Chapter 8 — Exercises

Forty-five problems on stereochemistry in reactions: inversion, retention, racemization, syn/anti addition, and asymmetric synthesis. ∗ = full solution in Appendix Answers to Selected Exercises.

Section A — Stereochemistry of substitution reactions

8.1∗ (routine) Predict stereochemistry for $S_N2$ on (R)-2-bromobutane with azide ($N_3^-$): (a) inversion to give (S)-2-azidobutane? (b) racemization? (c) retention?

8.2 (routine) Predict for $S_N1$ on (R)-3-bromo-3-methylpentane (tertiary). Expect racemization or stereospecific?

8.3 (routine) A student claims SN2 always gives "the opposite enantiomer." Is this strictly true? What if the substrate is achiral?

8.4 (moderate) Identify whether each reaction is concerted (one-step) or stepwise (with intermediate). Predict the stereochemical outcome: (a) (R)-2-bromobutane + I⁻ in DMSO (b) (R)-3-chloro-3-methylhexane in water/methanol (c) (R)-2-bromobutane + KOH (E2 elimination) (d) (R)-α-bromoamide + nucleophilic O

8.5 (moderate) A reaction of (R)-2-bromobutane gives a 90:10 mixture of (S):(R) substitution products. Mechanism: pure SN2 (would give 100% inversion) or mixed SN1/SN2 (gives mostly inversion + some racemization)? Argue from the data.

Section B — Stereochemistry of addition reactions

8.6 (routine) For an alkene + Br₂ addition (anti), predict: would you get syn or anti diastereomers when starting from (E)-2-butene?

8.7∗ (routine) Draw the product of (Z)-2-butene + OsO₄ (syn dihydroxylation). Confirm it is the meso-2,3-butanediol.

8.8 (routine) Draw the product of (E)-2-butene + OsO₄. Is it (R,R), (S,S), or meso?

8.9 (moderate) Predict the products of: (a) (E)-3-hexene + Br₂ → ? (b) (Z)-3-hexene + Br₂ → ?

Specify cis/trans dibromides; relative stereochemistry; whether enantiomers or meso.

8.10 (moderate) Hydroboration-oxidation of an alkene gives anti-Markovnikov + syn addition. Draw the product of (R)-3-methyl-1-pentene (chiral!) + BH₃ then H₂O₂/NaOH. Predict stereochemistry of the new C-OH bond relative to the existing stereocenter.

8.11 (challenge) Catalytic hydrogenation of cyclohexene with H₂/Pd gives cyclohexane. Now consider H₂/Pd on (R)-3-methylcyclohexene — what stereochemistry results from the existing chiral center? Explain syn delivery from the metal surface.

8.12 (challenge) Sharpless asymmetric epoxidation of an allylic alcohol with the (R,R)-tartrate catalyst gives one enantiomer of the epoxide preferentially. Sketch the mechanism and explain the chirality transfer.

Section C — Stereoselective vs stereospecific

8.13∗ (routine) Define and distinguish: stereospecific vs. stereoselective vs. enantioselective vs. diastereoselective.

8.14 (routine) Classify each as stereospecific, stereoselective, or both: (a) SN2 (b) Diels-Alder (c) Asymmetric hydrogenation with Rh-BINAP (d) Reduction of (E)-alkene by H₂/Pd (e) Reduction of (Z)-alkene by H₂/Pd

8.15 (moderate) A chiral catalyst gives a product with 80% ee. What is the ratio of enantiomers? What is the ratio of (S):(R) if the product is enriched in (S)?

8.16 (moderate) A reaction gives 70% (R) and 30% (S). What is the ee?

8.17 (challenge) A reaction is reported as "diastereoselective with a 4:1 ratio of diastereomers." A second reaction is reported as "diastereospecific." Which one is more impressive? Why?

Section D — Prochirality and re/si faces

8.18 (routine) For propanal (CH₃CH₂CHO), identify the re and si faces of the C=O group.

8.19 (moderate) A nucleophile attacks the re face of acetaldehyde (CH₃CHO). Predict the stereochemistry of the product (R or S).

8.20 (challenge) A chiral catalyst forces hydride delivery to the si face of a prochiral ketone. The product is observed to be (R). What does this tell you about the priority order of the substrate?

8.21 (challenge) Identify the diastereotopic protons in: (a) ethanol's CH₂ group (if attached to a chiral center, the H's are diastereotopic; but in plain ethanol, they're enantiotopic) (b) propan-2-ol's CH₃ groups (homotopic? enantiotopic? diastereotopic?) (c) (S)-2-bromobutan-1-ol's CH₂ at position 1

Section E — E2 stereochemistry

8.22 (routine) E2 elimination requires anti-periplanar geometry between the H being removed and the leaving group. For 2-bromobutane (achiral as drawn), draw the chair (Newman) conformation that allows E2.

