Organic Chemistry

278 Chapter 7 Further Reactions of Haloalkanes

3. Carbocations are stabilized by hyperconjugation: Tertiary are the most stable, followed by secondary. Primary and methyl cations are too unstable to form in solution. 4. Racemization often results when unimolecular substitution takes place at a chiral carbon. 5. Unimolecular elimination to form an alkene accompanies substitution in secondary and tertiary systems. 6. High concentrations of strong base may bring about bimolecular elimination. Expulsion of the leaving group accompanies removal of a hydrogen from the neighboring carbon by the base. The stereochemistry indicates an anti conformational arrangement of the hydrogen and the leaving group. 7. Substitution is favored by unhindered substrates and small, less basic nucleophiles. 8. Elimination is favored by hindered substrates and bulky, more basic nucleophiles.

Problems 25. What is the major substitution product of each of the following solvolysis reactions?

CH3 Br Cl CH2CH3 A A CH3CH2OH CF3CH2OH CH3OH (a) CH3CBr (b) (CH3)2CCH2CH3 (c) A CH3 O H Br B CH3 CH3 A A HCOH D2O A OD (d) COCH3 (e) CH3CCl (f) CH3CCl A A A CH3 CH3 CH3

26. For each reaction presented in Problem 25, write out the complete, step-by-step mechanism using curved-arrow notation. Be sure to show each individual step of each mechanism separately, and show the complete structures of the products of that step before going on to the next.

H3C Br 27. Write the two major substitution products of the reaction shown in the margin. (a) Write a /∑ mechanism to explain the formation of each of them. (b) Monitoring the reaction mixture reveals CH3OH that an isomer of the starting material is generated as an intermediate. Draw its structure and

explain how it is formed. ∑ / 28. Give the two major substitution products of the following reaction. H3C H

OSO2CH3

H3C C6H5 CH3CH2OH

H3C C6H5 H

29. How would each reaction in Problem 25 be affected by the addition of each of the following substances to the solvolysis mixture?

(a) H2O (b) KI (c) NaN3 (d) CH3CH2OCH2CH3 (Hint: Low polarity.) 30. Rank the following carbocations in decreasing order of stability.

ϩ CH H CH3 H CH2 3 ϩ

ϩ Problems Chapter 7 279

31. Rank the compounds in each of the following groups in order of decreasing rate of solvolysis in aqueous acetone.

CH3 CH3 CH3 A A A (a) CH3CHCH2CH2Cl CH3CHCHCH3 CH3CCH2CH3 A A Cl Cl O B OCCH3 Cl OH

(b)

Br Cl H3C Cl (c)

32. Give the products of the following substitution reactions. Indicate whether they arise through the SN1 or the SN2 process. Formulate the detailed mechanisms of their generation.

CH3 CH3CH2OH Excess CH3SH, CH3OH (a) (CH3)2CHOSO2CF3 uuuy (b) Br

(C6H5)3P, DMSO NaI, acetone (c) CH3CH2CH2CH2Br uuuuuy (d) CH3CH2CHClCH2CH3 uuvuy 33. Give the product of each of the following substitution reactions. Which of these transformations should proceed faster in a polar, aprotic solvent (such as acetone or DMSO) than in a polar, protic

solvent (such as water or CH3OH)? Explain your answer on the basis of the mechanism that you expect to be operating in each case. 1 2 1 2 (a) CH3CH2CH2Br 1 Na CN uy (b) (CH3)2CHCH2I 1 Na N3 uy (c) (CH3)3CBr 1 HSCH2CH3 uy (d) (CH3)2CHOSO2CH3 1 HOCH(CH3)2 uy

34. Propose a synthesis of (R)-CH3CHN3CH2CH3, starting from (R)-2-chlorobutane. 35. Two substitution reactions of (S)-2-bromobutane are shown here. Show their stereochemical outcomes.

