Attempts to prepare optically active iodides by

1-Chloro-4-isopropylcyclohexane exists as two stereoisomers: one cis and one trans. Treatment of either isomer with sodium ethoxide in ethanol gives 4-isopropylcyclohexene by an E2 reaction. 1- Chloro-4- isopropylcyclohexane 4-Isopropylcyclohexene CH3CH2O Na+ CH3CH2OH Cl The cis isomer undergoes E2 reaction several orders of magnitude faster than the trans isomer. How do you account for this experimental observation?

Predict whether each reaction proceeds predominantly by substitution (SN1 or SN2) or elimination (E1 or E2) or whether the two compete. Write structural formulas for the major organic product(s). (a) 1 methanol Br CH3O2Na1 (b) (c) methanol 1 Na1CN2 1 acetone Na1I2 C6H5 Cl Br

Knowing what you do about the regioselectivity of SN2 reactions, predict the product of hydrolysis of this compound. N Cl 1 H2O

Draw a structural formula for the most stable carbocation with each molecular formula. (a) C4H9 1 (b) C3H7 1 (c) C5H111 (d) C3H7O1

The reaction of 1-bromopropane and sodium hydroxide in ethanol occurs by an SN2 mechanism. What happens to the rate of this reaction under the following conditions? (a) The concentration of NaOH is doubled. (b) The concentrations of both NaOH and 1-bromopropane are doubled. (c) The volume of the solution in which the reaction is carried out is doubled.

From each pair, select the stronger nucleophile. (a) H2O or OH2 (b) CH3COO2 or OH2 (c) CH3SH or CH3S2 (d) Cl2 or I2 in DMSO (e) Cl2 or I2 in methanol (f) CH3OCH3 or CH3SCH3

Draw a structural formula for the product of each SN2 reaction. Where confi guration of the starting material is given, show the confi guration of the product. (a) CH3CH2CH2Cl 1 CH3CH2O2Na1 (e) CH3CH2CH2Cl 1 CH3C#C (h) CH3CH2CH2Br 1 Na1CN2 (g) O (f) 2Li1 CH2Br 1 Na1CN2 NH 1 CH3(CH2)6CH2Cl (c) (b) (CH3)3N (d) H3C Cl 1 CH3S2Na1 1 CH3I CH2Cl 1 NH3 acetone acetone acetone ethanol ethanol ethanol ethanol diethyl ether

Suppose you were told that each reaction in Problem 9.13 is a substitution reaction but were not told the mechanism. Describe how you could conclude from the structure of the haloalkane, the nucleophile, and the solvent that each reaction is an SN2 reaction

Treatment of 1,3-dichloropropane with potassium cyanide results in the formation of pentanedinitrile. The rate of this reaction is about 1000 times greater in DMSO than in ethanol. Account for this difference in rate. Cl Cl NC CN 1 1 2 KCN 2 KCl 1,3-Dichloropropane Pentanedinitrile

Treatment of 1-aminoadamantane, C10H17N, with methyl 2,4-dibromobutanoate in the presence of a nonnucleophilic base, R3N, involves two successive SN2 reactions and gives compound A. Propose a structural formula for compound A. O Br R3N NH2 OCH3 1 C15H23NO2 1 2 R3NH1Br2 Br 1- Aminoadamantane Methyl 2,4-dibromobutanoate A

Select the member of each pair that shows the greater rate of SN2 reaction with KI in acetone. (a) Cl Cl or (c) Cl or Cl (d) or (b) Cl Br Br Br or

Select the member of each pair that shows the greater rate of SN2 reaction with KN3 in acetone. (a) (b) Br Br Br Br or or

What hybridization best describes the reacting carbon in the SN2 transition state?

Each carbocation is capable of rearranging to a more stable carbocation. Limiting yourself to a single 1,2-shift, suggest a structure for the rearranged carbocation. (a) (b) (c) 1 1 1 1 1 1 (d) (e) (f)

Attempts to prepare optically active iodides by nucleophilic displacement on optically active bromides using I2 normally produce racemic iodoalkanes. Why are the product iodoalkanes racemic?

