MCAT Organic Chemistry · Lesson 4
Analyzing Organic Reactions
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5 sections
4.1 Acids and Bases
Acid and base react, making CB and CA. Reaction proceeds when conjugate products weaker than reactants.
- Definitions
- Lewis acid is electron acceptor.
- Electrophiles.
- Vacant p orbitals.
- Lewis base is electron donor.
- Nucleophiles, have lone pair of electrons.
- Often anions.
- Lewis acid and base interactions form coordinate covalent bonds — both e⁻ in bond came from starting atom.
- Bronsted–Lowry acid is proton donor.
- Bronsted–Lowry base is proton acceptor.
- Amphoteric water can act as acid or base.
- Water as acid becomes OH⁻.
- Water as base becomes H₃O⁺.
- Lewis acid is electron acceptor.
- Acid and Base Strength
- More acidic molecules have smaller pKa.
- Basic molecules have large pKa.
- pKa > -2 means strong acid, dissociate completely.
- Bond strength decreases down periodic table → acidity increases.
- More electronegative → higher acidity.
- Alpha-H's of carbonyl compounds are special — acidic hydrogens that are easily lost because enol/carbanion forms stabilized by resonance.
- Common functional groups
- Acidic ones: alcohols, aldehydes, ketones (at alpha carbon), carboxylic acids.
- Basic ones: amines and amides.
- In formation of peptide bonds the N atom can form coordinate bonds by donating lone pair to Lewis acid.
4.2 Nucleophiles, Electrophiles, and Leaving Groups
Describes nucleophiles (nucleus-loving), electrophiles (electron-loving), leaving groups and how solvent/structure affect reactivity.
- Nucleophiles
- Nucleus-loving species, have lone pairs or π bonds.
- CHON with negative sign = nucleophiles.
- Good nucleophiles are good bases.
- Nucleophile strength based on relative rates of rxn with common electrophile (kinetic property).
- Base strength is equilibrium/thermodynamic property.
- Nucleophilic attack based on reactivity of carboxylic acid derivatives: Anhydrides > carboxylic acids/esters > amides.
- Derivatives of higher reactivity can go to lower, but not lower to higher.
- More basic nucleophile = more reactive.
- Determined by
- Charge: increases with increasing e⁻ density (more -).
- Electronegativity: nucleophilicity decreases as electronegativity increases.
- Steric hindrance: bulky molecules less nucleophilic.
- Solvent: protic solvents hinder nucleophilicity by protonating nucleophile.
- Solvent effects
- Polar protic solvents: increase nucleophilicity down a periodic table (can H-bond). Examples: carboxylic acids, ammonia/amines, water/alcohol.
- F⁻ (CB of weak HF) is heavily solvated → less nucleophilic.
- I⁻ (CB of strong HI) less solvated → stronger nucleophile.
- Polar aprotic solvents: increase nucleophilicity up the table (no H-bonding). Examples: DMF, DMSO, acetone.
- Nonpolar solvents: not commonly used for nuc/elec reactions.
- Polar protic solvents: increase nucleophilicity down a periodic table (can H-bond). Examples: carboxylic acids, ammonia/amines, water/alcohol.
- Common strengths
- Strong nucleophiles: HO⁻, RO⁻, CN⁻, N₃⁻.
- Fair: NH₃, RCO₂⁻.
- Weak: H₂O, ROH, RCOOH.
- Electrophiles
- Electron-loving, positive/δ+ species that accept e⁻ pair.
- Electrophiles act as Lewis acids.
- Greater + charge → greater electrophilicity.
- Reactivity trend for carbonyl derivatives: Anhydrides > carboxylic acids/esters > amides.
- Anhydride = two carbonyl carbons connected by O.
- Leaving Groups
- Molecular fragments that retain e⁻ after heterolysis.
- Heterolytic rxns: bond breaks, both e⁻ go to one product.
- Best leaving groups stabilize extra e⁻ → weak bases = good LGs (conjugate bases of strong acids).
- Alkanes and H⁺ are never leaving groups.
