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4. The kinetics of the reaction of nucleophiles with primary (and most secondary) haloalkanes are second order, indicative of a bimolecular mechanism. This process is called bimolecular nucleophilic substitution (SN2 reaction). It is a concerted reaction, one in which bonds are simultaneously broken and formed. Curved arrows are typically used to depict the ow of electrons as the reaction proceeds. 5. The SN2 reaction is stereospeci c and proceeds by backside displacement, thereby producing inversion of con guration at the reacting center. 6. An orbital description of the SN2 transition state includes an sp2-hybridized carbon center, partial bond making between the nucleophile and the electrophilic carbon, and simultaneous partial bond breaking between that carbon and the leaving group. Both the nucleophile and the leaving group bear partial charges. 7. Leaving-group ability, a measure of the ease of displacement, is roughly proportional to the strength of the conjugate acid. Especially good leaving groups are weak bases such as chloride, bromide, iodide, and the sulfonates. 8. Nucleophilicity increases (a) with negative charge, (b) for elements farther to the left and down the periodic table, and (c) in polar aprotic solvents. 9. Polar aprotic solvents accelerate SN2 reactions because the nucleophiles are well separated from their counterions but are not tightly solvated. 10. Branching at the reacting carbon or at the carbon next to it in the substrate leads to steric hindrance in the SN2 transition state and decreases the rate of bimolecular substitution.

Problems
31. Name the following molecules according to the IUPAC system. (a) CH3CH2Cl (b) BrCH2CH2Br (c) CH3CH2CHCH2F
CH2CH3

(d) (CH3)3CCH2I

(e)

CCl3

(f) CHBr3

32. Draw structures for each of the following molecules: (a) 3-ethyl-2-iodopentane; (b) 3-bromo-1,1-dichlorobutane; (c) cis-1-(bromomethyl)-2-(2-chloroethyl)cyclobutane; (d) (trichloromethyl)cyclopropane; (e) 1,2,3-trichloro-2-methylpropane. 33. Draw and name all possible structural isomers having the formula C3H6BrCl. 34. Draw and name all structurally isomeric compounds having the formula C5H11Br. 35. For each structural isomer in Problems 33 and 34, identify all stereocenters and give the total number of stereoisomers that can exist for the structure. 36. For each reaction in Table 6-3, identify the nucleophile, its nucleophilic atom (draw its Lewis structure rst), the electrophilic atom in the substrate, and the leaving group. 37. A second Lewis structure can be drawn for one of the nucleophiles in Problem 36. (a) Identify it and draw its alternate structure (which is simply a second resonance form). (b) Is there a second nucleophilic atom in the nucleophile? If so, rewrite the reaction of Problem 36, using the new nucleophilic atom, and write a correct Lewis structure for the product. 38. For each reaction shown here, identify the nucleophile, its nucleophilic atom, the electrophilic atom in the substrate molecule, and the leaving group. Write the organic product of the reaction. (a) CH3I 1 NaNH2 S (c) O O (e) CH3Cl S CF3 NaI O (f) (b) (d)
Br NaSH NaN3 I

& H Cl

N CH3

KSeCN

Problems

Chapter 6

247

39. For each reaction presented in Problem 38, write out the mechanism using the curved-arrow notation. 40. A solution containing 0.1 M CH3Cl and 0.1 M KSCN in DMF reacts to give CH3SCN and KCl with an initial rate of 2 3 1028 mol L21 s21. (a) What is the rate constant for this reaction? (b) Calculate the initial reaction rate for each of the following sets of reactant concentrations: (i) [CH3Cl] 5 0.2 M, [KSCN] 5 0.1 M; (ii) [CH3Cl] 5 0.2 M, [KSCN] 5 0.3 M; (iii) [CH3Cl] 5 0.4 M, [KSCN] 5 0.4 M. 41. Write the product of each of the following bimolecular substitutions. The solvent is indicated above the reaction arrow. (a) CH3CH2CH2Br NaI (c) CH3I NaOCH(CH3)2 (e)
Acetone (CH3)2CHOH Acetone

