Enolizaciones mediadas por hexametildisilazida de litio: influencia de la trietilamina en las selectividades E/Z y
Peter F Godenschwager1, David B Collum
1Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, New York 14853-1301, USA.
Journal of the American Chemical Society
|June 19, 2008
Resumen
El hexametildisilazido de litio (LiHMDS) en trietilamina/tolueno enoliza rápidamente las cetonas y los ésteres con alta selectividad. Los enolados solvados con aminas mejoran las reacciones de aldol e Ireland-Claisen, mostrando una mejor diastereoselectividad y un reordenamiento acelerado.
Área de la Ciencia:
- Química orgánica es la química orgánica.
- Química sintética de la química sintética.
Sus antecedentes:
- El hexametildisilazido de litio (LiHMDS) es una base fuerte y no nucleofílica ampliamente utilizada en la síntesis orgánica.
- Los efectos de los disolventes influyen significativamente en la reactividad y la selectividad de los reactivos organometálicos.
Objetivo del estudio:
- Para investigar la enolización de cetonas y ésteres acíclicos utilizando LiHMDS en trietilamina (Et3N) /tolueno.
- Explorar las vías mecanicistas y los resultados estereoquímicos de las reacciones que involucran enolados solvados con Et3N.
- Para comparar la reactividad y la selectividad con los sistemas de disolventes tradicionales como el THF.
Principales métodos:
- Enolización de cetonas y ésteres utilizando LiHMDS en Et3N/tolueno.
- Estudios mecanicistas que emplean análisis espectroscópicos y cinéticos.
- Análisis estereoquímico de la condensación de aldol y los productos de reordenamiento de Ireland-Claisen.
Principales resultados:
- Se logró una enolización rápida de cetonas y ésteres acíclicos con alta selectividad E/Z.
- Los estudios mecánicos apoyaron un mecanismo basado en dímeros para LiHMDS en Et3N.
- Los enolados solvados con Et3N exhibieron mayor diastereoselectividad en las reacciones de aldol e Irlanda-Claisen en comparación con los enolados solvados con THF.
- Se observó una aceleración de 20 veces del reordenamiento Irlanda-Claisen, con evidencia de autocatálisis.
Conclusiones:
- El LiHMDS en Et3N/tolueno proporciona un método altamente selectivo y eficiente para generar enolados.
- Los enolados solvados con aminas ofrecen ventajas claras en la reactividad y el estereocontrol para las transformaciones posteriores.
- Los hallazgos destacan la importancia de la solución de aminas en la química organometálica y la optimización de la reacción.
Videos de Conceptos Relacionados
01:33Regioselective Formation of Enolates
As depicted in the figure below, the unsymmetrical ketones can form two possible enolates: less substituted or more substituted enolates. Usually, the thermodynamic enolates are formed from the more substituted α-carbon atom, while the kinetic enolates are formed faster by deprotonation from the less substituted position. The thermodynamic enolates have lower energy, so they are more stable. But the energy required to form kinetic enolates is less.
02:43E2 Reaction: Stereochemistry and Regiochemistry
Elimination reactions of alkyl halides can yield one or more alkenes depending on the specific regiochemical and stereochemical considerations. While the regiochemistry of the reaction governs the location of the double bond in the product, the stereochemical requirements often influence the geometry.
When a substrate with two different β hydrogens undergoes an E2 elimination, the presence of a strong base can yield two regioisomeric alkenes. The more-substituted alkene is the major product and...
When a substrate with two different β hydrogens undergoes an E2 elimination, the presence of a strong base can yield two regioisomeric alkenes. The more-substituted alkene is the major product and...
01:12Stereochemical Effects of Enolization
The chiral α-carbon of the carbonyl compound is the stereocenter of the molecule. As shown in the figure below, when such a carbonyl compound undergoes racemization under an acidic or basic condition, an achiral enol is formed.
01:10α-Alkylation of Ketones via Enolate Ions
Ketones with α protons are deprotonated by strong bases like lithium diisopropylamide (LDA) to form enolate ions. The anion is stabilized by resonance, and its hybrid structure exhibits negative charges on the carbonyl oxygen and the α carbon. This ambident nucleophile can attack an electrophile via two possible sites: the carbonyl oxygen, known as O-attack, or the α carbon, known as C-attack. The nucleophilic attack via the carbanionic site is preferred. This is due to the strong interaction...
02:43E1 Reaction: Stereochemistry and Regiochemistry
One of the critical aspects of the E1 reaction mechanism, as also observed in E2, is the regiochemistry, with multiple regioisomers obtained as products. In the example discussed, the presence of water as a weak base favors elimination over substitution to generate two alkenes. Given that alkenes’ stability increases with the number of alkyl groups across the double bond, typically, E1 reactions lead to the Zaitsev product, for this is more substituted and stable than the Hofmann product.
01:18Reactivity of Enols
Enols are a class of compounds where a hydroxyl group is attached to a carbon–carbon double bond, which implies that it is a vinyl alcohol. A carbonyl compound with an α hydrogen undergoes keto–enol tautomerism and remains in equilibrium with its tautomer, the enol form. Usually, the keto tautomer is present in a higher concentration than the enol tautomer due to the higher bond energy of C=O compared to C=C. Moreover, the direction of the keto–enol equilibrium is governed by factors like...