Draw a structural formula for the product of each SN1 reaction. Where confi guration of the starting material is given, show the confi guration of the product. Cl ethanol methanol 1 CH3CH2OH Cl (a) (b) 1 CH3OH Br 1 CH3OH acetic acid methanol CH3CCl 1 CH3COH CH3 CH3 (c) (d) O S enantiomer

Suppose that you were told that each reaction in Problem 9.22 is a substitution reaction but were not told the mechanism. Describe how you could conclude from the structure of the haloalkane or cycloalkene, the nucleophile, and the solvent that each reaction is an SN1 reaction

Alkenyl halides such as vinyl bromide, CH2"CHBr, undergo neither SN1 nor SN2 reactions. What factors account for this lack of reactivity?

Select the member of each pair that undergoes SN1 solvolysis in aqueous ethanol more rapidly. (a) (c) (e) Cl or Cl (b) Cl or or Cl Cl (d) Cl Cl Cl Cl or Br Br Br or (f) or

Account for the following relative rates of solvolysis under experimental conditions favoring SN1 reaction. Cl O Cl O Cl Relative rate of solvolysis (SN1) 0.2 1 109

Not all tertiary haloalkanes undergo SN1 reactions readily. For example, the bicyclic compound shown below is very unreactive under SN1 conditions. What feature of this molecule is responsible for such lack of reactivity? You will fi nd it helpful to examine a model of this compound. 1- Iodobicyclooctane

Show how you might synthesize the following compounds from a haloalkane and a nucleophile: CN (a) (e) CN (b) O O (c) O (d) SH (f) (g) SH

3-Chloro-1-butene reacts with sodium ethoxide in ethanol to produce 3-ethoxy-1- butene. The reaction is second order, fi rst order in 3-chloro-1-butene, and fi rst order in sodium ethoxide. In the absence of sodium ethoxide, 3-chloro-1-butene reacts with ethanol to produce both 3-ethoxy-1- butene and 1-ethoxy-2-butene. Explain these results

1-Chloro-2-butene undergoes hydrolysis in warm water to give a mixture of these allylic alcohols. Propose a mechanism for their formation. H2O CH3CH"CHCH2Cl 1-Chloro-2-butene 2-Buten-1-ol 3- Buten-2-ol (racemic) OH CH3CH"CHCH2OH 1 CH3CHCH"CH2

The following nucleophilic substitution occurs with rearrangement. Suggest a mechanism for formation of the observed product. If the starting material has the S confi guration, what is the confi guration of the stereocenter in the product? N Cl N NaOH OH H2O

Propose a mechanism for the formation of these products in the solvolysis of this bromoalkane. CH3CH2OH warm 1 1 HBr OCH2CH3 B

Solvolysis of the following bicyclic compound in acetic acid gives a mixture of products, two of which are shown. The leaving group is the anion of a sulfonic acid, ArSO3H. A sulfonic acid is a strong acid, and its anion, ArSO3 2, is a weak base and a good leaving group. Propose a mechanism for this reaction. CH3COH H H 1 OCCH3 O OSO2Ar O H H

Which compound in each set undergoes more rapid solvolysis when refl uxed in ethanol? Show the major product formed from the more reactive compound. Br Br Br (a) or (b) or Cl Br (c) or (d) or Cl Cl B

Account for the relative rates of solvolysis of these compounds in aqueous acetic acid. Br 1022 1027 10212 1 Br Br (CH3)3

A comparison of the rates of SN1 solvolysis of the bicyclic compounds (1) and (2) in acetic acid shows that compound (1) reacts 1011 times faster than compound (2). Furthermore, solvolysis of (1) occurs with complete retention of confi guration: the nucleophile occupies the same position on the one-carbon bridge as did the leaving 2OSO2Ar group. OSO2Ar (1) OSO2Ar (2) (a) Draw structural formulas for the products of solvolysis of each compound.(b)Account for the difference in rate of solvolysis of (1) and (2).(c) Account for complete retention of confi guration in the solvolysis of (1).

Draw structural formulas for the alkene(s) formed by treatment of each haloalkane or halocycloalkane with sodium ethoxide in ethanol. Assume that elimination occurs by an E2 mechanism. Br (a) (b) (e) (f) Cl Br Cl (c) Cl (d) Cl

Draw structural formulas of all chloroalkanes that undergo dehydrohalogenation when treated with KOH to give each alkene as the major product. For some parts, only one chloroalkane gives the desired alkene as the major product. For other parts, two chloroalkanes may work. (a) (b) (c) (d) (e) CH

