O-Chem Trends

Strong Ortho/Para directing groups

-NR2, -NHR, -OR, -OH, -OCH3, R-COOR’

strongly activating ortho/para directing groups push electron density into the benzene ring to activate the ring

donate through resonance to generate a very stable sigma complex

Moderately Activating Ortho/Para directing groups

-NHCOR, -OCOR, alkyl (-R)

Resonance donation (amides and esters) or hyper conjugation (alkyl)

Weakly Deactivating by ortho/para directing groups

Halogens

-F, -Cl, -Br, -I

Inductively withdraw (-I) —> slower overall but lone pairs donate by resonance —> ortho/para directing

Strongly Deactivating, Meta-Directing

-NO2, -CF3, −C≡N, -SO3H, -C(=O)R, -CO2R, -CHO, -COR, -CONH2, -NR3+, -CX3

Strong -I and/or -M

Sigma-complex most stabilized at meta

EAS Reaction

Benzene is a nucleophile. Anything that pushes electron density in activates and is ortho/para directing (except halogens), anything that pulls strongly out deactivates and is meta-directing.

Can this group by resonance into the ring? If yes, usually ortho/para and activating. If it is strongly withdrawing (C=O, NO2, CN, SO3H, NR3+), usually meta and deactivating.

Friedel-Crafts alkylation/acylation

Occurs when the aromatic ring is not too deactivated

Fails on rings with strongly deactivating groups (-NO2, CF3, -CN, SO3H, -COOR, -CHO, -COR, CONH2, -NR3+)

No strongly basic or Lewis-basic groups that will just bind AlCl3, instead of letting the ring react

No serious carbocation rearrangement issues

Friedel-Crafts acylation

Gives aryl ketone, no rearrangement, product is deactivated, usually only one acylation

Ar-C(=O)-R

Friedel-Crafts alkylation

Carbocation rearranggements possible, product is more activated than benzene

Electrophilicity of carbonyls and nitriles

Most Electrophilic to Least Electrophilic

1. Acid Chlorides (R-C(=O)-Cl)

2. Anyhydrides (R-(C=O)-O-(C=O)-R)

3. Aldehydes (R-C(=O)-H)

4. Ketones (R-(C=O)-CH3)

5. Esters (R-C(=O)-OR, amides (R-(C=O)-NR2)

6. Carboxylates (R-(C=O)-O^-)

7. Nitriles (R-CN)

Better leaving group —> more electrophilic

Less electron donation from attached groups —> more electrophilic

Resonance donation from heteroatom (OR, NR2) —> less electrophilic

Negative charge (carboxylate) —> very poor electrophile

Substituent effects on carboxylic acid acidity

Acidity is the stability of the conjugate base (carboxylate)

More acidic:

• Electron-withdrawing groups near carboxylic acid

  • -NO2, -CF3, -CN, halogens (especially at alpha-position)

  • More electron-withdrawing groups and closer to COOH —> more acidic

  • Resonance stabilization of conjugate base (ex: aromatic carboxylic acids[cyclic] vs aliphatic [linear])

Less acidic:

• Electron-donating groups near carboxylic acid

  • Alkyl, -OR, -NR2

• Push electron density into the carboxylate, destabilizing the negative charge

Equilibrium

Reaction:

• aA +bB ⇌ cC + dD

• K is the equilibrium constant

• K = [C]^c x [D]^d / [A]^a x [B]^b

Equilibrium constant meaning

• K >> 1: Products favored at equilibrium

• K << 1: Reactants favored at equilibrium

• K = 1: significant amounts of both

Ranking Amine (-NR3) Basicity

Basicity:

• Tendency to accept a proton

• Stability of the conjugate acid

Factors:

• Electron donation to N

  • increases basicity

  • alkyl groups donate by induction

  • alkyl amines generally more basic than ammonia

• Resonance delocalization of lone pair (decreases basicity)

  • Aniline and other aryl amines

    • Lone pair delocalized into ring —> less basic

  • Amides

    • lone pair delocalized into C=O —> very weak bases

• Hybridization

  • sp3 N (amines) > sp2 N (imines, anilines) > sp N (nitriles) in basicity

• Solubility and Sterics

  • Primary and secondary amines more basic than very bulky tertiary amines because their conjugate acids are better solvated

• Rough trend

  • Aliphatic secondary = primary amines > tertiary (bulky) > ammonia > aniline > amide

Aldol Condensation

Product is either B-hydroxy carbonyl (aldol) or alpha, B-unsaturated carbonyl (after dehydration)

C=O-C-C=O where the new C-C bond is between the alpha carbon of one carbonyl and the carbonyl carbon of another

Claisen Condensation

Ester + ester —> B-keto ester

COOR-CH2-C=O-R

Requires two esters with the same OR group (or intermolecular)

Acetoacetic ester synthesis

Begin with ethyl acetoacetate

Deprotonate active methylene —> alkylate —> decarboxylate —> substituted methyl ketone

Product is a methyl ketone where the methyl comes from the original active methylene

Strategy

β-keto ester → Claisen or acetoacetic

β-hydroxy or α,β-unsaturated carbonyl → aldol

1,3-dicarbonyl that lost CO₂ → malonic/acetoacetic-type synthesis

Active Methylene Compounds and Acidity

Active methylene = CH2 flanked by two strong electron-withdrawing groups, usually carbonyls

Examples:

• Malonate esters: CO2Et-CH2-CO2Et

• B-keto esters: -CO-CH2-CO2Et

• 1,3-diketones: -CO-CH2-CO-

Deprotonation gives an enolate stabilized by resonance to both carbonyls

More resonance structures and more EWG character —> more acidic

Ranking acidity of active methylenes

1,3-diketone > B-keto ester > Malonate ester > simple ketone/ester alpha-hydrogen

Additional electron withdrawing groups or closer positioning —> more acidic