When the following optically active alcohol is treated with HBr, a racemic mixture of

Assign a systematic name for each of the following compounds: (a) Cl (b) Br (c) Cl Br Br (d) F

For each of the following reactions, assume a concerted process is taking place and draw the mechanism: (a) Br SH + + NaSH NaBr (b) O + + NaOMe Na

For each of the following reactions assume a stepwise process is taking place and draw the mechanism: (a) Br O O Br O O + + @ @ (b) Cl NaCl NaI

When a nucleophile and electrophile are tethered to each other (that is, both present in the same compound), an intramolecular substitution reaction can occur, as shown. Assume that this reaction occurs via a concerted process and draw the mechanism. Br O O + Br @ @

For the substitution reaction shown below, assume a stepwise process is taking place and draw the mechanism. (Hint: Review the rules for drawing resonance structures, Section 2.10.) Br NaCl NaBr Cl + +

The reaction below exhibits a second-order rate equation: OH + + NaOH NaI I (a) What happens to the rate if the concentration of 1-iodopropane is tripled and the concentration of sodium hydroxide remains the same? (b) What happens to the rate if the concentration of 1-iodopropane remains the same and the concentration of sodium hydroxide is doubled? (c) What happens to the rate if the concentration of 1-iodopropane is doubled and the concentration of sodium hydroxide is tripled?

Draw the product for each of the following SN2 reactions: (a) (S)-2-Chloropentane and NaSH (b) (R)-3-Iodohexane and NaCl (c) (R)-2-Bromohexane and sodium hydroxide

When (S)-1-bromo-1-fluoroethane reacts with sodium methoxide, an SN2 reaction takes place in which the bromine atom is replaced by a methoxy group (OMe). The product of this reaction is (S)-1-fluoro-1-methoxyethane. How can it be that the starting material and the product both have the S configuration? Shouldnt SN2 involve a change in the configuration? Draw the starting material and the product of inversion, and then explain the anomaly.

Draw the transition state for each of the following SN2 reactions: (a) OH Br Br OH + + @ @ (b) O O O O @ I @ + + I (c) Cl + + NaOH OH NaCl (d) NaSH NaBr

In Problem 7.4, we saw that an intramolecular substitution reaction can occur when the nucleophilic center and electrophilic center are present in the same compound. Draw the transition state of the reaction in Problem 7.4.

Treatment of 5-hexen-1-ol with bromine affords a cyclic product: Br HO 2 NaBr Br O + The mechanism of this reaction involves several steps, one of which is an intramolecular SN2-like process: Br O H HO Br ! ! In this step, a bond is in the process of breaking, while another bond is in the process of forming. Draw the transition state of this SN2-like process, and identify which bond is being broken and which bond is being formed. Can you offer an explanation as to why this step is favorable?

Nicotine is an addictive compound found in tobacco, and choline is a compound involved in neurotransmission. The biosynthesis of each of these compounds involves the transfer of a methyl group from SAM. Draw a mechanism for both of these transformations: (a) N H H N N CH3 H N Nicotine SAM (b) SAM N OH H3C H3C N OH H3C CH3 CH3 Choline

The following reaction occurs via an SN1 mechanistic pathway: NaCl I Cl + NaI (a) What happens to the rate if the concentration of tert-butyl iodide is doubled and the concentration of sodium chloride is tripled? (b) What happens to the rate if the concentration of tert-butyl iodide remains the same and the concentration of sodium chloride is doubled?

Draw the carbocation intermediate generated by each of the following substrates in an SN1 reaction: (a) Br (b) Cl (c) I (d) Br

Identify which of the following substrates will undergo an SN1 reaction more rapidly. Explain your choice. Br or Br

Draw the products that you expect in each of the following SN1 reactions: (a) NaCl I ? (b) Br SH ? @ (c) O O ? Cl

Draw the two products that you expect in the following SN1 reaction and describe their stereoisomeric relationship: NaSH ?

