Predict the major product for each of the following intramolecular reactions: O (a) (b)

Assign a systematic (IUPAC) name to each of the following compounds: (a) H Br Br O (b) O (c) O (d) O H (e) H O

Draw the structure of each of the following compounds: (a) (S)-3,3-Dibromo-4-ethylcyclohexanone (b) 2,4-Dimethyl-3-pentanone (c) (R)-3-Bromobutanal

Provide a systematic (IUPAC) name for the compound below. Be careful: This compound has two chirality centers (can you find them?). O

Compounds with two ketone groups are named as alkane diones; for example: OO 2,3-Butanedione The compound above is an artificial flavor added to microwave popcorn and movietheater popcorn to simulate the butter flavor. Interestingly, this very same compound is also known to contribute to body odor. Name the following compounds: O O O O O O O (a) ( (b) c)

Identify the reagents necessary to achieve each of the following transformations: OH O (a) OH O H (b) O (c) H O (d) O O H (e) O (f)

Draw a mechanism for each of the following reactions: 1) EtMgBr 2) H2O O HO O HO + HCl Cl (a) (b)

For most ketones, hydrate formation is unfavorable, because the equilibrium favors the ketone rather than the hydrate. However, the equilibrium for hydration of hexafluoroacetone favors formation of the hydrate: Provide a plausible explanation for this observation. + H2O O F3C CF3 3CF CF3 HO OH > 99.99%

Draw a plausible mechanism for each of the following transformations: (a) O [H2SO4] excess MeOH MeO OMe H2O (b) [TsOH] excess EtOH O OEt OEt H2O (c) [H2SO4] excess EtOH O EtO OEt H2O (d) [TsOH] excess MeOH O MeO OMe H2O

Draw a plausible mechanism for each of the following reactions: (b) [H2SO4 O ] HO OH OO (a) HO OH [H2SO4] O O O H2O H2O

Predict the product of each of the following reactions: [H2SO4] excess MeOH O HO OH (a) ? [H2SO4] O H2O (b) H2O

Propose an efficient synthesis for each of the following transformations: O O O O O H H OH O O O O O Ph Ph OH (a) (c) (b

Predict the product(s) for each reaction below: (a) (c) OO H3O+ H3O+ H3O+ H3O+ (b) (d) OMe OMe OO O

Draw a plausible mechanism for the following transformation: OH O O HO [H2SO4]

Compound A has molecular formula C8H14O2. Upon treatment with catalytic acid, compound A is converted into the cyclic hemiacetal shown below. Identify the structure of compound A. O HO Compound A [H+]

Draw a plausible mechanism for each of the following transformations: N [TsOH] MeNH2 O (a) O [TsOH] EtNH2 N Et (b) H2O H2O

Predict the major product for each of the following reactions: [H+] NH3 [H+], O (a) (b) O NH2 H2O ? H2O ?

Predict the major product for each of the following intramolecular reactions: NH2 H O NH2 O [H+] ? [H+] (a) H2O (b) H2O ?

Identify the reactants that you would use to make each of the following imines: N (a) N N (b) (c)

Predict the product of each of the following reactions: O HONH2 [H+] (a) O H2NNH2 [H+] (b) ? ? H2O H2

Identify the reactants that you would use to make each of the following compounds: (a) (b) N OH N NH2

Draw a plausible mechanism for each of the following reactions: O N (a) [H2SO4] Et2NH O [H2SO4] Me2NH (b) N H2O H2O

Predict the major product for each of the following reactions: O (a) H N N H [H+] (b) [H+ ? ] ? O H2O H2O

Predict the major product for each of the following intramolecular reactions: O (a) (b) NH [H+] O H ? N [H+] H2O H2O ?

Identify the reactants that you would use to make each of the following enamines: (a) N (b) N (c)

Predict the product of the following two-step procedure and draw a mechanism for its formation: 1) [H+], H2NNH2, H2O 2) KOH / H2O, heat O ?

