Consider the following substitution reaction: Br H2O HBr

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

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 CC

Identify the stronger nucleophile: (a) \(\mathrm{NaSH}\) vs. \(\mathrm{H}_{2} \mathrm{~S}\) (c) Methoxide dissolved in (b) Sodium hydroxide vs. methanol vs. methoxide diswater solved 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 Cl +

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 OEt +

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) SH

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 =

Upon treatment with a strong base (such as NaOH), 2-naphthol (compound 1) is converted to its conjugate base (anion 2), which is then further converted into compound 3 upon treatment with butyl iodide (J. Chem. Ed. 2009, 86, 850852). (a) Draw the structure of 2, including a mechanism for its formation, and justify why hydroxide is a sufficiently strong base to achieve the conversion of 1 to 2. (b) Draw the structure of 3, including a mechanism of its formation. (c) Compound 3 is most easily purified via recrystallization in water. As such, the product would have to be thoroughly dried in order to utilize IR spectral analysis to verify the conversion of 1 to 3. Explain why a wet sample would interfere with the utility of IR spectral analysis in this case and explain how you would use IR spectral analysis to verify complete conversion of 1 to 3, assuming the product was properly dried. 1 2 3 NaOH I OH

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 RO

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 OSO2CH3 R Cl 1 2 @

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 HO O