The following reaction exhibits a second-order rate equation: Cl NaOH (a) What happens

Provide a systematic name for each of the following compounds: (a) (b) (c) (d)

Draw a bond-line structure for each of the following compounds: (a) 3-Isopropyl-2,4-dimethyl-2-pentene (b) 4-Ethyl-2-methyl-2-hexene (c) 1,2-Dimethylcyclobutene (The name of a cycloalkene will often not include a locant to specify the position of the p bond, because, by definition, it is assumed to be between C1 and C2.)

In Section 4.2, we learned how to name bicyclic compounds. Using those rules, together with the rules discussed in this section, provide a systematic name for the following bicyclic compound. In a case like this, the lowest number is assigned to a bridgehead (not to the p bond).

Classify each of the following alkenes as monosubstituted, disubstituted, trisubstituted, or tetrasubstituted: (a) (b) (c) (d) (e)

8.5 For each of the following alkenes, assign the configuration of the double bond as either E or Z: (a) (b) (c) F O (d) C

When a double bond has two identical groups (one on each vinylic position), we can use either cis-trans terminology or E-Z terminology, as seen in the following example: The configuration of this double bond can be designated as either trans or E. Both designations are acceptable. In most cases, cis = Z and trans = E. However, there are exceptions. For example: Cl This compound is trans, but Z. Explain this exception and then provide two other examples of exceptions.

Arrange each set of isomeric alkenes in order of stability: (a) (b)

Consider the following two isomeric alkenes. The first isomer is a monosubstituted alkene, while the second isomer is a disubstituted alkene. We might expect the second isomer to be more stable, yet heats of combustion for these two compounds indicate that the first isomer is more stable. Offer an explanation.

For each of the following elimination reactions, assume a concerted process is taking place and draw the mechanism: (a) Cl NaOH (b) OTs NaOEt (c) Br NaOMe

For each of the following elimination reactions, assume a stepwise process is taking place and draw the mechanism (first loss of the leaving group and then proton transfer): (a) Cl H2O (b) Br MeOH (c) I EtOH

Carefully read the following curved arrows shown and draw the expected alkene that is produced by this elimination reaction. Is this mechanism concerted or stepwise? EtO ? OTs

Draw the intermediate of the following elimination reaction, and then draw the curved arrows for the second step (the reaction between the intermediate and ethanol): ? EtOH Br

The following reaction exhibits a second-order rate equation: Cl NaOH (a) What happens to the rate if the concentration of chlorocyclopentane is tripled and the concentration of sodium hydroxide remains the same? (b) What happens to the rate if the concentration of chlorocyclopentane remains the same and the concentration of sodium hydroxide is doubled? (c) What happens to the rate if the concentration of chlorocyclopentane is doubled and the concentration of sodium hydroxide is tripled?

Arrange each set of compounds in order of reactivity toward an E2 process: (a) Br Br Br (b) Cl Cl Cl

Identify the major and minor products for each of the following E2 reactions: (a) Cl ? NaOEt (b) Cl ? t-BuOK (c) I ? NaOH (d) I ? t-BuOK (e) Br ? NaOH (f) Br ? t-BuOK

For each of the following reactions, identify whether you would use hydroxide or tert-butoxide to accomplish the desired transformation: (a) Cl (b) Br

Show two different methods for preparing each of the following alkenes using a sterically hindered base: (a) (b)

Identify the major and minor products for the E2 reaction that occurs when each of the following substrates is treated with a strong base: (a) Br (b) Br (c) Br (d) Cl (e) Cl (f) Cl (g) Cl (h)

Identify an alkyl halide that could be used to make the following alkene:

When menthyl chloride is treated with a strong base, only one elimination product is observed. Yet, when neomenthyl chloride is treated with a strong base, two elimination products are observed. Draw the products and explain. Cl Neomenthyl chloride Cl Menthyl chloride

Predict which of the following two compounds will undergo an E2 reaction more rapidly: Cl Cl

Predict the major and minor products for each of the following E2 reactions: (a) Cl ? NaOEt (b) Br ? NaOEt (c) Br ? NaOEt (d) I ? NaOEt (e) Br ? t-BuOK (f) Br ? t-BuOK

Draw an alkyl halide that will produce only one alkene upon treatment with a strong base.

