Answers to Selected Exercises

Full worked solutions for ~25% of exercises marked ∗ in each chapter. Enough to check your thinking; not enough to short-circuit learning. Read the question, attempt it fully, then compare.

Chapter 1

1.1∗ (a) Organic. (b) Inorganic. (c) Organic (but with inorganic history — urea from ammonium cyanate started the field). (d) Inorganic. (e) Organic. (f) Inorganic (typically). (g) Organic (salt of acetic acid). (h) Organic.

1.6∗ Carbon: 1s² 2s² 2p². Valence electrons: 4 (the 2s² and 2p² — the outermost shell). Valence of 4 follows because four electrons in four orbitals can pair with four other electrons.

1.11∗ Nitrogen's lone pair is typically required to avoid violating the octet. Carbon's four bonds leave no lone pair; it can make four σ bonds. Nitrogen's three bonds + one lone pair leave fewer positions for elaboration. Carbon's ability to be a true tetrahedral branch point is unique among biologically abundant atoms.

1.17∗ (a) 8. (b) 8. (c) 8. (d) 10. (e) 10.

1.21∗ Finkelstein: (a) SN2 substitution: C-Br → C-I. (b) I⁻ is the nucleophile; attacks backside of CH₃Br, displacing Br⁻. (c) NaI is soluble in acetone; NaBr is not. NaBr precipitates, removing Br⁻ and driving equilibrium forward (Le Chatelier).

Chapter 2

2.5∗ (a) H:O:H with two lone pairs on O. O has 2 bonds, 2 LP, formal charge 0. (b) H₃N: with lone pair. N has 3 bonds, 1 LP, fc 0. (c) CH₃-Cl: with 3 LP on Cl. Cl: 1 bond, 3 LP, fc 0. (d) H-C≡N: with LP on N. C has 2 bonds (1 to H, 1 to N as triple), N has 1 bond (as triple) + LP.

2.8∗ Wrong: student's CO₂ with 3 LP on each O and C only has 2 bonds + no LP (not octet). Correct: O=C=O with 2 LP per O, C with 4 bonds (2 double = 4 total).

2.15∗ (a) methane: C sp³. (b) ethylene: both C sp². (c) acetylene: both C sp. (d) formaldehyde: C sp². (e) HCN: C sp, N sp. (f) methanol: C sp³, O sp³. (g) DME: C's sp³, O sp³. (h) methylamine: C sp³, N sp³.

2.18∗ Ammonia: sp³, trigonal pyramidal (not tetrahedral in molecular geometry because one position is lone pair, not bonded atom).

2.24∗ For the allyl cation CH₂=CH-CH₂⁺: three p orbitals → three π MOs (ψ₁ bonding, ψ₂ non-bonding nodal at center, ψ₃ antibonding). Two π electrons fill ψ₁. The LUMO ψ₂ has its node on the central C, so charge density and reactivity are at the terminal carbons. This is the orbital basis of allyl resonance.

Chapter 3

3.1∗ (a) HCl is acid; H₂O is base. H₃O⁺ is conjugate acid; Cl⁻ is conjugate base. (b) H₂O is acid; NH₃ is base. NH₄⁺ is CA; OH⁻ is CB. (c) CH₃CO₂H is acid; NaOH (or OH⁻) is base. CH₃CO₂Na (or CH₃CO₂⁻) is CB; H₂O is CA. (d) HCl is acid; CH₃NH₂ is base. CH₃NH₃⁺ is CA; Cl⁻ is CB.

3.4∗ Acidity increases: CH₄ < NH₃ < H₂O < HF. pKa 50 < 38 < 15.7 < 3.2. Reason: within a row, electronegativity of the atom holding the charge dominates. F > O > N > C in electronegativity.

3.7∗ Most → least acidic: CH₃CHClCO₂H (α-Cl) > ClCH₂CH₂CH₂CO₂H (γ-Cl, but still some inductive) ≈ CH₃CH₂CHClCO₂H (β-Cl, modest effect) > CH₃CH₂CH₂CO₂H (none). Approx pKa: 2.85, 4.5, 4.05, 4.87. Position and count of Cl matter.

3.9∗ Acetylacetone's central CH₂ has 2 flanking C=O. Deprotonation gives an enolate that delocalizes the negative charge over BOTH carbonyl oxygens (3 resonance structures). Extra resonance = more stabilization = lower pKa (~9).

3.11∗ Most → least acidic: TFAOH > picric acid > acetic acid > phenol > methanol. Reasons: induction (TFAOH), resonance + induction (picric), resonance only (acetic, phenol), nothing (methanol).

3.13∗ (a) Acetic acid + methoxide → acetate + methanol. pKa(MeOH)=15.5 > pKa(AcOH)=4.76. K_eq = 10^10.7. Strongly forward. (b) NH₄⁺ + OH⁻ → NH₃ + H₂O. pKa(H₂O)=15.7 > pKa(NH₄⁺)=9.2. K_eq = 10^6.5. (c) MeOH + NaNH₂ → NaOMe + NH₃. pKa(NH₃)=38 > pKa(MeOH)=15.5. K_eq = 10^22.5. Essentially irreversible.

3.16∗ Use bicarbonate (HCO₃⁻). pKa(H₂CO₃)=6.35 > pKa(COOH)≈5, so carboxylate forms. But < pKa(alcohol) ≈ 16, so the alcohol stays protonated. Selective deprotonation of the acid.

Chapter 4

4.3∗ (a) 2-methylpropan-2-ol (tert-butanol). (b) 3-ethyl-2-methylpentane. (c) (2E)-3-methylpent-2-enoic acid. (d) N-methylpropan-2-amine. (e) cyclohexa-1,3-dien-1-ol (phenol's non-aromatic tautomer; not realistic, just for naming practice).

4.7∗ Identify all functional groups in ibuprofen: aromatic ring, alkyl branches, carboxylic acid. Parent: propanoic acid. Stereocenter at α-C. Active (S); inactive (R).