For each of the following substrates, determine whether an SN1 process will require a proton transfer at the beginning of the mechanism: (a) I (b) OH (c) Br (d) OH (e) OH (f) Cl

Will an SN1 process involving each of the following nucleophiles require a proton transfer at the end of the mechanism? (a) NaSH (b) H2S (c) H2O (d) EtOH (e) NaCN (f) NaCl (g) NaNH2 (h) NH3 (i) NaOMe (j) NaOEt (k) MeOH (l) KBr

For each of the following substrates, determine whether an SN1 process is likely to involve a carbocation rearrangement or not: (a) (b) OH (c) OH (d) OH (e) Br (f) Cl

Draw the mechanism for each of the following SN1 processes: HO (2R,3R)-3-methyl2-pentanol (a) HBr OH Br (b) OH HBr Br (c) H2O Br OH (d) EtOH OEt (e) OH OMe H2SO4 MeOH (f) H2SO4 MeOH OH MeO (g) NaSH Br SH (h) EtOH OEt

Identify the number of steps (patterns) for the mechanisms in Problems 7.21ah. For example, the patterns for the first two are: 7.21a: +H+ LG Nuc attack This mechanism exhibits a proton transfer before the two core steps. 7.21b: +H+ LG Nuc attack C+ rearrangement This mechanism exhibits a proton transfer before the two core steps as well as a carbocation rearrangement in between the two core steps. These patterns are not identical. Draw patterns for the other six problems. Then compare the patterns. There is only one pattern that is repeated. Identify the two problems that exhibit the same pattern and then describe in words why those two reactions are so similar.

Treatment of (2R,3R)-3-methyl-2-pentanol with H3O+ affords a compound with no chirality centers. Predict the product of this reaction and draw the mechanism of its formation. Use your mechanism to explain how both chirality centers are destroyed. HO (2R,3R)-3-methyl2-pentanol

Draw the mechanism for each of the following solvolysis reactions: (a) MeOH (solvolysis) Cl OMe (b) EtOH Br (solvolysis) O (c) (solvolysis) H2O OH (d) (solvolysis)

In Chapter 23, we will learn that treatment of ammonia with excess methyl iodide produces a quaternary ammonium salt. This transformation is the result of four sequential SN2 reactions. Use the tools we have learned in this chapter to draw the mechanism of this transformation. Your mechanism should have seven steps. NH3 Me N Me Me Me Excess MeI Quaternary ammonium salt

Identify whether each of the following substrates favors SN2, SN1, both, or neither: (a) Br (b) Cl (c) Br (d) Br (e) (f) Br (g) Br

Does each of the following nucleophiles favor SN2 or SN1? (a) OH (b) SH (c) O @ (d) NaOH (e) NaCN

Consider the structure of the compound below. (a) Identify each position where an SN2 reaction is likely to occur if the compound were treated with hydroxide. (b) Identify each position where an SN1 reaction is likely to occur if the compound were treated with water. TsO Cl Br Cl NH2 OMe

Does each of the following solvents favor an SN2 reaction or an SN1 reaction? (See Table 7.2.) (a) OH (b) S O (c) O OH (d) H N O (e) MeOH (f) CH3CN (g) HMPA (h) NH3

When used as a solvent, will acetone favor an SN2 or an SN1 mechanism? Explain. O Acetone

Determine whether each of the following reactions proceeds via an SN1 or SN2 mechanism and then draw the product(s) of the reaction: ? MeOH (a) Br ? Cl HMPA @ (b) H Br ? O H (c) (d) OTs NaCN DMF ? (e) H2O ? (f) Br NaCN DMSO ?

