Problems. C h a p t e r Problems

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1 Problems h a p t e r rown ethers and cryptands are examples of ionophores, polyethers that coordinate around metal ions, thus rendering them soluble in hydrophobic media. 7. Whereas nucleophilic ring opening of oxacyclopropanes by anions is at the less substituted ring carbon according to the rules of the S 2 reaction, acid-catalyzed opening favors the more substituted carbon, because of charge control of nucleophilic attack. 8. Sulfur has more diffuse orbitals than does oxygen. In thiols, the S bond is less polarized than the bond in alcohols, thus leading to diminished hydrogen bonding. ecause the S bond is also weaker than the bond, the acidity of thiols is greater than that of alcohols. 9. ote on color use: Throughout the main parts of the text, beginning in hapter 6, reacting species in mechanisms and most examples of new transformations are color coded red for nucleophiles, blue for electrophiles, and green for leaving groups. olor coding is not used in exercises, summaries of new reactions, or chapter-end problems. Problems 28. n which side of the equation do you expect each of the following equilibria to lie left or right)? a) 3 ) 3 1 K 12 3 ) 3 2 K b) pk a 5 9.2) c) 3 2 Li 3 2 Li pk a 40) d) 3 pk a 35) a a 2 2 pk a 38) 29. ive the expected major product of each of the following reactions. a) onc. I b) 3 ) onc. r c) onc. I d) 3 2 ) 3 onc. l 30. For each reaction in Problem 29, write out a detailed step-by-step mechanism. 31. For each of the following alcohols, write the structure of the alkyloxonium ion produced after protonation by strong acid; if the alkyloxonium ion is capable of losing water readily, write the structure of the resulting carbocation; if the carbocation obtained is likely to be susceptible to rearrangement, write the structures of all new carbocations that might be reasonably expected to form. a) b) 3 3 c) d) 3 ) 2 2 e) 3 ) f) 3 ) g) h) 3 3 ' Write all products of the reaction of each of the alcohols in Problem 31 with concentrated 2 S 4 under elimination conditions. 33. Write all sensible products of the reaction of each of the alcohols in Problem 31 with concentrated aqueous r.

2 R R 2 or R RR ) Reactions of lcohols section number R SR R M RX lkene R R RX Rl R R R R ase rvi) Metal M) X 2 S 4, R PX 3 Sl 2 R S 2 l R X or R X,, R i } & or R or, X 2, Lewis acid, or R R ),, R l R R R R, I 4 Substrate: E R & R , ,9-2, ,9-2, , , Substrate: 9-9, , R R or R ) R R l i R R R R R R f i i f R R R )

3 Problems h a p t e r ive detailed mechanisms and final products for the reaction of 3-methyl-2-pentanol with each of the reagents that follow. a) a b) oncentrated r c) Pr 3 d) Sl 2 e) oncentrated 2 S 4 at 130 f) Dilute 2 S 4 in 3 ) Primary alcohols are often converted into bromides by reaction with ar in 2 S 4. Explain how this transformation works and why it might be considered a superior method to that using concentrated aqueous r ar, 2S r 36. What are the most likely products) of each of the following reactions? a) 3 3 $ 32, 2S4 b) 3 2 onc. I 3 c) 2 onc. 2S 4, 180 d) 3 I ive the expected main product of the reaction of each of the alcohols in Problem 31 with Pr 3. ompare the results with those of Problem ive the expected products) of the reaction of 1-pentanol with each of the following reagents. a) K 12 3 ) 3 b) Sodium metal c) 3 Li d) oncentrated I e) oncentrated l f) FS 3 g) oncentrated 2 S 4 at 130 h) oncentrated 2 S 4 at 180 i) 3 S 2 l, 3 2 ) 3 j) Pr 3 k) Sl 2 l) K 2 r S m) P, 2 l 2 n) 3 ) S 4 as catalyst) 39. ive the expected products) of the reaction of trans-3-methylcyclopentanol with each of the reagents in Problem Suggest a good synthetic method for preparing each of the following haloalkanes from the corresponding alcohols. 3 3 l I c) a) l b) r d) 3 3 ) ame each of the following molecules according to IUP. a) 3 ) b) c) 3 3 d) l 2 22 ) e) f) # 3 g) 3 2 l Explain why the boiling points of ethers are lower than those of the isomeric alcohols. Would you expect the relative water solubilities to differ in a similar way? 43. Suggest the best syntheses for each of the following ethers. Use alcohols or haloalkanes or both as your starting materials. a) b) c) d) e) f)