4.12∗ Priority of suffixes in IUPAC: -oic acid > ester > amide > nitrile > aldehyde > ketone > alcohol > amine > ether > alkene/alkyne > alkane. So for a molecule containing both -COOH and -OH, the -COOH is the principal characteristic group and -OH becomes "hydroxy-" prefix.

4.18∗ Hydrogen bond donors vs acceptors: - CH₃OH: 1 donor (OH), 1 acceptor (O LPs). - CH₃OCH₃: 0 donors, 1 acceptor. - CH₃NH₂: 1 donor (NH), 1 acceptor (N LP). - CH₃CO₂H: 1 donor (OH), 2 acceptors (both Os).

Chapter 5

5.4∗ At 298 K, RT = 0.59 kcal/mol. ΔG = 0.9 kcal/mol → K = e^(−0.9/0.59) = e^(−1.53) = 0.22. With two equivalent gauche wells, total gauche:anti = 0.44:1, giving 70% anti, 30% gauche.

5.8∗ Cyclohexane chair: methyl substituent prefers equatorial. A-value(Me) = 1.74 kcal/mol. K = e^(−1.74/0.59) = e^(−2.95) = 0.053. So 5% axial, 95% equatorial.

5.13∗ For 1,3-dimethylcyclohexane: cis puts both methyls equatorial (or both axial). Equatorial-equatorial is far more stable (cis-1,3 is the more stable isomer). Trans-1,3 must have one axial, one equatorial (penalty: 1.74 kcal/mol). Compare to 1,2- and 1,4-, where cis/trans preferences reverse.

5.19∗ Activation energy from Arrhenius: k = A·exp(−E_a/RT). At 25°C and 35°C with k₂/k₁ = 2: E_a = R·T₁T₂/(T₂−T₁) · ln(k₂/k₁) = 8.314 × 298 × 308 / 10 × ln 2 ≈ 53 kJ/mol. The "rate doubles every 10°C" rule corresponds to E_a ≈ 50 kJ/mol.

Chapter 6

6.4∗ Degrees of unsaturation for C₆H₆: (2·6+2−6)/2 = 4. Benzene has three C=C + one ring = 4. Consistent.

6.9∗ A strong IR absorption at 1715 cm⁻¹ → ketone (or aldehyde, but the question specifies no peak near 2720 cm⁻¹, ruling out aldehyde C-H). Combined with no broad O-H at 2500-3300 → not a carboxylic acid. Conclusion: ketone.

6.14∗ Molecular ion at m/z 88, base peak at m/z 43 (= CH₃CO⁺ acylium). Loss of 45 = OCH₂CH₃ (ethoxy). Compound: methyl acetate? No — that's m/z 74. Try ethyl acetate (CH₃CO-O-C₂H₅): MW = 88. Yes. m/z 43 = acylium CH₃CO⁺; m/z 45 lost = ethoxy radical.

6.21∗ Nitrogen rule: odd MW → odd number of N atoms. M⁺• = 73 implies one N. C₃H₇NO satisfies it. Likely N,N-dimethylformamide (DMF) — but that's 73 with no major fragments at 28? Actually DMF MW = 73 fits.

Chapter 7

7.3∗ (a) (2R)-bromobutane. (b) (2S,3R)-bromochlorobutane. (c) meso (mirror plane between C2 and C3).

7.7∗ 2,3-dibromobutane: three stereoisomers — (2R,3R), (2S,3S), and meso (2R,3S). The first two are enantiomers; the meso is a diastereomer of each.

7.11∗ Specific rotation: [α] = α_obs / (c·ℓ). c = 0.5 g/mL, ℓ = 1 dm, α_obs = +6.6°. [α] = +6.6 / (0.5·1) = +13.2°. If pure enantiomer is +66°, then ee = 13.2/66 = 20%. So sample is 60% R, 40% S.

7.17∗ Atropisomer: BINOL — rotation around the binaphthyl C-C is restricted because the 2,2'-substituents collide. Half-life for racemization at room temp is years.

7.22∗ Resolution by diastereomeric salt: react racemic acid with single-enantiomer base (e.g., (S)-α-methylbenzylamine). The two salts are diastereomers — different solubilities. Crystallize one; filter; liberate the acid by acidification.

Chapter 8

8.2∗ SN2 on (S)-2-bromobutane gives (R)-2-butanol. Inversion. The leaving Br leaves with its electrons; OH comes in backside; the other three substituents "umbrella-flip."

8.6∗ SN1 on (R)-3-bromo-3-methylhexane gives planar carbocation. Water attacks both faces equally → racemic 3-methylhexan-3-ol. Ideal case predicts 50/50; in practice, slight retention bias because departing Br shields one face (ion pair).

8.11∗ Anti addition of Br₂ to (E)-2-butene: bromonium ion forms on either face; back-side opening gives (2R,3R) + (2S,3S) — a racemic pair of enantiomers. The cis isomer gives meso (2R,3S). So alkene geometry determines product stereochemistry (the hallmark of stereospecific reactions).

8.16∗ Felkin-Anh model for NaBH₄ + 2-methylcyclohexanone: hydride attacks opposite the largest α substituent. Major product is the equatorial alcohol with the methyl on the same face. Predict 60-80% one diastereomer.

8.21∗ Thalidomide racemizes in vivo because the C-H α to the imide carbonyl is acidic (pKa ~25 with enolate stabilized over the nitrogen too). Enolization → planar sp² center → reprotonation from either face → racemization. Half-life in blood ~6 h. So selling pure (R) is pharmacologically pointless.

Chapter 9

9.3∗ Ethanol ¹H NMR: three signals. - 3.7 ppm, quartet (J = 7 Hz), 2H: -CH₂- coupled to -CH₃. - 2.6 ppm, broad singlet, 1H: -OH (exchangeable; broad). - 1.2 ppm, triplet (J = 7 Hz), 3H: -CH₃ coupled to -CH₂-.