Draw the products that are expected for each of the following reactions: (a) O ? O H3O+ (b) N ? H3O+ (c) O O ? H3O+ (d) ? N(CH3)2 H3O+

Draw the products that are expected for each of the following reactions: (a) N ? Excess H3O+ (b) O O ? H3O+

As shown above, methenamine is hydrolyzed in aqueous acid to produce formaldehyde and ammonia. Draw a mechanism showing formation of one molecule of formaldehyde (the remaining five molecules of formaldehyde are each released via a similar sequence of steps). The release of each molecule of formaldehyde is directly analogous to the hydrolysis of an acetal. To get you started, the first two steps are provided below: N N N N N N N N H O H H H ! ! N N N H N H2O

Predict the major product for each of the following: O 2) Raney Ni 1) [H+], HS SH (a) ? O 2) Raney Ni 1) [H+], HS SH (b) ?

Draw the structure of the cyclic compound that is produced when acetone is treated with 1,3-propanedithiol in the presence of an acid catalyst. O HS SH Acetone 1,3-Propanedithiol

Predict the major product for each of the following reactions: ? 1) LAH 2) H2O O (a) ? NaBH4, MeOH H O (b) ? 1) LAH 2) H2O (c) O ? O NaBH4, MeOH (d)

When 2 moles of benzaldehyde are treated with sodium hydroxide, a reaction occurs in which 1 mole of benzaldehyde is oxidized (giving benzoic acid) while the other mole of benzaldehyde is reduced (giving benzyl alcohol): H O 1) NaOH 2) H3O+ OH O H H OH This reaction, called the Cannizzaro reaction, is believed to occur via the following mechanism: A hydroxide ion serves as a nucleophile to attack the carbonyl group of benzaldehyde. The resulting intermediate then functions as a hydride reducing agent by delivering a hydride ion to another molecule of benzaldehyde. In this way, one molecule is reduced while the other is oxidized. (a) Draw a mechanism for the Cannizzaro reaction, consistent with the description above. (b) What is the function of H3O+ in the second step? (c) Water alone is not sufficient to accomplish the function of the second step. Explain.

Predict the major product for each of the following: (a) O 1) EtMgBr 2) H2O ? (b) 1) PhMgBr 2) H2O ? O H (c) 1) PhMgBr 2) H3O+ ?

Identify the reagents necessary to accomplish each of the transformations below: OH OH OH (b) (a) M

Predict the major product for each of the following reaction sequences: 1) KCN, HCN 2) LAH 3) H2O O (a) H ? 1) KCN, HCl 2) H3O+, heat O (b) ?

Identify the reagents necessary to accomplish each of the transformations below: (a) OH OH OH O (b) OH OH NH2

Identify the reagents necessary to prepare each of the following compounds using a Wittig reaction: (a) (b) (d) (e) (c)

Consider the structure of beta-carotene, mentioned earlier in this chapter: -Carotene Design a synthesis of beta-carotene using the compound below as your only source of carbon atoms: Br

Identify the reagents necessary to accomplish each of the transformations below: (a) (b) OH

Predict the major product of each reaction below: O RCO3H (a) ? RCO3H (b) ? O H RCO3H (c) ?

Propose an efficient synthesis for each of the following transformations: (a) (b) (c) (d) OH OH OH e) (f) N Br (g) O O O EtO OEt

Using any compounds of your choosing, identify a method for preparing each of the following compounds. Your only limitation is that the compounds you use can have no more than two carbon atoms. For purposes of counting carbon atoms, you may ignore the phenyl groups of a Wittig reagent. That is, you are permitted to use Wittig reagents. (a) (d) (e) (h) NH OH HO O OH H2N OO O O N HO N (b) (f) (c) (g)

Compound A has molecular formula C10H10O and exhibits a strong signal at 1720 cm1 in its IR spectrum. Treatment with 1,2-ethanedithiol followed by Raney nickel affords the product shown. Identify the structure of compound A. 2) Raney Ni 1) [H+], HS SH

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

Draw the structure for each compound below: (a) Propanedial (b) 4-Phenylbutanal (c) (S)-3-Phenylbutanal (d) 3,3,5,5-Tetramethyl-4-heptanone (e) (R)-3-Hydroxypentanal (f) meta-Hydroxyacetophenone (g) 2,4,6-Trinitrobenzaldehyde (h) Tribromoacetaldehyde (i) (3R,4R)-3,4-Dihydroxy-2-pentanone

Draw all constitutionally isomeric aldehydes with molecular formula C4H8O and provide a systematic (IUPAC) name for each isomer.

