For each alkyl halide and nucleophile: [1] Draw the product of nucleophilic

Classify each alkyl halide as 1, 2, or 3. a. CH3CH2CH2CH2CH2 Br b. F c. CH3 C CHCH3 CH3 CH3 Cl d. I

Fluticasone is the inhaled anti-infl ammatory agent in the nasal spray Flonase and the asthma medication Advair. Classify the circled F atoms in fl uticasone as 1, 2, or 3. Why is it impossible to classify the remaining F atom as 1, 2, or 3 using the defi nitions in Section 7.1? F S F F H fluticasone H HO OCOC2H5 O O

Draw the structure of an alkyl bromide with molecular formula C6H13Br that fi ts each description: (a) a 1 alkyl bromide with one stereogenic center; (b) a 2 alkyl bromide with two stereogenic centers; (c) an achiral 3 alkyl bromide.

Give the IUPAC name for each compound. a. (CH3)2CHCH(Cl)CH2CH3 b. Br c. Br d. F

Give the structure corresponding to each name. a. 3-chloro-2-methylhexane d. 1,1,3-tribromocyclohexane b. 4-ethyl-5-iodo-2,2-dimethyloctane e. propyl chloride c. cis-1,3-dichlorocyclopentane f. sec-butyl bromide

Rank the compounds in each group in order of increasing boiling point. a. CH3CH2CH2I, CH3CH2CH2Cl, CH3CH2CH2F b. CH3(CH2)4CH3, CH3(CH2)5Br, CH3(CH2)5OH

An sp3 hybridized C Cl bond is more polar than an sp2 hybridized C Cl bond. (a) Explain why this phenomenon arises. (b) Rank the following compounds in order of increasing boiling point. Br Cl Cl

Although nonpolar compounds tend to dissolve and remain in fatty tissues, polar substances are more water soluble, and more readily excreted into an environment where they may be degraded by other organisms. Explain why methoxychlor is more biodegradable than DDT. C H CCl3 CH3O OCH3 methoxychlor

Identify the nucleophile and leaving group and draw the products of each reaction. a. Br + OCH2CH3 c. I N3 + b. Cl + NaOH d. Br + NaCN

CPC (cetylpyridinium chloride), an antiseptic found in throat lozenges and mouthwash, is synthesized by the following reaction. Draw the structure of CPC. N + Cl CPC

Which is the better leaving group in each pair? a. Cl , I b. NH3, NH2 c. H2O, H2S

Which molecules contain good leaving groups? a. CH3CH2CH2Br b. CH3CH2CH2OH c. CH3CH2OH2 d. CH3CH3

Does the equilibrium favor the reactants or products in each substitution reaction? a. Br + CH3CH2 NH2 CH3CH2 Br + NH2 b. I + CN CN + I

Should it be possible to convert CH3CH2CH2OH to CH3CH2CH2Cl by a nucleophilic substitution reaction with NaCl? Explain why or why not.

Identify the stronger nucleophile in each pair. a. NH3, NH2 b. CH3 , HO c. CH3NH2, CH3OH d. CH3COO , CH3CH2O

Classify each solvent as protic or aprotic. a. HOCH2CH2OH b. CH3CH2OCH2CH3 c. CH3COOCH2CH3

Identify the stronger nucleophile in each pair of anions. a. Br or Cl in a polar protic solvent c. HS or F in a polar protic solvent b. HO or Cl in a polar aprotic solvent

Rank the nucleophiles in each group in order of increasing nucleophilicity. a. OH, NH2, H2O b. OH, Br , F (polar aprotic solvent) c. H2O, OH, CH3COO

What happens to the rate of an SN2 reaction under each of the following conditions? a. [RX] is tripled, and [:Nu ] stays the same. c. [RX] is halved, and [:Nu ] stays the same. b. Both [RX] and [:Nu ] are tripled. d. [RX] is halved, and [:Nu ] is doubled.