Draw an alkyl halide that will produce exactly two stereoisomeric alkenes upon treatment with a strong base.

Draw an alkyl halide that will produce two constitutional isomers (but no stereoisomers) upon treatment with a strong base.

The following reaction occurs via an E1 mechanistic pathway: I EtOH Heat (a) What happens to the rate if the concentration of tert-butyl iodide is doubled and the concentration of ethanol is tripled? (b) What happens to the rate if the concentration of tert-butyl iodide remains the same and the concentration of ethanol is doubled?

Draw the carbocation intermediate generated by each of the following substrates in an E1 reaction: (a) Br (b) Cl (c) I (d) Br

Draw the carbocation intermediate generated when each of the following substrates is treated with sulfuric acid: (a) OH (b) OH (c) OH (d) OH

Identify the major and minor products for each of the following E1 reactions: (a) OH ? conc. H2SO4 Heat (b) Br ? EtOH Heat (c) ? OH conc. H2SO4 Heat (d) Br ?

Identify two different starting alcohols that could be used to make 1-methylcyclohexene. Then determine which alcohol would be expected to react more rapidly under acidic conditions. Explain your choice.

Draw only the major product for each of the following E1 reactions: (a) OH ? conc. H2SO4 Heat (b) HO ? conc. H2SO4 Heat

For each of the following substrates, determine whether an E1 process will require the use of an acid: (a) I (b) OH (c) OTs (d) OH (e) Br (f) OTs

For each of the following substrates, determine whether an E1 process might involve a carbocation rearrangement or not: (a) I (b) OH (c) OH (d) OH (e) Br (f) Cl

Draw a mechanism for each of the following E1 processes: (a) OH conc. H2SO4 Heat (b) Br EtOH Heat (c) Cl EtOH Heat (d) OH conc. H2SO4 Heat

Identify the pattern for each mechanism in Problem 8.34. For example, the pattern for Problem 8.34a is: +H+ LG H+ This mechanism is comprised of a proton transfer followed by the two core steps of an E1 process (loss of leaving group and then proton transfer). Draw patterns for the other three problems (8.34b8.34d). Then compare the patterns. Identify which two reactions exhibit the same exact pattern and then describe in words why those two reactions are so similar.

Identify which of the following methods is more efficient for producing 3,3-dimethylcyclohexene. Explain your choice. Br OH NaOEt EtOH conc. H2SO4 Heat

Draw a mechanism for each of the following E2 reactions: (a) Cl NaOMe (b) Br tBuOK (c) Br NaOH

In the next chapter, we will learn a method for preparing alkynes (compounds containing C#C triple bonds). In the following reaction, a dihalide (a compound with two halogen atoms) is treated with an excess of strong base (sodium amide), resulting in two successive E2 reactions. Draw a mechanism for this transformation. R Cl Cl R H H R R Excess NaNH2

Identify whether each of the following reagents would be a strong nucleophile or a weak nucleophile and also indicate whether it would be a strong base or a weak base: (a) OH (b) SH (c) O @ (d) Br@ (e) LiOH (f) MeOH (g) NaOMe (h) DBN

We have seen that NaH is a strong base but a weak nucleophile. In contrast, lithium aluminum hydride (LAH) is a reagent that can serve as a source of nucleophilic hydride ion: H Al Br H H H Li LAH @ ! In this case, LAH functions as a delivery agent of a nucleophilic hydride ion. We will see this reagent in many upcoming chapters. Explain why LAH is capable of functioning as a strong nucleophile while NaH is not.

Identify the mechanism(s) expected to operate when 1-bromobutane is treated with each of the following reagents: (a) NaOH (b) NaSH (c) t-BuOK (d) DBN (e) NaOMe

Identify the mechanism(s) expected to operate when 2-bromopentane is treated with each of the following reagents: (a) NaOEt (b) NaI/DMSO (c) DBU (d) NaOH (e) t-BuOK

Identify the mechanism expected to operate when 2-bromo-2-methylpentane is treated with each of the following reagents: (a) EtOH (b) t-BuOK (c) NaI (d) NaOEt (e) NaOH