In Chapter 23, we will learn several methods for making primary amines (RNH2). Each of these methods utilizes a different approach for forming the CON bond. One of these methods, called the Gabriel synthesis, forms the CON bond by treating potassium phthalimide with an alkyl halide: K N R H H R X N O O N R O O @ ! The first step of this process occurs via an SN2 mechanism. Using this information, determine whether the Gabriel synthesis can be used to prepare the following amine. Explain your answer. NH2

Identify the reagents you would use to accomplish each of the following transformations: (a) OH (b) OH Br (c) OH (d) Br SH (e) Br O O (f) OH Br (g) O (h) Br OH

What reagents would you use to accomplish a substitution with retention of configuration; for example: OH (R)-2-Butanol SH (R)-2-Butanethiol

Melphalan is a chemotherapy drug used in the treatment of multiple myeloma and ovarian cancer. Melphalan is an alkylating agent belonging to the nitrogen mustard family. Draw a likely mechanism for the alkylation process that occurs when a nucleophile reacts with melphalan: Melphalan O NH2 HO N Cl C

List the systematic name and common name for each of the following compounds: (a) Cl (b) Br (c) (d) Br (e) C

Draw all isomers of C4H9I and then arrange them in order of increasing reactivity toward an SN2 reaction.

For each of the following pairs of compounds, identify which compound would react more rapidly in an SN2 reaction. Explain your choice in each case. (a) Cl Cl (b) Br Br (c) Cl Cl (d) Br

In Chapter 10, we will see that an acetylide ion (formed by treatment of acetylene with a strong base) can serve as a nucleophile in an SN2 reaction: Acetylene H C C H Acetylide ion CH C H C C R Strong base @ R X This reaction provides a useful method for making a variety of substituted alkynes. Determine whether this process can be used to make the following alkyne. Explain your answer. H C

Identify the stronger nucleophile: (a) NaSH vs. H2S (b) Sodium hydroxide vs. water (c) Methoxide dissolved in methanol vs. methoxide dissolved in DMSO

For each pair of the following compounds, identify which compound would react more rapidly in an SN1 reaction. Explain your choice in each case. (a) Cl Cl (b) Br Br (c) Cl Cl (d) Cl OTs

Consider the following reaction: Br CN NaBr NaCN DMSO + (a) How would the rate be affected if the concentration of the alkyl halide is doubled? (b) How would the rate be affected if the concentration of sodium cyanide is doubled?

Consider the following reaction: H2O HBr OH Br + (a) How would the rate be affected if the concentration of the alcohol is doubled? (b) How would the rate be affected if the concentration of HBr is doubled?

Classify each of the following solvents as protic or aprotic: (a) DMF (b) Ethanol (c) DMSO (d) Water (e) Ammonia

Consider the following SN2 reaction: NaCN O DMF Br O CN (a) Assign the configuration of the chirality center in the substrate. (b) Assign the configuration of the chirality center in the product. (c) Does this SN2 process proceed with inversion of configuration? Explain.

Draw the transition state for the reaction between ethyl iodide and sodium acetate (CH3CO2Na).

(S)-2-Iodopentane undergoes racemization in a solution of sodium iodide in DMSO. Explain.

When the following optically active alcohol is treated with HBr, a racemic mixture of alkyl bromides is obtained: HBr H2O OH Br Racemic mixture + Draw the mechanism of the reaction, and explain the stereochemical outcome.

(R)-2-Pentanol racemizes when placed in dilute sulfuric acid. Draw a mechanism that explains this stereochemical outcome, and draw an energy diagram of the process.

List the following carbocations in order of increasing stability: ! ! ! !

Draw the carbocation intermediate that would be formed if each of the following substrates would participate in an SN1 reaction. In each case, identify the carbocation as being primary, secondary, or tertiary. (a) Cl (b) Br (c) I (d) Cl

Propose a mechanism for the following transformation: OH H2O HCl C

Draw the mechanism of the following reaction: NaBr Br O O ONa O +

Each of the following reactions proceeds via an SN1 mechanism and will have anywhere from two to five steps, as discussed in Section 7.6. Determine the number of steps for each reaction and then draw the mechanism in each case: (a) HCl MeOH Cl OMe + (b) NaCl NaSH Cl SH + (c) H2O HI OH + I (d) OTs TsOH EtOH OE

Identify the product(s) in each of the following reactions: (a) EtOH Br ? (b) OTs NaBr ? (c) OH HCl ? (d) NaCN DMSO ?