(b) (CH3)2CHCH2I NaCN

DMSO CH3OH

(d) CH3CH2Br NaSCH2CH3 (f) (CH3)2CHOSO2CH3 N(CH3)3

CH2Cl CH3CH2SeCH2CH3

(CH3CH2)2O

42. Determine the RyS designations for both starting materials and products in the following SN2 reactions. Which of the products are optically active?
H Cl Cl CH2CH3 [Cl Br

(a) CH3

(b) H3C H

H C CH3 2 I Br O B OCCH3

(c)
0 HO

O B OCCH3

(d)
0 HO

43. For each reaction presented in Problems 41 and 42, write out the mechanism using curved-arrow notation. 44. List the product(s) of the reaction of 1-bromopropane with each of the following reagents. Write no reaction where appropriate. (Hint: Carefully evaluate the nucleophilic potential of each reagent.) (a) H2O (f ) HCl (b) H2SO4 (g) (CH3)2S (c) KOH (h) NH3 (d) CsI (i) Cl2 (e) NaCN (j) KF

45. Formulate the potential product of each of the following reactions. As you did in Problem 44, write no reaction where appropriate. (Hint: Identify the expected leaving group in each of the substrates and evaluate its ability to undergo displacement.) (a) CH3CH2CH2CH2Br KOH (c)
CH3CH2OH

CH2Cl LiOCH2CH3
CH3CH2OH

CH3CH2OH

(e) CH3CH2CH2Cl KSCN (g) CH3CH2CH2OH KI (i) CH3CH2OCH2CH3 Na

OSO2CH3 A (a) (R)-CH3CHCH2CH3

DMSO

OH

H2O

46. Show how each of the following transformations might be achieved.

N3 A (S)-CH3CHCH2CH3 CH3 CH3 Br H CH3 H % H %
`Br

(c)
0 H

0 H

! SCH3

Cl

(b) CH3CH2I KCl

DMF

(d) (CH3)2CHCH2Br CsI (f ) CH3CH2F LiCl (h) CH3I NaSCH3

CH3OH CH3OH

CH3OH

O B (j) CH3CH2I KOCCH3

DMSO

(b)

H CH3O

H CH3O CH3

CN H

(d)

N A CH3

N H3C CH3

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Chapter 6

Properties and Reactions of Haloalkanes

47. Rank the members of each of the following groups of species in the order of basicity, nucleophilicity, and leaving-group ability. Brie y explain your answers. (a) H2O, HO2, CH3CO22; (b) Br2, Cl2, F2, I2; (c) 2NH2, NH3, 2PH2; (d) 2OCN, 2SCN; (e) F2, HO2, 2SCH3; (f) H2O, H2S, NH3. 48. Write the product(s) of each of the following reactions. Write no reaction as your answer, if appropriate. (a) CH3CH2CH2CH3 NaCl
Br H3C H NaI H3C H OH A (e) CH3CHCH3 NaCN OSO2CH3 A (g) CH3CHCH3 NaCN
CH3CH2OH CH3OH

(b) CH3CH2Cl NaOCH3

CH3OH

(c)
H

OSO2CH3 A (f) CH3CHCH3 HCN

Acetone

Cl A C } NaSCH3 (d) H G CH3CH2 CH3

Acetone

CH3CH2OH

(h) H3C

O CH3 B D KSCN SOCH2CH2CH G B CH3 O

NH3

CH3OH

(i) CH3CH2NH2 NaBr

DMSO

(j) CH3I NaNH2

49. For each reaction presented in Problem 48 that actually proceeds to a product, write out the mechanism using the curved-arrow notation.
N N PF6