When 1-chlorobutane is treated with ethanol, neither elimination process (E1 or E2) is observed at an appreciable rate: Cl No elimination products EtOH (a) Explain why an E2 reaction does not occur. (b) Explain why an E1 reaction does not occur. We mentioned that predicting the products of substitution and elimination reactions requires three discrete steps: 1. Determine the function of the reagent. 2. Analyze the substrate and determine the expected mechanism(s). 3. Consider any relevant regiochemical and stereochemical requirements. In the previous two sections, we explored the first two steps of this process. In this last section of the chapter, we explore the third and final step. After determining which mechanism(s) operate, the final step is to consider the regiochemical and stereochemical outcomes for each of the expected mechanisms. Table 8.2 provides a summary of guidelines that must be followed when drawing products. Table 8.2 does not contain any new information. All of the information can be found in this chapter and the previous chapter. The table is meant only as a summary of all of the relevant information, so that it is easily accessible in one location. The following SkillBuilder provides the opportunity to practice applying these guidelines. table 8.2 guidelines for determining the regiochemical and stereochemical outcome of substitution and elimination reactions regiochemical outcome stereochemical outcome SN2 The nucleophile attacks the a position, where the leaving group is connected. The nucleophile replaces the leaving group with inversion of configuration. SN1 The nucleophile attacks the carbocation, which is where the leaving group was originally connected, unless a carbocation rearrangement takes place. The nucleophile replaces the leaving group with racemization. E2 The Zaitsev product is generally favored over the Hofmann product, unless a sterically hindered base is used, in which case the Hofmann product will be favored. This process is both stereoselective and stereospecific. When applicable, a trans disubstituted alkene will be favored over a cis disubstituted alkene. When the b position of the substrate has only one proton, the stereoisomeric alkene resulting from anti-periplanar elimination will be obtained (exclusively, in most cases). E1 The Zaitsev product is always favored over the Hofmann product. The process is stereoselective. When applicable, a trans disubstituted alkene will be favored over a cis disubstituted alkene. need more PRACTICE? (c) Modifying the reactants can have a profound effect on the rate of elimination. What modification would you suggest to enhance the rate of an E2 process? (d) What modification would you suggest to enhance the rate of an E1 process?

When 3-chloro-2,2,4,4-tetramethylpentane is treated with sodium hydroxide, neither E2 nor SN2 products are formed. Explain. (Hint: See Figure 7.11 and the associated discussion.)

Identify the major and minor product(s) that are expected for each of the following reactions: (a) OTs ? NaCl DMSO (b) I ? NaOH (c) Br ? t-BuOK (d) Br ? DBN (e) I ? t-BuOK (f) I ? NaSH (g) Br ? NaOH (h) Br ? NaOEt (i) I ? EtOH Heat (j) Br ? NaOH (k) Br ? NaOMe (l) Br ? NaOMe (m) Br ? NaOH (n) Br ?

Compound A and compound B are constitutional isomers with molecular formula C3H7Cl. When compound A is treated with sodium methoxide, a substitution reaction predominates. When compound B is treated with sodium methoxide, an elimination reaction predominates. Propose structures for compounds A and B.

Compound A and compound B are constitutional isomers with molecular formula C4H9Cl. Treatment of compound A with sodium methoxide gives trans-2-butene as the major product, while treatment of compound B with sodium methoxide gives a different disubstituted alkene as the major product. (a) Draw the structure of compound A. (b) Draw the structure of compound B.

An unknown compound with molecular formula C6H13Cl is treated with sodium ethoxide to produce 2,3-dimethyl-2-butene as the major product. Identify the structure of the unknown compound.

Assign a systematic (IUPAC) name for each of the following compounds: (a) (b) (c

Using E-Z designators, identify the configuration of each CRC double bond in the following compound: Dactylyne A natural product isolated from marine sources

There are two stereoisomers of 1-tert-butyl-4-chloro-cyclohexane. One of these isomers reacts with sodium ethoxide in an E2 reaction that is 500 times faster than the reaction of the other isomer. Identify the isomer that reacts faster and explain the difference in rate for these two isomers.