Following are diastereomers (A) and (B) of 3-bromo-3,4-dimethylhexane. On treatment with sodium ethoxide in ethanol, each gives 3,4-dimethyl-3-hexene as the major product. One diastereomer gives the E alkene, and the other gives the Z alkene. Which diastereomer gives which alkene? Account for the stereoselectivity of each b-elimination. Me Me Br H (A) EtEt C9C H Me Br Me (B) EtEt C9C

Treatment of the following stereoisomer of 1-bromo-1,2-diphenylpropane with sodium ethoxide in ethanol gives a single stereoisomer of 1,2-diphenylpropene. Predict whether the product has the E confi guration or the Z confi guration. CH3CH2O2Na1 CH3CH2OH CH3 C6H5CH"CC6H5 1-Bromo- 1,2-diphenylpropane 1,2-Diphenylpropene Br H3C H H C6H5 C6H

Elimination of HBr from 2-bromonorbornane gives only 2-norbornene and no 1- norbornene. How do you account for the regioselectivity of this dehydrohalogenation? In answering this question, you will fi nd it helpful to look at molecular models of both 1-norbornene and 2-norbornene and to analyze the strain in each. 2-Bromonorbornane 2-Norbornene H Br H H H 1-Norbornene H H H H H H

Which isomer of 1-bromo-3-isopropylcyclohexane reacts faster when refluxed with potassium tert- butoxide, the cis isomer or the trans isomer? Draw the structure of the expected product from the faster reacting compound.

Consider the following statements in reference to SN1, SN2, E1, and E2 reactions of haloalkanes. To which mechanism(s), if any, does each statement apply? (a) Involves a carbocation intermediate. (b) Is fi rst order in haloalkane and fi rst order in nucleophile. (c) Involves inversion of confi guration at the site of substitution. (d) Involves retention of confi guration at the site of substitution. (e) Substitution at a stereocenter gives predominantly a racemic product. (f) Is fi rst order in haloalkane and zero order in base. (g) Is fi rst order in haloalkane and fi rst order in base. (h) Is greatly accelerated in protic solvents of increasing polarity. (i) Rearrangements are common. ( j) Order of reactivity of haloalkanes is 3 . 2 . 1. (k) Order of reactivity of haloalkanes is methyl . 1 . 2 . 3.

Arrange these haloalkanes in order of increasing ratio of E2 to SN2 products observed on reaction of each with sodium ethoxide in ethanol. CH3 CH3 CH3 Cl (a) CH3CH2Br CH (b) 3CHCH2Br (c) CH (d) 3CCH2CH3 CH3CHCH2CH2Br

When cis-4-chlorocyclohexanol is treated with sodium hydroxide in ethanol, it gives mainly the substitution product trans-1,4-cyclohexanediol (1). Under the same reaction conditions, trans-4- chlorocyclohexanol gives 3-cyclohexenol (2) and the bicyclic ether (3). CH3CH2OH NaOH CH3CH2OH NaOH cis-4-Chlorocyclohexanol Cl OH trans-4-Chlorocyclohexanol Cl OH (1) OH OH (2) (3) OH 1 O (a) Propose a mechanism for formation of product (1), and account for its confi guration. (b) Propose a mechanism for formation of product (2). (c) Account for the fact that the bicyclic ether (3) is formed from the trans isomer but not from the cis isomer.

Show how to convert the given starting material into the desired product. Note that some syntheses require only one step, whereas others require two or more. O O H H (a) (b) Br Cl (e) (d) (f) OH Br Br OH OH Br Br (c) OH Cl (g) (h) Br Br (i) B

The Williamson ether synthesis involves treatment of a haloalkane with a metal alkoxide. Following are two reactions intended to give benzyl tert-butyl ether. One reaction gives the ether in good yield and the other reaction does not. Which reaction gives the ether? What is the product of the other reaction, and how do you account for its formation? CH CH2Cl 3CO2K1 (a) 1 DMSO CH3 CH3 CH3COCH2 1 KCl CH3 CH3 CH2O2K (b) 1 1 CH3CCl DMSO CH3 CH3 CH3COCH2 1 KCl CH3 CH3

The following ethers can, in principle, be synthesized by two different combinations of haloalkane or halocycloalkane and metal alkoxide. Show one combination that forms ether bond (1) and another that forms ether bond (2). Which combination gives the higher yield of ether? (1) (2) (1) (2) (1) (2) (a) (b) CH (c) 39O9CCH3 CH3 CH3 CH2"CHCH29O9CH2CCH3 CH3 CH3 O9CH2CH