CH3CH2CH2CH2

CH3

1-Butyl-3-methylimidazolium (BMIM) hexafluorophosphate

OH

50. The substance 1-butyl-3-methylimidazolium (BMIM) hexa uorophosphate (margin) is a liquid at room temperature, even though it is a salt composed of positive and negative ions. BMIM and other ionic liquids constitute a new class of solvents for organic reactions, because they are capable of dissolving both organic and inorganic substances. More important, they are relatively benign environmentally, or green, because they can be easily separated from reaction products and reused virtually inde nitely. Therefore they do not constitute a waste-disposal problem, unlike conventional solvents. (a) How would you characterize BMIM as a solvent? Polar or nonpolar? Protic or aprotic? (b) How would changing the solvent from ethanol to BMIM affect the rate of the nucleophilic substitution reaction between sodium cyanide and 1-chloropentane? 51. (2S,3S)-3-Hydroxyleucine is an amino acid (Chapter 26) that is a key component in the structures of many depsipeptide antibiotics, such as sanjoinine (margin). (a) Find the part of the sanjoinine molecule that is derived structurally from (2S,3S )-3-hydroxyleucine. (b) Although many depsipeptide antibiotics occur in nature, the quantities available are too small to be useful pharmaceutically; thus these molecules must be synthesized. (2S,3S )-3-Hydroxyleucine, which is also not available in quantity from nature, must be synthesized as well. Possible starting materials are the four diastereomers of 2-bromo-3-hydroxy-4-methylpentanoic acid (margin). Draw structural formulas for each of these diastereomers and identify which of the four should be the best starting material for a preparation of (2S,3S )-3-hydroxyleucine. 52. Iodoalkanes are readily prepared from the corresponding chloro compounds by SN2 reaction with sodium iodide in acetone. This particular procedure is especially useful because the inorganic by-product, sodium chloride, is insoluble in acetone; its precipitation drives the equilibrium in the desired direction. Thus, it is not necessary to use excess NaI, and the process goes to completion in a very short time. Because of its great convenience, this method is named after its developer (the Finkelstein reaction). In an attempt to synthesize optically pure (R)-2-iodoheptane, a student prepared a solution of (S )-2-chloroheptane in acetone. In order to ensure success, he added excess sodium iodide and allowed the mixture to stir over the weekend. His yield of 2-iodoheptane was high, but, to his dismay, he found that his product was racemic. Explain. Using the information in Chapters 3 and 6, propose the best possible synthesis of each of the following compounds with propane as your organic starting material and any other reagents needed. [Hint: On the basis of the information in Section 3-7, you should not expect to nd very good answers for (a), (c), and (e). One general approach is best, however.] (a) 1-Chloropropane (d) 2-Bromopropane (b) 2-Chloropropane (e) 1-Iodopropane (c) 1-Bromopropane (f) 2-Iodopropane

NH2
(2S,3S)-3-Hydroxyleucine

OH

HO

*
NH O

O O NH

(
O (CH3)2N

NH

&

Sanjoinine

OH

O OH Br

53.

2-Bromo-3-hydroxy-4-methylpentanoic acid

Problems

Chapter 6

249

55. In each pair of molecules that follows, indicate the member of the pair that would be better suited in its indicated function for an SN2 reaction.

(a) Nucleophile: NH3, PH3

O B C O B C

(b) Substrate:

Br,

Br

(c) Solvent: H

N(CH3)2, H

NH2

(d) Leaving group: CH3OH, CH3SH

56. Rank each of the following sets of molecules in order of increasing SN2 reactivity. (a) CH3CH2Br, CH3Br, (CH3)2CHBr (b) (CH3)2CHCH2CH2Cl, (CH3)2CHCH2Cl, (CH3)2CHCl (c) CH3CH2Cl, CH3CH2I,
Cl

(d) (CH3CH2)2CHCH2Br, CH3CH2CH2CHBr, (CH3)2CHCH2Br A CH3 57. Predict the effect of the changes given below on the rate of the reaction
2 CH3Cl 1 2 OCH3 CH3OCH3 1 Cl . CH3OH

