enol+ether+adduct+with+alkenes+or+silyl+enol+ethers.">Carbon-carbon bond formation in reactions of PhIO&#183;HBF4-silyl enol ether adduct with alkenes or silyl enol ethers.</a> Journal of Organic Chemistry. 54 (11), 2605-2608 (1989).</li><li>Maksymenko, 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=Transition-metal-free+intermolecular+&#945;-arylation+of+ketones+via+enolonium+species.">Transition-metal-free intermolecular &#945;-arylation of ketones via enolonium species.</a> Organic Letters. 19 (23), 6312-6315 (2017).</li><li>Vita, M. V., Waser, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Azidation+of+&#946;-keto+esters+and+silyl+enol+ethers+with+a+benziodoxole+reagent.">Azidation of &#946;-keto esters and silyl enol ethers with a benziodoxole reagent.</a> Organic Letters. 15 (13), 3246-3249 (2013).</li><li>More, A., 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=&#945;-N-Heteroarylation+and+&#945;-azidation+of+ketones+via+enolonium+species.">&#945;-N-Heteroarylation and &#945;-azidation of ketones via enolonium species.</a> Journal of Organic Chemistry. 83, 2442-2447 (2018).</li><li>Xie, 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=Gold-catalyzed+hydration+of+haloalkynes+to+&#945;-halomethyl+ketones.">Gold-catalyzed hydration of haloalkynes to &#945;-halomethyl ketones.</a> Journal of Organic Chemistry. 78 (18), 9190-9195 (2013).</li><li>Patonay, T., Juh&#225;sz-T&#243;th, &. #. 2. 0. 1. ;., B&#233;nyei, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Base-induced+coupling+of+&#945;-azido+ketones+with+aldehydes+&#8722;+An+easy+and+efficient+route+to+trifunctionalized+synthons+2-azido-3-hydroxy+ketones,+2-acylaziridines,+and+2-acylspiroaziridines.">Base-induced coupling of &#945;-azido ketones with aldehydes &#8722; An easy and efficient route to trifunctionalized synthons 2-azido-3-hydroxy ketones, 2-acylaziridines, and 2-acylspiroaziridines.</a> European Journal of Organic Chemistry. 2002 (2), 285-295 (2002).</li><li>Li, C., Breit, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rhodium-catalyzed+chemo-+and+regioselective+decarboxylative+addition+of+&#946;-ketoacids+to+allenes:+Efficient+construction+of+tertiary+and+quaternary+carbon+Centers.">Rhodium-catalyzed chemo- and regioselective decarboxylative addition of &#946;-ketoacids to allenes: Efficient construction of tertiary and quaternary carbon Centers.</a> Journal of the American Chemical Society. 136 (3), 862-865 (2014).</li></ol>

No tenemos nada que revelar.

La preparación exitosa de especies enolonium de TMS-enolatos depende de varios factores. La reacción de lado importantes en el paso de preparación es el acoplamiento homo del material de partida por la reacción de una molécula de enolonium formado especies con una molécula de TMS-enolate. Por lo tanto, la exigencia de las condiciones de reacción es evitar esta dimerización asegurando la rápida reacción de lo reactivo de yodo hipervalente activado ácido Lewis con TMS-enolate añadido en relación con la tasa de...

