Chapter 7 — Exercises

Forty-six problems on stereoisomerism, chirality, R/S assignments, optical activity, and biological consequences. ∗ = full solution in Appendix Answers to Selected Exercises.

Section A — Recognizing stereocenters

7.1∗ (routine) Identify stereocenters (if any) in each molecule: (a) 2-chlorobutane (b) 2-chloropropane (c) 3-chloropentane (d) 3-methylhexane (e) 2-methylbutan-2-ol (f) cyclohexanol

7.2 (routine) Identify stereocenters in the anchor examples: aspirin, ibuprofen, acetaminophen, thalidomide. How many stereocenters does each have?

7.3 (routine) Does a $(CH_3)_3C$ group (tert-butyl) carbon have a stereocenter? Why or why not?

7.4 (moderate) Some nitrogens have four different substituents plus a lone pair. Why are these nitrogens typically not chiral centers in practice? (Hint: amine inversion.)

7.5 (moderate) Identify stereocenters in: (a) menthol (b) cholesterol (has 8 stereocenters) (c) aspartame (sweetener; has 2 stereocenters) (d) caffeine (none — why?)

Section B — R/S assignments

7.6∗ (routine) Assign R or S to each stereocenter: (a) (S)-2-butanol vs. (R)-2-butanol: confirm the assignment by CIP (b) CHFClBr (the central C is bonded to F, Cl, Br, H) (c) (S)-alanine (d) (R)-lactic acid (2-hydroxypropanoic acid)

7.7 (routine) For the following structures (described), assign R/S: (a) A carbon with: Br (up), OH (right), CH₃ (down), H (back, hashed wedge) (b) A carbon with: OH (up, wedge toward viewer), CH₂CH₃ (right), CH₃ (down), H (left, hashed) (c) A carbon with: NH₂ (front wedge), COOH (right), CH₃ (left), H (back hash)

7.8 (moderate) Assign R/S to the stereocenter in ibuprofen. Only one enantiomer is pharmacologically active; which? (Look it up if needed.)

7.9 (moderate) Assign R or S to: (a) (R)-glyceraldehyde (b) (R)-mandelic acid (2-hydroxy-2-phenylacetic acid) (c) (S)-2-bromopropan-1-ol (d) (R)-3-chloro-2-methylpropan-1-ol

7.10 (challenge) Assign R/S to the stereocenter of (S)-naproxen. Only the (S) form is the active anti-inflammatory; the (R) form is hepatotoxic.

Section C — Multiple stereocenters

7.11∗ (moderate) 2,3-dibromobutane has how many stereocenters? How many distinct stereoisomers exist? Draw them. Identify any meso compound.

7.12 (moderate) 2,3,4-trihydroxybutanal has three stereocenters. Maximum number of stereoisomers? Are any meso?

7.13 (routine) Natural tartaric acid is (2R,3R). Its enantiomer is? Its meso form is?

7.14 (moderate) Which of the following pairs are enantiomers, diastereomers, or the same compound? (a) (2R,3R)-2,3-dibromobutane and (2S,3S)-2,3-dibromobutane (b) (2R,3R)-2,3-dibromobutane and (2R,3S)-2,3-dibromobutane (c) (2R,3S)-2,3-dibromobutane and (2S,3R)-2,3-dibromobutane

7.15 (challenge) How many distinct stereoisomers of glucose (an aldohexose with four stereocenters) exist? Name a few and discuss which is the natural form.

7.16 (challenge) Cholesterol has 8 stereocenters. Maximum possible stereoisomers? In practice, only one is biological. Why?

Section D — Diastereomers vs enantiomers

7.17 (routine) Pair up: (a) Different physical properties: enantiomers / diastereomers? (b) Identical physical properties (in achiral environment): enantiomers / diastereomers? (c) Mirror images: enantiomers / diastereomers? (d) Separable by chromatography: enantiomers / diastereomers?

7.18 (moderate) A racemic mixture is what kind of stereoisomeric mixture? (a) Single enantiomer (b) 50:50 mix of two enantiomers (c) Mix of diastereomers (d) Pure single compound

7.19 (moderate) Define epimer. Give an example from the carbohydrate world.

Section E — Optical activity

7.20 (routine) If a pure enantiomer has $[\alpha]_D = +52°$, what rotation does its mirror image show? What does a racemic mixture show?

7.21∗ (moderate) A sample shows $[\alpha]_D = +40°$, and the pure enantiomer has $[\alpha]_D = +52°$. What is the enantiomeric excess (ee)?

7.22 (moderate) A solution contains 30% (R)-enantiomer and 70% (S)-enantiomer. What is the ee? Which is the major enantiomer?

7.23 (moderate) A 0.50 g sample of an unknown compound is dissolved in 10 mL water and put in a 1.0 dm polarimeter cell. The observed rotation is +1.0°. What is the specific rotation?

