Solved: Draw the carbocation intermediate that would be

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

bond in the following compound: Dactylyne A natural product isolated from marine sources O Br Br Cl

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

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)

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

6 (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 ? NaOH

Identify the sole product of the following reaction: C10H20 Br NaOEt

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 ? NaO

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.

pose 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 2) DBU

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 trans:cis