Starting with benzene and using any other

Rank each set of compounds in order of increasing acidity: COOH O2N COOH H3C COOH O COOH Br COOH O (a) OH Br O OH O Br OH O (b) Br

Malonic acid has two acidic protons: OH O HO O Malonic acid The pKa of the first proton (pK1) is measured to be 2.8, while the pKa of the second proton (pK2) is measured to be 5.7. (a) Explain why the first proton is more acidic than acetic acid (pKa=4.76). (b) Explain why the second proton is less acidic than acetic acid. (c) Draw the form of malonic acid that is expected to predominate at physiological pH. (d) For succinic acid (HO2CCH2CH2CO2H), pK1=4.2 (which is higher than pK1 for malonic acid) and pK2=5.6 (which is lower than pK2 for malonic acid). In other words, the difference between pK1 and pK2 is not as large for succinic acid as it is for malonic acid. Explain this observation.

Identify a systematic (IUPAC) name for each of the following compounds: OH O (a) NH2 O (b) Cl O (c) Note: Most of the Problems are available within , an online teaching and learning solution. O O (d) (e) CH3(CH2)4CO2H (f) CH3(CH2)3COCl (g) CH3(CH2)4CONH2

Identify the common name for each of the following compounds: O O O (a) OH O (b) H OH O (c) HO OH O O (d

Draw the structures of eight different carboxylic acids with molecular formula C6H12O2. Then, provide a systematic name for each compound and identify which three isomers exhibit chirality centers.

Draw and name all constitutionally isomeric acid chlorides with molecular formula C4H7ClO. Then provide a systematic name for each isomer.

Identify the reagents you would use to convert pentanoic acid into each of the following compounds: (a) 1-Pentanol (b) 1-Pentene (c) Hexanoic acid

Identify the reagents you would use to convert each of the following compounds into pentanoic acid: (a) 1-Pentene (b) 1-Bromobutane

Careful measurements reveal that para-methoxybenzoic acid is less acidic than benzoic acid, while meta-methoxybenzoic acid is more acidic than benzoic acid. Explain these observations.

Predict the major product(s) formed when hexanoyl chloride is treated with each of the following reagents: (a) CH3CH2NH2 (excess) (b) LAH (excess), followed by H2O (c) CH3CH2OH, pyridine (d) H2O, pyridine (e) C6H5CO2Na (f) NH3 (excess) (g) Et2CuLi (h) EtMgBr (excess), followed by H2O

Predict the major product(s) formed when cyclopentanecarboxylic acid is treated with each of the following reagents: (a) SOCl2 (b) LAH (excess), followed by H2O (c) NaOH (d) [H+], EtOH

Predict the major product(s) for each of the following reactions: OH O 1) xs LAH (a) 2) H2O ? OH O 1) SOCl2 2) xs (CH3) (b) 2NH ? NH2 O SOCl2 (c) ? OMe O 1) H3O+ 2) CH3COCl, (d) pyridine ? OMe O 1) DIBAH (e) 2) H2O ? OH O O O (f) ? N H Cl O (g) Pyridine ? O O 1) xs LAH 2) H2O ? (h) N O H3O+ (i) Heat ? O O H3O+ (j) ?

Identify the carboxylic acid and the alcohol that are necessary in order to make each of the following compounds via a Fischer esterification: O O (a) O O (b) (c) CH3CH2CO2C(CH3)3

Determine the structures of compounds A through F: OH D A E F B C 2) H2O 1) LiAl(OR)3H [H+] EtOH Na2Cr2O7 H2SO4, H2O SOCl2 xs NH3

Identify the reagents you would use to convert 1-bromopentane into each of the following compounds: (a) Pentanoic acid (b) Hexanoic acid (c) Pentanoyl chloride (d) Hexanamide (e) Pentanamide (f) Ethyl hexanoate

Starting with benzene and using any other reagents of your choice, show how you would prepare each of the following compounds: OH (a) N O (b) OH (c) O N O H (d)

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

When methyl benzoate bears a substituent at the para position, the rate of hydrolysis of the ester group depends on the nature of the substituent at the para position. Apparently, a methoxy substituent renders the ester less reactive, while a nitro substituent renders the ester more reactive. Explain this observation.