Identify the product of the following reaction: NaO ONa Br Br C4H8O2 + 2 NaBr

The following reaction is very slow. Identify the mechanism and explain why the reaction is so slow. Br NaOH OH H2O

The following reaction is very slow: Br OH HBr H2O + (a) Identify the mechanism. (b) Explain why the reaction is so slow. (c) When hydroxide is used instead of water, the reaction is very rapid. Draw the mechanism of this reaction and explain why it is so fast.

Identify the reagents you would use to achieve each of the following transformations: (a) OTs OH (b) OH CN (c) OH Br (d) Cl SH (e) O O B

Each of the following compounds can be prepared with an alkyl iodide and a suitable nucleophile. In each case, identify the alkyl iodide and the nucleophile that you would use. (a) OH (b) O O (c) CN (d) SH (e) OH (f) S

What products would you expect from the reaction between (S)-2-iodobutane and each of the following nucleophiles? (a) NaSH (b) NaSEt (c) NaCN

Below are two potential methods for preparing the same ether, but only one of them is successful. Identify the successful approach and explain your choice. ONa O NaOMe CH3

Identify the reagent you would use to accomplish each of the following transformations: (a) OH h bromocyclobutane (b) (CH3)3COH h tert-butyl chloride (c) CH3CH2Cl h CH3CH2OH

Consider the following SN2 reaction: Br SH NaBr NaSH DMSO + (a) Draw the mechanism of this reaction. (b) What is the rate equation of this reaction? (c) What would happen to the rate if the solvent is changed from DMSO to ethanol? (d) Draw an energy diagram of the reaction above. (e) Draw the transition state of this reaction.

Consider the following substitution reaction: Br H2O HBr OH + (a) Determine whether this reaction proceeds via an SN1 or SN2 process. (b) Draw the mechanism of this reaction. (c) What is the rate equation of this reaction? (d) Would the reaction occur at a faster rate if sodium bromide were added to the reaction mixture? (e) Draw an energy diagram of this reaction.

Consider the following substitution reaction: NaBr Br CN NaCN DMSO + (a) Determine whether this reaction proceeds via an SN1 or SN2 process. (b) Draw the mechanism of this reaction. (c) What is the rate equation of this reaction? (d) Would the reaction occur at a faster rate if the concentration of cyanide were doubled? (e) Draw an energy diagram of the reaction above.

Propose a mechanism for the following transformation: H2O OH

When the following ester is treated with lithium iodide in DMF, a carboxylate ion is obtained: O O LiI DMF O O Li @ ! + (a) Draw the mechanism of this reaction. (b) When the methyl ester is used as the substrate, the reaction is 10 times faster: MeI O O LiI DMF O O Li @ ! + Explain the increase in rate.

When (1R,2R)-2-bromocyclohexanol is treated with a strong base, an epoxide (cyclic ether) is formed. Suggest a mechanism for formation of the epoxide: Br OH O An epoxide Strong base

When butyl bromide is treated with sodium iodide in ethanol, the concentration of iodide quickly decreases but then slowly returns to its original concentration. Identify the major product of the reaction.

The following compound can react rapidly via an SN1 process. Explain why this primary substrate will undergo an SN1 reaction so rapidly. O OTs

Consider the reaction below. The rate of this reaction is markedly increased if a small amount of sodium iodide is added to the reaction mixture. The sodium iodide is not consumed by the reaction and is therefore considered to be a catalyst. Explain how the presence of iodide can speed up the rate of the reaction. Cl CN NaCN DMSO

Propose a mechanism for the following transformation: OH OH H3O+

The following reaction sequence was part of a stereocontrolled synthesis of cyoctol, used in the treatment of male pattern baldness (Tetrahedron 2004, 60, 95999614). The third step in this process employs an uncharged nucleophile, affording an ion pair as the product (anion and cation). (a) Draw the product of the reaction sequence, and describe the factors that make the third step favorable. (b) Suggest a reason for the function of the second step of this process. OMe OH 1) TsCl, pyridine 2) NaI 3) P ? Ph Ph Ph , heat Ph =

