Propose mechanisms for the formation and reactions of ethers and epoxides

Rank the given solvents in decreasing order of their ability to dissolve each compound. NaOAc naphthalene (a) Solutes (b) 2-naphthol ethyl ether water ethanol dichloromethane (c) OH Solvents

Aluminum trichloride (AlCl3) dissolves in ether with the evolution of a large amount of heat. (In fact, this reaction can become rather violent if it gets too warm.) Show the structure of the resulting aluminum chloride etherate complex.

In the presence of 18-crown-6, potassium permanganate dissolves in benzene to give purple benzene, a useful reagent for oxidizing alkenes in an aprotic environment. Use a drawing of the complex to show why KMnO4 dissolves in benzene and why the reactivity of the permanganate ion is enhanced.

Give a common name (when possible) and a systematic name for each compound. (a) CH3OCHCH2 (b) CH3CH2OCH(CH3)2 (c) ClCH2CH2OCH3 OCH2CH3 (d) OCH3 OCH3 (e) OH OCH3 (f) OCH3 (g) (h) CH3CCCH2OCH3 (i) OCH3

1,4-Dioxane is made commercially by the acid-catalyzed condensation of an alcohol. (a) Show what alcohol will undergo condensation, with loss of water, to give 1,4-dioxane. (b) Propose a mechanism for this reaction.

Name the following heterocyclic ethers. O (a) O Cl (b) O CH(CH3)2 O (c) O CH2CH3 H H CH3CH2 (d) OCH2CH3 Br O (e) O CH3 CH3 Br (f )

Propose a fragmentation to account for each numbered peak in the mass spectrum of n-butyl isopropyl ether.

Propose a Williamson synthesis of 3-butoxy-1,1-dimethylcyclohexane from 3,3-dimethylcyclohexanol and butan-1-ol.

Show how you would use the Williamson ether synthesis to prepare the following ethers. You may use any alcohols or phenols as your organic starting materials. (a) cyclohexyl propyl ether (b) isopropyl methyl ether (c) 1-methoxy-4-nitrobenzene (d) ethyl n-propyl ether (two ways) (e) benzyl tert-butyl ether (benzyl = PhCH2)

Show how the following ethers might be synthesized using (1) alkoxymercuration demercuration and (2) the Williamson synthesis. (When one of these methods cannot be used for the given ether, point out why it will not work.) (a) 2-methoxybutane (b) ethyl cyclohexyl ether (c) 1-methoxy-2-methylcyclopentane (d) 1-methoxy-1-methylcyclopentane (e) 1-isopropoxy-1-methylcyclopentane (f) tert-butyl phenyl ether

Explain why bimolecular condensation is a poor method for making unsymmetrical ethers such as ethyl methyl ether.

Propose a mechanism for the acid-catalyzed condensation of n-propyl alcohol to n-propyl ether, as shown above. When the temperature is allowed to rise too high, propene is formed. Propose a mechanism for the formation of propene, and explain why it is favored at higher temperatures.

Which of the following ethers can be formed in good yield by condensation of the corresponding alcohols? For those that cannot be formed by condensation, suggest an alternative method that will work. (a) dibutyl ether (b) ethyl n-propyl ether (c) di-sec-butyl ether

Propose a mechanism for the following reaction.

Predict the products of the following reactions. An excess of acid is available in each case. (a) ethoxycyclohexane + HBr (b) tetrahydropyran + HI (c) anisole (methoxybenzene) + HBr

Boron tribromide (BBr3) cleaves ethers to give alkyl halides and alcohols. ROR + BBr3 ROBBr2 + RBr ROBBr2 + 3 H2O ROH + B(OH)3 + 2 HBr The reaction is thought to involve attack by a bromide ion on the Lewis acidbase adduct of the ether with BBr3 (a strong Lewis acid). Propose a mechanism for the reaction of butyl methyl ether with BBr3 to give (after hydrolysis) butan-1-ol and bromomethane.

Show how you would synthesize butyl isopropyl sulfide using butan-1-ol, propan-2-ol, and any solvents and reagents you need.

