Organic Chemistry – Synthesis and Identification (Cambridge International AS & A Level 9701)
Learning Objectives & Assessment Objectives
- Design synthetic routes (forward and retrosynthetic) for given target molecules.
- Identify organic compounds using functional‑group tests, physical data and spectroscopic techniques (IR, ¹H NMR, MS).
- Recall key reagents and the mechanisms by which they operate.
- Apply IUPAC nomenclature and recognise structural, geometric and (where required) stereoisomerism.
Assessment Objectives (AO)
| AO | What is assessed |
|---|
| AO1 | Knowledge and understanding of concepts, terminology and factual information (e.g., functional‑group tables, reaction types, naming rules). |
| AO2 | Application of knowledge to solve problems – design synthesis routes, predict products, choose appropriate reagents. |
| AO3 | Analysis and evaluation – interpret spectroscopic data, critique synthetic strategies (step‑economy, protecting‑group use, safety, cost). |
1. Foundations of Organic Synthesis
Two complementary approaches are used throughout the syllabus:
- Forward synthesis – start from readily available reagents and apply a sequence of reactions to obtain the target.
- Retrosynthetic analysis – work backwards from the target, “disconnect” strategic bonds and propose simpler, commercially available precursors.
Effective planning must consider:
- Functional‑group compatibility and protecting‑group requirements.
- Reagent availability, cost, safety and environmental impact.
- Reaction conditions (temperature, solvent, catalyst).
- Overall yield, step‑economy, atom‑economy and scalability.
2. Functional Groups, Nomenclature & Hybridisation
2.1 Functional‑Group Table (required for the syllabus)
| Group | General Formula | IUPAC Example (≤6 C) | Common Name |
|---|
| Alkane | CnH2n+2 | methane, ethane, propane | Paraffin |
| Alkene | CnH2n | ethene, propene, 2‑butene | Olefin |
| Alkyne | CnH2n‑2 | ethyne, propyne, 2‑butyne | Acetylene |
| Alcohol | R–OH | ethanol, 2‑propanol, 2‑methyl‑1‑propanol | Hydroxy compound |
| Phenol | Ar–OH | phenol, p‑cresol | Ar‑hydroxy |
| Aldehyde | R–CHO | ethanal, propanal, 2‑methylpropanal | Formyl compound |
| Ketone | R–CO–R′ | propan‑2‑one (acetone), 2‑butanone | Carbonyl (non‑aldehyde) |
| Carboxylic acid | R–COOH | ethanoic acid, propanoic acid, 2‑methylpropanoic acid | Acid |
| Ester | R–COO–R′ | ethyl acetate, methyl benzoate | Acyl‑alkyl ether |
| Amide | R–CONH2 | ethanamide (acetamide), 2‑methyl‑propionamide | Carboxamide |
| Acyl chloride | R–COCl | acetyl chloride | Acid chloride |
| Amines | R–NH2 (primary) | ethanamine, 2‑methyl‑1‑propanamine | Amine |
| Halogenoalkane | R–X (X = Cl, Br, I) | chloroethane, 2‑bromopropane | Alkyl halide |
2.2 IUPAC Naming Conventions (syllabus requirement)
- Priority of functional groups – carboxylic acids > esters > amides > acid chlorides > aldehydes > ketones > alcohols > phenols > amines > alkenes > alkynes > alkanes.
- Numbering – give the longest chain containing the principal group; assign the lowest possible locants to that group.
- Substituent notation – replace the terminal “‑ane” of the parent hydrocarbon with “‑yl” (e.g., methyl, ethyl). “‑ylidene” denotes a doubly‑bonded substituent (e.g., methylene = “‑ylidene”).
- Multiple bonds – indicate position(s) and type (‑ene, ‑yne). When a multiple bond appears as a substituent use “‑ene‑yl” or “‑yne‑yl”.
- Examples:
- CH₃CH₂CH₂COOH → propanoic acid
- CH₃CH₂CH₂CH₂Cl → 1‑chlorobutane
- CH₃CH₂CH=CH₂ → but‑1‑ene
- CH₃CH₂C(=O)Cl → ethanoyl chloride
2.3 Hybridisation, σ/π Bonds & Geometry
| Hybridisation | Geometry | Bond Angles (°) | Typical Bonds |
|---|
| sp | Linear | 180 | Triple bond (σ + 2π), terminal alkyne C≡C, nitrile C≡N |
| sp² | Trigonal planar | 120 | C=C, C=O, aromatic C‑C |
| sp³ | Tetrahedral | 109.5 | All single bonds (σ) in alkanes, alcohols, amines, etc. |
| sp³d | Trigonal‑bipyramidal | 90 / 120 | PCl₅, SF₄ (hypervalent) |
| sp³d² | Octahedral | 90 | SF₆, [Co(NH₃)₆]³⁺ |
2.4 Isomerism (syllabus requirement)
- Structural (constitutional) isomers – differ in connectivity (e.g., n‑butanol vs. 2‑methyl‑1‑propanol).
