Chemistry - All Schemes

Direct Alkylation of Amines (R-Br)

• Nucleophilic attack of NH₃ (or amine) on alkyl halide.

• Yields ammonium salt intermediate.

• Risk of over-alkylation → mixture of 1°, 2°, 3°, and quaternary ammonium salts.

• Hard to control selectivity.

Alkylation Using Excess Ammonia (excess NH₃)

• Large excess NH₃ ensures it reacts before newly formed amines.

• Minimizes over-alkylation.

• Favors formation of primary amine.

• Alkyl halide is essentially “quenched” by NH₃ first.

Azide Substitution (1. R–X, 2. H₂,Pd/C)

• Azide ion (N₃⁻) performs SN2 substitution on primary alkyl halides.

• Forms an alkyl azide (R–N₃) with a new C–N bond.

• Azide is linear and a strong nucleophile; good for avoiding elimination.

• Useful as a synthetic equivalent of NH₂⁻ (but safer).

Azide Reduction to Amine (1. H₂/Pd–C or 2. LiAlH₄)

• Converts R–N₃ → R–NH₂ via reduction.

• H₂/Pd–C gives catalytic hydrogenation.

• LiAlH₄ gives hydride reduction in anhydrous conditions.

• No rearrangement occurs; preserves carbon skeleton.

Gabriel Synthesis (1. KOH, 2. R–X, 3. H₂N–NH₂)

• KOH deprotonates phthalimide to generate the nucleophilic imide anion.

• The imide anion performs an SN2 attack on the alkyl halide, forming a new C–N bond.

• Hydrazine cleaves the N–R bond, releasing the primary amine.

• Produces primary amines without risk of over-alkylation.

Deprotonation & Rearomatization (1. Base, 2. H₂/Pd–C or Fe/HCl)

• Base removes a proton, restoring aromaticity and forming the nitro-substituted benzene.

• The nitro group can then be reduced to an aniline using H₂, Pd/C.

• Alternatively, Fe, HCl performs chemoselective reduction of the nitro group.

• Produces primary aryl amines from nitroarenes.

Reductive Amination → Amines (H₂, Pd/C)

• The aldehyde or ketone reacts with ammonia to form an imine intermediate.

• A reducing agent (often NaBH₃CN) reduces the imine to a primary amine.

• Works for both aldehydes and ketones.

Reductive Amination to Secondary Amines (1. RNH₂, 2. RA)

• A primary amine reacts with the carbonyl to form an imine or iminium ion.

• Reduction converts this intermediate into a secondary amine.

• Allows controlled formation of N-monoalkylated products.

• Produces R¹R²CH–NHR.

Reductive Amination to Tertiary Amines (1. R₂NH, 2. RA)

• A secondary amine condenses with the carbonyl to form an iminium ion.

• A reducing agent converts it into a tertiary amine.

• Useful for synthesizing fully substituted amine centers.

• Produces R¹R²CH–NR₂.

Reduction of C–N (1. Na/EtOH, 2. H₂/Pd–C or Ni)

• Oximes (R¹R²C=NOH) are reduced by Na metal in EtOH to form primary or secondary amines.

• Nitriles (R–C≡N) are reduced by H₂ with Pd/C or Ni to give primary amines (R–CH₂NH₂).

• These reductions saturate the C–N multiple bond to yield the amine.

• Useful for converting oximes or nitriles into corresponding amines.

Nucleophilic Cyanide Substitution (1. R-X, 2. H₂/Pd–C or Ni)

• Cyanide (CN⁻) performs an SN2 attack on alkyl halides (R–X), forming nitriles (R–C≡N).

• The nitrile is then reduced to a primary amine, adding a new –CH₂NH₂ unit.

• This method extends the carbon chain by one carbon.

• Unlike azide, cyanide introduces –CH₂NH₂, not –NH₂ directly.

Reduction of Amides (1. LiAlH₄, 2. H₂O)

• LiAlH₄ reduces amides all the way to amines, breaking the C–O bond completely.

• The carbonyl carbon becomes the carbon attached to the resulting amine (no loss of carbon).

• Works for primary, secondary, and tertiary amides.

• Final aqueous workup (H₂O) releases the amine from the aluminum complex.