Enolatos son nucleófilos de carbono clásico en química orgánica y entre los más ampliamente usados. Umpolung de enolatos crear especie electrófila enolonium permite valiosas alternativas para producir cetonas α-funcionalizados como para permitir que nuevas reacciones no es posibles a través de la química clásica enolate. Enolonium especies se han propuesto como productos intermedios en numerosas reacciones, en particular reacciones con reactivos de yodo hipervalente. Estas reacciones incluyen α-halogenación, oxigenación y aminación1 , así como otras reacciones2,3,4,5.
Sin embargo, los alcances de estas reacciones fueron siempre limitados por la naturaleza transitoria de las especies reactivas de enolonium. Esta transitoriedad necesaria cualquier nucleófilo para estar presente en la mezcla de reacción durante la reacción de los enolatos de carbonilo con el reactivo de yodo hipervalente fuertemente oxidante. Por lo tanto, no se podía utilizar cualquier nucleófilo propenso a la oxidación, como alquenos, compuestos aromáticos ricos del electrón (heterociclos).
En el último año, hemos superado estas limitaciones mediante el desarrollo de las condiciones en que las especies de enolonium se formaron como un intermediario independiente en un paso seguido por la adición del nucleófilo en un segundo paso. Este protocolo permite no sólo el tipo clásico de funcionalización como cloración6, sino también el uso de nucleófilos de carbono oxidable, como allylsilanes6,8, enolatos1,6, 7y electrones compuestos aromáticos ricos9, dando por resultado la formación de enlace C-C. El método allylation es favorable a la formación de centros cuaternarios y terciarios. El método de cetonas cetonas constituye formal funcionalización de C-H de los aromáticos compuesto sin necesidad de una dirección de grupo9. Recientemente hemos reportado la adición de azoles y azidas10 como bien11. Se espera que la presentación detallada del protocolo para ayudar en la introducción de estos métodos en la caja de herramientas del día a día del químico orgánico sintético.

<table>
	<tbody>
		<tr>
			<td>Chlorotrimethylsilane, 98+%</td>
			<td>Alfa Aesar</td>
			<td>A13651</td>
			<td>TMS-Cl</td>
		</tr>
		<tr>
			<td>Boron trifluoride diethyl etherate, 98+%</td>
			<td>Alfa Aesar</td>
			<td>A15275</td>
			<td>BF3*Et2O</td>
		</tr>
		<tr>
			<td>2-Methylindole, 98+%</td>
			<td>Alfa Aesar</td>
			<td>A10764</td>
			<td>2-Me-indole</td>
		</tr>
		<tr>
			<td>Hydroxy(tosyloxy) iodobenzene, 97%</td>
			<td>Alfa Aesar</td>
			<td>L15701</td>
			<td>Koser&#39;s reagent</td>
		</tr>
		<tr>
			<td>Acetophenone, &#62;98%</td>
			<td>Merck</td>
			<td>800028</td>
			<td></td>
		</tr>
		<tr>
			<td>n-Butyllithium solution 1.6M in hexanes</td>
			<td>Aldrich</td>
			<td>186171</td>
			<td>nBuLi</td>
		</tr>
		<tr>
			<td>BIS(ISOPROPYL)AMINE</td>
			<td>Apollo</td>
			<td>OR1090</td>
			<td>DIPA</td>
		</tr>
		<tr>
			<td>Trimethylsilyl azide, 94%</td>
			<td>Alfa Aesar</td>
			<td>L00173</td>
			<td>TMS-N3</td>
		</tr>
	</tbody>
</table>

a two-step protocol for umpolung functionalization of ketones via enolonium species

Α-funcionalización de cetonas vía umpolung de enolatos por reactivos de yodo hipervalente es un concepto importante en química orgánica sintética. Recientemente, hemos desarrollado una estrategia de dos etapas para cetona enolate umpolung que ha permitido el desarrollo de métodos para la desinfección con cloro, azidation y aminación con azoles. Además, hemos desarrollado C C reacciones bond – formando cetonas y allylation. En el corazón de estos métodos es la preparación de las especies de enolonium intermedio y altamente reactiva antes de la adición de un reactivo nucleófilo. Esta estrategia es una reminiscencia de la preparación y utilización de metal enolatos en química sintética clásica. Esta estrategia permite el uso de nucleófilos que serían incompatibles con los reactivos de yodo hipervalente fuertemente oxidante. En este trabajo se presenta un protocolo detallado para cloración, azidation, N-heteroarylation, cetonas y allylation. Los productos incluyen motivos frecuentes en productos medicinalmente activos. Este artículo será grandemente ayudar a otros en el uso de estos métodos.

Representante de resultados, siguiendo el protocolo, se dan en la figura 1 y se discuten en la sección de discusión. En particular, una gama muy grande de diferentes cetonas puede utilizarse con éxito en la reacción para dar los productos en buenas producciones como puede verse para el azidation11. El alcance de la reacción para la introducción de los azoles en la α-posición de cetonas incluye la mayor parte del nitrógeno com?...