4 380 h a p t e r 9 Further Reactions of lcohols and the hemistry of Ethers 44. Write the expected major products) of each of the following attempted ether syntheses. a) l DMS l b) MP 3 c) 3 I DMS d) 3 ) 2 3 ) r 3)2 e) l yclohexanol f) I DMS 45. For each reaction in Problem 44, write out a detailed step-by-step mechanism. ~ r trans-2-romocyclooctanol [ 46. For each synthesis proposed in Problem 44 that is not likely to give a good yield of ether product, suggest an alternative synthesis beginning with suitable alcohols or haloalkanes that will give a superior result. int: See Problem 25 in hapter 7.) 47. a) What would be the product of reaction of trans-2-bromocyclooctanol margin) with a? b) ompare the effect of entropy on the transition state of this reaction with its effect in the reactions presented in Figure 9-6 and in Exercise Propose efficient syntheses for each of the following ethers, using haloalkanes or alcohols as starting materials. 3 a) b) c) 3 3 d) 49. ive the major products) of each of the following reactions. a) Excess conc. I b) 3 3 ) 2 Excess conc. r c) Excess conc. I d) 3 Excess conc. r e) 3 3 Excess conc. r f) ] 2-2 Excess conc. r 50. ive the expected major product of reaction of 2,2-dimethyloxacyclopropane with each of the following reagents. a) Dilute 2 S 4 in 3 c) Dilute, aqueous r e) 3 MgI, then 1, Propose a synthesis of b) a 12 3 in 3 d) oncentrated r f) 6 5 Li, then 1, beginning with cyclohexanone,, and 3-bromopropanol. [int: eware of a possible pitfall in planning this synthesis recall S e c t i o n 8-9 ). ] 52. leavage of tertiary butyl ethers requires the use of an aqueous acid hapter 7, Problem 57, and Section 9-8). Why do strong bases not cleave ethers other than oxacyclopropanes)?

5 [ Problems h a p t e r Provide an IUP name for each of the structures pictured below.? 3 a) b) c) 2 l d) e) f) 54. ive the major products) of each of the following reactions. int: The strained oxacyclobutanes react like oxacyclopropanes.) a) a 2, 3 b) 3 &~ a S 2 3, 3 2 c) Excess conc. r d) Dilute l in e) 3 3 a 3 in 3 f) LilD 4, 3 2) 2 2., 2 g) 1. 3)2Mgl, 32)2 2., h) 2. 1., 2 Li, 3 2) For each alcohol in Problem 51 of hapter 8, suggest a synthetic route that starts with an oxacyclopropane if possible). 56. ive the major products) expected from each of the reactions shown below. Watch s t e r e o c h e m i s t r y. ~ ~ a) & 3 3 Dilute 2 S4 in ame each of the following compounds according to IUP. ~ ~ b) & LilD4, 32)2 2., 2 a) 2 S b) S 3 c) S 3 d) F 3 S 2 l 58. In each of the following pairs of compounds, indicate which is the stronger acid and which is the stronger base. a) 3 S, 3 ; b) S 2, 2 ; c) 3 S 1, 2 S. 59. ive reasonable products for each of the following reactions. a) l l 2 ne equivalent a 2 S b) r KS c) [ ) KS 3 d) r S e) S 3 3 I 2 Excess f) 2 2 S