O B HCOH (S)-CH3CH2CHBrCH3

O B O HCOϪNaϩ, DMSO B (S)-CH CH CHBrCH 3 2 3 OCCH3 % 36. Propose a stereocontrolled synthesis of cis-1-acetoxy-3-methylcyclopentane (margin), starting from trans-1-chloro-3-methylcyclopentane. ( 37. The two seemingly similar reactions shown below differ in their outcomes. CH3 cis-1-Acetoxy- NaOH, CH CH OH 3 2 3-methylcyclopentane CH3CH2CH2CH2Br uuuuuuy CH3CH2CH2CH2OH

NaSH, CH3CH2OH CH3CH2CH2CH2Br uuuuuuy CH3CH2CH2CH2SH The ! rst proceeds in high yield. The yield of the product in the second, however, is diminished

by the formation of (CH3CH2CH2CH2)2S in substantial quantities. Discuss the formation of this by-product mechanistically, and explain why it occurs in the second case but not in the ! rst. 38. Write all possible E1 products of each reaction in Problem 25. 39. Formulate the complete step-by-step mechanisms for all the E1 processes that you identi! ed in Problem 38. 280 Chapter 7 Further Reactions of Haloalkanes

40. Write the products of the following elimination reactions. Specify the predominant mechanism (E1 or E2) and formulate it in detail.

NaNH2, NH3 KOC(CH3)3, (CH3)3 COH (a) (CH3CH2)3CBr uvuuuy (b) CH3CH2CH2CH2Cl uuuuuuuvuy Cl

NaOCH3, CH3OH Excess KOH, CH3CH2OH (c) CH (d) CH3 A Br

41. From the list of reagents (a) – (f) below, choose all those that are most likely to give primarily (i) SN2 reaction with primary RX; (ii) E2 reaction with primary RX; (iii) SN2 reaction with secondary RX; (iv) E2 reaction with secondary RX.

(a) NaSCH3 in CH3OH (b) (CH3)2CHOLi in (CH3)2CHOH (c) NaNH2 in liquid NH3 (d) KCN in DMSO O in B (e) (f ) CH3CH2CH2CONa in DMF N N A A Li H

42. Predict the major product(s) that should form from reaction between 1-bromobutane and each of the following substances. By which reaction mechanism is each formed — SN1, SN2, E1, or E2? If it appears that a reaction will either not take place or be exceedingly slow, write “no reaction.” Assume that each reagent is present in large excess. The solvent for each reaction is given.

(a) KCl in DMF (b) KI in DMF (c) KCl in CH3NO2 (d) NH3 in CH3CH2OH (e) NaOCH2CH3 in CH3CH2OH (f ) CH3CH2OH (g) KOC(CH3)3 in (CH3)3COH (h) (CH3)3P in CH3OH (i) CH3CO2H 43. Predict the major product(s) and mechanism(s) for reaction between 2-bromobutane (sec-butyl bromide) and each of the reagents in Problem 42. 44. Predict the major product(s) and mechanism(s) for reaction between 2-bromo-2-methylpropane (tert-butyl bromide) and each of the reagents in Problem 42. 45. Three reactions of 2-chloro-2-methylpropane are shown here. (a) Write the major product of each transformation. (b) Compare the rates of the three reactions. Assume identical solution polarities and reactant concentrations. Explain mechanistically.

H2S, CH3OH (CH3)3CCl O B Ϫ ϩ CH3CO K , CH3OH (CH3)3CCl

Ϫ ϩ CH3O K , CH3OH (CH3)3CCl

46. Give the major product(s) of the following reactions. Indicate which of the following mechanism(s) is in operation: SN1, SN2, E1, or E2. If no reaction takes place, write “no reaction.”

F KBr, CH2Cl KOC(CH ) A acetone (a) 3 3, (b) CH CHCH CH (CH3)3COH 3 2 3 H I CH2CH3

H2O (c) H3C Br (d) NaNH2, liquid NH3 H Problems Chapter 7 281

Br A C NaOCH2CH3, CH3CH2OH } H NaI, nitromethane (e) (CH3)2CHCH2CH2CH2Br (f) H3C & CH2CH2CH3 CH2CH3

Excess OH KOH, KCN, CH3CH2OH (g) CH3OH (h) Cl CH2CH2CH2Br H

I CH2CH3

NaSH, CH3CH2OH (i) OSO2 CH3 (j) CH OH A 3 (R)-CH3CH2CHCH3 Br O A B KOH, CH3CH2OH CH3COH (k) (CH3)3CCHCH3 (l) CH3CH2Cl

47. Fill in the blanks in the following table with the major product(s) of the reaction of each haloalkane with the reagents shown.

