Chem 232. Problem Set 4. Table. Substrate Types and the Choice of S N 1 of S N 2

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1 Chem 232 D. J. Wardrop Problem et 4 Does the nucleophilic substitution of substrate X proceed via an N 2 or N 1 mechanism? is a perennial question in rganic Chemistry. Use the table below as a guide to the likelihood of each mechanism taking place for a given substrate. Table. ubstrate Types and the Choice of N 1 of N 2 Type of electrophilic carbon atom N 1 mechanism? N 2 mechanism? methyl (CH 3 -X) no very good primary alkyl (RCH 2 -X) no good secondary alkyl (R 2 CH-X) yes yes tertiary alkyl (R 3 C-X) very good no allylic (CH 2 =CH-CH 2 -X) yes good benzylic (ArCH 2 -X) yes good Question 1. a. An aqueous solution containing 10 g of optically pure (2,3R)-2-chloro-5-hexyne-3-ol was diluted to 5 dl with CHCl 3 and placed in a polarimeter tube 5 cm long. The measured rotation was 5.50º. Using the equation below, determine the specific rotation ([α] D ). Hint: all values have been given with the correct units for use in the equation below. b. The solution above was mixed with 5 dl of a solution containing 20 g of racemic 2-chloro-5- hexyne-3-ol. Calculate the enantiomeric excess (ee) of this solution. c. Draw the structural formula for (2,3R)-2-chloro-5-hexyne-3-ol. d. What is the stereochemical relationship between (2,3R)-2-chloro-5-hexyne-3-ol and (2R,3R)-2- chloro-5-hexyne-3-ol?

2 Question 2. Upon heated in a solution of sodium ethoxide in ethanol, compound 1 (C 7 H 15 Br) underwent reaction to yield a mixture of alkenes 2 and 3, which both have the molecular formula C 7 H 14. Catalytic hydrogenation of both 2 and 3 gave only 3-ethylpentane. uggest structures for compounds 1, 2 and 3 consistent with these observations. 1 C 7 H 15 Br EtNa 2 C 7 H 14 (alkene) 3 C 7 H 14 (alkene) 3 3-ethylpentane Question 3. The following sequence of reactions form part of a total synthesis of the powerful anticancer agent fumagillol (4). H H Me H H TsCl, Et 3 N pyridine, CH 2 Cl 2 r.t., 12 h 2 (C 21 H 30 6 ) t-buk t-buh, r.t. H 88%, 2 steps Me H 1 3 H Me H 4 CMe 2 a. Draw the structure of synthetic intermediate 2. b. Draw a reasonable arrow-pushing mechanism for the conversion of 2 to epoxide 3. c. Using the Cahn Ingold Prelog (CIP) priority rules, determine the absolute configuration and assign an R or descriptor to each chirality center in 4.

3 Question 4. Two common tests for alkyl chlorides used in undergraduate laboratories is to treat them with a solution of AgN 3 in ethanol or a solution of NaI in acetone. The reactions give an alkyl nitrate and an alkyl iodide, respectively. Both inorganic products, AgCl and NaCl precipitate out of their respective solvents, thereby providing a visual confirmation that an alkyl chloride reacted. Tertiary, secondary and primary alkyl chlorides can be distinguished from one another by the relative rates of precipitation. The rate of precipitation of AgCl in ethanol is fastest for tertiary alkyl chlorides; primary alkyl chlorides do not react at all. This trend is reversed for the NaI test. Here, primary alkyl chlorides react fastest; tertiary alkyl chlorides do not react at all. Answer the questions below based on these observations. R Cl + AgN 3 R N 2 + AgCl (s) solvent = ethanol R Cl + NaI R I + NaCl (s) solvent = acetone a. Write the mechanistic descriptor ( N 1, N 2, E1, E2, or AdE) for each reaction in the box above the reaction arrows. b. Provide a detailed explanation that accounts for the observed trend in precipitation rate when alkyl halides react with AgN 3 in ethanol. Use complete sentences. c. Provide a detailed explanation that accounts for the observed trend in precipitation rate when alkyl chlorides react with NaI in acetone. Use complete sentences.

4 Question 4. Draw the major organic product for each of the reaction schemes below. Where appropriate, ensure that you include the stereochemistry of the product. 1. Br 2, CH 2 Cl 2 H 1. HBr 2. t-buk 2. t-buk 3. H 2, Pd-C stereochemistry? N H 1. MsCl, pyridine 1. HBr, H 2 2 N 2. t-buk 2. NaCN, DMF Me Ts Ts Na 2 ( 2- anion) C 9 H 18 NaMe Me Cl AcH MeH Ts Bn NaCN DMF

5 Question 5. a. Rank each compound/anion in order of increasing nucleophilicity (1 = least nucleophilic; 5 = most nucleophilic). H 3 C Na NaH CH 3 H NaBr H 3 C H b. Rank in order of increasing rate of N 2 substitution (1 = slowest rate; 5 = fastest rate). Br Br H 3 C Br Br Br c. Rank each carbocation in order of increasing stability (1 = least stable; 4 = most stable). H C H H 3 C CH 3 H 3 C C CH H 3 CH 3 C CH3 C CH 3 d. Rank the rate of N 1 substitution in each of the solvents below. (1 = slowest rate; 4 = fastest rate). H 3 C H H 3 C H H H H H (ε = 6) (ε = 33) (ε = 78) (ε = 58) e. Rank in order of increasing leaving group ability (1 = poorest leaving group; 5 = best leaving group). H 3 C F H H F 3 C Br

6 Question 6. alacinol (4) was isolated by Muraoka and co-workers in 1997 from the dried roots and stems of alacia reticulata (Kotala himbutu in inghalese), a large climbing plant found throughout the forests of outhern India and ri Lanka. Extracts of this herb, prepared by soaking the bark and roots in water overnight, have long been employed in traditional Indian, or Ayurvedic, medicine for the treatment of type II diabetes. hown below is a total synthesis of this natural product. Bn Bn Bn Ph acetone (solvent) 75 C, 12 h + Bn Bn Ph Bn (33%) H H H + H H Bn Bn 5 Bn 4 a. Write reasonable arrow-pushing mechanism for the reaction of 1 and 2 to form sulfonium-sulfate salt 3. b. Indicate how many stereogenic (chiral) centers are present in salacinol (4), noting that the sulfonium ion center (R 3 + ) is itself a stereogenic center. c. Using the Cahn Ingold Prelog (CIP) priority rules, determine the absolute configuration and assign an R or descriptor to each chirality center in 1, 2, 4 and 5. Note that under the CIP rule, lone pairs (:) are assigned a lower priority than hydrogen atoms. d. Provide a simple explanation as to why cyclic sulfate 2 undergoes nucleophilic substitution with thioether 1, but is inert to cyclic ether 5.!