6 382 h a p t e r 9 Further Reactions of lcohols and the hemistry of Ethers 60. ive the structures of compounds,, and with stereochemistry) from the information in the following scheme. int: is acyclic.) To what compound class does the product belong? 2 3S2l, 3 2 ) 3, 2 l 2 a 2 S,, DMF Excess S S 3 3 * $ S J M 61. In an attempt to make 1-chloro-1-cyclobutylpentane, the following reaction sequence was employed. The actual product isolated, however, was not the desired molecule but an isomer of it. Suggest a structure for the product and give a mechanistic explanation for its formation. int: See hapter Integration Problem 9-26.) l Mg, 32)2 Mgl , 2 l onc. l not 62. Suggest better methods for the final step in Problem In an early study of the stereochemistry of nucleophilic displacements, optically pure R)-1-deuterio-1-pentanol was treated with 4-methylphenylsulfonyl tosyl) chloride to make the corresponding tosylate. The tosylate was then treated with excess ammonia to convert it to 1-deuterio-1-pentanamine: R) D R)-1-Deuterio-1-pentanol 3 S2l Excess D 2 1-Deuterio-1-pentanamine r D 3 DMS a) Describe the stereochemistry that you expect to observe at 1 of both the intermediate tosylate and the final amine. b) When the reaction sequence is actually carried out, the expected results are not obtained. Instead, the final amine is isolated as a 70 : 30 mixture of S)- and R)-1-deuterio-1- pentanamine. Suggest a mechanistic explanation. int: Recall that reaction of an alcohol with a sulfonyl chloride displaces chloride ion, which is a nucleophile.) 64. What is the product of the reaction shown in the margin? Pay attention to stereochemistry at the reacting centers.) What is the kinetic order of this reaction? 65. Propose syntheses of the following molecules, choosing reasonable starting materials on the basis of the principles of synthetic strategy introduced in preceding chapters, particularly in Section 8-9. Suggested positions for carbon carbon bond formation are indicated by wavy lines S 3 3 a) b) ive efficient syntheses of each of the following compounds, beginning with the indicated starting material. a) trans-1-romo-2-methylcyclopentane, from cis-2-methylcyclopentanol b) from 3-pentanol

7 Problems h a p t e r c) 3-hloro-3-methylhexane, from 3-methyl-2-hexanol d) S, from 2-bromoethanol two equivalents) 67. ompare the following methods of alkene synthesis from a general primary alcohol. State the advantages and disadvantages of each one. R 2 2 2S 4, 180 Pr 3 RP 2 R 2 2 r K 3)3 RP Sugars, being polyhydroxylic compounds hapter 24), undergo reactions characteristic of a l c o h o l s. I n o n e o f t h e l a t e r s t e p s i n g l y c o l y s i s t h e m e t a b o l i s m o f g l u c o s e ), o n e o f t h e g l u - cose metabolites with a remaining hydroxy group, 2-phosphoglyceric acid, is converted into 2-phosphoenolpyruvic acid. This reaction is catalyzed by the enzyme enolase in the presence of a Lewis acid such as Mg 21. a) ow would you classify this reaction? b) What is the possible role of the Lewis acidic metal ion? P 3 2 P 3 2 Enolase, Mg2 D 2 2 P 2 2-Phosphoglyceric acid 2-Phosphoenolpyruvic acid 69. The formidable-looking molecule 5-methyltetrahydrofolic acid abbreviated 5-methyl-F 4 ) is the product of sequences of biological reactions that convert carbon atoms from a variety of simple molecules, such as formic acid and the amino acid histidine, into methyl groups. E Formic acid 2 2 f istidine Four steps Seven steps Methyltetrahydrofolic acid 5-Methyl-F 4 ) 2 2 M D The simplest synthesis of 5-methyltetrahydrofolic acid is from tetrahydrofolic acid F 4 ) and trimethylsulfonium ion, a reaction carried out by microorganisms in the soil. 3 S 3 S F 4 D Trimethylsulfonium ion 3 5-Methyl-F 4

8 384 h a p t e r 9 Further Reactions of lcohols and the hemistry of Ethers a) an this reaction be reasonably assumed to proceed through a nucleophilic substitution mechanism? Write the mechanism, using the electron-pushing arrow notation. b) Identify the nucleophile, the nucleophilic and electrophilic atoms participating in the reaction, and the leaving group. c) n the basis of the concepts presented in Sections 6-7, 6-8, 9-2, and 9-9, are all the groups that you identified in b) behaving in a reasonable way in this reaction? Does it help to know that species such as 3 S 1 are very strong acids e.g., pk a of 3 S 2 1 is 27)? 70. The role of 5-methyl-F 4 Problem 69) in biology is to serve as a donor of methyl groups to small molecules. The synthesis of the amino acid methionine from homocysteine is perhaps the best-known example Methyl-F S omocysteine 2 F S 3 Methionine For this problem, answer the same questions that were posed in Problem 69. The pk a of the circled hydrogen in F 4 is 5. Does this cause a problem with any feature of your mechanism? In fact, methyl transfer reactions of 5-methyl-F 4 require a proton source. Review the material in Section 9-2, especially the subsection titled aloalkanes from primary alcohols and X. Then suggest a useful role for a proton in the reaction illustrated here. 71. Epinephrine adrenalin; see also hapter 6 pening) is produced in your body in a two-step process that accomplishes the transfer of a methyl group from methionine Problem 70) to norepinephrine see reactions 1 and 2 below). a) Explain in detail what is going on mechanistically in these two reactions, and analyze the role played by the molecule of TP. b) Would you expect methionine to react directly with norepinephrine? Explain. c) Propose a laboratory synthesis of epinephrine from norepinephrine. Reaction S 3 PPP 2 R S 2 R 4 P 3 10 Methionine TP S-denosylmethionine Triphosphate Reaction 2 S-denosylmethionine 2 R D 2 2 orepinephrine * S 2 R Epinephrine 2 3