- Geometric (cis/trans) isomers – arise from restricted rotation about C=C; use cis/trans or E/Z notation (CIP rules). The Cambridge syllabus accepts “cis/trans”.
- Optical isomerism – chiral centres give enantiomers; not examined at AS level but may appear in A‑Level questions.
- Meso compounds – not required for the Cambridge syllabus; a brief note is included to avoid confusion.
3. Core Syllabus Topics
3.1 Hydrocarbons (Alkanes, Alkenes, Alkynes)
- General formulas: CnH2n+2 (alkanes), CnH2n (alkenes), CnH2n‑2 (alkynes).
- Physical properties: non‑polar, low boiling points, insoluble in water, combustible.
- Key reactions:
- Combustion: CnH2n+2 + (3n+½) O₂ → n CO₂ + (n+1) H₂O.
- Free‑radical halogenation (alkanes) – Cl₂ or Br₂, hv; regio‑selectivity follows the stability of the resulting radical.
- Electrophilic addition (alkenes & alkynes) – HBr, H₂O, H₂, halogens, etc.; Markovnikov vs. anti‑Markovnikov control.
- Hydrogenation (alkenes/alkynes) – H₂, Pd/C, Pt, Ni; converts multiple bonds to single bonds.
- Cracking (thermal or catalytic) – breaks C–C bonds to give shorter alkanes/alkenes.
- Polymerisation (addition) – e.g., ethene → polyethylene (radical or Ziegler‑Natta catalysis).
3.2 Halogen Compounds (Halogenoalkanes)
- Classification: primary, secondary, tertiary; allylic and benzylic halides are especially reactive.
- Synthesis:
- From alcohols: R–OH + HX (conc.) → R–X + H₂O.
- From alkanes: free‑radical halogenation (Cl₂/Br₂, hv).
- Reactivity trends – C–X bond strength: C–I > C–Br > C–Cl > C–F; thus reactivity follows I > Br > Cl > F.
- Key reactions:
- SN1 (tertiary, allylic, benzylic) – carbocation intermediate; polar protic solvent.
- SN2 (primary, methyl) – concerted backside attack; polar aprotic solvent.
- E1 (tertiary, weak base) – carbocation intermediate; often competes with SN1.
- E2 (strong base, anti‑periplanar geometry) – concerted elimination; favoured for primary/secondary halides with strong bases.
3.3 Hydroxy Compounds (Alcohols & Phenols)
- Physical properties – hydrogen bonding leads to higher boiling points; soluble in water if ≤3 carbons (alcohols) or if phenolic OH is present.
- Preparation:
- Hydration of alkenes (acid‑catalysed) – e.g., ethene + H₂O → ethanol.
- Reduction of carbonyls (NaBH₄, LiAlH₄).
- From halogenoalkanes – SN2 with OH⁻ (primary) or via Grignard reagent + water.
- Typical reactions:
- Oxidation – primary alcohol → aldehyde (PCC) → carboxylic acid (KMnO₄, Jones); secondary alcohol → ketone (CrO₃/H₂SO₄).
- Substitution – conversion to halides (HX), tosylates (TsCl) or mesylates (MsCl) for further SN2/E2 steps.
- Dehydration – strong acid (H₂SO₄) or acid catalyst (Al₂O₃) gives alkenes (E1 mechanism).
- Formation of ethers – Williamson ether synthesis (R‑X + RO⁻ → R‑OR).
- Phenols – undergo electrophilic aromatic substitution (activating, ortho/para directing).
- Diagnostic tests:
- Lucas test – tertiary alcohols react instantly with conc. HCl/ZnCl₂, secondary slower, primary no reaction.
- Chromic acid test – primary & secondary alcohols oxidise (colour change from orange to green).
3.4 Carbonyl Compounds (Aldehydes & Ketones)
- General formula – R–CHO (aldehyde) or R–CO–R′ (ketone).
- Preparation:
- Oxidation of primary alcohols (PCC, Jones) → aldehydes or acids.
- Oxidation of secondary alcohols → ketones.
- Friedel‑Crafts acylation – aromatic ring + acyl chloride/AlCl₃ → aryl ketone.
- Reactions:
- Nucleophilic addition – Grignard or organolithium reagents give alcohols; NaBH₄/LiAlH₄ give alcohols (reduction).
- Acetal formation – aldehyde/ketone + 2 ROH + H⁺ (protecting group).
