Problem Set 9 – Reactions of carboxylic acid and their derivatives

1. Propose a sequence of reactions to effect the following conversions:

a. 3,5-dinitrobenzoyl chloride from benzene

b. phenylethanoic acid from toluene

c. butanoic acid from ethanol

d. 4-phenyl-4-heptanol from methyl benzoate

2. Propose a synthesis of CH₃¹³CH₂CO₂H using ¹³CO₂ as source of ¹³C.

3. Tropic acid is isolated from atropine, an alkaloid found in Atropa belladona (deadly nightshade). Its molecular formula is C₉H₁₀O₃. Tropic acid forms benzoic acid on oxidation with hot KMnO₄. Tropic acid also reacts with HBr to form compound “A”, C₉H₉O₂Br. Compound “A” reacts with alcoholic KOH to give atropic acid, C₉H₈O₂. On catalytic hydrogenation, atropic acid forms hydratropic acid, C₉H₁₀O₂. Hydratropic acid may be synthesized by treating the Grignard reagent formed from 1-chloro-1-phenylethane with dry ice followed by acid workup. Oxidation of tropic acid gives a dicarboxylic acid, C₉H₈O₄.

a. What is the structure of hydratropic acid?

b. What is the structure of atropic acid?

c. What is the structure of the dicarboxylic acid?

d. What is the structure of tropic acid?

4. Give a structure of compound “X”, C₃H₅ClO₂, consistent with the following ¹H NMR data:

d = 1.73 (3H, doublet), d = 4.47 (1H, quartet), d = 11.22 (1H, singlet).

5. Identify the reagents in the following scheme:

6. Write the structure(s) of the organic product(s) of the following reactions:

a. propyl benzoate + i) LiAlH₄ ii) H₃O⁺

b. 5-hydroxypentanoic acid + D

c. acetic anhydride + 1-propanol

d. butanoyl chloride + lithium diphenylcuprate

7. Compound “A”, C₆H₁₃NO, produces a gas on heating with aqueous NaOH. When the resulting solution is acidified and extracted with ether, compound “B” is isolated. “C” is formed when “B” is heated with acidic methanol. Reduction of “C” with LiAlH₄ yields methanol and 4-methyl-1-pentanol. What are the structures of “A”, “B” and “C”?

8. (S)-Ibuprofen is an antiinflammatory drug. Racemic ibuprofen can be synthesized from benzene:

Benzene + (CH₃)₂CHCOCl/AlCl₃ ® “A”

“A” + Zn(Hg)/HCl ® “B”

“B” + CH₃COCl/AlCl₃ ® “C” (para substitution occurs)

“C” + NaCN/H₂SO₄ ® “D”

“D” + H₃O⁺ ® ibuprofen

Give the structures of “A”, “B”, “C”, “D” and ibuprofin.

9. Progesterone is a hormone, secreted by the corpus luteum. It is involved in the control of pregnancy. It can be synthesized from stigmasterol, obtained from soybean.

stigmasterol (C₂₉H₄₈O) + acetic anhydride ® “A” (C₃₁H₅₀O₂)

“A” + Br₂ ® “B” (C₃₁H₅₀O₂Br₂)

“B” + O₃, then Ag₂O ® “C” (C₂₄H₃₆O₄Br₂)

“C” + Zn/CH₃CO₂H ® “D” (C₂₄H₃₆O₄)

“D” + C₂H₅OH/H⁺ ® “E” (C₂₆H₄₀O₄)

“E” + C₆H₅MgBr, then H₂O ® “F” (C₃₆H₄₆O₃)

“F” + H₃PO₄ ® “G” (C₃₆H₄₄O₂)

“G” + Br₂ then CrO₃/H⁺ ® “H” (C₂₃H₃₄O₃Br₂)

“H” + Zn/CH₃CO₂H ® “I” (C₂₃H₃₄O₃)

“I” + H₃O⁺/D ® “J” (C₂₁H₃₂O₂) pregnenolone

pregnenolone + Br₂ then CrO₃/H⁺ ® “K” (C₂₁H₃₀O₂Br₂)

“K” + Zn/CH₃CO₂H ® progesterone (C₂₁H₃₀O₂)

What are the structures of pregnenoline and of progesterone?

10. In clinical studies with atherosclerotic patients it was found that one of the metabolites of the hyperlipidemia drug (Z)-3-methyl-4-phenyl-3-butenamide is compound “A” which has the formula C₁₁H₁₅NO₂. When heated with aqueous acid, the following lactone is formed along with NH₄⁺:

a. What is the structure of metabolite “A”?

b. Write a mechanism for its transformation into the lactone.