3 Arrange the following alkenes in order of increasing stability:

For each pair of compounds identify which compound would react more rapidly in an E1 reaction: (a) Cl Cl (b) Cl Cl

Identify the stronger base: (a) NaOH vs. H2O (b) Sodium ethoxide vs. ethanol

(2S,3S)-2-Bromo-3-phenylbutane undergoes an E2 reaction when treated with a strong base to produce (E)-2-phenyl-2-butene. Use Newman projections to explain the stereochemical outcome of this reaction.

Consider the following reaction: Br NaOEt EtOH (a) How would the rate be affected if the concentration of tert-butyl bromide is doubled? (b) How would the rate be affected if the concentration of sodium ethoxide is doubled?

Consider the following reaction: Br EtOH (a) How would the rate be affected if the concentration of tert-butyl bromide is doubled? (b) How would the rate be affected if the concentration of ethanol is doubled?

When (R)-3-bromo-2,3-dimethylpentane is treated with sodium hydroxide, four different alkenes are formed. Draw all four products and rank them in terms of stability. Which product do you expect to be the major product?

When 3-bromo-2,4-dimethylpentane is treated with sodium hydroxide, only one alkene is formed. Draw the product and explain why this reaction has only one regiochemical outcome.

Predict the major product for each of the following E2 reactions: (a) Br ? NaOH (b) Br ? NaOH (c) Br ? KOC(CH3) 3 (d) Br ? KOC(CH3) 3

Draw the most stable E1 product that can be produced in each of the following reactions: (a) Br ? H2O Heat (b) OH ? conc. H2SO4 Heat

Predict the stereochemical outcome for each of the following E2 reactions. In each case, draw only the major product of the reaction. (a) Br ? NaOH (b) Cl ?

Identify the sole product of the following reaction: C10H20

For each of the following descriptions draw the structure of a compound that fits the description. (Note: There are many correct answers for each of these problems.) (a) An alkyl halide that produces four different alkenes when treated with a strong base (b) An alkyl halide that produces three different alkenes when treated with a strong base (c) An alkyl halide that produces two different alkenes when treated with a strong base (d) An alkyl halide that produces only one alkene when treated with a strong base

How many different alkenes will be produced when each of the following substrates is treated with a strong base? (a) 1-Chloropentane (b) 2-Chloropentane (c) 3-Chloropentane (d) 2-Chloro-2-methylpentane (e) 3-Chloro-3-methylhexane

In each of the following cases draw the structure of an alkyl halide that will undergo an E2 elimination to yield only the indicated alkene: (a) ? E2 (b) ? E2 (c) ? E2 (d) ? E2

Consider the following reaction: OH conc. H2SO4 Heat (a) Draw a mechanism for this reaction. (b) What is the rate equation of this reaction? (c) Draw an energy diagram for the reaction.

Draw the carbocation intermediate that would be formed if each of the following substrates participated in a stepwise elimination process (E1). In each case, identify the intermediate carbocation as being primary, secondary, or tertiary. One of the substrates does not undergo an E1 reaction. Identify which one and explain why. (a) Cl (b) Br (c) I (d) Cl

Draw the transition state for the reaction between tert-butyl chloride and sodium hydroxide.

The following three reactions are similar, differing only in the configuration of the substrate. One of these reactions is very fast, one is very slow, and the other does not occur at all. Identify each reaction and explain your choice. Br NaOH Br NaOH Br NaOH

1-Bromobicyclo[2.2.2]octane does not undergo an E2 reaction when treated with a strong base. Explain why not.

For each pair of the following compounds identify which compound would react more rapidly in an E2 reaction: (a) Cl Cl (b) Br Br

Indicate whether you would use sodium ethoxide or potassium tert-butoxide to achieve each of the following transformations: (a) Br (b) Br (c) Br (d) Br

Explain why the following reaction yields the Hofmann product exclusively (no Zaitsev product at all) even though the base is not sterically hindered: Br NaOEt EtOH

Propose a mechanism for each of the following transformations: (a) OH conc. H2SO4 Heat (b) OH conc. H2SO4 Heat (c) OH conc. H2SO4 Heat (d) I EtOH Heat (e) I NaOEt EtOH

