A leaving group departs and a π bond (double bond) forms. Almost always tested alongside SN1/SN2.
E2 — One Step (Concerted)
B⁻ removes H from Cβ while LG departs from Cα simultaneously — electrons from the C–H bond form the new C=C π bond.
Strong/bulky base (e.g. OH⁻, t-BuO⁻, LDA), high temp. Anti-periplanar = H and LG must be 180° apart. Zaitsev’s rule: more substituted alkene favoured. Rate = k[Sub][B⁻] — 2nd order, hence E2.
Dr. Donnelly’s tip: On the MCAT, you’re rarely asked “draw the mechanism.” Instead, you must predict which pathway (SN1/SN2/E1/E2) dominates. Use the decision tree below.
The SN1/SN2/E1/E2 Decision Tree
3
Nucleophilic Addition to Carbonyls
The carbonyl (C=O) is the most important functional group on the MCAT. Nucleophile attacks electrophilic carbonyl carbon of aldehydes/ketones.
Nucleophilic Addition to C=O
Nu⁻ attacks the electrophilic carbonyl C (sp²), π bond breaks, electrons go to O. The tetrahedral alkoxide intermediate is then protonated.
Key sub-reactions you must know:
NaBH₄ / LiAlH₄ Reduction
H⁻ delivered to carbonyl C. NaBH₄ = mild (ketones/aldehydes). LiAlH₄ = strong (also esters, acids).
CN⁻ attacks C=O → tetrahedral product with both OH and CN. Important for amino acid synthesis.
4
Nucleophilic Acyl Substitution
Nucleophile attacks carbonyl of a carboxylic acid derivative; the leaving group departs (addition-elimination). Directly connects to biochemistry (peptide bonds, ester bonds in lipids).
Addition-elimination: Nu attacks → tetrahedral intermediate → LG departs. C=O reforms.
Reactivity order (know this cold):
Better leaving group = more reactive • N lone pair donates into C=O = least reactive
Key reactions:
Fischer Esterification
Reversible. Acid-catalysed. Driven forward by excess alcohol or removal of H₂O.
Saponification
Irreversible (OH⁻ is a strong nucleophile). This is how soap is made from fats.
Amide Formation (from Acid Chloride)
Acid chlorides are the most reactive acyl derivatives — react rapidly with amines. Cl⁻ is an excellent leaving group.
5
Aldol Reaction & Aldol Condensation
Enolate attacks a carbonyl, forming a β-hydroxy carbonyl. With heat, dehydration gives an α,β-unsaturated carbonyl. Key C–C bond-forming reaction.
Water breaks the ester bond. Acid or base catalysed. Reverse of Fischer esterification.
Amide Hydrolysis
Requires strong acid/base + heat (amide bond is very stable). Key for peptide digestion.
Ester Condensation (Fischer)
Acid + alcohol condense, losing H₂O. Acid-catalysed, reversible. Same as Fischer esterification.
Amide Condensation (Peptide Bond)
Acid + amine condense to form amide (peptide bond). Fundamental to protein synthesis.
Glycosidic Bond Hydrolysis (Maltose → 2 Glucose)
H₂O breaks the glycosidic bond. C1 gets OH from water. The glycosidic O stays on C4, picking up H from water. Catalysed by acid or enzymes (e.g. maltase).
Glycosidic Bond Formation (2 Glucose → Maltose + H₂O)
OH from C1 + H from C4 leave as H₂O. C4's O stays as the glycosidic bridge. Reverse = hydrolysis.
8
Keto-Enol Tautomerism
Interconversion between keto form (C=O, C–H) and enol form (C=C, O–H). Acid or base catalysed. Foundation for aldol, α-halogenation, and all enolate chemistry.
MCAT focus: Keto form is thermodynamically favoured. Enol is the reactive form. α-hydrogens are acidic because of resonance stabilisation of the enolate.
Tier 2
Know Well
Tested regularly. Conceptual understanding is usually sufficient — you won’t be asked to draw full mechanisms.
9 Electrophilic Addition to Alkenes
Electrophile (H⁺) adds across C=C double bond. Markovnikov: H adds to the less substituted C, placing the nucleophile (Br⁻, OH) on the more substituted C (via the more stable carbocation intermediate).
HBr Addition (Markovnikov)
Acid-Catalysed Hydration (Markovnikov)
Hydroboration-Oxidation (Anti-Markovnikov, syn)
Halogenation (anti addition via bromonium ion)
Anti-Markovnikov (BH₃/H₂O₂): B adds to the less substituted C, while H adds to the more substituted C, followed by oxidation that replaces boron with an –OH group on the same face (syn addition). Halogenation (Br₂): Br atoms add to opposite faces via a bromonium ion intermediate (anti addition).
10 Electrophilic Aromatic Substitution
Electrophile replaces H on benzene ring. Know directing effects.
NH₂ donates electron density into the ring (activating), directing E⁺ to ortho and para positions.
Deactivating / Meta Directors: –NO₂, –CN, –COR, –COOH
Electron-withdrawing groups deactivate the ring and direct E⁺ to the meta position.
Halogens (–F, –Cl, –Br): Deactivating but Ortho-Para Directing
Halogens are the exception: they withdraw electron density (deactivating) but their lone pairs donate into the ring, directing ortho/para.
11 Epoxide Ring Opening
Nucleophile attacks the strained 3-membered ring (anti/backside). In base, Nu⁻ does an SN2 attack on the less substituted C (less steric hindrance). In acid, H⁺ protonates O first, building δ⁺ on the more substituted C, so the weaker nucleophile attacks there instead.
General Mechanism
Acid Conditions: H⁺ protonates the epoxide O
Step 1: H⁺ protonates the epoxide O, weakening C–O bonds. Step 2: δ⁺ builds on the more substituted C2, so the nucleophile attacks there.