Hofmann Rearrangement (1. Br₂, 2. NaOH or KOH, H₂O)

• A primary amide reacts with Br₂ and base to form an N-bromoamide intermediate.

• Rearrangement occurs (migration of R- group) to generate an isocyanate.

• The isocyanate is hydrolyzed to a carbamic acid, which is unstable.

• Carbamic acid spontaneously loses CO₂, yielding a primary amine with one fewer carbon.

Curtius Rearrangement (1. NaN₃, 2. Δ, 3. H₂O)

• An acyl chloride reacts with NaN₃ to form an acyl azide.

• Upon heating (Δ), the acyl azide undergoes rearrangement, releasing N₂ gas.

• Rearrangement produces an isocyanate intermediate.

• Hydrolysis of the isocyanate yields a primary amine with one fewer carbon (plus CO₂).

Diazotization of Primary Amines (NaNO₂, HCl)

• NaNO₂ and HCl react to form nitrous acid (HONO).

• HONO is converted under acidic conditions into the nitrosyl cation (NO⁺).

• The amine attacks NO⁺, forming N-nitrosamine intermediates.

• Further protonation and dehydration produce the diazonium salt (R–N≡N⁺ Cl⁻).

Aromatic Diazonium Substitution

• Aniline (Ar–NH₂) is converted to the diazonium salt (Ar–N₂⁺ Cl⁻) using NaNO₂/HCl.

• The diazonium group acts as a versatile leaving group for substitution.

Sandmeyer Reactions (Ar–NH₂ → Ar–X using Cu(I) salts)

• An aromatic amine is first converted to its diazonium salt with NaNO₂ and aqueous HX.

• Cu(I) salts (CuCl, CuBr, CuCN) promote substitution of the diazonium group.

• The reaction installs Cl, Br, or CN onto the aromatic ring depending on the Cu(I) reagent.

Aryl Diazonium → Aryl Iodide (1. NaNO₂/H₂SO₄, 2. KI)

• Aniline is converted into the aryl diazonium salt under acidic nitrosation conditions.

• Iodide from KI acts as a nucleophile toward the diazonium intermediate.

• The –N₂⁺ group is displaced by I⁻, releasing N₂ gas.

• Produces an aryl iodide with all substituents retained.

Aryl Diazonium → Aryl Fluoride (1. NaNO₂/HCl, 2. HBF₄)

• Aniline is first transformed into its diazonium chloride via NaNO₂/HCl.

• Treatment with HBF₄ yields the tetrafluoroborate diazonium salt.

• Thermal decomposition releases N₂ and BF₃, inserting fluoride onto the ring.

• Final product is an aryl fluoride preserving original substituents.

Diazonium Salts - Phenol (1. NaNO₂/H₂SO₄, 2. Cu₂O, Cu²⁺, H₂O)

• The aniline is converted to a diazonium salt under acidic nitrosation conditions.

• Copper(I/II) oxides in water promote substitution of the diazonium group.

• The –N₂⁺ group is displaced by OH, releasing N₂ gas.

• Final product is a phenol retaining all original aromatic substituents.

Diazo Coupling (NaNO₂ / HCl)

• Convert aniline to a diazonium salt using nitrous acid.

• Diazonium ion acts as a strong electrophile toward activated aromatic rings.

• Rings with EDGs undergo rapid electrophilic aromatic substitution.

• Produces brightly colored azo compounds (Ar–N=N–Ar) due to extended conjugation.

Making Tosylates (TsCl / pyridine)

• Alcohols react with tosyl chloride (TsCl) in pyridine.

• Forms tosylates (ROTs), which convert a poor leaving group (–OH) into an excellent one (–OTs).

• Reaction occurs via nucleophilic attack of the alcohol oxygen on sulfur.

• Pyridine neutralizes HCl formed during the process.

Making Sulfonamides (ArSO₂Cl + amine)

• Amines react with sulfonyl chlorides (ArSO₂Cl) to make sulfonamides.

• Nitrogen acts as the nucleophile and attacks sulfur.

• Reaction proceeds similarly to tosylate formation (nucleophilic substitution at S).

• Produces stable sulfonamides (R–NH–SO₂–Ar).

Sulfonamide Alkylation (1. Strong base, 2. R′–X, 3. H₃O⁺)

• Strong base (NaNH₂ or NaH) deprotonates the sulfonamide N–H.