Draw the structure of the transition state in each of the following SN2 reactions. a. CH3CH2CH2 Cl OCH3 CH3CH2CH2 OCH3 Cl + + b. Br SH SH Br

Draw an energy diagram for the reaction in Problem 7.22a. Label the axes, the starting material, the product, and the transition state. Assume the reaction is exothermic. Label H and Ea.

Draw the product of each SN2 reaction and indicate stereochemistry. a. C Br + OCH2CH3 H D CH3CH2 b. I + CN

Which compound in each pair undergoes a faster SN2 reaction? a. CH3CH2 Cl CH or 3 Cl c. Br Br or b. Cl Cl or

Explain why (CH3)3CCH2Br, a 1 alkyl halide, undergoes SN2 reactions very slowly.

Nicotine, a toxic and addictive component of tobacco, is synthesized from A using SAM. Write out the reaction that converts A into nicotine. nicotine CH3 N N H H A N H N

What happens to the rate of an SN1 reaction under each of the following conditions? a. [RX] is tripled, and [:Nu ] stays the same. c. [RX] is halved, and [:Nu ] stays the same. b. Both [RX] and [:Nu ] are tripled. d. [RX] is halved, and [:Nu ] is doubled.

Draw the products of each SN1 reaction and indicate the stereochemistry of any stereogenic centers. a. CH3 C (CH3)2CH CH2CH3 Br H2O b. CH3COO H CH3 CH3CH2 Cl

Draw the structure of a 1, 2, and 3 carbocation, each having molecular formula C4H9 + . Rank the three carbocations in order of increasing stability

Rank the following carbocations in order of increasing stability. a. (CH3)2CCH2CH3 (CH3)2CHCH2CH2 (CH3)2CHCHCH3 + + + b. CH2 + + CH3 CH3 +

Which alkyl halide in each pair reacts faster in an SN1 reaction? a. (CH3)3CBr (CH3) or 3CCH2Br c. CH3 Br Br or b. Br or Br

What is the likely mechanism of nucleophilic substitution for each alkyl halide? a. C Br H CH3 CH3 C CH3 CH3 b. Br c. Br d. Br

For each alkyl halide and nucleophile: [1] Draw the product of nucleophilic substitution; [2] determine the likely mechanism (SN1 or SN2) for each reaction. a. Cl CH + 3OH c. I CH3CH2O + b. Br + SH d. Br + CH3OH

Draw the products (including stereochemistry) for each reaction. a. H Br + H2O b. Cl + C H C H D

Which compound in each pair reacts faster in nucleophilic substitution? a. CH3CH2CH2Cl or CH3CH2CH2I c. (CH3)3COH or (CH3)3COH2 + b. (CH3)3CBr or (CH3)3CI d. CH3CH2CH2OH or CH3CH2CH2OCOCH3

Which solvents favor SN1 reactions and which favor SN2 reactions? a. CH3CH2OH b. CH3CN c. CH3COOH d. CH3CH2OCH2CH3

For each reaction, use the identity of the alkyl halide and nucleophile to determine which substitution mechanism occurs. Then determine which solvent affords the faster reaction. a. (CH3)3CBr (CH3)3COH HBr or H2O H2O + + (CH3)2C O b. Cl CH3OH CH3OH OCH3 + + HCl or DMSO c. OH Br OH Br + + or DMF H2O d. H Cl CH3O CH3OH OCH3 Cl + + or HMPA

Rank the following carbocations in order of increasing stability. a. CH3CH2CH2CH2CH C + H b. CH3CH2CH2CH2C + HCH3 c. CH3CH2CH2CH2CH2C + H2

What alkyl halide and nucleophile are needed to prepare each compound? a. CN b. (CH3)3CCH2CH2SH c. OH d. CH3CH2 CCH

The ether, CH3OCH2CH3, can be prepared by two different nucleophilic substitution reactions, one using CH3O as nucleophile and the other using CH3CH2O as nucleophile. Draw both routes.