7.24 (challenge) A drug's racemate has zero rotation. Adding a chiral catalyst converts some (R) to (S) (asymmetric synthesis). The product has $[\alpha]_D = +30°$, and the pure (S) is +50°. What's the % ee of the product?

Section F — Fischer projections

7.25 (routine) Draw (R)-glyceraldehyde as a Fischer projection.

7.26 (moderate) Convert this Fischer projection to a 3D (wedge-dash) drawing: CHO on top, H on the right, OH on the left, CH₂OH on bottom (for a central stereocenter).

7.27 (moderate) For the natural D-glucose Fischer projection (CHO top, CH₂OH bottom), the OH groups are: C2 right, C3 left, C4 right, C5 right. Confirm D vs L. (The D form has the lowest numbered stereocenter OH on the right.)

7.28 (moderate) Convert (S)-alanine from its Fischer projection (NH₂ left, H right, CH₃ bottom, COOH top) to a 3D wedge-dash drawing.

Section G — Alkene geometry (E/Z)

7.29 (routine) Assign E or Z to each alkene: (a) 2-pentene with CH₃CH₂ and CH₃ on opposite sides (b) 2-chloro-2-butene (with Cl on one sp² C, two methyls and H) (c) 1-chloro-1-bromoethylene ($CHCl = CBrH$)

7.30 (routine) Why is the (E) isomer of 2-butene more thermally stable than (Z)? (Steric argument.)

7.31 (moderate) Draw all four possible stereoisomers of 2,4-hexadiene (two conjugated alkenes, each with possible geometry). Which are enantiomers? Which are diastereomers?

7.32 (challenge) trans-Cyclooctene is the smallest stable trans-cycloalkene. Why is it strained? How could you measure its strain energy?

Section H — Biological chirality

7.33 (moderate) Thalidomide: the (R) enantiomer is a sedative and the (S) is a teratogen. Given that the two enantiomers racemize in vivo, explain why prescribing only (R) does not avoid the teratogenic risk.

7.34 (moderate) Glucose is D-(+). Fructose is D-(-). Both have the same D/L classification but different rotations. Why?

7.35 (moderate) Natural amino acids (except glycine) are all L-configuration (S at the α-carbon, except cysteine which is R because of the different priority of S vs. its other substituents). Why is glycine special?

7.36 (challenge) Amino acids in the food you eat — are they chiral or racemic? What about amino acids produced by industrial fermentation?

7.37 (challenge) D-glucose and L-glucose: which can your body metabolize? Why?

Section I — Resolution and asymmetric synthesis

7.38 (moderate) A chemist has a racemic mixture of 2-bromobutane. Suggest 3 strategies to obtain pure (S)-2-bromobutane.

7.39 (moderate) A pharmaceutical chemist needs (S)-naproxen. The fastest route is direct asymmetric hydrogenation of the corresponding alkene with a chiral Rh catalyst. Sketch the strategy. Why is this preferred to making the racemate and resolving?

7.40 (challenge) Pasteur's classic resolution of tartaric acid (1848) used hand-picking of crystals. Explain the chemistry. Why doesn't this work for most racemates?

7.41 (challenge) A modern chiral HPLC column with a cyclodextrin stationary phase can separate (R) and (S) ibuprofen. Sketch why this works.

Section J — Atropisomerism and beyond

7.42 (challenge) 1,1'-Binaphthyl has restricted rotation about the central C-C bond. Why is it chiral? Define atropisomerism.

7.43 (challenge) An allene with two different terminal substituents (R₂C=C=CR'₂) is chiral. Explain why this constitutes axial chirality.

Section K — Cumulative

7.44 (challenge) Menthol has three stereocenters — how many stereoisomers exist? The (−)-menthol is the natural one with cooling taste; (+)-menthol tastes bitter. Explain.

7.45 (challenge) A chemist synthesizes a drug and gets a racemic mixture. The FDA requires separate enantiomer testing. Walk through how the chemist would: (a) confirm the product is racemic; (b) separate the two enantiomers; (c) test each.

Section L — Preview problems

7.46 (challenge) Chapter 8 will cover the stereochemistry of reactions. Predict: if (R)-2-butanol is converted to its tosylate (an SN2 leaving-group conversion with no change at the stereocenter), is the tosylate (R) or (S)? Then if (R)-2-butyl tosylate undergoes SN2 substitution by iodide, is the product (R) or (S) configuration at the former stereocenter?

Notes for instructors: Common stumbling blocks for Chapter 7: (1) confusing R/S with +/-; (2) forgetting that meso compounds are achiral despite having stereocenters; (3) struggling with CIP when comparing similar groups (need to apply rule 3 carefully); (4) confusing diastereomers (separable, different properties) with enantiomers (identical in achiral environment, only optical rotation differs); (5) not visualizing the perspective for R/S assignment (mental rotation skills).