9.8∗ For -CH=CH- of styrene: vicinal coupling. Cis: J ≈ 6-12 Hz; trans: J ≈ 12-18 Hz. Styrene (E) shows J ≈ 17 Hz. Use J to assign geometry.

9.13∗ DEPT-135 of an unknown: signals up = CH/CH₃; down = CH₂; absent = quaternary. Combine with ¹³C count to count CH₃/CH₂/CH/Cq directly.

9.18∗ HMBC: ²-³J correlations from H to C. Excellent for connecting fragments across the molecule (e.g., quaternary aromatic carbons that no proton sits on). Compared with COSY (H-H ³J only), HMBC carries assignment across the carbonyl or quaternary center.

Chapter 10

10.1∗ CH₃-Br + OH⁻ → CH₃-OH + Br⁻. OH⁻ attacks C from backside of Br. TS: 5-coordinated trigonal-bipyramidal carbon. Br⁻ leaves with its electrons. Stereochem: inversion (Walden), though invisible here without a stereocenter.

10.5∗ Rate dependence: doubling [Nu] doubles rate; doubling [substrate] doubles rate; doubling solvent polarity (protic) decreases rate (solvation of Nu suppresses its reactivity). All confirm bimolecular concerted mechanism.

10.11∗ Nucleophile ranking in protic solvent: I⁻ > Br⁻ > Cl⁻ > F⁻ (polarizability, weak solvation of heavy anions). In aprotic (DMSO/DMF): reversed — F⁻ > Cl⁻ > Br⁻ > I⁻ (basicity dominates when desolvation is free).

10.17∗ Williamson: NaOCH₃ + CH₃CH₂Br → CH₃OCH₂CH₃ + NaBr. Use the less hindered alkyl halide partner. SN2 fails on tertiary R-X.

Chapter 11

11.2∗ Hydride shift: 2-bromo-3-methylbutane + AgNO₃/MeOH → 2-methylbut-2-yl cation after H shift → tertiary > secondary by ~15 kcal/mol. Major product: 2-methoxy-2-methylbutane.

11.7∗ SN1 rate order: 3° > 2° > 1° >> CH₃. Driven by carbocation stability (hyperconjugation count: 3° has 9 β-C-H bonds, 1° has 3).

11.13∗ Solvolysis of (R)-3-chloro-3-methylhexane in 80% aqueous ethanol: SN1 dominant; product racemic. Some E1 (ratio ~3:1 SN1:E1 in this solvent). The minor alkene is Zaitsev (most substituted).

11.18∗ Pinacol rearrangement: 2,3-dimethylbutane-2,3-diol + H⁺ → loss of water → tertiary cation → 1,2-methyl shift → resonance-stabilized oxocarbenium → product 3,3-dimethylbutan-2-one (pinacolone).

Chapter 12

12.3∗ E2 of (1R,2R)-1-bromo-2-methylcyclohexane: H and Br must be anti-periplanar (both axial). Only one such β-H, on C2 (the one trans to Br). Product: 3-methylcyclohex-1-ene (only).

12.8∗ E2 of 2-bromo-2,3-dimethylbutane: - With NaOEt (small base): Zaitsev → 2,3-dimethyl-2-butene (tetrasubstituted, major). - With KOtBu (bulky base): Hofmann → 2,3-dimethyl-1-butene (less substituted, major).

12.14∗ Compare E1cb (deprotonation first, then LG loss) with E1 (LG first, then deprotonation): E1cb is favored when the α-H is unusually acidic (β to EWG) and the LG is poor. Example: aldol dehydration.

12.19∗ Why does (E)-1-bromo-2-phenylpropene undergo SN1 at sp² carbon a million times slower than at sp³ carbon? Because the vinyl carbocation is destabilized: empty sp orbital cannot accept hyperconjugation, and the geometry doesn't allow π-system overlap.

Chapter 13

13.1∗ Decision flowchart applied: 1. CH₃Br + NaOH/DMSO → SN2 (1° substrate, strong Nu, aprotic). 2. (CH₃)₃CCl + EtOH 50°C → SN1/E1 mix (3°, weak Nu, protic). 3. 2-bromobutane + NaOEt → E2 dominant (2°, strong base). 4. 2-bromobutane + EtOH → SN1/E1 mix (2°, weak Nu). 5. Cyclohexyl bromide + NaCN/DMF → SN2 (2°, strong Nu, aprotic). 6. PhCH₂Cl + NaOH/H₂O → SN1 (resonance-stabilized cation). 7. CH₂=CH-Cl + NaOH → no reaction (vinyl halide, neither SN1 nor SN2 viable).

13.6∗ Substrate sensitivity ranking (which is most sensitive to changing nucleophile?): SN2 substrates most sensitive (Nu in rate law). SN1 substrates almost insensitive to Nu identity (Nu enters after RDS).

13.11∗ Why does adding KI to an alkyl-Cl + alcohol reaction accelerate it? Iodide is more nucleophilic in many solvents; it converts R-Cl to R-I (fast SN2), and R-I solvolyzes faster than R-Cl. Iodide is a catalyst.

Chapter 14

14.2∗ Aspirin retrosynthesis: - Aspirin = salicylic acid + acetic anhydride. - Salicylic acid = sodium phenoxide + CO₂ (Kolbe-Schmitt). - Sodium phenoxide = phenol + NaOH.

14.6∗ Synthesize 2-methylbutanenitrile from 1-bromobutane (limit: only C₁-C₄ starting materials): 1. 1-bromobutane + NaCN/DMF → pentanenitrile (SN2). But this gives wrong skeleton. Alternative: 1-bromopropane + Mg/Et₂O → PrMgBr; + CH₃CHO → 2-butanol; PBr₃ → 2-bromobutane; NaCN → 2-methylbutanenitrile. Multi-step.

14.10∗ Functional-group interconversion: alcohol → carboxylic acid via PCC (to aldehyde) then Jones (CrO₃/H₂SO₄) or directly with KMnO₄. Or alcohol → tosylate → cyanide (SN2) → hydrolysis. Both work; the latter adds a carbon.