Give the IUPAC name for each compound. a. C CH3 CH3 CH3 CH2CH2F c. (CH3)3CCH2Br e. Br I g. (CH3)3CCH2CH(Cl)CH2Cl b. I d. Br Cl f. Cl Cl h. I H (Also, label this compound as R or S.)

Give the structure corresponding to each name. a. isopropyl bromide e. 1-bromo-4-ethyl-3-fl uorooctane b. 3-bromo-4-ethylheptane f. (3S)-3-iodo-2-methylnonane c. 1,1-dichloro-2-methylcyclohexane g. (1R,2R)-trans-1-bromo-2-chlorocyclohexane d. trans-1-chloro-3-iodocyclobutane h. (5R)-4,4,5-trichloro-3,3-dimethyldecane

Classify each alkyl halide in Problem 7.44 as 1, 2, or 3. When a compound has more than one halogen, assign each separately

Draw the eight constitutional isomers having the molecular formula C5H11Cl. a. Give the IUPAC name for each compound (ignoring R and S designations). b. Label any stereogenic centers. c. For each constitutional isomer that contains a stereogenic center, draw all possible stereoisomers, and label each stereogenic center as R or S

Which compound in each pair has the higher boiling point? a. (CH3)3CBr or CH3CH2CH2CH2Br b. I or Br c. Br or

Draw the substitution product that results when CH3CH2CH2CH2Br reacts with each nucleophile. a. OH d. OCH(CH3)2 g. NH3 b. SH e. C CH h. NaI c. CN f. H2O i. NaN3

Which of the following molecules contain a good leaving group? a. OH b. CH3CH2CH2CH2Cl c. d. OH2 + e. CH3CH2NH2 f. CH3CH2CH2I

Rank the species in each group in order of increasing leaving group ability. a. OH, F , NH2 c. Br , Cl , I b. H2O, NH2, OH d. NH3, H2S, H2O

Which of the following nucleophilic substitution reactions will take place? a. NH2 + I I + NH2 b. CH3O CH3CH2I + I CH 3CH2OCH3 + c. OH F + F + OH d. CN + I I + CN

What nucleophile is needed to convert A to each substitution product? Br A a. SCH3 b. OCH(CH3)2 c. C C CH3 d. N(CH3)3 + + Br

Rank the species in each group in order of increasing nucleophilicity. a. CH3 , OH, NH2 d. CH3NH2, CH3SH, CH3OH in acetone b. H2O, OH, SH in CH3OH e. OH, F , Cl in acetone c. CH3CH2S , CH3CH2O , CH3COO in CH3OH f. HS , F , Cl in CH3OH

Classify each solvent as protic or aprotic. a. (CH3)2CHOH c. CH2Cl2 e. N(CH3)3 b. CH3NO2 d. NH3 f. HCONH2

Why is the amine N atom more nucleophilic than the amide N atom in CH3CONHCH2CH2CH2NHCH3?

Consider the following SN2 reaction: Br CN CN acetone + + Br a. Draw a mechanism using curved arrows. b. Draw an energy diagram. Label the axes, the reactants, products, Ea, and H. Assume that the reaction is exothermic. c. Draw the structure of the transition state. d. What is the rate equation? e. What happens to the reaction rate in each of the following instances? [1] The leaving group is changed from Br to I ; [2] The solvent is changed from acetone to CH3CH2OH; [3] The alkyl halide is changed from CH3(CH2)4Br to CH3CH2CH2CH(Br)CH3; [4] The concentration of CN is increased by a factor of fi ve; and [5] The concentrations of both the alkyl halide and CN are increased by a factor of fi ve.