Propose a mechanism for this reaction. O ClCH2CH2OH H2C9CH2 Na2CO3, H2O

Each of these compounds can be synthesized by an SN2 reaction. Suggest a combination of haloalkane and nucleophile that will give each product. (a) CH3OCH3 (b) CH3SH (c) CH3CH2CH2PH2 (d) CH3CH2CN (e) CH3SCH2C(CH3)3 (f) (CH3)3NH+ Cl2 O C6H5COCH2C6H5 (g) N3 (R)-CH3CHCH2CH2CH3 (h) (i) CH2"CHCH2OCH(CH3)2 ( j) CH2"CHCH2OCH2CH"CH2 (k) 1N H Cl2 H (l) O O

OH is a very poor leaving group. However, many alcohols react with alkyl or aryl sulfonyl chlorides to give sulfonate esters. R3N R9OH 1 R9S9Cl R9O9S9R' 1 HCl O O O O (a) Explain what this change does to the leaving group ability of the substituent. (b) Suggest the product of the following reaction. DMSO CH3CH29O9S9C6H5 1 CH3S2Na1

Suggest a product of the following reaction. HI is a very strong acid. CH3CH2OCH2CH3 1 2HI

Use the roadmap you made for problem 6.54, 7.29, and 8.28, and update it to contain the reactions in the Key Reactions section as well as Table 9.1 of this chapter. Because of their highly specifi c nature, do not use reactions 3 and 5 or entry 7 of Table 9.1 on your roadmap.

Write the products of the following sequences of reactions. Refer to your roadmap to see how the combined reactions allow you to navigate between the different functional groups. (a) 1. Br2 and light 2. 1 Equivalent of NaOEt 3. Br2 / H2O An alkane (b) 1. HBr in the presence of peroxides and light 2. NaCN An alkene (c) 1. Br2 and light 2. KOtBu 3. O3 4. (CH3)2S An alkane (d) 1. 1 equivalent of NaNH2 2. 3. H2 / Lindlar's catalyst 4. HCl 5. NaN3 Br An a

Using your roadmap as a guide, show how to convert butane into 2-butyne. Show all reagents and all molecules synthesized along the way. Butane 2-Butyne

Using your roadmap as a guide, show how to convert 2-methylbutane into racemic 3- bromo-2- methyl-2-butanol. Show all reagents and all molecules synthesized along the way. 2-Methylbutane 3- Bromo-2-methyl-2-butanol (racemic) ? HO HO Br B

Using your roadmap as a guide, show how to convert cyclohexane into hexanedial. Show all reagents and all molecules synthesized along the way. Cyclohexane Hexanedial ? H H O O

Using your roadmap as a guide, show how to convert cyclohexane into racemic 3-bromocyclohexene. Show all reagents and all molecules synthesized along the way. Cyclohexane 3-Bromocyclohexene (racemic) ? Br Br

Another important pattern in organic synthesis is the construction of C!C bonds. Using your roadmap as a guide, show how to convert propane into hex-1-en-4-yne. You must use propane as the source of all of the carbon atoms in the hex-1-en-4-yne product. Show all reagents needed and all molecules synthesized along the way. Propane Hex-1-en-4-yne ?

Using your roadmap as a guide, show how to convert propane into butyronitrile. You must use propane and sodium cyanide as the source of all of the carbon atoms in the butyronitrile product. Show all reagents and all molecules synthesized along the way. Propane Sodium cyanide Butyronitrile ? NaCN N

Fluticasone is a glucocorticoid drug that has been used to treat asthma. In the synthesis of fl uticasone, the following transformation is used that involves a limiting amount of sodium iodide. Analyze the structure using the chemistry you have learned in this chapter, and draw the product of the reaction. O NaI acetone O O HO F F H H CH3 CH3 CH3 O Cl S

The following reaction sequence was used in the synthesis of several derivatives of prostaglandin C2. Analyze the structure using the chemistry you have learned in this chapter, and draw the structures of the synthetic intermediates A and B. 1. NaNH2, THF(solvent) NaCN DMSO (racemic) (racemic) (racemic) 2. A B O O

The following reaction was used in the synthesis of various prostaglandin derivatives. Analyze the structure using the chemistry you have learned in this chapter, and draw the product of the reaction. excess tBuOK O Br H O OH OH HO tBuOH