• The nitrogen anion attacks an alkyl halide (R′–X) via SN2 to give an N-alkyl sulfonamide.

• Acidic workup cleaves the sulfonyl protecting group.

• Final product: a secondary amine (R–NHR′).

Jones Oxidation (Na₂Cr₂O₇)

• Strong oxidation of aldehydes → carboxylic acids.

• Strong oxidation of 1° alcohols → carboxylic acids.

• 2° alcohols → ketones.

• Cannot stop at aldehyde; pushes fully to acid.

• Acetone is solvent.

NaBH₄ Reduction (NaBH₄, EtOH)

• Reduces aldehydes & ketones → alcohols.

• Does not reduce esters, amides, or carboxylic acids.

• Safe with protic solvents (EtOH, MeOH).

• Selective for carbonyls in complex molecules.

KMnO₄ Oxidation (KMnO₄, heat)

• Strong oxidation: aldehydes/1° alcohols → acids.

• 2° alcohols → ketones.

• Cleaves alkenes → carbonyls or acids.

• Very aggressive, over-oxidation common.

PCC Oxidation (PCC with solvent CH₂Cl₂)

• 1° alcohols → aldehydes (no over-oxidation).

• 2° alcohols → ketones.

• Works under anhydrous conditions.

• Milder than Jones/KMnO₄.

Swern Oxidation (DMSO, (COCl)₂, Et₃N)

• 1° alcohols → aldehydes.

• 2° alcohols → ketones.

• No heavy metals.

• Cold (–78°C) required.

Ozonolysis (O₃ → Zn/HCl or DMS)

• Cleaves alkenes → two carbonyls.

• Reductive workup → aldehydes/ketones.

• Oxidative workup → acids/ketones.

• Exact cleavage of double bond.

LiAlH₄ Reduction (1. LiAlH₄ 2. H₃O⁺)

• Reduces aldehydes → 1° alcohols.

• Reduces ketones → 2° alcohols.

• Reduces esters/acids/amides → alcohols/amines.

• Must be quenched carefully with water after reaction.

Grignard (1. R–MgBr 2. H₃O⁺)

• Nucleophilic R⁻ attack on carbonyl carbon.

• Aldehydes → 2° alcohols (add one R).

• Ketones → 3° alcohols (add one R).

• Adds C–C bonds (key carbon chain-building reaction).

Tollens Oxidation (Ag₂O, OH⁻ → H₃O⁺)

• Selective aldehyde oxidation → carboxylate → acid.

• Leaves alcohols/ketones unchanged.

• Produces silver mirror.

• Mild & chemoselective.

Wittig Reaction (Ph₃P=CH₂)

• Converts carbonyl C=O → C=C.

• Aldehydes → terminal alkenes with =CH₂.

• Replaces oxygen entirely.

• Good for stereoselective alkene formation; opposite of ozonolysis.

Weak Hydride Reduction (LTBA) (Li(t-BuO)₃, cold)

• Selective reduction of acid chlorides → aldehydes.

• Stops before alcohol stage.

• Requires cold conditions (–78°C).

• More selective than LiAlH₄.

DIBAL-H Reduction (DIBAL-H → H₃O⁺)

• Esters → aldehydes (controlled low temp).

• Excess/warm → alcohols.

• Nitriles → aldehydes (via imine).

• Temperature-sensitive.

Friedel–Crafts Acylation (RCOCl, AlCl₃)

• Benzene → aryl ketone.

• No rearrangements.

• Product deactivates the ring.

• Clean one-substitution reaction.

Alkyne Hydration (HgSO₄, H₂SO₄, H₂O)

• Terminal alkyne → methyl ketone (Markovnikov).

• Proceeds via enol → keto.

• Needs Hg²⁺ catalyst.

• Internal alkynes → ketones.

General Acetal Formation (2 ROH, H⁺)

• Carbonyl → acetal (protected form).

• Hemiacetal intermediate.

• Stable in base.

• Deprotected with aqueous acid.

Cyclic Acetal Formation (with diol) (HOCH₂CH₂OH, cat. H⁺)

• Carbonyl + diol → 5-membered cyclic acetal.

• Excellent protecting group.

• Stable in base, removable in acid.

• Driven by intramolecular ring closure.