Substitution vs. Elimination: Identify the major and minor product(s) for each of the following reactions: (a) Cl ? t-BuOK (b) OTs ? NaOH (c) OH ? conc. H2SO4 Heat (d) OTs ? NaCl DMSO (e) Br ? NaOEt (f) Br ? NaOEt (g) Br ? NaOEt EtOH (h) Br ? NaOEt EtOH (i) Br ? NaOEt EtOH (j) Br ? KOC(CH3) 3 (k) Br ? NaOMe (l) Cl ? NaOH

When 2-bromo-2-methylhexane is treated with sodium ethoxide in ethanol, the major product is 2-methyl-2-hexene. (a) Draw a mechanism for this reaction. (b) What is the rate equation of this reaction? (c) What would happen to the rate if the concentration of base is doubled? (d) Draw an energy diagram for this reaction. (e) Draw the transition state of this reaction.

Predict the major product for each of the following reactions: (a) Cl ? NaSH (b) OTs ? DBN (c) I ? NaOH H2O (d) Br ? H2O Heat (e) OTs ? O K @ ! (f ) I ? O K @ ! (g) OTs ? NaOH H2O (h) OTs ? NaOH H2O (i) Br ? NaOMe MeOH (j) Br ? O K @ !

Draw all constitutional isomers of C4H9Br and then arrange them in order of increasing reactivity toward an E2 reaction.

Propose a mechanism that explains formation of the following product: OH conc. H2SO4 Heat

(S)-1-Bromo-1,2-diphenylethane reacts with a strong base to produce cis-stilbene and trans-stilbene: Br trans-Stilbene (major product) cis-Stilbene + NaOEt (a) This reaction is stereoselective, and the major product is transstilbene. Explain why the trans isomer is the predominant product. To do so, draw the Newman projections that lead to formation of each product and compare their stability. (b) When (R)-1-bromo-1,2-diphenylethane is used as the starting substrate, the stereochemical outcome does not change. That is, trans-stilbene is still the major product. Explain.

Propose a mechanism for the following transformation: OH conc. H2SO4 Heat

Propose a mechanism of formation for each of the following products: OTs OEt OEt + + EtOH Heat

There are many stereoisomers of 1,2,3,4,5,6-hexachlorocyclohexane. One of those stereoisomers undergoes E2 elimination thousands of times more slowly than the other stereoisomers. Identify which stereoisomer and explain why it is so slow toward E2.

Predict which of the following substrates will undergo an E1 reaction more quickly. Explain your choice. or Br Br

Pladienolide B is a macrocyclic (large-ring) natural product isolated from an engineered strain of the bacterium Streptomyces platensis. An enantioselective, 31-step synthesis of it was reported in 2012 an improvement over a previously reported 59-step approach (Org. Lett. 2012, 14, 47304733): OH O O O O O OH OH (a) Identify the trisubstituted p bond and determine whether it has the E or Z configuration. (b) How many total stereoisomers are possible for pladienolide B? (c) Draw the enantiomer of pladienolide B. (d) Draw the diastereomer that is identical to pladienolide B except for the configuration of each of the chirality centers directly connected to an ester oxygen. (e) Draw the diastereomer that is identical to pladienolide B except for the configuration of the disubstituted p bond that is outside of the ring.

Steroids (covered in Chapter 26) and their derivatives are among the most widely used therapeutic agents. They are used in birth control, hormone replacement therapy, and the treatment of inflammatory conditions and cancer. New stereoid derivatives are discovered regularly by systematically modifying the structure of known steroids and testing the resulting derivatives for therapeutic properties. As part of a synthetic strategy for preparing a class of promising steroid derivatives, compound 1a was treated with TsCl and pyridine followed by sodium acetate (CH3CO2Na) to give compound 2a (Tetrahedron Lett. 2010, 51, 69486950). OH CH3 CH3 H O R R O 1 1a : R = R = H 1b : R = H; R = D 1c : R = D; R = H O O O O (a) Sodium acetate functions as a base in this instance. Draw the structure of 2a. (b) Deuterium (D) is an isotope of hydrogen, and deuterons will typically behave very much like protons (although small differences in reaction rates are typically observed). If 1b or 1c were treated with TsCl and pyridine, followed by sodium acetate, 2b or 2c would be produced, respectively. Identify which product (2b or 2c) is expected to contain deuterium and justify your choice.