Rank the alkyl halides in each group in order of increasing SN2 reactivity. a. Br Br Br b. Br Br Br c. Br Br Br

Draw the products of each SN2 reaction and indicate the stereochemistry where appropriate. a. CH3 C H C + OCH3 D Cl c. Cl + OCH2CH3 H b. I + OH d. Br + CN

Classify each carbocation as 1, 2, or 3. a. CH3CH2CHCH2CH3 + b. + c. (CH3)2CHCH2CH2 + d. CH2CH3 + e. + f. CH2

Rank the carbocations in each group in order of increasing stability. a. + + + b. CH2 + +

The following order of stability is observed for three carbocations: CCl3CH2 + < CH3CH2 + < CH3OCH2 + ; that is, CCl3CH2 + is the least stable and CH3OCH2 + is the most stable. Offer an explanation.

Consider the following SN1 reaction. CH3 C I CH3 CH2CH3 CH3 C OH2 + H2O CH3 CH2CH3 I + + a. Draw a mechanism for this reaction using curved arrows. b. Draw an energy diagram. Label the axes, starting material, product, Ea, and H. Assume that the starting material and product are equal in energy. c. Draw the structure of any transition states. d. What is the rate equation for this reaction? e. What happens to the reaction rate in each of the following instances? [1] The leaving group is changed from I to Cl ; [2] The solvent is changed from H2O to DMF; [3] The alkyl halide is changed from (CH3)2C(I)CH2CH3 to (CH3)2CHCH(I)CH3; [4] The concentration of H2O is increased by a factor of fi ve; and [5] The concentrations of both the alkyl halide and H2O are increased by a factor of fi ve.

Rank the alkyl halides in each group in order of increasing SN1 reactivity. a. Br Br Br c. Br Br Br b. Br Br Br

Which SN1 reaction in each pair is faster? a. (CH3)3CCl + H2O (CH3)3CI + H2O c. Cl Cl + + H2O H2O b. Br Br + + CH3OH CH3OH d. I I CH3CH2OH DMSO CH3CH2OH CH3CH2OH

Draw the products of each SN1 reaction and indicate the stereochemistry when necessary. a. Br + H2O CH3CH2 CH3 C c. Br + CH3CH2OH b. CH3CH2 C Cl CH3 CH3 + CH3OH d. Br + H2O

Draw a stepwise mechanism for the following reaction that illustrates why two substitution products are formed. Explain why 1-bromo-2-hexene reacts rapidly with a weak nucleophile (CH3OH) under SN1 reaction conditions, even though it is a 1 alkyl halide. CH3CH2CH2CH CHCH2Br CH3OH CH3CH2CH2CH CHCH2OCH3 + CH3CH2CH2CHCH + 1-bromo-2-hexene CH2 HBr OCH3

Draw the products of each nucleophilic substitution reaction. a. Br (CH3)3C CN acetone b. Br CN acetone (CH3)3C

Diphenhydramine, the antihistamine in Benadryl, can be prepared by the following two-step sequence. What is the structure of diphenhydramine? C H Br [1] NaH [2] (CH3)2NCH2CH2OH diphenhydramine

Draw a stepwise, detailed mechanism for the following reaction. Use curved arrows to show the movement of electrons. Br OCH2CH3 OCH2CH3 + + HBr CH3CH2OH

When a single compound contains both a nucleophile and a leaving group, an intramolecular reaction may occur. With this in mind, draw the product of the following reaction. C O OH OH C7H10O2 Br + H2O + O O Br C Br

Nicotine can be made when the following ammonium salt is treated with Na2CO3. Draw a stepwise mechanism for this reaction. N N N nicotine CH3 NH2CH3 Na2CO3 NaHCO3 NaBr Br Br

Explain each of the following statements. a. Hexane is not a common solvent for either SN1 or SN2 reactions. b. (CH3)3CO is a stronger base than CH3CH2O . c. (CH3)3CBr is more reactive than (CH3)2C(CF3)Br in SN1 reactions. d. (CH3)3CBr reacts at the same rate with F and H2O in substitution reactions even though F has a net negative charge. e. When optically active (2R)-2-bromobutane is added to a solution of NaBr in acetone, the solution gradually loses optical activity until it becomes optically inactive.