Hydrazone Formation (PhNHNH₂, pH 4–5)

• Carbonyl → C=N–NHPh (hydrazone).

• Dehydration product from hydrazine/hydrazide reacting with an aldehyde or ketone.

• Formed via condensation (loss of H₂O).

• Product = hydrazone: Carbonyl oxygen replaced by =N–NHPh (or =N–NH₂ for hydrazine).

Benzylic Halogenation Radicalization

• Generic free radical halogenation reaction.

• Reacts with a halogen (X₂) along heat or light.

• Proceeds via hydrogen abstraction to form a free radical.

EAS Halogenation

• To create a strong electrophile either AlCl₃ or FeBr₃ is needed. 

• Carbocation intermediate is formed. 

• Formulates a benzene ring with a halogen attached.

EAS Nitration

• Acid (i.e. H₂SO₄) reacts with HNO₃ to form a unstable electrophile.

• Benzene reacts with the electrophile.

• Adds NO₂ to the benzene.

EAS Sulfonation

• Forms its conjugate base and acid as byproducts.

• Benzene reacts with unstable electrophile.

• Forms a benzene with a HSO₃ group attached.

• Needs acid and heat to react.

EAS Alkylation

• Reacts with AlCl₃/FeCl₃.

• Alkyl group is attached.

• Carbocation rearrangement can occur.

EAS Acylation

• Reacts with AlCl₃/FeCl₃.

• Adds carbonyl group to benzene; forms a ketone.

• No carbocation rearrangement.

Clemmensen Reduction

• Reacts using Zn(Hg) and HCl.

• Needs heat.

• Uses acidic conditions.

• Takes off the =O.

Wolff-Kishner (H₂N-NH₂, KOH, heat)

• Reacts using several reagents.

• Uses basic conditions.

• Takes off the =O.

Oxidative Degradation (1. Hot KMnO₄, KOH 2. H₃O⁺)

• Hot KMnO₄ with KOH for first reaction, then H₃O⁺ for second reaction.

• Leads to benzoic acid formation. 

Nitro → Aniline (Fe/HCl)

• Conversion of NO₂ to NH₂ (nitro to aniline).

• However, other substituents on the benzene can react.

• Fe, HCl can ensure no other reactions occur other than NO₂ → NH₂.

Racemization (acid/base catalysis)

• Acid/base removes α-H → enolate/enol forms.

  • α-Carbon next to carbonyl.

• Reprotonation gives loss of stereochemistry.

• Produces racemic mixture from chiral ketone.

Epimerization (catalytic acid/base)

• Acid/base catalysis forms enolate at α-C.

• Reprotonation flips configuration → epimer formed.

  • Cyclic Ketones.

• Equilibrium favors the more stable chair conformer.

• Base can drive formation of a specific epimer (>20:1).

Acid-Mediated Halogenation (Cl₂, CH₃CO₂H)

• Enol formation occurs under acidic conditions.

• Enol reacts with Cl₂ to install chlorine at the α-carbon.

• Reaction is monochlorination (no over-halogenation).

• Works for aryl and alkyl ketones, giving α-chloro ketones.

Base-Mediated Halogenation (Br₂, NaOH)

• Enolate forms rapidly under strong base, making α-substitution very fast.

• Poly-halogenation at the α-carbon (unlike acid) → haloform. 

• Single bromination.

• Produces an α-bromoketone under strongly basic, irreversible conditions.

Haloform Reaction (X₂, NaOH)

• Converts a methyl ketone (R–CO–CH₃) into a carboxylate salt.

• Requires three successive α-halogenations under basic conditions.

• The trihalomethyl group (–CX₃) is cleaved to form haloform (CHX₃).

• Produces R–COO⁻ Na⁺ + CHX₃ (chloroform, bromoform, or iodoform).

Hell-Volhard-Zelenksy Reaction (X₂, P → PX₃)

• Converts R–COOH into α-haloacids (R–CO–CHX–OH).

• X₂ + P generates PX₃, activating the α-position.

• Halogenation occurs at the α-carbon next to the carbonyl.

• Workup with H₂O yields the α-halo carboxylic acid.

HVZ Halide Displacement (H₂O, Base → H₃O⁺)

• Performs SN2 substitution at the α-carbon.