8.23 (moderate) For trans-1-bromo-2-methylcyclohexane, E2 elimination requires the H being removed and the Br to be anti-periplanar (both axial in the chair). For each chair conformer, identify which gives a productive E2 transition state.

8.24 (challenge) Trans-1-tert-butyl-4-bromocyclohexane: explain why E2 is slow despite the substrate being a secondary halide (the tert-butyl group locks the chair with Br equatorial; no anti-periplanar H is available; need to invert chair).

Section F — Diels-Alder stereospecificity

8.25 (routine) Diels-Alder of (E)-2-butenal (E-crotonaldehyde) with cyclopentadiene. Predict cis or trans relative stereochemistry of the substituents on the bicyclic product.

8.26 (moderate) Diels-Alder of (Z)-1,2-dichloroethylene + cyclopentadiene: which diastereomer? cis or trans dichloride?

8.27 (challenge) Hetero-Diels-Alder of an enone with a 1-amino-1,3-butadiene gives a dihydropyridine. Why is this stereospecific?

Section G — Asymmetric synthesis examples

8.28 (moderate) Sketch the Sharpless asymmetric epoxidation of trans-cinnamyl alcohol using (S,S)-tartrate. Predict the product configuration.

8.29 (moderate) Asymmetric hydrogenation of an alkene with (S)-BINAP-Rh: predict whether the new stereocenter is (R) or (S).

8.30 (challenge) Kinetic resolution: a chiral catalyst reacts with one enantiomer of a racemate at 100x the rate of the other. After 50% conversion, what's the ee of the unreacted starting material?

8.31 (challenge) Dynamic kinetic resolution (DKR): a substrate racemizes faster than it reacts; combined with kinetic resolution, all the substrate converts to one product enantiomer. Sketch the strategy.

Section H — Diastereoselectivity in carbonyl addition

8.32 (moderate) Felkin-Anh model: for (R)-2-methylpropanal (or chiral 2-methylbutanal), nucleophile addition gives a major diastereomer. Sketch the Felkin-Anh TS.

8.33 (challenge) Cram chelation model applies when the α-substituent has a coordinating group. Sketch how a Lewis acid + a chiral β-hydroxyaldehyde gives the chelated TS.

Section I — Thalidomide and α-stereolability

8.34 (moderate) Thalidomide has a chiral α-carbonyl center. Why does it racemize in aqueous solution?

8.35 (challenge) Modern thalidomide use (multiple myeloma): the drug is given to non-pregnant patients. Why is α-racemization not a concern in this context?

8.36 (challenge) Suggest a structural modification to thalidomide that would prevent α-racemization. Why might this also alter pharmacology?

Section J — Cumulative

8.37 (challenge) A research paper reports "synthesis of (S)-(-)-X with 95% ee from prochiral Y using catalyst Z." Decode this language: what was the starting material? What was made? What was the product purity?

8.38 (challenge) A graduate student does an SN2 on (R)-2-bromobutane and gets a 90% ee (S)-2-iodobutane. The textbook says SN2 is 100% stereospecific. Explain the 10% deviation.

8.39 (challenge) A chemist wants to make pure (S)-2-iodobutane from (R)-2-bromobutane. Strategy: use SN2. But what if there's also some SN1 happening? How would they detect it (via stereochemistry)?

Section K — Conformations and stereochemistry

8.40 (moderate) Why does cis-1,2-dimethylcyclohexane have one stable chair (ax-eq); trans-1,2-dimethylcyclohexane has two equivalent chairs (both diaxial = both diequatorial)? Connect to ring flip.

8.41 (challenge) For trans-1-bromo-2-methylcyclohexane with -OH attack via SN2: in which chair conformation does the SN2 happen? (Hint: the Br must be axial for back-side attack to be unhindered.)

Section L — Open-ended

8.42 (challenge) A drug candidate has 3 stereocenters. The pharmacology depends on getting the (R,S,R) configuration. Sketch a strategy for total synthesis.

8.43 (challenge) "Mechanism predicts stereochemistry; observed stereochemistry tells you the mechanism." Apply this principle to: a substrate of (R)-2-iodobutane reacts with NaI in acetone; the product is (R,S)-2-iodobutane (some racemization). What does this say about the mechanism?

8.44 (challenge) A reaction's TS has a 3-membered ring opened by anti-attack. Predict the stereochemistry. (Hint: the bromonium opening of an alkene + Br₂.)

8.45 (challenge) Why does Diels-Alder retain the geometry of both diene and dienophile in the product? Explain in terms of the concerted pericyclic mechanism.

Notes for instructors: Common stumbling blocks for Chapter 8: (1) confusing inversion/retention/racemization; (2) confusing stereospecific vs stereoselective; (3) misapplying re/si nomenclature; (4) forgetting that SN1/E1 with planar carbocation racemize; (5) overlooking the role of catalyst chirality in asymmetric synthesis. Computational exercises: simulate a SN2 transition state in Avogadro/WebMO and visualize the Walden inversion.