Watch this Scientific Journal Video about A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species at JoVE.com

A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species

Se describe un protocolo de dos pasos una olla de umpolung de enolatos de cetonas a las especies enolonium y adición de un nucleófilo a la α-posición. Nucleófilos incluyen cloruro, azida, azoles, alil-silanes y compuestos aromáticos.

Un protocolo de dos etapas para funcionalización de Umpolung de cetonas vía Enolonium especies

&#945;-Functionalization of ketones via umpolung of enolates by hypervalent iodine reagents is an important concept in synthetic organic chemistry. ...

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9.9K vistas.  Ariel University. Se describe un protocolo de dos pasos una olla de umpolung de enolatos de cetonas a las especies enolonium y adición de un nucleófilo a la α-posición. Nucleófilos incluyen cloruro, azida, azoles, alil-silanes y compuestos aromáticos.

Video: A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species

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.

Síntesis de derivados Antiviral tetrahidrocarbazol por fotoquímica y catalizada por ácido CH funcionalización a través de intermedios peróxidos (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 ...

Investigación

Química

A Protocol for the Production of Gliadin-cyanoacrylate Nanoparticles for Hydrophilic Coating

This article presents a protocol for the production of protein-based nanoparticles that changes the hydrophobic surface to hydrophilic by a simple spray coating. These nanoparticles are produced by the polymerization reaction of alkyl cyanoacrylate on the surface of cereal protein (gliadin) molecules. Alkyl cyanoacrylate is a monomer that instantly polymerizes at RT when it is applied to the surface of materials. Its polymerization reaction is initiated by the trace amounts of weakly basic or nucleophilic species on the surface, including moisture. Once polymerized, the polymerized alkyl cyanoacrylates show a strong affinity with the object materials because nitrile groups are in the backbone of poly (alkyl cyanoacrylate). Proteins also work as initiator for this polymerization because they contain amine groups that can initiate the polymerization of cyanoacrylate. If aggregated protein is used as an initiator, protein aggregate is surrounded by the hydrophobic poly(alkyl cyanoacrylate) chains after the polymerization reaction of alkyl cyanoacrylate. By controlling the experimental condition, particles in the nanometer range are produced. The produced nanoparticles readily adsorb to the surface of most materials including glass, metals, plastics, wood, leather, and fabrics. When the surface of a material is sprayed with the produced nanoparticle suspension and rinsed with water, the micellar structure of nanoparticle changes its conformation, and the hydrophilic proteins are exposed to the air. As a result, the nanoparticle-coated surface changes to hydrophilic.

This article presents a protocol for the production of protein-based nanoparticles that changes the hydrophobic surface to hydrophilic. The produced nanoparticle is an assembly of gliadin-cyanoacrylate diblock copolymers. Spray coating with the produced nanoparticle changes the surface of target material to a hydrophilic surface.

Un protocolo para la producción de nanopartículas gliadina-cianoacrilato para el recubrimiento hidrofílico

This article presents a protocol for the production of protein-based nanoparticles that changes the hydrophobic surface to hydrophilic by a simple spray ...

Rapid High-throughput Species Identification of Botanical Material Using Direct Analysis in Real Time High Resolution Mass Spectrometry

We demonstrate that direct analysis in real time-high resolution mass spectrometry can be used to produce mass spectral profiles of botanical material, and that these chemical fingerprints can be used for plant species identification. The mass spectral data can be acquired rapidly and in a high throughput manner without the need for sample extraction, derivatization or pH adjustment steps. The use of this technique bypasses challenges presented by more conventional techniques including lengthy chromatography analysis times and resource intensive methods. The high throughput capabilities of the direct analysis in real time-high resolution mass spectrometry protocol, coupled with multivariate statistical analysis processing of the data, provide not only class characterization of plants, but also yield species and varietal information. Here, the technique is demonstrated with two psychoactive plant products, Mitragyna speciosa (Kratom) and Datura (Jimsonweed), which were subjected to direct analysis in real time-high resolution mass spectrometry followed by statistical analysis processing of the mass spectral data. The application of these tools in tandem enabled the plant materials to be rapidly identified at the level of variety and species.

