CHEM 109C: Electrophilic Aromatic Substitution (EAS) and Substituent Effects

Vocabulary flashcards covering aromatic substituent directing and activating effects, EAS mechanisms, reagents, and limitations of Friedel–Crafts reactions from the CHEM 109C notes.

$$-\text{NH}_2, -\text{NHR}, -\text{NR}_2$$

Strongly activating, ortho/para-directing substituent groups whose nitrogen lone pair donates electron density into the ring by resonance.

$$-\text{OH}, -\text{O}^-$$

Strongly activating, ortho/para-directing substituent groups whose oxygen lone pair donates electron density into the ring by resonance.

$$-\text{OR}$$

Moderately activating, ortho/para-directing substituent group.

$-\text{NHCOR}$ (amide N)

Moderately activating, ortho/para-directing substituent group whose nitrogen lone pair is shared in resonance with the adjacent $\text{C}=\text{O}$ group.

$-\text{OCOR}$ (ester O)

Moderately activating, ortho/para-directing substituent group.

$$-R\text{ (alkyl)}, -\text{Ph}, -\text{CH}=\text{CH}_2$$

Weakly activating, ortho/para-directing substituent groups that donate electron density through hyperconjugation or induction.

$$-\text{F}, -\text{Cl}, -\text{Br}, -\text{I}$$

Weakly deactivating, ortho/para-directing substituents whose inductive electron withdrawal outweighs their resonance electron donation ($\text{induction} > \text{resonance}$).

$$-\text{CHO}, -\text{COR}, -\text{COOH}, -\text{COOR}, -\text{CONH}_2$$

Moderately deactivating, meta-directing carbonyl-containing substituent groups.

$$-\text{NO}_2, -\text{CN}, -\text{SO}_3\text{H}, -\text{CF}_3, -\text{NR}_3^+$$

Strongly deactivating, meta-directing substituent groups.

Halogen Directing and Deactivating Mechanism

Induction withdraws more electron density than resonance donates, making halogens deactivating overall; however, the halogen lone pair stabilizes the ortho/para sigma complex, directing substitution to the ortho and para positions.

Ortho/Para-Directing Mechanism of Electron Donors

Electrophilic attack at the ortho or para position places the positive charge directly on the carbon bearing the donating substituent, allowing the substituent's lone pair to contribute an additional resonance structure where every atom has a full octet.

Meta-Directing Mechanism of Electron-Withdrawing Groups (EWGs)

Ortho and para attack places a positive charge directly adjacent to the $\delta+$ atom of the electron-withdrawing group, which is highly destabilizing; meta attack avoids placing the positive charge on this carbon.

Relative Activating Ability of $-\text{NHCOR}$ vs. $-\text{NH}_2$

$-\text{NHCOR}$ is a weaker activating group than $-\text{NH}_2$ because the nitrogen lone pair is partially delocalized into the carbonyl group ($\text{C}=\text{O}$).

$\text{Br}_2, \text{FeBr}_3$ EAS Reagents

Reagents that generate a $\text{Br}-\text{Br}-\text{FeBr}_3$ complex ($``\text{Br}^+"$) electrophile to convert an aromatic ring into an aryl bromide.

$\text{HNO}_3, \text{H}_2\text{SO}_4$ EAS Reagents

Reagents that generate the nitronium ion ($\text{NO}_2^+$) electrophile to convert an aromatic ring into a nitroarene.

Fuming $\text{H}_2\text{SO}_4\text{ (SO}_3\text{)}$

Reagent that generates the electrophile $^+\text{SO}_3\text{H}$ to synthesize a sulfonic acid; this reaction is reversible with $\text{H}_3\text{O}^+$ and heat, allowing the sulfonate group to serve as a blocking group.

Friedel–Crafts Alkylation ($\text{RCl}, \text{AlCl}_3$)

A reaction that generates a carbocation electrophile to produce an alkylbenzene; it is prone to carbocation rearrangement and polyalkylation.

Friedel–Crafts Acylation ($\text{RCOCl}, \text{AlCl}_3\text{; then H}_2\text{O}$)

A reaction that generates an acylium ion electrophile to produce an aryl ketone without carbocation rearrangement, stopping cleanly after one acylation.

Rate-Determining Step of EAS

The step in which the electrophile attacks the aromatic ring to form the sigma complex (arenium ion), during which ring aromaticity is lost.

Failure Conditions of Friedel–Crafts Reactions

Friedel–Crafts reactions give no reaction if the ring possesses a meta director, if the ring bears an amine ($-\text{NH}_2, -\text{NHR}, -\text{NR}_2$) that coordinates to $\text{AlCl}_3$, or if the halide reactant is vinyl or aryl.

Synthesis of Straight-Chain Alkylbenzenes

A two-step pathway consisting of Friedel–Crafts acylation followed by reduction of the carbonyl ($\text{C}=\text{O}$) to a methylene group ($\text{CH}_2$) using Wolff–Kishner ($\text{H}_2\text{NNH}_2, \text{HO}^-, \text{heat}$) or Clemmensen ($\text{Zn}(\text{Hg}), \text{HCl}$) conditions.

Friedel–Crafts Monoacylation Control

The tendency of Friedel–Crafts acylation to stop after a single addition because the introduced acyl/ketone group is electron-withdrawing and deactivates the ring toward further electrophilic attack.