Chapter 15

15.3∗ Heats of hydrogenation rank alkenes by stability: - Ethylene: 137 kJ/mol (least stable). - 2-butene cis: 120; trans: 115. - 2-methyl-2-butene: 113. - 2,3-dimethyl-2-butene: 111 (most stable; tetrasubstituted). More substituted = more stable.

15.7∗ HBr + 2-methyl-2-butene: Markovnikov → H to less-substituted C (C3), Br to more-substituted C (C2). Major product: 2-bromo-2-methylbutane (via 3° cation).

15.13∗ Bromonium ion on (Z)-3-hexene: Br₂ adds anti → (3R,4R) or (3S,4S) (a racemic pair). The cis alkene + anti addition = racemic. Trans alkene + anti = meso.

15.18∗ Rearrangement during HCl addition: 3-methyl-1-butene + HCl → initial 2° cation at C2 → 1,2-hydride shift → 3° cation at C3 → Cl⁻ adds → 2-chloro-2-methylbutane (major) plus 3-chloro-2-methylbutane (minor).

Chapter 16

16.4∗ Hydroboration of 2-methyl-2-butene: BH₃ adds with B at less-substituted C (anti-Markovnikov, syn). Then H₂O₂/NaOH replaces B with OH retention. Net: H to more-substituted C, OH to less-substituted C. Product: 3-methyl-2-butanol.

16.9∗ Compare hydroxylations: OsO₄/NMO gives syn-diol (1,2 from same face). MCPBA then H₃O⁺ gives anti-diol (epoxide opens with backside attack). So cis-2-butene + OsO₄ → meso diol; + mCPBA/H₃O⁺ → racemic threo diol.

16.14∗ Ozonolysis of 1-methylcyclohexene with Zn/AcOH workup → ring-opened keto-aldehyde: 6-oxoheptanal.

16.19∗ Halohydrin from propene + Br₂/H₂O: bromonium opens at the more-substituted C (Markovnikov, because that C bears more carbocation character). Product: 1-bromo-2-propanol.

16.23∗ Sharpless asymmetric epoxidation needs an allylic alcohol. Uses (+)-DIPT or (−)-DIPT with Ti(OiPr)₄ and TBHP. Memorize the mnemonic: (+)-DIPT puts O on bottom face when allylic OH is up-right.

Chapter 17

17.3∗ Terminal alkyne pKa ≈ 25. Use NaNH₂ in liq NH₃ (pKa NH₃ = 38). Cannot use NaOH (pKa H₂O = 15.7; deprotonation 10⁹⁻fold uphill). Cannot use Grignards as bases here without losing them.

17.7∗ Acetylide + epoxide (e.g., propylene oxide): SN2-style opening at less-hindered C. Gives homopropargyl alcohol. Then H₂/Lindlar → cis-allylic alcohol. Useful for natural product cis-double-bond installation.

17.13∗ Hydration: - HgSO₄/H₂SO₄ → Markovnikov → methyl ketone (from terminal alkyne, with H attached at the terminal C). - BH₃·THF then H₂O₂/NaOH → anti-Markovnikov → aldehyde.

17.17∗ Lindlar = Pd/CaCO₃ poisoned with Pb(OAc)₂ and quinoline; gives cis-alkene. Na in liq. NH₃ gives trans-alkene (radical anion mechanism). Two complementary methods on the same triple bond.

Chapter 18

18.3∗ Radical chain for Cl₂ + CH₄ under light: - Init: Cl₂ → 2 Cl• (hν). - Prop1: Cl• + CH₄ → HCl + CH₃•. - Prop2: CH₃• + Cl₂ → CH₃Cl + Cl•. - Term: 2 Cl• → Cl₂ (etc.).

18.8∗ Selectivity: 3° > 2° > 1° per H for radical halogenation. With Cl₂ (very reactive): low selectivity (~5:4:1 by H). With Br₂ (less reactive, later TS): high selectivity (~1600:80:1). Hammond postulate explains.

18.13∗ NBS in CCl₄ at low concentration delivers Br• to allylic/benzylic positions. The bromonium-ion side reaction (to alkene) is suppressed because [Br₂] is kept low. Allylic vs vinyl-double-bond reactivity: BDE allylic C-H (~88 kcal/mol) << vinyl C-H (~111).

18.18∗ Lipid peroxidation: vitamin E (α-tocopherol) intercepts a lipid radical (LOO•) by H-atom transfer. The resulting tocopheroxyl radical is stable (resonance into the chromanol ring) and is reduced back by vitamin C. Antioxidant chain-breaking.

Chapter 19

19.3∗ 1,3-Butadiene + HBr at low T → 1,2-adduct (kinetic, 3-bromo-1-butene). At high T → 1,4-adduct (thermodynamic, 1-bromo-2-butene, more substituted alkene). Hammond postulate: low T traps the first product; high T equilibrates.

19.8∗ Diels-Alder of cyclopentadiene + maleic anhydride: cis-endo bicyclic anhydride. Endo by Alder's rule (secondary orbital interaction); cis because the syn-addition is concerted.

19.13∗ FMO analysis of "normal" Diels-Alder: diene HOMO + dienophile LUMO interact. EWG on dienophile lowers its LUMO → faster reaction. EDG on diene raises its HOMO → faster. Both effects compatible.

19.18∗ Intramolecular Diels-Alder of a triene: tether length and geometry dictate which diene-dienophile pairing forms. The endo TS is again preferred when secondary orbital overlap exists. Useful for cis-fused bicyclics in steroid and terpenoid synthesis.

Chapter 20

20.3∗ Hückel 4n+2 check: - Cyclobutadiene: 4 π electrons → antiaromatic (4n, n=1). - Benzene: 6 → aromatic (4n+2, n=1). - Cyclopentadienyl anion: 6 → aromatic. - Cycloheptatrienyl cation (tropylium): 6 → aromatic. - Cyclopentadienyl cation: 4 → antiaromatic.