A method for species identification of botanical material by direct analysis in real time-high resolution mass spectrometry and multivariate statistical analysis is presented.

Rápida de alto rendimiento Identificación de Especies de material botánico Uso del análisis directo en tiempo real de alta resolución Espectrometría de Masas

We demonstrate that direct analysis in real time-high resolution mass spectrometry can be used to produce mass spectral profiles of botanical material, ...

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.

Un protocolo para las reacciones de litiación segura usando reactivos orgánicos de litio

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

Protocol for the Solid-phase Synthesis of Oligomers of RNA Containing a 2'-O-thiophenylmethyl Modification and Characterization via Circular Dichroism

Solid-phase synthesis has been used to obtain canonical and modified polymers of nucleic acids, specifically of DNA or RNA, which has made it a popular methodology for applications in various fields and for different research purposes. The procedure described herein focuses on the synthesis, purification, and characterization of dodecamers of RNA 5&#39;-[CUA CGG AAU CAU]-3&#39; containing zero, one, or two modifications located at the C2&#39;-O-position. The probes are based on 2-thiophenylmethyl groups, incorporated into RNA nucleotides via standard organic synthesis and introduced into the corresponding oligonucleotides via their respective phosphoramidites. This report makes use of phosphoramidite chemistry via the four canonical nucleobases (Uridine (U), Cytosine (C), Guanosine (G), Adenosine (A)), as well as 2-thiophenylmethyl functionalized nucleotides modified at the 2&#39;-O-position; however, the methodology is amenable for a large variety of modifications that have been developed over the years. The oligonucleotides were synthesized on a controlled-pore glass (CPG) support followed by cleavage from the resin and deprotection under standard conditions, i.e., a mixture of ammonia and methylamine (AMA) followed by hydrogen fluoride/triethylamine/N-methylpyrrolidinone. The corresponding oligonucleotides were purified via polyacrylamide electrophoresis (20% denaturing) followed by elution, desalting, and isolation via reversed-phase chromatography (Sep-pak, C18-column). Quantification and structural parameters were assessed via ultraviolet-visible (UV-vis) and circular dichroism (CD) photometric analysis, respectively. This report aims to serve as a resource and guide for beginner and expert researchers interested in embarking in this field. It is expected to serve as a work-in-progress as new technologies and methodologies are developed. The description of the methodologies and techniques within this document correspond to a DNA/RNA synthesizer (refurbished and purchased in 2013) that uses phosphoramidite chemistry.

Protocol for the Solid-phase Synthesis of Oligomers of RNA Containing a 2'-O-thiophenylmethyl Modification and Characterization via Circular Dichroism

This article provides a detailed procedure on the solid-phase synthesis, purification, and characterization of dodecamers of RNA modified at the C2&#39;-O-position. UV-vis and circular dichroism photometric analyses are used to quantify and characterize structural aspects, i.e., single-strands or double-strands.

Protocolo para la síntesis en fase sólida de oligómeros de ARN que contiene un 2&#39;-<emO</em&gt; -tiofenilmetilo Modificación y caracterización mediante dicroísmo circular

Solid-phase synthesis has been used to obtain canonical and modified polymers of nucleic acids, specifically of DNA or RNA, which has made it a popular ...

Fabrication and Testing of Catalytic Aerogels Prepared Via Rapid Supercritical Extraction

Protocols for preparing and testing catalytic aerogels by incorporating metal species into silica and alumina aerogel platforms are presented. Three preparation methods are described: (a) the incorporation of metal salts into silica or alumina wet gels using an impregnation method; (b) the incorporation of metal salts into alumina wet gels using a co-precursor method; and (c) the addition of metal nanoparticles directly into a silica aerogel precursor mixture. The methods utilize a hydraulic hot press, which allows for rapid (&#60;6 h) supercritical extraction and results in aerogels of low density (0.10 g/mL) and high surface area (200-800 m2/g). While the work presented here focuses on the use of copper salts and copper nanoparticles, the approach can be implemented using other metal salts and nanoparticles. A protocol for testing the three-way catalytic ability of these aerogels for automotive pollution mitigation is also presented. This technique uses custom-built equipment, the Union Catalytic Testbed (UCAT), in which a simulated exhaust mixture is passed over an aerogel sample at a controlled temperature and flow rate. The system is capable of measuring the ability of the catalytic aerogels, under both oxidizing and reducing conditions, to convert CO, NO and unburned hydrocarbons (HCs) to less harmful species (CO2, H2O and N2). Example catalytic results are presented for the aerogels described.