Identify the reagents necessary to accomplish each of the following transformations: OH O Cl O O O O OR O NH2 O O H

DEET is the active ingredient in many insect repellants, such as OFFTM. Starting with meta- bromotoluene and using any other reagents of your choice, devise an efficient synthesis for DEET. N O N,N-Diethyl-m-toluamide (DEET) Br m-Bromotoluene

Predict the products that are formed when diphenyl carbonate is treated with excess methyl magnesium bromide. O O O 1) Excess MeMgBr 2) H3O+

When acetic acid is treated with isotopically labeled water ( 18O, shown in red) in the presence of a catalytic amount of acid, it is observed that the isotopic label becomes incorporated at both possible positions of acetic acid. Draw a mechanism that accounts for this observation. OH O OH O OH O [H+] H2O +

Phosgene is highly toxic and was used as a chemical weapon in World War I. It is also a synthetic precursor used in the production of many plastics. (a) When vapors of phosgene are inhaled, the compound rapidly reacts with any nucleophilic sites present (OH groups, NH2 groups, etc.), producing HCl gas. Draw a mechanism for this process. (b) When phosgene is treated with ethylene glycol (HOCH2CH2OH), a compound with molecular formula C3H4O3 is obtained. Draw the structure of this product. (c) Predict the product that is expected when phosgene is treated with excess phenylmagnesium bromide, followed by water.

Fluphenazine is an antipsychotic drug that is administered as an ester prodrug via intramuscular injection: S N N N O CF3 O Fluphenazine decanoate The hydrophobic tail of the ester is deliberately designed to enable a slow release of the prodrug into the bloodstream, where the prodrug is rapidly hydrolyzed to produce the active drug. (a) Draw the structure of the active drug. (b) Draw the structure of and assign a systematic name for the carboxylic acid that is produced as a by-product of the hydrolysis step.

Benzyl acetate is a pleasant-smelling ester found in the essential oil of jasmine flowers and is used in many perfume formulations. Starting with benzene and using any other reagents of your choice, design an efficient synthesis for benzyl acetate.

Aspartame (below) is an artificial sweetener used in diet soft drinks and is marketed under many trade names, including Equal and Nutrasweet. In the body, aspartame is hydrolyzed to produce methanol, aspartic acid, and phenylalanine. The production of phenylalanine poses a health risk to infants born with a rare condition called phenylketonuria, which prevents phenylalanine from being digested properly. Draw the structures of aspartic acid and phenylalanine. Aspartame N O O O NH2 OH H O

Draw a plausible mechanism for each of the following transformations: Cl O O O Pyridine OH (a) O O HO O OH 1) NaOH 2) H3O+ (b) O O OH OH (c) O 1) NaOH 2) H3O+ Cl O Cl O N O N O H H (d) H2N NH2 Excess pyridine O O OH OH 1) Excess EtMgBr 2) H2O (e)

Ethyl trichloroacetate is significantly more reactive toward hydrolysis than ethyl acetate. Explain this observation.

Draw the structure of the diol that is produced when the following carbonate is heated under aqueous acidic conditions: O O O H3O+ Heat

Pivampicillin is a penicillin prodrug: Pivampicillin N O N S O 2 HNH O O O O The prodrug ester group (in red) enables a more rapid delivery of the prodrug to the bloodstream, where the ester group is subsequently hydrolyzed by enzymes, releasing the active drug. (a) Draw the structure of the active drug. (b) What is the name of the active drug (see the Medically Speaking box at the end of Section 21.12)?