20.8∗ Pyridine vs pyrrole basicity: pyridine N has its lone pair in sp² in the plane, not part of the π system → free to protonate (pKa BH⁺ = 5.2). Pyrrole N lone pair is in the π system → loss on protonation breaks aromaticity (pKa BH⁺ = −4). So pyridine is a normal weak base; pyrrole is a very weak base.

20.14∗ NICS (Nucleus-Independent Chemical Shift): probes ring current. NICS(0) at ring center: aromatic = strongly negative (benzene −10 ppm); antiaromatic = positive; non-aromatic ≈ 0. A computational diagnostic of aromaticity beyond electron count.

20.19∗ Graphene = single sheet of sp² C, fully conjugated 2D aromatic system. Geim-Novoselov isolated it by tape exfoliation. Properties: zero band gap, exceptional carrier mobility, transparent, mechanically strongest known material per unit thickness.

Chapter 21

21.3∗ Halogenation of benzene: Br₂ alone doesn't react. Add FeBr₃: Lewis acid coordinates Br₂, polarizing Br-Br. Heterolysis gives "Br⁺-FeBr₄⁻." Br⁺ attacks ring → arenium intermediate → rearomatization → PhBr + HBr.

21.7∗ Friedel-Crafts alkylation of benzene with 1-chloropropane + AlCl₃: expect 1-propylbenzene; actually isopropylbenzene (cumene) major because 1° cation rearranges to 2° before attacking ring. FC alkylation is plagued by rearrangement, polysubstitution, and not working on deactivated rings.

21.13∗ Friedel-Crafts acylation has no carbocation rearrangement (acylium is resonance-stabilized) and no over-acylation (product carbonyl deactivates the ring). Then reduce the ketone with Clemmensen or Wolff-Kishner to deliver the alkyl group rearrangement-free.

21.17∗ Industrial ibuprofen (BHC route, 3 steps): isobutylbenzene + FC acylation with Ac₂O/HF → ketone; H₂/Raney Ni → alcohol; CO/Pd → ibuprofen. Atom economy ~80% vs old Boots route (~40%). E-factor down by factor of 6.

Chapter 22

22.3∗ Activating: -OH, -OR, -NH₂, -NR₂, -O⁻, -alkyl. Deactivating: -NO₂, -CN, -CF₃, -SO₃H, -CO₂H, -CO₂R, -CHO, -C(O)R, -NR₃⁺. Special: halogens deactivate by induction but direct o/p by resonance.

22.7∗ Predict EAS site: chlorobenzene + HNO₃/H₂SO₄ → ortho + para (halogen is o/p-director, though deactivator). Mostly para (steric). Yields: para ~70%, ortho ~28%, meta ~2%.

22.13∗ Hammett ρ: for ArOH ionization, ρ = +2.2. EWGs on the ring stabilize phenolate → enhance acidity. Plot of log K vs σ for a substituent series should be linear; the slope is ρ.

22.18∗ Multi-step synthesis: para-bromoaniline from benzene? Direct: bromination of aniline gives 2,4,6-tribromo (too activated). Solution: protect NH₂ as acetanilide (NHAc, less activating, sterics push to para) → Br₂ → para-Br-acetanilide → hydrolyze → para-bromoaniline.

Chapter 23

23.3∗ SNAr requires (a) EWG ortho or para to LG, (b) good LG (F often best — surprising — because rate-determining step is Meisenheimer formation, where C-F polarization helps; F leaves in second step). Order: F > Cl > Br > I.

23.8∗ Benzyne mechanism: chlorobenzene + NaNH₂/NH₃ → deprotonation ortho to Cl → loss of Cl⁻ → benzyne → addition of NH₃ → aniline + meta-substituted byproduct (from attack on either end of triple bond). Confirmed by ¹⁴C labeling (Roberts 1953).

23.13∗ Birch reduction of anisole: Na/NH₃/EtOH. EDG (-OMe) directs reduction such that the product is the 2,5-dihydro isomer with the OMe on the sp² carbon. Compare with benzoic acid (EWG), where the EWG ends up on sp³.

23.18∗ Side-chain benzylic radical bromination with NBS: PhCH₃ + NBS, hv, CCl₄ → PhCH₂Br. Selectivity: benzylic C-H (88 kcal/mol BDE) far weaker than aromatic C-H. The aromatic ring is untouched.

Chapter 24

24.3∗ Carbonyl reactivity ranking (toward Nu addition): acyl halide > anhydride > aldehyde > ketone > ester > amide > carboxylate. Reasons: (a) LG ability (RCO-X breakdown), (b) resonance donation (amide N >> ester O >> acyl Cl).

24.7∗ Steric and electronic factors in a hindered ketone: di-tert-butyl ketone is essentially inert to nucleophilic addition (steric); pentafluoroacetone is highly reactive (electronic). Both effects independently observable.

24.13∗ Why is glucose so stable as the cyclic hemiacetal? Five OHs and one CHO can form intramolecular hemiacetal — a 6-ring (pyranose) or 5-ring (furanose). Equilibrium favors β-pyranose (~64%) at 25°C: all substituents equatorial.

Chapter 25

25.3∗ Grignard + ketone → tertiary alcohol after aqueous workup. With cyclohexanone + EtMgBr: 1-ethylcyclohexan-1-ol. The MgBr-O intermediate is converted to alcohol on H₃O⁺ quench.

25.8∗ Wittig: Ph₃P=CHR + R'CHO → RCH=CHR' + Ph₃P=O. Stabilized ylide (R = EWG) → E-alkene; non-stabilized (R = alkyl) → Z-alkene. The phosphine oxide is the byproduct.

25.14∗ Acetal protection: dialdehyde + ethylene glycol/p-TsOH → bis-cyclic-acetal. Now stable to Grignard (basic). After Grignard installation elsewhere, hydrolyze in aqueous acid to regenerate aldehyde. Worked example for protecting one carbonyl during reaction at another.