• Water acts as the nucleophile under basic conditions.

• Forms an α-hydroxy acid after acid workup.

• Overall: R–CHX–COOH → R–CHOH–COOH.

HVZ Amination (NH₃, 2 equiv)

• Ammonia performs SN2 attack at the α-carbon.

• Requires excess NH₃ to drive substitution.

• Produces the α-amino acid (as NH₃⁺ product).

• Halide leaves as NH₄X.

Alkylation of β-Dicarbonyl Enolates (NaOEt and/or LDA / R–Br)

• NaOEt generates the stabilized enolate of ethyl acetoacetate for monoalkylation.

• Enolate attacks primary alkyl halides (R–Br) via SN2, giving α-alkylacetoacetates.

• A stronger base (e.g., LDA or KOtBu) is needed to fully deprotonate the second α-H for dialkylation.

• Second alkylation gives α,α-dialkylated β-keto esters (R and R′ introduced).

Michael Addition [soft nucleophile + α,β-unsaturated carbonyl]

• Conjugate 1,4-addition to an alkene activated by an electron-withdrawing group (EWG).

• Nucleophile attacks the β-carbon, forming a stabilized enolate.

• Enolate is then protonated to give the final Michael adduct.

• Works best with soft nucleophiles (enolates, amines, thiolates).

Enamine Alkylation [R³–X]

• The enamine reacts with the alkyl halide first at nitrogen (N-alkylation, reversible).

• The system equilibrates back to the enamine, which then performs C-alkylation at the α-carbon (irreversible).

• Forms a C-alkylated iminium intermediate.

• Hydrolysis yields the final α-alkylated carbonyl and regenerates the amine.

Enamine Acylation [R³COCl]

• Initial N-acylation is reversible.

• Reaction proceeds to C-acylation (irreversible).

• Net result: α-acylated product after hydrolysis.

• Forms an enammonium byproduct.

Ester Formation w/ Acyl Chloride (Pyridine)

• Acts as a weak, non-nucleophilic base.

• Neutralizes HCl formed during esterification.

• Prevents protonation of the alcohol nucleophile.

• Helps drive formation of the ester product.

Amide Formation w/ Acyl Chloride (Pyridine)

• Serves as the nucleophile that attacks the acid chloride.

• Requires ≥2 equivalents: one to react, one to neutralize HCl.

• Prevents protonation of the attacking amine.

• Drives formation of the amide product.

Nitrile Hydrolysis (HCl, H₂O)

• Cyanohydrin becomes a carboxylic acid. 

• All nitriles can be made from S_N2 geometry.

Hydrolysis of Acid Anhydride (H₂O)

• Water attacks one carbonyl of the anhydride.

• Produces a carboxylic acid and a carboxylate.

• Reaction is driven by relief of anhydride strain.

• No base required, but reaction generates an acidic product.

Amine–Anhydride Reaction [Anhydride + ≥2 eq Amine]

• Amine attacks one carbonyl of the anhydride, forming a tetrahedral intermediate.

• Collapse of the intermediate gives the amide and a carboxylate (or protonated acid if weak base present).

• Extra equivalent of amine neutralizes the acid formed during the reaction.

Alcoholysis of Anhydride (ROH, pyridine)

• Alcohol attacks one carbonyl of the anhydride.

• Forms an ester + carboxylate.

• Pyridine acts as weak base to neutralize acid formed.

• Selective way to make esters from anhydrides.

Aminolysis of Anhydride (R₂NH ≥ 2 equiv)

• Amine attacks the anhydride to form an amide + carboxylate.

• Requires excess amine to neutralize the acid formed.

• Very fast due to strong nucleophilicity of amines.

• Common method to make amides from anhydrides.

Intramolecular Anhydride Formation (Heat, 200–300 °C)

• Diacids with appropriately spaced COOH groups dehydrate when heated.

• Forms a cyclic anhydride + water.

• Favored when a 5- or 6-membered ring can form (stable ring size).

Fischer Esterification (ROH, cat. H⁺)

• Formation of an ester from a carboxylic acid and an alcohol.

• Acid catalyst drives nucleophilic attack and dehydration.

• Reaction is reversible and reaches an equilibrium.

Acid-Catalyzed Ester Hydrolysis [H⁺, Δ]

• Ester + H₂O ⇌ Carboxylic acid + Alcohol.