Dexon (below) is a polyester that is spun into fibers and used for surgical stitches that dissolve over time, eliminating the need for a follow-up procedure to remove the stitches. The ester groups are slowly hydrolyzed by enzymes present in the body, and in this way, the stitches are dissolved over a period of several months. Hydrolysis of the polymer produces glycolic acid, which is readily metabolized by the body. Draw the structure of glycolic acid. Identify a systematic name for glycolic acid. Dexon O O O O O O O O

Draw the structure of the polymer produced when the following two monomers are allowed to react with each other: Cl Cl O O HO OH

Identify what monomers you would use to produce the following polymer: N O N H H O O O N H N H

meta-Hydroxybenzoyl chloride is not a stable compound, and it polymerizes upon preparation. Show a mechanism for the polymerization of this hypothetical compound.

Propose an efficient synthesis for each of the following transformations: OH O OO (a) NH2 O N (b) O N O (c) OMe O H SS (d) COOH O O (e) OH (f) OH O O O O O (g)

Starting with benzene and using any other reagents of your choice, devise a synthesis for acetaminophen: Acetaminophen (Tylenol) N HO O H

Draw a plausible mechanism for the following transformation: OH O O O O O HO H3O+

A carboxylic acid with molecular formula C5H10O2 is treated with thionyl chloride to give compound A. Compound A has only one signal in its 1 H NMR spectrum. Draw the structure of the product that is formed when compound A is treated with excess ammonia.

A compound with molecular formula C10H10O4 exhibits only two signals in its 1 H NMR spectrum: a singlet at 4.0 (I = 3H) and a singlet at 8.1 (I = 2H). Identify the structure of this compound.

Describe how you could use IR spectroscopy to distinguish between ethyl acetate and butyric acid.

Describe how you could use NMR spectroscopy to distinguish between benzoyl chloride and para- chlorobenzaldehyde.

A compound with molecular formula C8H8O3 exhibits the following IR, 1 H NMR, and 13C NMR spectra. Deduce the structure of this compound. Proton NMR Carbon NMR 1 2 2 3 180 160 140 120 100 80 60 40 20 0 12 11 10 9 8 7 6 5 3 4 Chemical Shift (ppm) Chemical Shift (ppm) 172.8 167.9 118.3 64.1 139.4 128.0 Wavenumber (cm1) 4000 3500 3000 2500 2000 1500 1000 % Transmittance 0 20 40 60 80 100

Propose a mechanism for the following transformation, and explain how you could use an isotopic labeling experiment to verify your proposed mechanism: O O HO R HO O O [H2SO4] R

N-Acetylazoles undergo hydrolysis more readily than regular amides. Suggest a reason for the enhanced reactivity of N-acetylazoles toward nucleophilic acyl substitution:

Dimethylformamide (DMF) is a common solvent: Dimethylformamide H N CH3 CH3 O (a) The 1 H NMR spectrum of DMF exhibits three signals. Upon treatment with excess LAH followed by water, DMF is converted into a new compound that exhibits only one signal in its 1 H NMR spectrum. Explain. (b) Based on your answer to part a, how many signals do you expect in the 13C NMR spectrum of DMF?

Olefin metathesis (2005 Nobel Prize) using the Grubbs catalyst has emerged as one of the most important tools for the organic chemist (e.g., 2 to 3). Metathesis substrate 2 can be prepared from 1 in three steps, shown below (Org. Lett. 2000, 2, 791794). Show the product of each synthetic step. Ph OH 1) NaH, then 2) DIBAH 3) Ph3P CH2 Br CO2Et Ph O Ph O Grubbs catalyst 1 2 3

Aminotetralins are a class of compounds currently being studied for their promise as antidepressant drugs. The following conversion was employed during a mechanistic study associated with a synthetic route for preparing aminotetralin drugs (J. Org. Chem. 2012, 77, 55035514). Propose a three-step synthesis for this process. CH3 CO2H Three steps Br CH3 Br CH3