Draw all constitutionally isomeric aldehydes with molecular formula C5H10O and provide a systematic (IUPAC) name for each isomer. Which of these isomers possesses a chirality center?

Draw all constitutionally isomeric ketones with molecular formula C6H12O and provide a systematic (IUPAC) name for each isomer.

Explain why the IUPAC name of a compound is unlikely to have the suffix -1-one.

For each pair of the following compounds, identify which compound would be expected to react more rapidly with a nucleophile: (a) O O H (b) O F3C CF3 O H3C CH3

Draw the products of each Wittig reaction below. If two stereoisomers are possible, draw both stereoisomers: (a) O Ph Ph Ph P Ph H ? (b) O Ph Ph Ph Ph Ph P H ?

Draw the structure of the alkyl halide needed to prepare each of the following Wittig reagents and then determine which Wittig reagent will be the more difficult to prepare. Explain your choice: Ph Ph Ph P Ph H Ph Ph Ph P

Show how a Wittig reaction can be used to prepare each of the following compounds. In each case, also show how the Wittig reagent would be prepared: (a) (b)

Choose a Grignard reagent and a ketone that can be used to produce each of the following compounds: (a) 3-Methyl-3-pentanol (b) 1-Ethylcyclohexanol (c) Triphenylmethanol (d) 5-Phenyl-5-nonano

You are working in a laboratory, and you are given the task of converting cyclopentene into 1,5-pentanediol. Your first thought is simply to perform an ozonolysis followed by reduction with LAH, but your lab is not equipped for an ozonolysis reaction. Suggest an alternative method for converting cyclopentene into 1,5-pentanediol. For help, see Section 13.4 (reduction of esters to give alcohols).

Predict the major product(s) from the treatment of acetone with the following: (a) [H+], NH3, (-H2O) (b) [H+], CH3NH2, (-H2O) (c) [H+], excess EtOH, (-H2O) (d) [H+], (CH3)2NH, (-H2O) (e) [H+], NH2NH2 , (-H2O) (f) [H+], NH2OH, (-H2O) (g) NaBH4, MeOH (h) MCPBA (i) HCN, KCN (j) EtMgBr followed by H2O (k) (C6H5)3PRCHCH2CH3 (l) LAH followed by H2O

Propose a plausible mechanism for the following transformation: [H+] EtOH O O O HO H

Devise an efficient synthesis for the following transformation (recall that aldehydes are more reactive than ketones): H O O HO H

Treatment of catechol with formaldehyde in the presence of an acid catalyst produces a compound with molecular formula C7H6O2. Draw the structure of this product. OH OH Catechol

Predict the major product(s) for each reaction below. (c) O (C6H5) 3P=CH2 (a) O 1) LAH 2) H2O (b) O 1) PhMgBr 2) H2O ? ? ?

Starting with cyclopentanone and using any other reagents of your choosing, identify how you would prepare each of the following compounds: (b) (d) O O (c) OH COOH (a

Glutaraldehyde is a germicidal agent that is sometimes used to sterilize medical equipment too sensitive to be heated in an autoclave. In mildly acidic conditions, glutaraldehyde exists in a cyclic form (below right). Draw a plausible mechanism for this transformation: [H3O+] O O HO O OH H H Glutaraldehyde

Predict the major product(s) obtained when each of the following compounds undergoes hydrolysis in the presence of H3O+: (c) O O (a) N (b) N (e) OCH3 O (d)

Identify all of the products formed when the compound below is treated with aqueous acid: N O O N Excess H3O+ ?

Draw a plausible mechanism for each of the following transformations: N H3O+ O H N H (a) N H3O+ O (b) H (c) H2N OH HO O H [H+] O O H2O

Predict the major product(s) for each of the following reactions: O N NH2 CH3 [H+] ( ) (a) ? (c) O CH3CO3H ? (e) O [H+] N H ? O (f) [H+] NH2 ? (d) O CH3CO3H ? O (b) 1) PhMgBr 2) H2O ? H2O ( ) H2O ( )

Identify the starting materials needed to make each of the following acetals: O O (a) O OEt (b) (c) OO

Using ethanol as your only source of carbon atoms, design a synthesis for the following compound: O O

Propose an efficient synthesis for each of the following transformations: O (a) O O O (b) O O O O

The compound below is believed to be a wasp pheromone. Draw the major product formed when this compound is hydrolyzed in aqueous acid: O O

Propose an efficient synthesis for each of the following transformations: (a) (b) Br Br MeO OMe O O (c)

Draw a plausible mechanism for the following transformation: NH2 NH2 N N O O [H2SO4] ( H ) 2

When cyclohexanone is treated with H2O, an equilibrium is established between cyclohexanone and its hydrate. This equilibrium greatly favors the ketone, and only trace amounts of the hydrate can be detected. In contrast, when cyclopropanone is treated with H2O, the resulting hydrate predominates at equilibrium. Suggest an explanation for this curious observation.