Here we present protocols for preparing and testing catalytic aerogels by incorporating metal species into silica and alumina aerogel platforms. Methods for preparing materials using copper salts and copper-containing nanoparticles are featured. Catalytic testing protocols demonstrate the effectiveness of these aerogels for three-way catalysis applications.

Fabricación y pruebas de Aerogels catalíticos preparados vía rápida extracción supercrítica

Protocols for preparing and testing catalytic aerogels by incorporating metal species into silica and alumina aerogel platforms are presented. Three ...

The MPLEx Protocol for Multi-omic Analyses of Soil Samples

Mass spectrometry (MS)-based integrated metaproteomic, metabolomic, and lipidomic (multi-omic) studies are transforming our ability to understand and characterize microbial communities in environmental and biological systems. These measurements are even enabling enhanced analyses of complex soil microbial communities, which are the most complex microbial systems known to date. Multi-omic analyses, however, do have sample preparation challenges, since separate extractions are typically needed for each omic study, thereby greatly amplifying the preparation time and amount of sample required. To address this limitation, a 3-in-1 method for the simultaneous extraction of metabolites, proteins, and lipids (MPLEx) from the same soil sample was created by adapting a solvent-based approach. This MPLEx protocol has proven to be both simple and robust for many sample types, even when utilized for limited quantities of complex soil samples. The MPLEx method also greatly enabled the rapid multi-omic measurements needed to gain a better understanding of the members of each microbial community, while evaluating the changes taking place upon biological and environmental perturbations.

A protocol is presented for simultaneously extracting metabolites, proteins, and lipids from a single soil sample, allowing reduced sample preparation times and enabling multi-omic mass spectrometry analyses of samples with limited quantities.

El protocolo MPLEx para Multi-omic análisis de muestras de suelo

Mass spectrometry (MS)-based integrated metaproteomic, metabolomic, and lipidomic (multi-omic) studies are transforming our ability to understand and ...

Separation of Aldehydes and Reactive Ketones from Mixtures Using a Bisulfite Extraction Protocol

The purification of organic compounds is an essential component of routine synthetic operations. The ability to remove contaminants into an aqueous layer by generating a charged structure provides an opportunity to use extraction as a simple purification technique. By combining the use of a miscible organic solvent with saturated sodium bisulfite, aldehydes and reactive ketones can be successfully transformed into charged bisulfite adducts that can then be separated from other organic components of a mixture by the introduction of an immiscible organic layer. Here, we describe a simple protocol for the removal of aldehydes, including sterically-hindered neopentyl aldehydes and some ketones, from chemical mixtures. Ketones can be separated if they are sterically unhindered cyclic or methyl ketones. For aliphatic aldehydes and ketones, dimethylformamide is used as the miscible solvent to improve removal rates. The bisulfite addition reaction can be reversed by basification of the aqueous layer, allowing for the re-isolation of the reactive carbonyl component of a mixture.

Here, we present a protocol to remove aldehydes and reactive ketones from mixtures by a liquid-liquid extraction protocol directly with saturated sodium bisulfite in a miscible solvent. This combined protocol is rapid and facile to perform. The aldehyde or ketone can be re-isolated by the basification of the aqueous layer.

Separación de aldehidos y cetonas reactivas de mezclas mediante un protocolo de extracción de bisulfito

The purification of organic compounds is an essential component of routine synthetic operations. The ability to remove contaminants into an aqueous layer ...

