Lecture 16: Acyl Transfer Reactions I

Vocabulary practice flashcards covering fundamental definitions, molecular orbital theory, leaving group trends, reactivity orders, and mechanisms for Lecture 16: Acyl Transfer Reactions I.

Acyl Group

A functional group with the general structure $R-C(=O)-$ consisting of a carbonyl group bound to an alkyl or aryl group with an open valence on the carbonyl carbon.

Nucleophilic Acyl Substitution

A two-step addition-elimination reaction in which an incoming nucleophile attacks a carbonyl group bearing a leaving group to form a tetrahedral intermediate, followed by elimination of the leaving group to regenerate the carbonyl.

Tetrahedral Intermediate (TI)

An $sp^3$-hybridized intermediate formed in the first addition step of nucleophilic acyl substitution, possessing a negative charge on the carbonyl oxygen and four groups bonded to the central carbon.

Operative LUMO in Acyl Transfer

The carbonyl $\pi^*_{C=O}$ orbital attacked by the incoming nucleophile, in contrast to direct substitution ($S_N2$) which would incorrectly require attack at the higher-energy $\sigma^*_{C-LG}$ orbital.

Carboxylic Acid Derivatives (CADs)

A family of carbonyl compounds—principally acid chlorides, acid anhydrides, esters, and amides—bearing a heteroatom leaving group bonded directly to the acyl carbon that can be synthesized from carboxylic acids.

CAD Relative Reactivity Order

The universal reactivity trend of carboxylic acid derivatives toward nucleophiles: $\text{acid chloride} > \text{acid anhydride} > \text{ester} > \text{amide}$.

Electrophilicity Difference: Ester vs. Amide

Esters are more electrophilic than amides because oxygen is more electronegative than nitrogen ($EN_O > EN_N$), meaning oxygen donates its lone pair less effectively into $\pi^*_{C=O}$, rendering the carbonyl carbon more electron-poor and placing the new $\pi^*_{C=O}$ LUMO at lower energy.

Orbital Overlap Mismatch in Acid Chlorides

The poor physical orbital overlap between the small carbon $2p$ orbital and the larger, more diffuse chlorine $3p$ orbital across a longer $C-Cl$ bond, resulting in minimal lone pair delocalization and making acid chlorides more electrophilic than esters.

Carboxylic Acid Derivative MO Interaction Diagram

A diagram illustrating the mixing of the carbonyl $\pi^*_{CO}$ LUMO with heteroatom lone pairs ($n_N$, $n_O$, $n_{Cl}$); orbital overlap destabilizes and raises the new $\pi^*_{CO}$ LUMO highest in amides, moderately in esters, and least in acid chlorides.

Leaving Group Basicity in CADs

The ranking of leaving group ability inversely based on base strength and conjugate acid $pK_a$: $Cl^-$ ($pK_a(HCl) = -8$, weakest base/best leaving group) $>$ ${}^-OR$ ($pK_a(HOR) = 16$) $>$ ${}^-NR_2$ ($pK_a(HNR_2) \approx 35$, very strong base/worst leaving group).

Irreversible Leaving Groups in Acyl Transfer

The least basic leaving groups—iodide, bromide, and chloride—whose conjugate acids have negative $pK_a$ values ($-10$, $-9$, and $-8$ respectively), causing their elimination from the tetrahedral intermediate to be irreversible.

Reversible Leaving Groups in Acyl Transfer

Relatively poor leaving groups such as fluoride ($pK_a = +3$), thiolate ($pK_a = +7$), cyanide ($pK_a = +9.2$), hydroxide ($pK_a = +14$), and alkoxide ($pK_a = +16$) that can still leave reversibly from the tetrahedral intermediate.

Carboxylic Acid Derivative Interconversion Hierarchy

The systematic synthetic relationship where more reactive CADs can be converted into less reactive CADs, all CADs can be hydrolyzed with $H_2O$ to carboxylic acids, and only carboxylic acids can be converted back to acid chlorides using $SOCl_2$.

Thionyl Chloride ($SOCl_2$)

The inorganic reagent used to convert carboxylic acids into acid chlorides, thereby enabling the entry into all other carboxylic acid derivatives.

Saponification

The base-promoted hydrolysis of an ester carried out with aqueous sodium hydroxide ($NaOH_{(aq)}$) followed by acidic workup ($H_3O^+$) to yield a carboxylic acid and an alcohol.

Thermodynamic Driving Force of Saponification

The rapid and irreversible proton transfer from the formed carboxylic acid ($pK_a \approx 5$) to the alkoxide leaving group ($pK_a \approx 16$), resulting in a $\Delta pK_a > 10$ that drives ester hydrolysis to completion as a carboxylate salt.

Basic Amide Hydrolysis Conditions

Forcing reaction conditions requiring high concentrations of base, high temperatures, and prolonged heating due to the poor electrophilicity of amides and the extremely poor leaving group ability of amide ions (${}^-NR_2$).