Reagent

Haloalkane H2O NaSeCH3 NaOCH3 KOC(CH3)3

CH3Cl

CH3CH2CH2Cl

(CH3)2CHCl

(CH3)3CCl

48. Indicate the major mechanism(s) (simply specify SN2, SN1, E2, or E1) required for the formation of each product that you wrote in Problem 47. 49. For each of the following reactions, indicate whether the reaction would work well, poorly, or not at all. Formulate alternative products, if appropriate.

NaOH, acetone (a) CH3CH2CHCH3 CH3CH2CHCH3 A A Br OH H Cl H CN

H3C H3C A A HCN, CH3OH CH3OH (c) (b) CH3CHCH2Cl CH3CHCH2OCH3

CH3 A Nitromethane H C (d) CH3OOC CH2CH2CH2CH2OH 3 A O CH3SO2O H3C

H3CHCH2I 3C CH2SCH3 NaN3, CH3OH (e) NaSCH3, CH3OH (f) CH3CH2CH2Br uuuuuy CH3CH2CH2N3

1 NaI, nitromethane CH3I 2 (g) (CH3)3CCl uuuuuuy (CH3)3CI (h) (CH3CH2)2O uuuy (CH3CH2)2OCH3 1 I

CH3OH NaBr, CH3OH (i) CH3I uuuy CH3OCH3 (j) (CH3CH2)3COCH3 uuuuuy (CH3CH2)3CBr 282 Chapter 7 Further Reactions of Haloalkanes

CH3 CH3

A NaOCH2CH3, CH3CH2OH A (k) CH3CHCH2CH2Cl CH3CHCHP CH2

NaOCH2CH3, CH3CH2OH (l) CH3CH2CH2CH2Cl CH3CH2CHP CH2

50. Propose syntheses of the following molecules from the indicated starting materials. Make use of any other reagents or solvents that you need. In some cases, there may be no alternative but to employ a reaction that results in a mixture of products. If so, use reagents and conditions that will maximize the yield of the desired material (compare Problem 53 in Chapter 6).

(a) CH3CH2CHICH3, from butane (b) CH3CH2CH2CH2I, from butane (c) (CH3)3COCH3, from methane (d) Cyclohexene, from cyclohexane and 2-methylpropane S (e) Cyclohexanol, from cyclohexane (f) , from 1,3-dibromopropane S

CH3 51. [(1-Bromo-1-methyl)ethyl]benzene, shown in the margin, undergoes solvolysis in A a unimolecular, strictly ! rst-order process. The reaction rate for [RBr] 5 0.1 M RBr in 9:1 RBr ϭ CBrO 24 21 21 A acetone : water is measured to be 2 3 10 mol L s . (a) Calculate the rate constant k from these data. What is the product of this reaction? (b) In the presence of 0.1 M LiCl, the rate is CH3 found to increase to 4 3 1024 mol L21s21, although the reaction still remains strictly ! rst order.

Calculate the new rate constant kLiCl and suggest an explanation. (c) When 0.1 M LiBr is present instead of LiCl, the measured rate drops to 1.6 3 1024 mol L21s21. Explain this observation, and write the appropriate chemical equations to describe the reactions.