Base Conditions: Nu attacks less substituted C (SN2 backside)
12 Transesterification
One ester is converted to another by swapping the alcohol portion. Reversible — driven by excess of new alcohol.
R–CO–OR′ + R″OH → R–CO–OR″ + R′OH
Example: Methyl ester → Ethyl ester
The OCH₃ leaves and is replaced by OCH₂CH₃ from the incoming alcohol. Key in lipid/biodiesel chemistry.
Biochem link: Cyclic sugars are hemiacetals/hemiketals. Glycosidic bonds are acetals. Acetal formation is reversible in acid but stable in base (protecting group strategy).
14 Claisen Condensation
Two esters react (strong base) to form a β-keto ester. Ester analogue of the aldol reaction.
2 × R–CH₂–COOR′ [base] → β-keto ester + R′OH
STEP 1Base removes α-H → enolate
STEP 2Enolate attacks carbonyl C of 2nd ester (new C–C bond)
STEP 3OR′ leaves, C=O reforms → β-keto ester
Biochem link: Fatty acid synthesis uses Claisen-type condensation (via thioester — the thiolate is a better leaving group than alkoxide).
15 Conjugate (Michael) Addition
With α,β-unsaturated carbonyls, the nucleophile can attack the carbonyl C (1,2-addition) or the β-C (1,4-addition). Which pathway dominates depends on the nucleophile strength.
Strong Nu⁻ (RMgBr, RLi) → 1,2-Addition (direct to C=O)
Strong Nu attacks C=O directly (kinetic control). C=C double bond is unchanged.
Nu⁻ attacks β-C (position 4), electrons shift through conjugated system
STEP 2
Enolate intermediate forms (O⁻ at position 1)
STEP 3
Tautomerisation: enolate → keto form (H adds to C3, C=O reforms)
Called "1,4" because overall: H adds to O (position 1) and Nu adds to β-C (position 4). The enolate intermediate tautomerises to the more stable keto form.
Key point: Strong Nu (RLi, RMgBr) → 1,2 (C=C intact, new bond to C=O carbon). Weak Nu (enolates, cuprates, RSH, amines) → 1,4 Michael (C=O intact, new bond to β-C).
16 Free Radical Halogenation
Radical chain reaction: alkane C–H replaced by C–X. Three phases: initiation, propagation, termination.
R–H + X₂ [hν or heat] → R–X + HX
INITIATION
Homolytic cleavage of X–X by light or heat
PROPAGATION
Two steps that repeat in a chain
Step 1: X• abstracts H from R–H
Step 2: R• abstracts X from X–X (regenerates X•)
TERMINATION
Two radicals combine — chain stops
Selectivity: Br₂ is highly selective (favours 3° C–H, more stable radical). Cl₂ is less selective (reacts with almost any C–H). Radical stability: 3° > 2° > 1° > methyl.
17 Decarboxylation
Loss of CO₂ from a carboxylic acid. Requires C=O at the β-position for the six-membered cyclic transition state.
β-keto acid [heat] → ketone + CO₂
Mechanism
The β-C=O oxygen grabs the α-H. The C–COOH bond breaks simultaneously, releasing CO₂ as gas. The enol tautomerises to the more stable ketone.
Biochem link: Pyruvate → acetaldehyde + CO₂ (requires TPP cofactor). Isocitrate → α-ketoglutarate + CO₂ in Krebs cycle. Acetoacetate → acetone + CO₂ in ketone body metabolism.
Tier 3
Recognise the Concept
Can appear on the MCAT but less frequently. Know the product and key concept — you won’t need full mechanisms.
18 Diels-Alder Reaction
[4+2] cycloaddition. Conjugated diene (4 π electrons) + dienophile (2 π electrons) → cyclohexene. Concerted, syn addition — no intermediates.
Mechanism
All 3 pairs of π electrons move simultaneously (concerted): C1=C2 π → new C1–C6 σ bond, C3=C4 π → new C4–C5 σ bond, C5=C6 π → new C2=C3 π bond. Two new σ bonds form (closing the ring), one π bond remains (C2=C3). Diene must be in s-cis conformation. Works best with electron-rich diene + electron-poor dienophile (e.g. with C=O or CN).
19 Wittig Reaction
Phosphorus ylide + aldehyde/ketone → alkene. Converts C=O to C=C at the exact same position.
R₂C=O + Ph₃P=CHR′ → R₂C=CHR′ + Ph₃P=O
The ylide C becomes part of the new C=C. Ph₃P=O byproduct (very stable P=O bond drives the reaction).
20 Wolff-Kishner & Clemmensen Reduction
Both reduce C=O all the way to CH₂ (complete deoxygenation). Same product, different conditions — know which is acid vs base!
Wolff-Kishner — BASIC conditions
Clemmensen — ACIDIC conditions
21 Hofmann Elimination & Rearrangement
Elimination: Quaternary ammonium + base → less substituted alkene (anti-Zaitsev). Rearrangement: Amide + Br₂/NaOH → amine (one fewer carbon).
Tier 3 study strategy: Don’t spend more than 10% of your organic chemistry study time here. If you see one of these on the MCAT, the passage will usually explain the reaction — your job is to interpret it using Tier 1 concepts (nucleophilic attack, leaving group quality, thermodynamics vs. kinetics).
Master Tier 1 first. Only move to Tier 2 when you can identify all 8 Tier 1 reactions, their products, mechanisms, and stereochemistry from memory. Tier 3 reactions are low-probability — the passage will usually explain them.
mcatdoctor.com • Dr. Stuart Donnelly • Oxford Ph.D. • 20+ years of private MCAT tutoring Pair this guide with the Reaction Roadmap for a complete C/P organic chemistry strategy.
