Aromatic and Heteroaromatic Chemistry - Electrophilic Aromatic Substitution (SEAr)

This set covers the rate, regioselectivity, electronic effects, and key named reactions for Electrophilic Aromatic Substitution (SEAr) on substituted benzenes, phenols, and anilines.

Activating Groups

Electron-donating substituents (+M, +I) that increase the electron density on the aromatic ring, making $S_{E} ext{Ar}$ faster and occur under milder conditions compared to benzene.

Deactivating Groups

Electron-withdrawing substituents (-M, -I) that decrease the electron density on the aromatic ring, making $S_{E} ext{Ar}$ slower and requiring more forcing conditions compared to benzene.

Inductive Effect ($I$)

Electronic effects that travel along $ext{\sigma}$ bonds over short distances, originating from differences in electronegativity.

Mesomeric Effect ($M$)

Electronic effects that travel along $ext{\pi}$ bonds over long distances, originating from resonance and conjugation.

Wheland Intermediate

The cationic intermediate formed during electrophilic aromatic substitution; its transition state is modeled using the Hammond postulate and is stabilized by electron-donating groups.

Meta-directing (m-directing)

Regioselectivity typical of electron-withdrawing groups (e.g., $NO_2$, $CN$, $COR$) where attack at the meta position avoids unfavorable resonance structures with adjacent positive charges.

Ortho, para-directing (o,p-directing)

Regioselectivity typical of electron-donating groups (e.g., $-OR$, $-NR_2$, alkyl) or halogens, where the Wheland intermediate is stabilized by inductive effects or a 4th resonance form.

Halogens in $S_{E} ext{Ar}$ ($F, Cl, Br, I$)

Substituents that are deactivating due to their $-I$ effect but $o,p$-directing due to their $+M$ effect, which allows for a 4th resonance form.

$pKa$ of Phenol ($PhOH$)

The value is approximately $10$, making phenols more acidic than alcohols (e.g., Water $pKa = 15.7$, Methanol $pKa = 15.5$) due to resonance stabilization of the phenolate anion.

Kolbe-Schmitt Reaction

The reaction of the anionic sodium phenolate with neutral $CO_2$ (a weak electrophile) to produce salicylic acid, a precursor to aspirin.

Reimer-Tiemann Reaction

The synthesis of phenolic aldehydes (mostly ortho) using phenol, chloroform ($CHCl_3$), and $NaOH$ via a dichlorocarbene intermediate.

Dichlorocarbene

A neutral, electrophilic, divalent carbon species with 6 valence electrons ($:CCl_2$) generated by the $ext{\alpha}$-elimination of $HCl$ from chloroform in the presence of base.

Lederer-Manasse Reaction

The reaction of phenol with formaldehyde ($HCHO$) and $NaOH$ to produce ortho-hydroxymethyl phenol.

Basicity of Aniline ($PhNH_2$)

Anilines are less basic than aliphatic amines; the $pKa$ of the conjugated acid ($PhNH_3^+$) is $4.6$, compared to $10.6$ for $EtNH_3^+$.

Clemmensen Reduction

A one-step acidic method to reduce carbonyl groups ($C(O)R$) to methylene groups ($CH_2R$) using amalgamated zinc ($Sn(Hg)$) in $HCl$.

Wolff-Kishner Reduction

A two-step basic method to reduce carbonyls to methylene groups using hydrazine ($NH_2NH_2$) to form a hydrazone, followed by treatment with $KOH$ and heat.

Mozingo Reduction

A two-step reducing method using 1,3-propanedithiol to form a thioketal, followed by hydrogen and Raney nickel for desulfurization to a methylene group.

Nitration of Nitrobenzene conditions

Requires forcing conditions: $HNO_3$, $H_2SO_4$ at $100\,^{\circ}C$ to overcome the deactivating effect of the nitro group.

Nitration of Toluene product ratio

Yields $62\%$ ortho, $5\%$ meta, and $33\%$ para products; para is often preferred over ortho in larger alkyl groups due to the absence of steric clashes.