52. In this chapter we have encountered many examples of SN1 solvolysis reactions, all of which proceed according to the following scheme:

ðšOH2 ϩ ϩ

Rate ϭ k [RX] Rate ϭ k [R ][Nu " ] 1 1 Ϫ ϩ 2 2 RX Xϩ R R" OH2

Loss of a proton gives the ! nal product. Although there is considerable evidence for the inter- mediacy of a carbocation, it is not directly observed normally because its combination with a

nucleophile is so rapid. Recently, examples of SN1 solvolyses have been found that give rise to very unusual observations. One example is

CH2CF3 A Cl O A A CF3CH2OH CH3OC OCH3 CH3O C OCH3 H H

Upon mixing the colorless substrate and solvent, a reddish-orange color is observed immediately, signaling the formation of an intermediate carbocation. This color fades over a period of about a minute, and analysis of the solution reveals the presence of the ! nal product in 100% yield. (a) There are two reasons for the buildup of a detectable concentration of carbocation in this case. One is that the carbocation derived from dissociation of this particular substrate is unusually stable (for reasons we will explore in Chapter 22). The other is that the solvent (2,2,2- tri" uoroethanol) is an unusually poor nucleophile, even compared with ordinary alcohols such as ethanol. Suggest an explanation for the poor nucleophilicity of the solvent. (b) What can

you say about the relative rates of the two steps (rate1 and rate2), and how do they compare to those in the usual SN1 reaction mechanism? (c) How might increasing carbocation stability and decreasing solvent nucleophilicity affect the relative magnitudes of rate1 and rate2 in an SN1 process? (d) Write the complete mechanism for the reaction above. 53. Match each of the following transformations to the correct reaction pro! le shown here, and draw the structures of the species present at all points on the energy curves marked by capital letters. Problems Chapter 7 283

(i) (ii)

A C

E E D

Reaction coordinate Reaction coordinate

(iii) (iv)

I E K G E E J F M

H L N

Reaction coordinate Reaction coordinate

(a) (CH3)3CCl 1 (C6H5)3P uy (b) (CH3)2CHI 1 KBr uy (c) (CH3)3CBr 1 HOCH2CH3 uy (d) CH3CH2Br 1 NaOCH2CH3 uy 54. Formulate the structure of the most likely product of the following reaction of 4-chloro-4-methyl- 1-pentanol in neutral polar solution.

Cl A (CH3)2CCH2CH2CH2OH HClϩ C6H12O

In strongly basic solution, the starting material again converts into a molecule with the molecular

formula C6H12O, but with a completely different structure. What is it? Explain the difference between the two results. 55. The following reaction can proceed through both E1 and E2 mechanisms.

CH3 CH3 A A NaOCH3, CH3OH C6H5CH2CCl C6H5CHPPC(CH3)2 ϩ C6H5CH2CCH2 A CH3

24 21 24 21 21 The E1 rate constant kE1 5 1.4 3 10 s and the E2 rate constant kE2 5 1.9 3 10 L mol s ; 0.02 M haloalkane. (a) What is the predominant elimination mechanism with 0.5 M NaOCH3? (b) What is the predominant elimination mechanism with 2.0 M NaOCH3? (c) At what concentration of base does exactly 50% of the starting material react by an E1 route and 50% by an E2 pathway? 56. The compound below is an example of a methyl ester. Methyl esters react with lithium iodide to give lithium carboxylate salts. The solvent in this example is pyridine (margin).

Ϫ ϩ N ON OCH3 ON O Li C E C E Pyridine

LiϩIϪ ϩ CH3I pyridine

Suggest several experiments that would allow you to determine the likely mechanism of this process. 284 Chapter 7 Further Reactions of Haloalkanes

57. Ethers containing the 1,1-dimethylethyl (tert-butyl) group are readily cleaved with dilute, strong acid, as shown in the example below.

CH 3 H3C A CF3CO2H, H2O G OCOOCH3 OH ϩ CPCH2 A G H3C CH3

Suggest a plausible mechanism for this process. What role might the strong acid play? 58. Give the mechanism and major product for the reaction of a secondary haloalkane in a polar aprotic solvent with the following nucleophiles. The pKa value of the conjugate acid of the nucleophile is given in parentheses. 2 2 (a) N3 (4.6) (b) H2N (35) (c) NH3 (9.5) 2 2 2 (d) HSe (3.7) (e) F (3.2) (f) C6H5O (9.9) 2 (g) PH3 (212) (h) NH2OH (6.0) (i) NCS (20.7) 59. Cortisone is an important steroidal anti-in" ammatory agent. Cortisone can be synthesized ef! - ciently from the alkene shown here.