Mustard gas, ClCH2CH2SCH2CH2Cl, was used as a poisonous chemical agent in World War I. Mustard gas is much more toxic than a typical primary alkyl chloride. Its toxicity stems from its ability to alkylate amino groups on important metabolic enzymes, rendering the enzymes inactive. (a) Propose a mechanism to explain why mustard gas is an exceptionally potent alkylating agent. (b) Bleach (sodium hypochlorite, NaOCl, a strong oxidizing agent) neutralizes and inactivates mustard gas. Bleach is also effective on organic stains because it oxidizes colored compounds to colorless compounds. Propose products that might be formed by the reaction of mustard gas with bleach.

Show how you would use a protecting group to convert 4-bromobutan-1-ol to hept-5-yn-1-ol.

Show how you would accomplish the following transformations. Some of these examples require more than one step. (a) 2-methylpropene 2,2-dimethyloxirane (b) 1-phenylethanol 2-phenyloxirane (c) 5-chloropent-1-ene tetrahydropyran (d) 5-chloropent-1-ene 2-methyltetrahydrofuran (e) 2-chlorohexan-1-ol 1,2-epoxyhexane

The 2001 Nobel Prize in Chemistry was awarded to three organic chemists who have developed methods for catalytic asymmetric syntheses. An asymmetric (or enantioselective) synthesis is one that converts an achiral starting material into mostly one enantiomer of a chiral product. K. Barry Sharpless (The Scripps Research Institute) developed an asymmetric epoxidation of allylic alcohols that gives excellent chemical yields and greater than 90% enantiomeric excess. The Sharpless epoxidation uses tert-butyl hydroperoxide, titanium(IV) isopropoxide, and a dialkyl tartrate ester as the reagents. The following epoxidation of geraniol is typical.

Propose mechanisms for the epoxidation and ring-opening steps of the epoxidation and hydrolysis of trans-but-2-ene shown above. Predict the product of the same reaction with cis-but-2-ene.

Cellosolve® is the trade name for 2-ethoxyethanol, a common industrial solvent. This compound is produced in chemical plants that use ethylene as their only organic feedstock. Show how you would accomplish this industrial process.

Show the rest of the mechanism for formation of the cyclized intermediate in Figure 14-6.

Propose a complete mechanism for the reaction of cyclopentene oxide with sodium methoxide in methanol.

Predict the major product when each reagent reacts with ethylene oxide. (a) NaOCH2CH3 (sodium ethoxide) (b) NaNH2 (sodium amide) (c) NaSPh (sodium thiophenoxide) (d) PhNH2 (aniline) (e) KCN (potassium cyanide) (f) NaN3 (sodium azide)

Predict the major products of the following reactions, including stereochemistry where appropriate. (a) 2,2-dimethyloxirane + H+ >H2 18O (oxygen-labeled water) (b) 2,2-dimethyloxirane + H18O- >H2 18O (c) (2S,3R)-2-ethyl-2,3-dimethyloxirane + CH3O- >CH3OH (d) (2S,3R)-2-ethyl-2,3-dimethyloxirane + H+ >CH3OH

Give the expected products of the following reactions. Include a protonation step where necessary. (a) 2,2@dimethyloxirane + isopropylmagnesium bromide (b) propylene oxide + n-butyllithium (c) cyclopentyloxirane + ethyllithium

Draw and name ethers and heterocyclic ethers, including epoxides. Predict their relative boiling points, solubilities, and solvent properties.

Determine the structure of ethers from their spectra, and predict their characteristic absorptions and fragmentations.