Draw a stepwise, detailed mechanism for the following reaction. CH3NH2 CH3NH3 (excess) Cl + + + N Cl Cl N N CH3

When (6R)-6-bromo-2,6-dimethylnonane is dissolved in CH3OH, nucleophilic substitution yields an optically inactive solution. When the isomeric halide (5R)-2-bromo-2,5-dimethylnonane is dissolved in CH3OH under the same conditions, nucleophilic substitution forms an optically active solution. Draw the products formed in each reaction, and explain why the difference in optical activity is observed.

Fill in the appropriate reagent or starting material in each of the following reactions. a. I O c. N3 N3 b. Cl C CH d. SH SH

Benzalkonium chloride (A) is a weak germicide used in topical antiseptics and mouthwash. A can be prepared from amines B or C by SN2 reaction with an alkyl chloride. (a) What alkyl chloride is needed to prepare A from B? (b) What alkyl chloride is needed to prepare A from C? CH3 CH3 benzalkonium chloride A B C CH2 (CH2)17CH3 CH3(CH2)17N(CH3) N CH2N(CH3 2 )2

Suppose you have compounds AD at your disposal. Using these compounds, devise two different ways to make E. Which one of these methods is preferred, and why? I ONa CH3I A C E NaOCH3 B D OCH3

Muscalure, the sex pheromone of the common housefl y, can be prepared by a reaction sequence that uses two nucleophilic substitutions. Identify compounds AD in the following synthesis of muscalure. CH3(CH2)7CH2Br CH3(CH2)11CH2Br NaH NaH HCCH A B C D + H2 + H2 addition of H2 (1 equiv) H H C C CH3(CH2)7CH2 CH2(CH2)11CH3 muscalure

We will return often to nucleophilic substitution, in particular the SN2 reaction, in subsequent chapters. In each instance we will concentrate on the nucleophile, rather than the alkyl halide, as we have done in this chapter. By using different nucleophiles, nucleophilic substitution allows the synthesis of a wide variety of organic compounds with many different functional groups. With this in mind, draw the products of each two-step sequence. (Hint: Step [1] in each part involves an acidbase reaction that removes the most acidic hydrogen from the starting material.) a. OH [1] NaH [2] CH3Br (Chapter 9) c. [1] NaOCH2CH3 [2] C6H5CH2Br CH2(CO2CH2CH3)2 (Chapter 23) b. [1] NaNH2 [2] CH3CH2Br CH3CH2CH2 CCH (Chapter 11)

Explain why quinuclidine is a much more reactive nucleophile than triethylamine, even though both compounds have N atoms surrounded by three R groups. N triethylamine CH3CH2 quinuclidine N CH2CH3 CH2CH3

Draw a stepwise mechanism for the following reaction sequence. O [1] NaH [2] CH3Br O O CH3 CH3 + + H2 NaBr major product minor product

As we will learn in Chapter 9, an epoxide is an ether with an oxygen atom in a three-membered ring. Epoxides can be made by intramolecular SN2 reactions of intermediates that contain a nucleophile and a leaving group on adjacent carbons, as shown. SN2 base C HO H H H H Br C intramolecular H H H H epoxide C O C C O H H H H Br C + Br Assume that each of the following starting materials can be converted to an epoxide by this reaction. Draw the product formed (including stereochemistry) from each starting material. Why might some of these reactions be more diffi cult than others in yielding nucleophilic substitution products? a. (CH3)3C OH Br b. (CH3)3C OH Br c. (CH3)3C OH Br d. (CH3)3C OH Br

When trichloride J is treated with CH3OH, nucleophilic substitution forms the dihalide K. Draw a mechanism for this reaction and explain why one Cl is much more reactive than the other two Cls so that a single substitution product is formed. O Cl Cl HCl J K Cl O OCH3 Cl Cl + CH3OH (1 equiv)