Consider the three constitutional isomers of dioxane (C4H8O2): O O 1,2-Dioxane O O 1,3-Dioxane O O 1,4-Dioxane One of these constitutional isomers is stable under basic conditions as well as mildly acidic conditions and is therefore used as a common solvent. Another isomer is only stable under basic conditions but undergoes hydrolysis under mildly acidic conditions. The remaining isomer is extremely unstable and potentially explosive. Identify each isomer and explain the properties of each compound.

Propose an efficient synthesis for each of the following transformations: (b) Br OH CN (d) O O (a) O O (c) CN Br (f) O H (h) O O (e) NH (g) N

Compound A has molecular formula C7H14O and reacts with sodium borohydride in methanol to form an alcohol. The 1 H NMR spectrum of compound A exhibits only two signals: a doublet (I = 12) and a septet (I = 2). Treating compound A with 1,2-ethanedithiol (HSCH2CH2SH) under acidic conditions, followed by Raney nickel gives compound B. (a) How many signals will appear in the 1 H NMR spectrum of compound B? (b) How many signals will appear in the 13C NMR spectrum of compound B? (c) Describe how you could use IR spectroscopy to verify the conversion of compound A to compound B.

Using the information provided below, deduce the structures of compounds A, B, C, and D: C B A (C9H10O) (C10H12) D (C11H16O) 1) O3 1) EtMgBr 2) DMS 2) H2O AlCl3 N [H+], (CH3) 2NH ( H )

Identify the structures of compounds A to D below and then identify the reagents that can be used to convert cyclohexene into compound D in just one step. H3O+ A H2CrO4 B NH2NH2 [H+] C KOH /H2O Heat D ( H )

Identify the structures of compounds A to E below: Br2 FeBr3 A Mg B C PCC E D 1) H O H 2) H2O HO OH [H+], H2O

An aldehyde with molecular formula C4H6O exhibits an IR signal at 1715 cm-1 . (a) Propose two possible structures that are consistent with this information. (b) Describe how you could use 13C NMR spectroscopy to determine which of the two possible structures is correct.

A compound with molecular formula C9H10O exhibits a strong signal at 1687 cm-1 in its IR spectrum. The 1 H and 13C NMR spectra for this compound are shown below. Identify the structure of this compound. 9 7 8 6 5432 1 Proton NMR Carbon 13 NMR 199.9 136.7 31.3 7.9 132.5 128.3 127.7 2 3 2 3 200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) Chemical Shift (ppm)

A compound with molecular formula C13H10O produces a strong signal at 1660 cm1 in its IR spectrum. The 13C NMR spectrum for this compound is shown below. Identify the structure of this compound. 196.7 137.5 132.4 130.0 128.3 200 190 180 170 160 150 140 130 120 110 100 Carbon 13 NMR Chemical Shift (ppm)

A ketone with molecular formula C9H18O exhibits only one signal in its 1 H NMR spectrum. Provide a systematic (IUPAC) name for this compound.

Draw a plausible mechanism for each of the following transformations: O N H3O+ (a) HO O H + H3C CH3 N HH H3O+ [H2SO4] (b) (c) (d) O OCH3 NH2NH2 H O O H H + N N H OH O O O O [H2SO4] OH ! [TsOH] O (e) [H2SO4] (f) OH O OCH3 OCH3 OCH3 OH OO HO OH

Under acid-catalyzed conditions, formaldehyde polymerizes to produce a number of compounds, including metaformaldehyde. Draw a plausible mechanism for this transformation: H O H [H3O+] OO O Metaformaldehyde

The following transformation was employed during synthetic studies toward the total synthesis of cyclodidemniserinol trisulfate, found to inhibit HIV-1 integrase (Tetrahedron Lett. 2009, 50, 4587 4591). Propose a four-step synthesis to accomplish this transformation. EtO O O OR OR S S OO Four steps

Propose an efficient synthesis for the conversion of the following ketone to the following ether. One of these compounds has nearly twice as many signals in its 1 H NMR spectrum than the other compound. Identify the compound that is expected to produce fewer signals, and explain your choice. (J. Org. Chem. 2001, 66, 20722077).