• Requires acid catalyst and heat.

• Reversible reaction.

• Proceeds through protonation and water attack.

Base-Mediated Ester Hydrolysis (Saponification) [NaOH]

• Ester + NaOH → Carboxylate salt + Alcohol.

• Irreversible due to carboxylate formation.

• No acid catalyst required.

• Acid workup gives the free carboxylic acid.

Acid-Catalyzed Lactonization [cat. H⁺]

• Forms a cyclic ester (lactone) from a hydroxy acid via intramolecular attack.

• Requires acid catalysis.

• Water is lost in the ring-closing step.

• Produces a stable lactone in equilibrium.

Base-Mediated Lactone Opening [NaOH]

• Hydroxide opens the lactone to give a hydroxy-carboxylate.

• Reaction is driven by formation of the carboxylate salt.

• Ring is irreversibly cleaved under basic conditions.

• Final protonation gives the hydroxy acid if desired.

Amide Formation from Esters [Amine]

• Ester reacts with an amine to form an amide.

• Alcohol (ROH) is released as the leaving group.

• Works with primary or secondary amines.

• Net substitution at the carbonyl.

Amide Formation from Acids [DCC]

• Carboxylic acid and amine combine to form an amide.

• Carbodiimide (e.g., DCC) activates the acid for coupling.

• Enables direct amide formation from unreactive carboxylic acids.

Keto–Enol Tautomerism [cat. acid or base]

• Enol content increases when an adjacent C=O stabilizes it (intramolecular H-bonding).

• Enol is stabilized further through resonance.

• Keto and enol forms interconvert reversibly.

• Ratio depends on structural stabilization shown in the scheme.

Tautomerization and Racemization [cat. acid or base]

• Enolate/enol formation removes the chiral center’s configuration.

• Re-protonation can occur from either face, forming enantiomers.

• Regeneration of the keto form yields a 50:50 racemic mixture.

Enolate Quenching with D₂O [acid or base]

• Enolate treated with D₂O gives deuterium incorporation at the α-position.

• Works under catalytic acid or base conditions.

• Replaces α-H atoms with D atoms.

• Reaction occurs because D₂O serves as the proton (deuteron) source.

α-Halogenation (Acid-Mediated) [Cl₂, CH₃CO₂H]

• Ketone undergoes selective α-chlorination.

• Acid conditions favor monohalogenation.

• Chlorine substitutes one α-H.

• Product is an α-chloro ketone.

α-Halogenation (Base-Mediated) [Br₂, aq. NaOH]

• Ketone is converted to an enolate under base.

• Enolate reacts with Br₂ to install α-Br.

• Reaction proceeds efficiently under aqueous base.

• Gives an α-bromo ketone.

Haloform Reaction [X₂, aq. NaOH]

• Methyl ketones undergo exhaustive α-halogenation to form a trihalomethyl ketone.

• Base promotes cleavage to give a carboxylate salt.

• The trihalomethyl group departs as a haloform (CHX₃).

• Produces chloroform, bromoform, or iodoform depending on X.

Hell–Volhard–Zelinsky (HVZ Reaction) [X₂, P; H₂O]

• Converts carboxylic acids into α-haloacids (X = Cl or Br).

• X₂ and phosphorus generate PX₃ in situ to activate the acid.

• First forms an α,α-dihalogenated intermediate.

• Hydrolysis yields the α-halo carboxylic acid.

Enolate Formation with LDA (LDA, THF, cold)

• Formed by deprotonation of diisopropylamine with n-BuLi (pKa ~ 38).

• Very strong base but non-nucleophilic due to steric hindrance.

• Removes the least hindered α-proton, giving the kinetic enolate.

• Low temperature (–78 °C, THF) reinforces fast, selective deprotonation.

Monoalkylation of Ethyl Acetoacetate (1. NaOEt, 2. R-X)

• Ethyl acetoacetate is deprotonated at the α-carbon by sodium ethoxide (NaOEt).

• The resulting enolate reacts with an alkyl halide (R–Br) to form the monoalkylated product.

• Enolate formation is reversible, so the reaction is slower and can give mixtures.

Dialkylation Requires a Stronger Base

• After monoalkylation, the α-hydrogen becomes much less acidic (less stable)

• NaOEt is too weak to deprotonate the product.