HOCH2 O O O A C P H3C H3C / OH % ∞ O % ∑ O N H3C H3C % % ≥ H } K HO O Alkene Cortisone

Of the following three chlorinated compounds, two give reasonable yields of the alkene shown above by E2 elimination with base, but one does not. Which one does not work well, and why? What does it give during attempted E2 elimination? (Hint: Consider the geometry of each system.)

O O O

O O O O O O H3C H3C H3C % ∞ Cl % ∞ Cl % ∞ O [ O ≈ O H3C H3C H3C % ≥ % ≥ % ≥ Cl H H HO} HO} HO} ACB

60. The chemistry of derivatives of trans-decalin is of interest because this ring system is part of the structure of steroids. Make models of the brominated systems (i and ii) to help you answer the following questions.

CH3 CH3 % %

≥ ≥ 0 CH3 ≥ CH3 Br Br i ii

(a) One of the molecules undergoes E2 reaction with NaOCH2CH3 in CH3CH2OH considerably faster than does the other. Which molecule is which? Explain. (b) The following deuterated analogs of systems i and ii react with base to give the products shown. Problems Chapter 7 285

CH3 CH3 % % NaOCH CH , CH CH OH 2 3 3 2 (All D retained) D#≥ ≥ ≥ D H 0 CH3 CH3 Br i-deuterated

CH3 CH3 % % NaOCH CH , CH CH OH 2 3 3 2 (All D lost) D#≥ ≥ ≥ H H ≥ CH3 CH3 Br ii-deuterated

Specify whether anti or syn eliminations have taken place. Draw the conformations that the molecules must adopt for elimination to occur. Does your answer to (b) help you in solving (a)?

Team Problem 61. Consider the general substitution-elimination reactions of the bromoalkanes.

Nu/base R O Br uuuy R O N u 1 alkene

How do the reaction mechanisms and product formation differ when the structure of the substrate and reaction conditions change? To begin to unravel the nuances of bimolecular and unimolecular substitution and elimination reactions, focus on the treatment of bromoalkanes A through D under conditions (a) through (e). Divide the problem evenly among yourselves so that each of you tackles the questions of reaction mechanism(s) and qualitative distribution of product(s), if any. Reconvene to discuss your conclusions and come to a consensus. When you are explaining a reaction mechanism to the rest of the team, use curved arrows to show the " ow of electrons. Label the stereochemistry of starting materials and products as R or S, as appropriate.

D D ´ ´ Br 0 ≥ Br Br Br A B C D

O O B B Ϫ ϩ (a) NaN3, DMF (b) LDA, DMF (c) NaOH, DMF (d) CH3CO Na , CH3COH (e) CH3OH

Preprofessional Problems 62. Which of the following haloalkanes will undergo hydrolysis most rapidly?

(a) (CH3)3CF (b) (CH3)3CCl (c) (CH3)3CBr (d) (CH3)3CI 63. The reaction

H3C Ϫ CH3O G (CH ) CCl CPCH2 3 3 D H3C

is an example of which of the following processes?

(a) E1 (b) E2 (c) SN1 (d) SN2 286 Chapter 7 Further Reactions of Haloalkanes

64. In this transformation,

H2O, acetone A CH3CH2C(CH3)2 A OH

what is the best structure for A?

CH3 A (a) BrCH2CH2CH(CH3)2 (b) CH3CH2CBr A CH3

CH3 A (c) CH3CH2CH (d) CH3CHCH(CH3)2 A A CH2Br Br

65. Which of the following isomeric carbocations is the most stable?

ϩ CH2 ϩ CH3 (a) (b)

CH3 CH3 (c) (d) ϩ ϩ

66. Which reaction intermediate is involved in the following reaction?

Br2, hv 2-Methylbutane 2-bromo-3-methylbutane (not the major product)

(a) A secondary radical (b) A tertiary radical (c) A secondary carbocation (d) A tertiary carbocation