The following reaction sequence was part of a stereocontrolled synthesis of cyoctol, used in the treatment of male pattern baldness (Tetrahedron 2004, 60, 95999614). The third step in this process employs an uncharged nucleophile, affording an ion pair as the product (anion and cation). (a) Draw the product of the reaction sequence, and describe the factors that make the third step favorable. (b) Suggest a reason for the function of the second step of this process. OMe OH 1) TsCl, pyridine 2) NaI 3) P ? Ph Ph Ph , heat Ph =

Bromotriphenylmethane (compound 1) can be converted to 2a or 2b or 2c upon treatment with the appropriate nucleophile (J. Chem. Ed. 2009, 86, 853855). (a) Draw a mechanism for the conversion of 1 to 2b. (b) In all three cases, conversion of 1 to 2 is observed to be nearly instantaneous (the reaction occurs extremely rapidly). Justify this observation with any drawings that you feel are necessary. (c) IR spectroscopy is an ideal tool for monitoring the conversion of 1 to 2a, while other forms of spectroscopy will be better suited for monitoring the conversion of 1 S 2b or 1 S 2c. Explain. 1 Ph Ph Ph Br 2 Ph Ph Ph OR Ph = 2a: R = H 2b: R = CH3 2c: R = CH2CH3

A common method for confirming the proposed structure and stereochemistry of a natural product is to achieve a total synthesis of the proposed structure and then compare its spectroscopic properties (Chapters 15 and 16) with those of the natural product. This technique was used to verify the structure of ()-cameroonanol, a compound isolated from the essential oil of the flowering plant Echniops giganteus (Org. Lett. 2000, 2, 27172719). During the synthesis of ()-cameroonanol, the following reaction was employed. Draw a plausible mechanism for this transformation. O H O H Br K O ! @

Thienamycin is a potent antibacterial agent isolated from the fermentation broth of the soil microorganism Streptomyces cattleya. The following SN2 process was utilized in a synthesis of thienamycin (J. Am. Chem. Soc. 1980, 102, 61616163). (a) Draw the product of this process (compound 3). (b) The nucleophile exhibits a six-membered ring with two sulfur atoms, called a dithiane ring. Explain why the dithiane ring in compound 3 exists primarily in two conformations, while the dithiane ring in compound 2 exists primarily in one conformation. N O SiMe3 SiMe3 I S S Li SN2 + 1 2 3

Optically pure 2-octyl sulfonate was treated with varying mixtures of water and dioxane, and the optical purity of the resulting product (2-octanol) was found to vary with the ratio of water to dioxane, as shown in the following table (J. Am. Chem. Soc. 1965, 87, 287291). Given that dioxane possesses fairly nucleophilic oxygen atoms, provide a complete mechanism that explains the variation in the products optical purity due to changes in solvent composition. O S OR O O O O H2O (dioxane) OH Excellent leaving group (R)-2-Octyl sulfonate (optically pure) (S)-2-Octanol Solvent ratio (water : dioxane) Optical purity of (S)-2-octanol 25 : 75 77% 50 : 50 88% 75 : 25 95% 100 : 0 100%

Cyclopropyl chloride (1) cannot generally be converted into cyclopropanol (4) through a direct substitution reaction, because undesired, ring-opening reactions occur. The following represents an alternative method for preparing cyclopropanol (Tetrahedron Lett. 1967, 8, 49414944). Cl OH MgCl O O O O NaOH Mg H3O+ 1 2 3 4 @ ! (a) Compound 2 is a powerful nucleophile, and for our purposes, we will treat MgCl+ as a counterion. The transformation of 2 into 3 is accomplished via an SN2-type process. Draw a mechanism for this process and identify the leaving group. (b) Explain why the conversion of 2 to 3 is an irreversible process. (c) Under aqueous acidic conditions, 3 can be converted into 4 either via an SN1 process or via an SN2 process. Draw a complete mechanism for each of these pathways. (d) During conversion of 3 to 4, another alcohol (ROH) is formed as a byproduct. Draw the structure of this alcohol.