25.19∗ Reductive amination: cyclohexanone + n-propylamine + NaBH(OAc)₃/AcOH → N-propylcyclohexylamine. Mechanism: iminium ion forms, then reduced. The bulky borohydride reduces iminium faster than ketone — chemoselective.

Chapter 26

26.3∗ Fischer esterification: carboxylic acid + alcohol + H₂SO₄ (cat.) → ester + H₂O. Mechanism: protonate C=O, alcohol attack, tetrahedral intermediate, proton shuffle, loss of water. Drive by Dean-Stark or excess alcohol.

26.8∗ Saponification: triglyceride + 3 NaOH → glycerol + 3 RCO₂Na (soap). Mechanism: OH⁻ attacks ester C=O → tetrahedral → loss of OR. Irreversible because RCO₂⁻ doesn't undergo retro-saponification (carboxylate is unreactive).

26.14∗ Aspirin's COX inhibition: aspirin's ester is electrophilic; serine OH of COX-1 attacks → acetylated serine (covalent inhibitor) + salicylic acid byproduct. This is nucleophilic acyl substitution by an enzyme nucleophile. Mechanism explains aspirin's irreversibility.

26.19∗ β-lactam in penicillin: 4-membered ring strain (~25 kcal/mol). Transpeptidase serine attacks → opens β-lactam → acyl-enzyme intermediate cannot hydrolyze → permanent enzyme inactivation. Bacteria die.

Chapter 27

27.3∗ Acidity of α-H: simple ketone pKa ~20. β-keto ester pKa ~11 (two carbonyls stabilize enolate). β-diketone pKa ~9. 1,3,5-triketone pKa ~5. Each additional carbonyl drops pKa ~10.

27.8∗ LDA (i-Pr₂NLi) deprotonates ketones quantitatively at −78 °C, generating the lithium enolate. Kinetic enolate (less substituted) under these conditions; thermodynamic enolate (more substituted) with NaH/THF at warm temperature.

27.13∗ α-Halogenation under acid: catalyst is the enol (slow step is enolization). Under base: catalyst is the enolate (fast deprotonation, then fast halogenation). Acidic conditions give mono; basic give multi-halogenation (each subsequent halogen activates further halogenation by stabilizing the next enolate).

27.18∗ Thalidomide α-stereolability: the α-C to the imide carbonyl bears one H. In vivo at pH 7, the C-H is sufficiently acidic (pKa ~25, somewhat lowered by imide flanking) for enolization to occur on the timescale of hours. Racemization renders any single-enantiomer drug racemic in the body. (S)-enantiomer is teratogenic; (R) is sedative.

Chapter 28

28.3∗ Aldol of acetaldehyde with itself, NaOH: enolate of one CH₃CHO + carbonyl of another → 3-hydroxybutanal. Heat → dehydration → but-2-enal (crotonaldehyde). E1cb mechanism for the loss of water.

28.8∗ Crossed aldol: directed crossed aldol with LDA. Preformed lithium enolate of one carbonyl + add the other (the electrophilic one, often less enolizable). Avoids the 4-product mess of simple crossed aldol.

28.13∗ Dieckmann: diethyl adipate + NaOEt/EtOH → 6-membered β-keto ester (2-oxocyclohexane-1-carboxylate). Mechanism is intramolecular Claisen — enolate attacks the other ester carbonyl. Equilibrium driven by deprotonation of the β-keto-ester product (pKa ~11, vs starting material pKa ~25).

28.18∗ Fatty acid biosynthesis is iterative Claisen: acetyl-CoA + malonyl-ACP → β-ketoester → reduce → dehydrate → reduce → saturated acyl-ACP. Repeat. Each cycle adds 2 carbons. Decarboxylation of malonyl provides the thermodynamic drive.

Chapter 29

29.3∗ 1,2 vs 1,4 (Michael) selectivity: - Hard Nu (RMgX, LiAlH₄, RLi): 1,2-addition. - Soft Nu (R₂CuLi, RS⁻, enamines, stabilized enolates): 1,4-addition. - Reason: HSAB. Hard Nu prefers hard carbonyl C; soft Nu prefers soft β-C (LUMO has larger coefficient there in many cases).

29.8∗ Robinson annulation: MVK (methyl vinyl ketone) + cyclohexanone enolate → Michael adduct → intramolecular aldol → dehydrate → bicyclic enone. Foundational for steroid synthesis (Woodward, cortisone).

29.14∗ Ibrutinib is a covalent BTK inhibitor: it bears an α,β-unsaturated amide (acrylamide) Michael acceptor. The cysteine SH of BTK adds to the acrylamide via Michael — covalent, near-irreversible inhibitor. Designed selectivity comes from binding pocket complementarity.

29.19∗ Stork enamine: cyclohexanone + pyrrolidine → enamine. Now C nucleophile. + MVK → Michael adduct (1,4). Hydrolyze enamine → 1,5-diketone, ready for aldol cyclization. Equivalent to the Robinson but with enamine pre-form for cleaner selectivity.

Chapter 30

30.3∗ Amine basicity: aliphatic 1° > NH₃ > aryl. Aliphatic R-NH₂ pKa(BH⁺) ≈ 10; aniline pKa(BH⁺) = 4.6. Reason: aniline lone pair is delocalized into ring → less available for protonation.

30.8∗ Gabriel synthesis: phthalimide + NaH → potassium phthalimide; + R-X (1°) → N-alkylphthalimide; hydrazinolysis (H₂N-NH₂) → primary amine + phthalhydrazide. Yields a pure 1° amine without polyalkylation.

30.13∗ Reductive amination: cyclohexanone + n-butylamine + NaBH(OAc)₃ → N-butylcyclohexanamine. NaBH(OAc)₃ is mild — reduces iminium faster than ketone. Useful for installing secondary amines without overalkylation.

30.18∗ Sandmeyer: ArN₂⁺ + CuCl/CuBr/CuCN → ArCl/ArBr/ArCN. Mechanism: radical Cu(I)/Cu(II) cycle. Powerful method for halogen installation in aryl positions where direct halogenation is impractical.