Devise efficient laboratory syntheses of ethers and epoxides, including the following: (a) The Williamson ether synthesis (b) Alkoxymercuration-demercuration (c) Peroxyacid epoxidation (d) Base-promoted cyclization of halohydrins (e) Formation of silyl ethers (Problems 14-34, 40, 41, 42, 43, 45, 46, and 53)

Predict the products of reactions of ethers and epoxides, including the following: (a) Cleavage and autoxidation of ethers (b) Acid- and base-promoted opening of epoxides (c) Reactions of epoxides with organometallic reagents (d) Cleavage of silyl ethers (Problems 14-33, 36, 46, 50, and 51)

Propose mechanisms for the formation and reactions of ethers and epoxides. (Problems 14-39, 47, 48, 49, 53, and 54)

Write structural formulas for the following compounds. (a) ethyl isopropyl ether (b) di-n-butyl ether (c) 2-ethoxyoctane (d) divinyl ether (e) allyl methyl ether (f) cyclohexene oxide (g) cis-2,3-epoxyhexane (h) (2R,3S)-2-methoxypentan-3-ol (i) trans-2,3-dimethyloxirane

Give common names for the following compounds. (a) (CH3)2CHOCH(CH3)CH2CH3 (b) (CH3)3COCH2CH(CH3)2 (c) PhOCH2CH3 (d) ClCH2OCH2CH2CH3 H OH H OCH3 (e) OCH3 (f ) O CH3 (g) O (h) (i) O O CH3 (j)

Give IUPAC names for the following compounds. (a) CH3OCH(CH3)CH2OH (b) PhOCH2C

Glycerol (propane-1,2,3-triol) is a viscous syrup with molecular weight 92 g/mol, boiling point \(290^{\circ}C\), and density 1.24 g/mL. Transforming the three hydroxy groups into their trimethylsilyl ethers (using chlorotrimethylsilane and a tertiary amine) produces a liquid that flows easily, has molecular weight 309 g/mol, boiling point approximately \(180^{\circ}C\), and density 0.88 g/mL. Draw the structures of these two compounds, and explain why glycerol has a lower molecular weight but a much higher boiling point and density.

Predict the products of the following reactions. (a) sec-butyl isopropyl ether + concd. HBr, heat (b) 2-ethoxy-2-methylpentane + concd. HBr, heat (c) di-n-butyl ether + hot concd. NaOH (d) di-n-butyl ether + Na metal (e) ethoxybenzene + concd. HI, heat (f) 1,2@epoxyhexane + H+, CH3OH (g) trans@2,3@epoxyoctane + H+, H2O (h) propylene oxide + methylamine (CH3NH2) (i) potassium tert@butoxide + n@butyl bromide O (1) PhLi phenyllithium (2) H3O+ (j) mCPBA, CH2Cl2 (k) O HBr (l) O CH3O, CH3OH (m) CH3OH, H+

Show how you would make the following ethers, using only simple alcohols and any needed reagents as your starting materials. (a) 1-methoxybutane (b) 2-ethoxy-2-methylpropane (c) benzyl cyclopentyl ether (d) trans-2-methoxycyclohexanol (e) the TIPS ether of (d) (f) cyclohexyl cyclopentyl ether

(A true story.) An inexperienced graduate student moved into a laboratory and began work. He needed some diethyl ether for a reaction, so he opened an old, rusty 1-gallon can marked “ethyl ether” and found there was half a gallon left. To purify the ether, the student set up a distillation apparatus, started a careful distillation, and went to the stockroom for the other reagents he needed. While he was at the stockroom, the student heard a muffled “boom.” He quickly returned to his lab to find a worker from another laboratory putting out a fire. Most of the distillation apparatus was embedded in the ceiling. (a) Explain what probably happened. (b) Explain how this near-disaster might have been prevented.

Grignard reactions are often limited by steric hindrance. While Grignard reagents react in high yield with ethylene oxide and monosubstituted epoxides, yields are often lower with disubstituted epoxides. Tri- and tetrasubstituted epoxides react with difficulty, if at all. (a) Show how to make these alcohols by a Grignard reacting with an epoxide. (i) 2 ways OH (ii) OH (b) These alcohols cannot be made by a Grignard plus an epoxide. Show the reagents that would be required and why that reaction would be unlikely to succeed. OH (i ) (ii) OH

(a) Show how you would synthesize the pure (R) enantiomer of 2-butyl methyl sulfide, starting with pure (R)-butan-2-ol and any reagents you need. (b) Show how you would synthesize the pure (S) enantiomer of the product, still starting with (R)-butan-2-ol and any reagents you need.