- Cyanohydrin formation – NaCN + H⁺ → R‑CH(OH)‑CN.
- Oxidation – aldehydes → carboxylic acids (Tollens, Fehling, KMnO₄).
- Diagnostic tests:
- Tollens’ reagent – silver mirror for aldehydes.
- Fehling’s solution – brick‑red precipitate for aldehydes.
- 2,4‑DNP test – yellow precipitate for both aldehydes and ketones.
3.5 Amines (Primary, Secondary, Tertiary)
- Basicity – nitrogen lone pair accepts a proton; basicity decreases from primary > secondary > tertiary due to steric hindrance and solvation.
- Preparation:
- Reduction of nitro compounds (Sn/HCl, Fe/HCl, H₂/Pd‑C).
- Alkylation of ammonia (Gabriel synthesis) – KCN + 2‑bromoethanol → phthalimido‑ethyl → hydrazinolysis → primary amine.
- Reductive amination – aldehyde/ketone + amine + NaBH₃CN.
- Key reactions:
- Nucleophilic substitution – amines act as nucleophiles (SN2) to give alkyl amines.
- Acylation – amine + acyl chloride → amide (protecting group).
- Diazotisation (primary aromatic amines) – NaNO₂/HCl at 0 °C → diazonium salt (used for Sandmeyer reactions).
- Diagnostic tests:
- Hinsberg test – primary amines give two layers (organic & aqueous), secondary give one, tertiary give none.
- Acid‑base extraction – amines move to aqueous HCl layer.
3.6 Carboxylic Acids and Derivatives
- Acid strength – pKₐ ≈ 4–5 for simple aliphatic acids; resonance stabilises the conjugate base.
- Derivatives covered in the syllabus: esters, amides, acid chlorides, anhydrides.
- Preparation:
- Fischer esterification – RCOOH + ROH ⇌ ester + H₂O (conc. H₂SO₄, reflux).
- Acid chloride – RCOOH + SOCl₂ (or PCl₅) → RCOCl + SO₂ + HCl.
- Anhydride – acid chloride + carboxylic acid → anhydride + HCl.
- Amide – acid chloride + amine → amide + HCl.
- Reactions:
- Acid‑base neutralisation – acid + base → salt + H₂O.
- Reduction – LiAlH₄ reduces acids, esters, amides → alcohols (or amines from amides).
- Hydrolysis – ester or amide + acid/base → carboxylic acid (or amine).
- Decarboxylation – heating β‑keto acids or malonic esters gives CO₂ loss.
- Diagnostic tests:
- Carboxylic acid – turns litmus red; forms hydrogen‑bonded dimers (IR broad O‑H at 2500–3300 cm⁻¹).
- Ester – characteristic IR C=O stretch at 1735–1750 cm⁻¹; pleasant fruity smell.
3.7 Aromatic Compounds
- Benzene – planar, sp² hybridised, 6 π‑electrons (Hückel rule).
- Substituent effects:
- Activating groups (–OH, –NH₂, –OR) – ortho/para directors, increase reactivity.
- Deactivating groups (–NO₂, –CF₃, –COOH) – meta directors, decrease reactivity.
- Electrophilic aromatic substitution (EAS) – key steps: formation of σ‑complex → deprotonation → regeneration of aromaticity.
- Typical EAS reactions:
- Nitration – HNO₃/H₂SO₄ → nitrobenzene.
- Sulphonation – SO₃/H₂SO₄ → benzenesulphonic acid.
- Halogenation – Br₂/FeBr₃ → bromobenzene.
- Friedel‑Crafts alkylation – R‑Cl/AlCl₃ (limited by poly‑alkylation).
- Friedel‑Crafts acylation – RCOCl/AlCl₃ → aryl ketone (no poly‑acylation).
4. Reaction Mechanisms & Typical Transformations
4.1 Electrophilic Addition to Alkenes & Alkynes
General pattern: π‑bond attacks electrophile → carbocation (or cyclic bromonium) intermediate → nucleophile attacks.
- Markovnikov rule – electrophile adds to the carbon bearing more hydrogens; nucleophile ends up on the more substituted carbon.
- Example: HCl + prop‑1‑ene → 2‑chloropropane (major product).
- Anti‑Markovnikov addition – e.g., HBr with peroxides proceeds via a radical chain mechanism giving the opposite regiochemistry.
- Hydration (acid‑catalysed) – H₂O adds across C=C to give alcohols.
- Halogen addition – Br₂ or Cl₂ adds to give vicinal dihalides (via bromonium/chloronium ion).
4.2 Electrophilic Aromatic Substitution (EAS)
Key steps: formation of an arenium ion (σ‑complex) → deprotonation → regeneration of aromaticity.