Chapter 31

31.3∗ Retrosynthetic disconnection of atorvastatin (Lipitor): the molecule has 4 stereocenters, a heteroaromatic pyrrole, a 1,3-diol, and an N-aryl amide. Key disconnections: - Amide → aryl amine + carboxylic acid (acyl substitution). - Stereochemistry → enantioselective aldol or asymmetric reduction. - Pyrrole → Paal-Knorr synthesis (1,4-diketone + RNH₂).

31.8∗ AI retrosynthesis (Synthia, ASKCOS, IBM RXN): trained on millions of literature reactions. Suggests disconnections by pattern-matching. Useful as brainstorm partner; cannot guarantee novelty or feasibility — humans still pick.

31.13∗ Protecting group strategy: silyl ethers (TMS, TBS, TIPS) protect alcohols; benzyl ethers protect alcohols against bases; acetals protect aldehydes; Boc/Cbz protect amines. Each chosen for orthogonal cleavage (TBS by F⁻; benzyl by H₂/Pd; Boc by TFA; Cbz by H₂).

Chapter 32

32.3∗ Open-chain D-glucose → β-D-glucopyranose: C5-OH attacks C1 aldehyde → cyclic hemiacetal. Anomer: α (OH down, axial in 4C1 conformation) ~36%; β (OH up, equatorial) ~64%. β preferred because all substituents equatorial.

32.8∗ Mutarotation: pure α-D-glucose ([α]_D = +112°) in water reopens to acyclic → closes to either α or β → final [α]_D = +52.5° (equilibrium 36:64 α:β).

32.13∗ Glycosidic bond formation: glucose + glucose → maltose (α-1,4) or cellobiose (β-1,4). Biosynthesis uses UDP-glucose as activated donor. Hydrolysis: maltose by amylase; cellobiose only by cellulase. Humans lack cellulase → can't digest cellulose. Bacteria in cow rumen do.

32.18∗ HbA1c (glycated hemoglobin): glucose nonenzymatically forms an imine with N-terminus of hemoglobin β-chain → Amadori rearrangement → stable ketoamine. Lifetime of hemoglobin ~120 days → HbA1c reports 3-month avg blood glucose.

Chapter 33

33.3∗ Zwitterion of glycine: at pH 7, both -COOH (pKa 2.4) and -NH₃⁺ (pKa 9.6) are charged. Net zero charge. Below pI (5.97), net +; above, net −. Used in protein purification by isoelectric focusing.

33.8∗ SPPS (Merrifield): amino acid loaded on resin via C-terminus. Iterative cycle: deprotect Fmoc (piperidine) → couple next AA with HBTU/DIEA activation → wash → repeat. Final cleavage with TFA releases peptide and removes side-chain protections.

33.13∗ Protein structure levels: 1° (sequence), 2° (α-helix, β-sheet from H-bonds), 3° (tertiary fold), 4° (multi-subunit assembly). Each level depends on the previous. Anfinsen showed 1° encodes 3°.

33.18∗ AlphaFold predicts 3° structure from 1° using transformer attention + MSA. Median accuracy on CASP14 ~95% (within 1Å on backbone). Solved a 50-year-old problem. Limitations: dynamics, flexible loops, post-translational modifications still hard.

Chapter 34

34.3∗ β-Oxidation of fatty acids (4 steps per cycle): (1) FAD-dependent dehydrogenation α,β; (2) hydration; (3) NAD⁺-dependent oxidation of β-OH → β-keto; (4) thiolysis (CoA-SH) → shortened acyl-CoA + acetyl-CoA. Each cycle removes 2 C.

34.8∗ Isoprene rule: terpenes built from C₅ isoprene units (dimethylallyl-PP + isopentenyl-PP). Head-to-tail joining: geranyl-PP (C₁₀) → farnesyl-PP (C₁₅) → squalene (C₃₀). Cyclize squalene → lanosterol → cholesterol (50+ steps in vivo).

34.13∗ Cholesterol biosynthesis from acetyl-CoA: 3 acetyl-CoA → HMG-CoA → mevalonate (HMG-CoA reductase; statins inhibit here!) → isoprenoid PPs → squalene → lanosterol → cholesterol. Total atoms: 18 acetyl-CoA → cholesterol (C₂₇).

34.18∗ Statins (atorvastatin etc.) are competitive inhibitors of HMG-CoA reductase. The mevalonate-like statin head group occupies the active site; the lipophilic tail provides binding affinity. Reduces hepatic cholesterol → upregulated LDL receptors → lower plasma cholesterol.

Chapter 35

35.3∗ Aspirin (covalent COX inhibitor), ibuprofen (reversible NSAID), acetaminophen (mechanism debated — central COX-2 inhibition + endocannabinoid?). All three: pain/fever. Aspirin alone: irreversible platelet effect → antithrombotic.

35.8∗ Lipinski "Rule of 5": MW ≤ 500, log P ≤ 5, HBD ≤ 5, HBA ≤ 10. Predicts oral bioavailability for passive permeation across gut wall. Biologics, transported drugs violate.

35.13∗ Bioisostere: replace -COOH with tetrazole (CN₄H) — similar pKa, similar geometry, often better membrane permeability (less ionized at gut pH). Example: losartan tetrazole vs original carboxylic acid.

35.18∗ PROTAC (PROteolysis TArgeting Chimera): bifunctional molecule, ligand-A binds target protein, linker, ligand-B binds E3 ubiquitin ligase. Target gets ubiquitinated → degraded by proteasome. Catalytic (one PROTAC degrades many targets) vs inhibitor (stoichiometric). Thalidomide derivatives = E3 ligase (cereblon) binders → PROTAC half = full circle from thalidomide tragedy to thalidomide as molecular glue.

Chapter 36

36.3∗ Oxidation states in CH₃OH: C is −2 (each H is +1, O is −2, sum to 0). In CH₂O: C is 0. In HCO₂H: C is +2. In CO₂: C is +4. Track on oxidation ladder.