• A strong, non-nucleophilic base such as potassium tert-butoxide (KOtBu) is required.

• This strong base forms a second enolate, which then reacts with another alkyl halide (R′–Br) to give the dialkylated product.

Amide → Carboxylic Acid (H₃O⁺, Heat)

• Protonate carbonyl to increase electrophilicity.

• Water attacks to form tetrahedral intermediate.

• –NH₂ becomes –NH₃⁺ and leaves.

• Carbonyl reforms, giving the carboxylic acid.

Dehydration of Primary Amides to Nitriles (P₄O₁₀ or acetic anhydride)

• Converts primary amides (R-CONH₂) into nitriles (R-C≡N).

• Reaction requires heat (Δ).

• By-products: H₃PO₄ (from P₄O₁₀) or CH₃CO₂H (from Ac₂O).

Catalytic Hydrogenation (H₂, Pd/C)

• Replaces the halogen with a hydrogen (X → H).

• Catalytic hydrogenation breaks the C–X bond.

• Works best for benzyl, allyl, and primary alkyl halides.

• Produces a fully reduced alkane as the final product.

The Iodoform Reaction (I₂ / OH⁻)

• Oxidizes methyl ketones (or secondary alcohols that become them).

• Forms a carboxylate by cleaving the C–CH₃ bond.

• Produces CHI₃ (iodoform) as a yellow precipitate.

• Diagnostic test: only works if the carbonyl has a –CO–CH₃ group.

Baeyer–Villiger Oxidation (peroxyacid, e.g., mCPBA)

• Converts ketones → esters by inserting an oxygen next to the carbonyl.

• Uses a peracid (ArCO₃H) as the oxidizing reagent.

• Migrating group (R) shifts onto the peroxide oxygen during reaction.

• Follows migratory aptitude: tertiary > secondary > phenyl > primary > methyl.

Alkene Epoxidation (peroxyacid, e.g., mCPBA)

• Converts alkenes → epoxides in one step.

• Reaction is concerted, preserving stereochemistry.

• Forms a three-membered cyclic ether.

• Occurs via oxygen transfer from the peracid to the C=C bond.

Grignard Carboxylation (Mg metal → Grignard; CO₂; H₃O⁺)

• Converts alkyl or aryl halides → carboxylic acids.

• Mg inserts into C–X bond forming RMgX (Grignard reagent).

• Grignard attacks CO₂, forming a carboxylate.

• Acid workup protonates to give the carboxylic acid.

Retro-Aldol Reaction [Base (⁻OH or :B)]

• Base deprotonates the β-hydroxy group, forming an alkoxide.

• Alkoxide collapses, breaking the C–C bond between α- and β-carbons.

• Electrons flow to regenerate the carbonyl on the α-carbon.

• Produces the original enolate + carbonyl starting materials (reaction is reversible).

Retro-Aldol with Ketones + Dehydration [NaOH, Δ]

• Ketone forms β-hydroxy ketone (aldol) in equilibrium.

• Retro-aldol favored for ketones unless dehydration occurs.

• Heat drives E1cB dehydration of aldol → α,β-unsaturated ketone.

• Removing H₂O pushes equilibrium toward product formation.

Aldol Condensation [Base + Heat (Δ)]

• β-hydroxy carbonyl undergoes base-promoted dehydration

• Base removes α-H → forms enolate that pushes out OH⁻

• C=O reforms as C–O bond collapses, eliminating water

• Product is an α,β-unsaturated carbonyl; conjugation drives reaction to completion

Crossed Aldol Reaction [weak base (RO⁻ or HO⁻)]

• Weak bases form multiple enolates, giving no selectivity.

• Each enolate can attack the other carbonyl, producing multiple aldol additions.

• Alkoxide intermediates are protonated → β-hydroxy carbonyls.

• Final outcome: a mixture of crossed aldol products.

Intramolecular Aldol Condensation [base, heat]

• Enolate forms and attacks an intramolecular carbonyl, creating a ring.

• 5- and 6-membered rings form fastest (lowest strain + favorable geometry).

• Larger rings (7+) form slowly due to entropic and geometric penalties.

• Ketone electrophiles react more slowly than aldehydes → affects which ring forms.