- Leaving groups and nucleophiles have opposite functions — a weaker base (better LG) is replaced by stronger base (nucleophile) in substitution.
- Nucleophilic substitution reactions
- Occurs when nucleophile is stronger base (more reactive) than leaving group.
- SN1
- Unimolecular nucleophilic substitution.
- First step is rate-limiting: LG leaves → carbocation.
- More substituted carbocation is more stable.
- Rate depends on [substrate]: .
- Nucleophilic attack on carbocation → substitution product (usually racemic).
- First-order kinetics.
- SN2
- One-step concerted reaction: nucleophile attacks while LG leaves (backside attack).
- Requires strong nucleophile + low steric hindrance (less substituted carbon reactive).
- Substrates: alkyl halide, tosylate, mesylate.
- .
- SN2 gives inversion of configuration (R → S). Stereospecific.
4.3 Oxidation–Reduction rxns
Defines oxidation states, oxidation vs reduction, common oxidizing/reducing agents and typical organic oxidations/reductions.
- Oxidation state
- Hypothetical charge if all bonds were ionic.
- Calculated from molecular formula (e.g., CH₄ = -4; CO₂ = 0).
- For ions, oxidation state = charge.
- Definitions
- Oxidation = increase in oxidation state (loss of e⁻).
- Reduction = decrease in oxidation state (gain of e⁻).
- Reduction often corresponds to increase in # of bonds to H.
- Oxidizing agents
- Accept e⁻ (are reduced).
- Good agents: high affinity for e⁻ or high oxidation states.
- Primary alcohols → aldehydes → carboxylic acids (with strong oxidant).
- Reactions feature increase in # of bonds to O.
- Example: secondary alcohol (2-butanol) + dichromate → butanone.
- Reducing agents
- Donate e⁻ (are oxidized).
- When C–X (X more EN) replaced by C–H or C–less EN → reduction.
- Good agents: Na, Mg, Al, Zn (low EN, low IE).
- Metal hydrides (e.g., LAH) provide H⁻; LAH reduces C=O → C–OH.
4.4 Chemo selectivity
Chemoselectivity is preferential reaction of one functional group in presence of others; factors include oxidation state, sterics, and protecting groups.
- Chemo selectivity = preferential rxn of one functional group when others present.
- Reactive locations
- Redox reagent will act on highest priority / most oxidized functional group.
- More oxidized functional group is more reactive in nucleophilic/electrophilic and redox rxns.
- Carbonyl carbon is electrophilic (δ+) and target for nucleophiles.
- α-H more acidic than regular C–H due to enolate resonance → can be deprotonated to form enolate.
- Substitution trends
- SN1 prefers 3° > 2° > 1° (carbocation stability).
- SN2 prefers 1° > 2° >>> 3° (steric hindrance).
- Steric protection
- Bulky groups prevent nucleophile from reaching electrophile — can mask reactive sites.
- Protecting groups: convert reactive functional group to less reactive form (e.g., convert aldehyde/ketone → acetal/ketal) before reductions.
- Reduction example
- Molecule with COOH and aldehyde/ketone: reduction may reduce all groups.
- Protect aldehyde/ketone as acetal/ketal prior to using LAH.
4.5 Steps to Problem Solving
Practical roadmap to predict major products: identify functional groups, reactivity, reagents, and stereochemical outcomes.
- Know nomenclature.
- Identify functional groups.
- Do they act as acids/bases? How oxidized is C?
- Identify other reagents.
- Identify the most reactive functional group.
- Identify the first step of rxn.
- If acid/base → protonation or deprotonation.
- If nucleophile → attack electrophile.
- If redox → most oxidized functional group will be oxidized/reduced.
- How do these steps affect the molecule?
- Consider stereospecificity/stereoselectivity (e.g., SN2 inversion).
- Major product determined by differences in strain or stability — more strained are less likely; conjugation → more stable.
- Example
- Diol is protecting group for aldehydes and ketones, used before LAH.
- Alcohol is likely to be oxidized.
- Ethanol → ethanoic acid using potassium dichromate .
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