36.8∗ PCC selectively oxidizes 1° alcohols to aldehydes (stops at aldehyde, doesn't go to acid). Jones (CrO₃/H₂SO₄) goes through to carboxylic acid. Swern (DMSO/oxalyl chloride/Et₃N) also stops at aldehyde. Reasons: PCC and Swern lack water, so no hydrate intermediate to oxidize.

36.13∗ Sharpless asymmetric dihydroxylation: OsO₄/(DHQD)₂-PHAL/K₃Fe(CN)₆/K₂CO₃. Adds two OHs syn to alkene face controlled by chiral cinchona ligand. ee typically 80-99% for most alkene classes. 2001 Nobel.

36.18∗ NAD⁺/NADH biological reduction: NAD⁺ + 2e⁻ + H⁺ → NADH. Hydride transfer from carbon (e.g., lactate → pyruvate run in reverse: pyruvate + NADH → lactate + NAD⁺). NADH is a hydride source; the nicotinamide ring's quaternary N is the electrophilic position.

Chapter 37

37.3∗ Pd catalytic cycle (Suzuki): Pd(0) + ArX → oxidative addition → Pd(II)ArX. Transmetalation: + ArB(OH)₂/base → Pd(II)Ar-Ar'. Reductive elimination → Ar-Ar' + Pd(0). Returns to start.

37.8∗ Heck reaction (Pd, ArX + alkene): OA gives Pd(II)Ar. Alkene coordinates, inserts into Pd-Ar (carbopalladation). β-H elimination gives Pd-H and product. Base regenerates Pd(0). Net: ArX + CH₂=CHR → ArCH=CHR + HX. Useful for styrene/alkene constructions.

37.13∗ Grubbs G1 vs G2: G1 is a Ru-PCy₃ benzylidene; G2 has an N-heterocyclic carbene (NHC) ligand replacing one PCy₃ — much more reactive and tolerant of EWGs. Mechanism: metallacyclobutane intermediate (Chauvin).

37.18∗ Ziegler-Natta polymerization: TiCl₄/AlEt₃ for polyethylene, also gives isotactic polypropylene. Modern metallocenes (Kaminsky, e.g., Cp₂ZrCl₂/MAO) give same with better control of stereo and MW.

Chapter 38

38.3∗ Artemisinin: anti-malarial from Artemisia annua; isolated by Tu Youyou (Nobel 2015). Endoperoxide (1,2,4-trioxane) is pharmacophore. Activated by Fe(II) in malaria parasite → radical cascade → parasite death. Many total syntheses (Schmid, Avery, Singh). Semisynthesis from artemisinic acid (yeast platform) is industrial.

38.7∗ Woodward's strychnine synthesis (1954): 29 steps from indole to strychnine — first total synthesis of a complex alkaloid. Demonstrated stereo-control and disconnection strategy that would define the field.

38.13∗ Convergent synthesis: build two roughly equal-sized fragments separately, then couple. n steps in series in a linear synthesis → cumulative low yield. Two n/2 paths converging → much higher overall yield. Example: terpenes built from prenyl + farnesyl halves.

38.18∗ Modern total synthesis tools: cross-coupling (Pd, Ni), C-H activation, biocatalysis, photoredox, flow chemistry, AI-assisted retrosynthesis (Synthia). The synthetic toolbox expands every decade.

Chapter 39

39.3∗ Pericyclic reaction classes: - Cycloaddition ([4+2], [2+2]): two π systems combine. - Electrocyclic: open chain ↔ ring (one π converted to σ or vice versa). - Sigmatropic: σ bond migrates. - Group transfer: e.g., ene reaction.

39.8∗ Woodward-Hoffmann for thermal [4+2] (Diels-Alder): suprafacial-suprafacial allowed by orbital symmetry (HOMO_diene + LUMO_dienophile match phases on both ends). Photochemical [2+2] same way. Crossed (thermal [2+2] suprafacial-suprafacial) forbidden by symmetry.

39.13∗ [3,3]-sigmatropic Cope and Claisen: 6-electron chair-like TS, suprafacial-suprafacial, all-syn. Claisen drives forward thermodynamically by forming C=O. Aliphatic Cope is degenerate without thermodynamic asymmetry; aromatic Cope (Cope of vinyl naphthalene) gains aromaticity.

39.18∗ Vitamin D photochemistry: 7-dehydrocholesterol in skin + UVB → conrotatory electrocyclic ring opening → previtamin D → thermal [1,7]-H shift → vitamin D₃. Body uses this UV-driven cascade; not enough sunlight → deficiency.

Chapter 40

40.3∗ Atom economy: AE = MW(product) / Σ MW(reactants) × 100%. Diels-Alder: 100% (all atoms in product). Wittig: only ~50% (Ph₃P=O byproduct). Friedel-Crafts: ~75% (HCl byproduct).

40.8∗ E-factor: kg waste / kg product. Pharma typical 25-100; bulk chemicals 1-5; petrochemicals <0.1. Goal in process chemistry: minimize E-factor, often through catalyst recycling, solvent reduction, atom-efficient routes.

40.13∗ Sitagliptin (Januvia) green evolution: - Gen 1: linear, 8 steps, organic solvents, chiral auxiliary, 30% overall yield, E-factor ~50. - Gen 2: asymmetric hydrogenation with Rh-josiphos, ~70% yield, E-factor ~20. - Gen 3: transaminase biocatalysis (engineered by Codexis), 92% yield, water solvent, E-factor ~5. Three Presidential Green Chemistry Awards.

40.18∗ Photoredox catalysis: visible-light absorbed by Ru(bpy)₃²⁺ or Ir complex → excited state → single-electron transfer to/from substrate → radical intermediate → product. Enables previously inaccessible bond forming under mild conditions (no high heat, no peroxide initiators).

Selected full solutions across all 40 chapters. ~25% of each chapter's exercises are starred and worked here. The rest are left for you — answers without work are not learning.