Lecture 13: Irreversible Addition to Aldehydes and Ketones

Vocabulary practice flashcards covering nucleophilic addition mechanisms, hydride reducing agents (NaBH4, LiAlH4), organometallic nucleophiles (Grignard and organolithium reagents), stereochemistry, and retrosynthetic strategies from Lecture 13.

Aldehyde vs. Ketone Electrophilicity

The reactivity trend establishing that aldehydes are more electrophilic than ketones due to reduced steric hindrance and fewer alkyl groups donating electron density into the empty $\pi^*_{\text{C}=\text{O}}$ orbital via hyperconjugation.

Carbonyl Hyperconjugation Orbital Alignment

The stereoelectronic interaction in ketones where a neighbouring $\sigma_{\text{C}-\text{H}}$ orbital donates electron density into the empty $\pi^*_{\text{C}=\text{O}}$ LUMO; in aldehydes, this stabilization is absent because the formyl $\text{H } 1s$ orbital lies directly in the nodal plane.

Hydride Reagent HOMO Energy Hierarchy

The orbital energy ranking where $\sigma_{\text{Al}-\text{H}}$ lies higher in energy than $\sigma_{\text{B}-\text{H}}$, which in turn lies higher than $\sigma_{\text{C}-\text{H}}$, explaining why $\text{LiAlH}_4$ acts as a significantly stronger nucleophile than $\text{NaBH}_4$.

Sodium Borohydride ($\text{NaBH}_4$)

A mild hydridic reducing agent with a lower-energy $\sigma_{\text{B}-\text{H}}$ HOMO that is stable in protic solvents like $\text{H}_2\text{O}$ or $\text{CH}_3\text{OH}$, reducing aldehydes and ketones through hydride delivery followed by reversible solvent protonation.

Lithium Aluminium Hydride ($\text{LiAlH}_4$)

A powerful hydridic reducing agent and strong base that reacts exothermically with protic solvents; it requires non-protic ether solvents for the nucleophilic addition step, followed by a separate acidic workup step ($\text{H}_3\text{O}^+$) to protonate the resulting alkoxide.

Alkoxide Intermediate

The negatively charged tetrahedral species ($\text{R}_2\text{C}(\text{Nu})\text{O}^-$) formed immediately upon irreversible nucleophilic attack at the carbonyl carbon prior to protonation.

Organolithium Reagent ($\text{R}-\text{Li}$)

A strong organometallic nucleophile and base prepared by reacting an organohalide with two equivalents of lithium metal ($2\,\text{Li}\,(s)$) in ether, reacting synthetically as a carbanion ($\text{R}^-$).

Grignard Reagent ($\text{R}-\text{MgX}$)

An organomagnesium reagent prepared by reacting an organohalide with magnesium metal ($\text{Mg}\,(s)$) in ether ($\text{X} = \text{Br}, \text{Cl}, \text{I}$), serving as a powerful carbon nucleophile and strong base.

Polar Covalent Bond (Organometallics)

A carbon-metal bond polarized toward carbon ($\text{C}^{\delta-}-\text{M}^{\delta+}$) due to the electronegativity difference between carbon ($2.5$) and electropositive metals like lithium ($1.0$) or magnesium ($1.2$), enabling the carbon to react as a nucleophilic carbanion.

Acidic Workup ($\text{H}_3\text{O}^+$ Quench)

A distinct second stage introduced only after nucleophilic addition is complete in $\text{LiAlH}_4$, organolithium, or Grignard reactions to safely protonate the alkoxide intermediate to yield the neutral alcohol.

Aprotic Ether Solvent

A solvent devoid of acidic protons (such as diethyl ether) required when working with $\text{LiAlH}_4$, organolithiums, or Grignard reagents to prevent premature acid-base destruction of the reagent.

Prochiral Carbonyl Addition

The nucleophilic attack occurring with equal probability on the front and back faces of a planar, achiral aldehyde or unsymmetrical ketone, producing a $1:1$ racemic mixture ($+/-$) of enantiomers.

Diastereoselective Carbonyl Addition

The nucleophilic addition to a carbonyl compound containing an existing stereocenter, where facial bias creates diastereotopic faces and yields a mixture of diastereomers.

Carboxylation of Grignard Reagents

The nucleophilic addition of a Grignard reagent ($\sigma_{\text{C}-\text{Mg}}$ HOMO) into carbon dioxide ($\pi^*_{\text{C}=\text{O}}$ LUMO of $\text{CO}_2$), which yields a carboxylic acid after an acidic workup ($\text{HCl}$).

Functional Group Incompatibility (Grignards)

The principle that an organohalide possessing an electrophilic carbonyl group cannot form a stable Grignard reagent, as the newly formed organomagnesium will immediately self-react intermolecularly or intramolecularly.

Retrosynthetic Arrow ($\Rightarrow$)

A double-lined open arrow designating the analytical strategy of 'thinking backwards' from a desired target product to appropriate starting materials.