Surface Functionalization of Metal-Organic Frameworks for Improved Moisture Resistance

Metal-organic frameworks (MOFs) are a class of porous inorganic materials with promising properties in gas storage and separation, catalysis and sensing. However, the main issue limiting their applicability is their poor stability in humid conditions. The common methods to overcome this problem involve the formation of strong metal-linker bonds by using highly charged metals, which is limited to a number of structures, the introduction of alkylic groups to the framework by post-synthetic modification (PSM) or chemical vapour deposition (CVD) to enhance overall hydrophobicity of the framework. These last two usually provoke a drastic reduction of the porosity of the material. These strategies do not permit to exploit the properties of the MOF already available and it is imperative to find new methods to enhance the stability of MOFs in water while keeping their properties intact. Herein, we report a novel method to enhance the water stability of MOF crystals featuring Cu2(O2C)4&#160;paddle-wheel units, such as HKUST (where HKUST stands for Hong Kong University of Science &#38; Technology), with the catechols functionalized with alkyl and fluoro-alkyl chains. By taking advantage of the unsaturated metal sites and the catalytic catecholase-like activity of CuII ions, we are able to create robust hydrophobic coatings through the oxidation and subsequent polymerization of the catechol units on the surface of the crystals under anaerobic and water-free conditions without disrupting the underlying structure of the framework. This approach not only affords the material with improved water stability but also provides control over the function of the protective coating, which enables the development of functional coatings for the adsorption and separations of volatile organic compounds. We are confident that this approach could also be extended to other unstable MOFs featuring open metal sites.

Robust functional catechol coatings were produced in one step by direct reaction of the material known as HKUST with synthetic catechols under anaerobic conditions. The formation of homogeneous coatings surrounding the entire crystal is ascribed to the biomimetic catalytic activity of Cu(II) dimers on the external surface of the crystals.

Funcionalización de superficies de Metal-Organic Frameworks para resistencia a la humedad mejorada

Metal-organic frameworks (MOFs) are a class of porous inorganic materials with promising properties in gas storage and separation, catalysis and sensing. ...

Automation of a Positron-emission Tomography (PET) Radiotracer Synthesis Protocol for Clinical Production

The development of new positron-emission tomography (PET) tracers is enabling researchers and clinicians to image an increasingly wide array of biological targets and processes. However, the increasing number of different tracers creates challenges for their production at radiopharmacies. While historically it has been practical to dedicate a custom-configured radiosynthesizer and hot cell for the repeated production of each individual tracer, it is becoming necessary to change this workflow. Recent commercial radiosynthesizers based on disposable cassettes/kits for each tracer simplify the production of multiple tracers with one set of equipment by eliminating the need for custom tracer-specific modifications. Furthermore, some of these radiosynthesizers enable the operator to develop and optimize their own synthesis protocols in addition to purchasing commercially-available kits. In this protocol, we describe the general procedure for how the manual synthesis of a new PET tracer can be automated on one of these radiosynthesizers and validated for the production of clinical-grade tracers. As an example, we use the ELIXYS radiosynthesizer, a flexible cassette-based radiochemistry tool that can support both PET tracer development efforts, as well as routine clinical probe manufacturing on the same system, to produce [18F]Clofarabine ([18F]CFA), a PET tracer to measure in vivo deoxycytidine kinase (dCK) enzyme activity. Translating a manual synthesis involves breaking down the synthetic protocol into basic radiochemistry processes that are then translated into intuitive chemistry &#34;unit operations&#34; supported by the synthesizer software. These operations can then rapidly be converted into an automated synthesis program by assembling them using the drag-and-drop interface. After basic testing, the synthesis and purification procedure may require optimization to achieve the desired yield and purity. Once the desired performance is achieved, a validation of the synthesis is carried out to determine its suitability for the production of the radiotracer for clinical use.

Automation of a Positron-emission Tomography PET Radiotracer Synthesis Protocol for Clinical Production

Positron-emission tomography (PET) imaging sites that are involved in multiple early clinical research trials need robust and versatile radiotracer manufacturing capabilities. Using the radiotracer [18F]Clofarabine as an example, we illustrate how to automate the synthesis of a radiotracer using a flexible, cassette-based radiosynthesizer and validate the synthesis for clinical use.

Automatización de un protocolo de emisión de positrones la tomografía (PET) radiosonda síntesis de producción clínica

The development of new positron-emission tomography (PET) tracers is enabling researchers and clinicians to image an increasingly wide array of biological ...