Compounds 1 and 2 exhibit an oxetane ring (a four-membered ring containing an oxygen atom), which is a very important structural feature in a number of natural products. For example, an oxetane ring is present in the structure of taxol, used in the treatment of breast cancer. When either 1 or 2 is treated with TsCl and pyridine, followed by t-BuOK, the Zaitsev elimination product dominates, despite the use of a sterically hindered base (Tetrahedron Lett. 2007, 48, 83538355). Determine the stereochemical outcome for each of these processes and draw the expected product in each case. Use Newman projections to justify your answers. Ph OH O Ph OH 1 2 O

Compound 1 is observed to undergo debromination upon treatment with DMF to afford an alkene. The E isomer (compound 2) is obtained exclusively (none of the Z isomer is observed). A concerted mechanism (shown below) has been refuted by the observation that diastereomers of 1 also afford the E isomer exclusively when treated with DMF (J. Org. Chem. 1991, 56, 25822584): Br H Br H 1 H O N 2 (DMF) (a) Explain why the mechanism shown is inconsistent with this observation. (b) Classify this reaction as stereoselective or stereospecific and explain your choice.

The following sequence of reactions was performed during a synthesis of (+)-coronafacic acid, a key component in the plant toxin coronatine (J. Org. Chem. 2009, 74, 24332437). Predict the product of this reaction sequence and justify the regiochemical outcome of the second reaction. 1) TsCl, pyridine O O OH CO2CH3

We have seen that an E2 reaction generally proceeds from a conformation in which the b proton is anti-periplanar to the leaving group. A similar geometric requirement is also observed for other types of reactions such as the one below (J. Am. Chem. Soc. 2010, 132, 25302531). Under acidic conditions, compound 1 rearranges to form mechanistic intermediate 2, which then undergoes three additional mechanistic steps (along with the loss of an N2 leaving group) to give product 3. The conversion of 1 S 2 is beyond the scope of our current discussion. Draw a mechanism for the final three steps, as described: (x) The alkyl group anti-periplanar to the N+ 2 group undergoes a 1,2-shift to allow a backside displacement of N2. (y) The alcohol oxygen attacks the resulting carbocation. (z) The resulting oxonium ion is deprotonated. N N N O R HO R O O R R N3 Several mechanistic steps x y z 1 2 3 !

When 2-iodobutane is treated with a variety of oxyanion bases in DMSO at 50 C, the percentage of 1-butene formed among total butenes is found to be dependent on the choice of base, as seen in the chart below (J. Am. Chem. Soc. 1973, 95, 34053407): Name of Base Structure of Base % 1-Butene (in total butenes) Potassium benzoate O OK 7.2 Potassium phenoxide OK 11.4 Sodium 2,2,2- trifluoroethoxide NaOCH2CF3 14.3 Sodium ethoxide NaOEt 17.1 (a) Identify the trend observed by comparing the basicity of the oxyanion bases and then describe the correlation between reactivity (base strength) and selectivity (specifically regioselectivity). (b) The pKa of 4-nitrophenol is 7.1. Based on the trend in the previous part of this problem, provide an estimate for the percentage of 1-butene that is expected if 2-iodobutane is treated with the conjugate base of 4-nitrophenol in DMSO at 50 C.

During a recent total synthesis of (+)-aureol, a potential anticancer agent isolated from a marine sponge, the following Lewis acid catalyzed rearrangement was employed (Org. Lett. 2012, 14, 47104713). Provide a plausible mechanism for this biosynthetically inspired process (Hint: review Section 3.9) and make sure to include a rationale for the observed stereochemistry of the product. H OH OAc OAc BF3

When the given 2-butyl compounds are treated with t-BuOK in t-BuOH at 50 C, the major product is generally 1-butene (as expected with a sterically hindered base), while the minor products are cis-2- butene and trans-2-butene. In cases where the leaving group is a halogen (I, Br, or Cl), the trans alkene is favored over the cis alkene. However, the cis isomer becomes the favored 2-alkene when the leaving group is a tosylate group (J. Am. Chem. Soc. 1965, 87, 55175518). Provide a transition state argument, including relevant Newman projections, that explains this difference. Y t-BuOK t-BuOH + Y I Br Cl OTs 2.2 1.4 1.3 0.6