Steroidal derivatives are important pharmacologically and biologically, and they continue to be a popular backbone in the search for new biologically active steroid hormone analogues. Propose a possible three-step synthesis for the conversion of steroid 1 to steroid 2, an intermediate in the synthesis of pentacyclic steroids (Tetrahedron Lett. 2012, 53, 18591862). H H H OCH3 OCH3 OCH3 H OH H3CO H3CO O H H H H O O O Three steps 1 2 H H

Allylic bromide 2 was recently used as a key fragment in progress toward the total synthesis of an analogue of amphidinolide N, a potent cytotoxic agent isolated from the marine organism Amphidinium sp. (Org. Biomol. Chem. 2006, 4, 21192157). Propose an efficient synthesis of bromide 2 from carboxylic acid 1. OH O SiMe3 SiMe3 OSiMe2t-Bu OSiMe2t-Bu O O Br O O Compound 1 Compound 2

Compound 3 (below) was used as an intermediate in a recently reported synthesis of the g-secretase inhibitor BMS-708163 (Tetrahedron Lett. 2010, 51, 65426544). Compound 3 was made from compound 1 via the two-step process shown below. (a) Compound 1 cannot be directly converted into compound 3 upon treatment with aqueous sodium hydroxide, because undesired side products would occur. Identify the possible side products. (b) Draw a complete mechanism for the two-step synthesis below. Br NC F OH NC F 1 2 O NC F 3 O DMF OK O NaOMe MeOH

The m- and p-substituted methyl benzoates listed in the table below were treated with NaOH in dioxane and water. The rate constants of saponification, k, are also listed in the table (J. Am. Chem. Soc. 1961, 83, 42144216). Provide structural explanations for the trend observed in the rate constants by comparing the effects of the various substituents on the rate constant. Include all necessary resonance structures in your discussion. O OCH3 Y m- or p-substituted methyl benzoate NaOH Dioxane:water (3:2) 35 C O ONa Y + CH3OH p- and m-Substituted Methyl Benzoates k (M1 min1 ) Methyl p-nitrobenzoate 102 Methyl m-nitrobenzoate 63 Methyl m-chlorobenzoate 9.1 Methyl m- bromobenzoate 8.6 Methyl benzoate 1.7 Methyl p-methylbenzoate 0.98 Methyl p-methoxybenzoate 0.42 Methyl p-aminobenzoate 0.06

Prostaglandins (Section 26.7) are a group of structurally related compounds that function as biochemical regulators and exhibit a wide array of activity, including the regulation of blood pressure, blood clotting, gastric secretions, inflammation, kidney function, and reproductive systems. The following two-step transformation was employed by E. J. Corey during his classic prostaglandin synthesis (J. Am. Chem. Soc. 1970, 92, 397398). Identify the reagents that you would use to convert compound 1 to compound 3 and draw the structure of compound 2. MeO 1 2 HO 3 HO O OMe O

The following two-step rearrangement was the cornerstone of the first stereoselective total synthesis of quadrone, a biologically active natural product isolated from an Aspergillus fungus (J. Org. Chem. 1984, 49, 40944095). Propose a plausible mechanism for this transformation. 1) NaH 2) H2SO2 CO2H OMs O O H2O

During recent studies to determine the absolute stereochemistry of a bromohydrin, the investigators observed an unexpected skeletal rearrangement (Tetrahedron Lett. 2008, 49, 68536855). Provide a plausible mechanism for the formation of epoxide 2 from bromohydrin 1. O O H H Br HO NaH O O H H O 1 2

During a recent total synthesis of englerin A, a potent cytotoxic natural product isolated from the stem bark of a Tanzanian plant, the investigators observed the following (unusual) base-catalyzed ring contraction (Angew. Chem. Int. Ed. 2009, 48, 91059108). Propose a plausible mechanism for this transformation. O H H O O H H O O CHO NaOMe