Compound 1 was prepared during a recent synthesis of 1-deoxynojirimycin, a compound with application to HIV chemotherapy (Org. Lett. 2010, 12, 136139). Upon formation, compound 1 rapidly undergoes ring contraction in the presence of chloride ion to form compound 2. Propose a plausible mechanism that includes a justification for the stereochemical outcome. N O O Cl CH2Ph R N CH2Ph O O OSO2CH

Halogenated derivatives of toluene will undergo hydrolysis via an SN1 process: Z X Y The rate of hydrolysis is dependent on two main factors: (1) the stability of the leaving group and (2) the stability of the intermediate carbocation. The following are rates of hydrolysis ( 104 min) for halogenated derivatives of toluene at 30 C in 50% aqueous acetone (J. Am. Chem. Soc. 1951, 73, 2223): Z = H Z = Cl Z = Br X = H, Y = Cl 0.22 2.21 31.1 X = Cl, Y = Cl 2.21 110.5 2122 X = Br, Y = Br 6.85 1803 1131 Using these data, answer the following questions: (a) Using Figure 7.28, determine whether chloride or bromide is the better leaving group and explain your choice. Then, determine whether the hydrolysis data support your choice. Explain. (b) Determine whether a carbocation is stabilized by an adjacent chloro group (i.e., a chlorine atom attached directly to C+). Justify your choice by drawing resonance structures for the carbocation. (c) Determine whether a carbocation is stabilized by an adjacent bromo group (i.e., a bromine atom attached directly to C+). Justify your choice by drawing resonance structures for the carbocation. (d) Determine whether a carbocation is more greatly stabilized by an adjacent chloro group or an adjacent bromo group. (e) For these hydrolysis reactions, determine which factor is more important in determining the rate of hydrolysis: the stability of the leaving group or the stability of the carbocation. Explain your choice.

Bimolecular substitution reactions commonly occur at sp3 - hybridized centers but generally do not occur at sp2 -hybridized centers. This selectivity is clearly observed in the conversion of 2 to 3 in the reaction sequence shown below. However, the conversion of 3 to 4 appears to be a rare example of an SN2-type process occurring at an sp2 -hybridized center (J. Am. Chem. Soc. 2004, 126, 6868 6869). (a) Draw the structures of 2 and 3. (b) In the conversion of 3 to 4, sodium amide (NaNH2) functions as a base, and ammonia is the solvent. Draw a mechanism for the conversion of 3 to 4 and make sure to show the transition state for this process. (c) Explain how the stereochemical outcome of this transformation is consistent with an SN2-type process. Br OH 2 1 TsCl pyridine 3 NaNH2 NH3 78 C N Ph NH2 Ph 4 Ph =

When the following alkyl bromide is treated with sodium acetate in CH3CN, two products are formed. The minor product retains the three-membered ring of the starting material, whereas the major product features a four-membered ring (J. Org. Chem. 2012, 77, 31813190). Provide a plausible mechanism that explains the formation of these two products. (Hint: You might find inspiration for your answer in the medically speaking application at the end of the chapter.) N Br R N O R N O R R = CH2Ar Minor Major O O O O CH3CN

Biotin (compound 4) is an essential vitamin that plays a vital role in several important physiological processes. A total synthesis of biotin, developed by scientists at Hoffmann-La Roche, involved the preparation of compound 1 (J. Am. Chem. Soc. 1982, 104, 64606462). Conversion of 1 to 4 required removal of the OH group, which was achieved in several steps. First, the OH group was replaced with Cl by treating 1 with SOCl2 to give 3. The mechanism for the conversion of 1 to 3 proceeds via intermediate 2, which has an excellent leaving group (SO2Cl). Ejection of this leaving group causes the liberation of SO2 gas and a chloride ion, which can occur if 2 is attacked by a chloride ion in an SN2 reaction. As such, we expect the transformation of 2 to 3 to proceed via inversion of configuration. However, X-ray crystallographic analysis of compound 3 revealed that the transformation occurred with a net retention of configuration, as shown. Propose a mechanism that explains this curious result. (Hint: You might find it helpful to reference the medically speaking application in Section 7.9.) SOCl2 S N N H H O OH 1 S N N H H O O S Cl O 2 HO O Cl O S N N H H O Cl 3 Cl O S N N H H O 4 H