9 Problems h a p t e r a) nly the trans isomer of 2-bromocyclohexanol can react with sodium hydroxide to form an oxacyclopropane-containing product. Explain the lack of reactivity of the cis isomer. [int: Draw the available conformations of both the cis and trans isomers around the 1 2 bonds compare Figure 4-12). Use models if necessary.] b) The synthesis of some oxacyclopropane-containing steroids has been achieved by use of a two-step procedure starting with steroidal bromoketones. Suggest suitable reagents for accomplishing a conversion such as the following one. } 3 0 r 3 [ 3 } 0 3 c) Do any of the steps in your proposed sequence have specific stereochemical requirements for the success of the oxacyclopropane-forming step? 73. Freshly cut garlic contains allicin, a compound responsible for the true garlic odor see hemical ighlight 9-4). Propose a short synthesis of allicin, starting with 3-chloropropene. 2 P 2 S š S 2 P 2 llicin Team Problem 74. There are four diastereomers D, margin) of 4S)-2-bromo-4-phenylcyclohexanol. s a team, formulate their structures and draw each diastereomer in the most stable chair conformation see Table 4-3; the D8 value for axial versus equatorial 6 5 is 2.9 kcal mol 21 ). Divide your team into equal groups to consider the outcome of the reaction of each isomer with base 2 ). Fast ) 5 6?? Slow ) 5 6 ` ` R or S R or S Er S0 6 5 Diastereomers D of 4S)-2-bromo-4- phenylcyclohexanol Fast ) [ote: Enols are unstable with respect to isomerization to the corresponding ketone hapters 13 and 18).] ote: 6 5 equals Enol D Slow a) Using the curved-arrow formalism Section 6-3), show the flow of electrons in the attack of the base on the various cyclohexane conformers. Reconvene and present your mechanisms to your teammates, justifying the structural assignments of D. Find an explanation for the qualitative rate differences and the divergent course of the reactions of and versus and D. b) When compounds D are exposed to conditions favoring bromide dissociation in the presence of g 1 salts to accelerate heterolysis with formation of insoluble gr),,, and D give the same products as those obtained on treatment with base. Discuss the mechanism as a group. c) uriously, compound traverses another pathway under the conditions described in b); that is, rearrangement to the aldehyde E. Discuss a possible mechanism for this ring contraction. int: Keep in mind the principles outlined in Section 9-3. The mechanism proceeds through a hydroxycation. What is the driving force for its formation?) & 6 5 E )

10 386 h a p t e r 9 Further Reactions of lcohols and the hemistry of Ethers Preprofessional Problems 75. The compound whose structure is ) is best named IUP) a) 3,5-dimethylcyclopentyl ether c) cis-3,5-dimethyloxacyclohexane b) 3,5-dimethylcyclopentane-oxo d) trans-3,5-dimethyloxacyclohexane 76. The first step in the detailed mechanism for the dehydration of 1-propanol with concentrated 2 S 4 would be a) loss of 2 c) protonation of the alcohol e) elimination of 2 by the alcohol 77. Identify the nucleophile in the following reaction: RX 1 2 uy R 1 1 X 2 a) X 2 b) 1 c) 2 d) R e) RX b) formation of a sulfate ester d) loss of 1 by the alcohol 78. Which is the method of choice for preparing the ether 3 2 ) 3 3? a) 3 r ) 3 2 K 1 b) 3 2 ) Mgr c) 3 2 ) 3 Mgr 1 3 d) 3 2 ) 3 r K 1