(a) Change substrate from CH3Cl to CH3I; (b) change nucleophile from CH3O2 to CH3S2; (c) change substrate from CH3Cl to (CH3)2CHCl; (d) change solvent from CH3OH to (CH3)2SO. 58. The following table presents rate data for the reactions of CH3I with three different nucleophiles in two different solvents. What is the signi cance of these results regarding relative reactivity of nucleophiles under different conditions? Nucleophile Cl2 Br2 NCSe2 krel , CH3OH 1 20 4000 krel , DMF 1.2 3 106 6 3 105 6 3 105

59. Explain the outcome of the following transformations mechanistically. (a) HSCH2CH2Br NaOH
CH3CH2OH

S
DMF

(b) BrCH2CH2CH2CH2CH2Br NaOH

Excess

(c) BrCH2CH2CH2CH2CH2Br NH3

Excess

CH3CH2OH

N H

60.

SN2 reactions of halocyclopropane and halocyclobutane substrates are very much slower than those of analogous acyclic secondary haloalkanes. Suggest an explanation for this nding. (Hint: Consider the effect of bond-angle strain on the energy of the transition state; see Figure 6-4.)

61. Nucleophilic attack on halocyclohexanes is also somewhat retarded compared with that on acyclic secondary haloalkanes, even though in this case bond-angle strain is not an important factor. Explain. (Hint: Make a model, and refer to Chapter 4 and Section 6-9.)

54. Propose two syntheses of trans-1-methyl-2-(methylthio)cyclohexane (shown in the margin), beginning with the starting compound (a) cis-1-chloro-2-methylcyclohexane; (b) trans-1-chloro-2methylcyclohexane.

SCH3 CH3

250

Chapter 6

Properties and Reactions of Haloalkanes

Team Problem
62. Compounds A through H are isomeric bromoalkanes with the molecular formula C5H11Br. With your team, draw all eight constitutional isomers. Indicate any stereocenter(s), but do not label it (them) as R or S until you have completed your analysis. Using the data below, assign structures to A through H. Divide the problem into equal parts to share the effort of nding a solution. Reconvene and discuss your analysis. At this point, you should indicate the stereochemistry with wedged and hashed lines as appropriate. Treatment of compounds A through G with NaCN in DMF followed second-order kinetics and showed the following relative rates: A > B . C . D > E . F .. G Compound H does not undergo the SN2 reaction under the preceding conditions. Compounds C, D, and F were found to be optically active, each having S absolute con guration at the stereocenter. Substitution reactions of D and F with NaCN in DMF proceeded with inversion of con guration, while treatment of C in the same way proceeded with retention of conguration.

Preprofessional Problems
63. The SN2 reaction mechanism best applies to (a) cyclopropane and H2 (c) KOH and NaOH (b) 1-chlorobutane and aqueous NaOH (d) ethane and H2O

64. The reaction CH3Cl 1 OH2 CH3OH 1 Cl2 is rst order in both chloromethane and hydroxide. Given the rate constant k 5 3.5 3 1023 mol L21 s21, what is the observed rate at the following concentrations? [CH3Cl] 5 0.50 mol L21 (a) 2.6 3 1025 mol L21 s21 (d) 1.75 3 1023 mol L21 s21 (a) F2 (b) Cl2 [OH2] 5 0.015 mol L21 (c) 2.6 3 1023 mol L21 s21

(b) 2.6 3 1026 mol L21 s21 (e) 1.75 3 1025 mol L21 s21 (c) Br2 (d) I2

65. Which ion is the strongest nucleophile in aqueous solution? (e) all of these are equally strong 66. Only one of the following processes will occur measurably at room temperature. Which one?
F O Cl (a)

(b) Nq C
CH3 O I

CH3 O I

(c) Nq N

(d) kO P Ok k k

CH2 P CH2