The reaction of cyclohexanone with the given optically pure aminoester resulted in the formation of two enamines that were conformational isomers of each other (Tetrahedron Lett., 1969, 10, 4233 4236). Draw the structures of the two isomers using wedges and dashes to indicate stereochemistry. Explain why the two enamines interconvert very slowly at room temperature. O N CO2Et TsOH + H H2O ?

Which of the following is the correct sequence of reactions needed to transform ketone 1 into aldehyde 2, or will all three routes produce the desired product? (J. Org. Chem. 2003, 68, 64556458). Explain your choice(s). O O H Sequence A Sequence B Sequence C 1) 2) H2SO4, heat 3) AcOH, H2O 1) 1) 2) H2SO4, heat 2) H2SO4, heat 3) O3, DMS 3) BH3THF H2O2, NaOH 4) PCC

Furo[2,3-b]indoles are compounds whose structural features are present in many natural products with biological activity. In a recently reported method for the synthesis of furo[2,3-b]indoles, the conversion of compound 1 to compound 2 was accomplished in just two steps (Tetrahedron Lett. 2010, 51, 44944496). Propose a twostep synthesis for this transformation. CHO NO2 NO2 CHO 1 2

In a Bamford-Stevens-Shapiro reaction, a sulfonylhydrazone (1) undergoes base-catalyzed decomposition to give a vinyl lithium species (2) which can then react with an electrophile, such as compound 3. This reaction was recently employed in the total synthesis of frondosin B, a marine natural product with potential application in cancer chemotherapy (Chem. Sci. 2010, 1, 3742). Formation of 2 is believed to occur via a process that is mechanistically analogous to the Wolff-Kishner reduction. Draw a plausible mechanism for the conversion of 1 to 2. N N H S R R R O O Li 1 2 3 O O O (+)-Frondosin B O t-BuLi (2 equiv)

A convenient method for achieving the transformation below involves treatment of the ketone with Wittig reagent 1 followed by acid-catalyzed hydration (Chem. Ber. 1962, 95, 25142525): O O 1) PPh3 MeO H 2) H3O+ 1 (a) Predict the product of the Wittig reaction. (b) Propose a plausible mechanism for the acid-catalyzed hydration to form the aldehyde.

During a recent synthesis of hispidospermidin, a fungal isolate and an inhibitor of phospholipase C, the investigators employed a novel, aliphatic Friedel-Crafts acylation (J. Am. Chem. Soc. 1998, 120, 40394040). The following acid chloride was treated with a Lewis acid, affording two products in a 3:2 ratio. Propose a plausible mechanism for the formation of compounds 1 and 2. COCl H H AlCl3 O Cl + O 1 2

During a recent total synthesis of kibdelone C, a cytotoxic natural product isolated from soil bacteria, the investigators treated compound 1 with acetone and catalytic aqueous acid to afford acetal 2 (J. Am. Chem. Soc. 2011, 133, 99569959). Propose a plausible mechanism for this transformation. OMe OMe Br OH O O OH OH OMe OMe Br O O OH

Treatment of the following ketone with LAH affords two products, A and B. Compound B has a molecular formula of C8H14O and exhibits strong signals at 3305 cm-1 (broad) and 2117 cm-1 in its IR spectrum (J. Am. Chem. Soc. 2006, 128, 64996507): OTf O OTf OH A + 1) LAH B (C8H14O) 2) H2O ? (a) Using the following 1 H NMR data, deduce the structure of compound B: 0.89 d (6H, singlet), 1.49 d (1H, broad singlet), 1.56 d (2H, triplet), 1.95 d (1H, singlet), 2.19 d (2H, triplet), 3.35 d (2H, singlet). (b) Provide a plausible mechanism to account for the formation of compound B. (Hint: Tf = triflate, Section 7.8.)