- Typical reagents: NO₂⁺ (nitration), SO₃ (sulphonation), AlCl₃ + alkyl/ acyl halide (Friedel‑Crafts).
- Directing effects:
- Activating groups (–OH, –NH₂, –OR) → ortho/para.
- Deactivating groups (–NO₂, –CF₃, –COOH) → meta.
4.3 Nucleophilic Substitution (SN1 & SN2)
| Feature | SN1 | SN2 |
|---|
| Rate law | First order in substrate only | Second order (substrate + nucleophile) |
| Intermediate | Carbocation (stable tertiary > secondary > primary) | None – concerted |
| Solvent | Polar protic (stabilises carbocation) | Polar aprotic (enhances nucleophile) |
| Typical substrate | 3° alkyl halide, allylic/benzylic halide | 1° alkyl halide, methyl halide |
| Stereochemistry | Racemisation (planar carbocation) | Inversion of configuration (Walden inversion) |
4.4 Elimination (E1 & E2)
- E1 – two‑step: ionisation → deprotonation. Favoured by weak bases, tertiary substrates, polar protic solvents.
- E2 – concerted, requires a strong base and anti‑periplanar geometry. Favoured by primary or secondary substrates with strong bases (NaOEt, t‑BuOK).
- Competition with substitution follows the substrate‑base rule (e.g., NaOH in ethanol → SN1/E1; NaOEt → SN2/E2).
4.5 Oxidation & Reduction of Carbonyl Compounds & Alcohols
| Reagent | Transformation | Notes |
|---|
| NaBH₄ | Aldehyde/ketone → primary/secondary alcohol | Selective; does not reduce esters, amides, acids. |
| LiAlH₄ | Ester, acid, amide → alcohol (or amine from amide) | Strong, moisture‑sensitive; dry ether required. |
| KMnO₄ (cold, dilute) | Alkene → syn‑diol; primary alcohol → aldehyde; secondary alcohol → ketone | Cold conditions prevent over‑oxidation. |
| KMnO₄ (hot, conc.) | Alkene → dicarboxylic acid; primary alcohol → carboxylic acid | |
| CrO₃/H₂SO₄ (Jones) | Secondary alcohol → ketone; primary alcohol → carboxylic acid | Strong oxidiser; aqueous work‑up required. |
| PCC (pyridinium chlorochromate) | Primary alcohol → aldehyde (no further oxidation) | Mild, avoids over‑oxidation. |
4.6 Esterification & Acyl‑Halide Formation
- Fischer esterification – RCOOH + ROH ⇌ ester + H₂O (conc. H₂SO₄, reflux, removal of water by Dean‑Stark).
- Acyl‑chloride preparation – RCOOH + SOCl₂ → RCOCl + SO₂ + HCl (pyridine often scavenges HCl).
- Acyl chlorides react readily with:
- Alcohols → esters (catalysed by base).
- Amines → amides.
- Water → carboxylic acid (hydrolysis).
4.7 Carbon‑Carbon Bond Formation
- Grignard reagents (RMgX) – add to carbonyls (aldehydes → secondary alcohols; ketones → tertiary alcohols; esters → tertiary alcohol after two additions). Performed in dry ether, 0 °C → reflux.
- Organolithium reagents (RLi) – stronger bases/nucleophiles; used when Grignard reagents are unsuitable (e.g., with acidic protons).
- Friedel‑Crafts alkylation – AlCl₃‑catalysed addition of alkyl halides to activated aromatic rings (limited by poly‑alkylation).
- Friedel‑Crafts acylation – AlCl₃‑catalysed addition of acyl chlorides to aromatic rings; gives aryl ketones and avoids poly‑substitution.
- aldol condensation – enolate of aldehyde/ketone + carbonyl → β‑hydroxy carbonyl → dehydration → α,β‑unsaturated carbonyl.
5. Retrosynthetic Analysis – Systematic Approach
- Identify all functional groups and determine the principal group (highest IUPAC priority).
- Locate strategic C–C bonds that can be formed by a known reaction (e.g., carbonyl addition, EAS, Grignard addition, aldol condensation).
- “Disconnect” those bonds to generate simpler precursors that are commercially available or easily prepared.
- Check for protecting‑group requirements (only when a functional group would be incompatible with a planned step).
- Decide whether a linear or convergent route gives the best overall yield, step‑economy and safety profile.
Worked Example 1 – Synthesis of Isobutylbenzene (2‑Methyl‑1‑phenyl‑propane)
- Target analysis – aromatic ring bearing an isobutyl substituent.
- Key disconnection – C–C bond formed by Friedel‑Crafts alkylation (benzene + 2‑methyl‑1‑propyl halide).
- Retro‑steps
- 2‑Methyl‑1‑propyl chloride ⇐ 2‑