(a) Predict the values of m>z and the structures of the most abundant fragments you would observe in the mass spectrum of di-n-propyl ether. (b) Give logical fragmentations to account for the following ions observed in the mass spectrum of 2-methoxypentane: 102, 87, 71, 59, 31.

The following reaction resembles the acid-catalyzed cyclization of squalene oxide. Propose a mechanism for this reaction. CH2OH O CH3 OH H+ H2O

Show how you would convert hex-1-ene to each of the following compounds. You may use any additional reagents and solvents you need. (a) 2-methoxyhexane (b) 1-methoxyhexane (c) 1-methoxyhexan-2-ol (d) 2-methoxyhexan-1-ol (e) 1-phenylhexan-2-ol (f) 2-methoxy-1-phenylhexane

Both LiAlH4 and Grignard reagents react with carbonyl compounds to give alkoxide ion intermediates (that become protonated in an aqueous workup). Those alkoxides can react with 1 or methyl alkyl halides or tosylates to give ethers. Show how the following ethers can be formed in this two-step process. As starting materials you may use any reactants containing 7 carbons or fewer. (a) O O (b) (c) O

Give the structures of intermediates A through H in the following synthesis of trans-1-cyclohexyl-2-methoxycyclohexane. (1) E (2) H3O+ heat H2SO4 (1) Hg(OAc)2, CH3OH (2) NaBH4 Mg, ether heat concd. HBr OH B C (gas) D A F G H mCPBA Na product C +

Give the structures of the intermediates represented by letters in this synthesis. OCH3 J L M O N Q K K P O OH OH TsCl pyridine KO-tBu TIPSCl Et3N Mg ether ether TEMPO 1 equiv. NaOCl LiAlH4 ether H3O+ H3O+ Bu4N+ F

(Another true story.) An organic lab student carried out the reaction of methylmagnesium iodide with acetone \(\left(\mathrm{CH}_{3} \mathrm{COCH}_{3}\right)\), followed by hydrolysis. During the distillation to isolate the product, she forgot to mark the vials she used to collect the fractions. She turned in a product of formula \(\mathrm{C}_{4} \mathrm{H}_{10} \mathrm{O}\) that boiled at \(35^{\circ} \mathrm{C}\). The IR spectrum showed only a weak O-H stretch around \(3300 \mathrm{~cm}^{-1}\) , and the mass spectrum showed a base peak at m/z 59. The NMR spectrum showed a quartet (J = 7 Hz) of area 2 at \(\delta 3.5\) and a triplet (J = 7 Hz) of area 3 at \(\delta 1.3\). Propose a structure for this product, explain how it corresponds to the observed spectra, and suggest how the student isolated this compound.

Show how you would synthesize the following ethers in good yield from the indicated starting materials and any additional reagents needed. (a) cyclopentyl n-propyl ether from cyclopentanol and propan-1-ol (b) n-butyl phenyl ether from phenol and butan-1-ol (c) 2-ethoxyoctane from an octene (d) 1-methoxydecane from a decene (e) 1-ethoxy-1-methylcyclohexane from 2-methylcyclohexanol (f) trans-2,3-epoxyoctane from octan-2-ol

Show how you would convert 3-bromocyclohexanol to the following diol. You may use any additional reagents you need. HO Br HO OH (several steps) CH3 CH2CH3

There are two different ways of making 2-ethoxyoctane from octan-2-ol using the Williamson ether synthesis. When pure (-)@octan@2@ol of specific rotation -8.24 is treated with sodium metal and then ethyl iodide, the product is 2-ethoxyoctane with a specific rotation of -15.6. When pure (-)@octan@2@ol is treated with tosyl chloride and pyridine and then with sodium ethoxide, the product is also 2-ethoxyoctane. Predict the rotation of the 2-ethoxyoctane made using the tosylation/sodium ethoxide procedure, and propose a detailed mechanism to support your prediction.

(a) When ethylene oxide is treated with anhydrous HBr gas, the major product is 1,2-dibromoethane. When ethylene oxide is treated with concentrated aqueous HBr, the major product is ethylene glycol. Use mechanisms to explain these results. (b) Under base-catalyzed conditions, several molecules of propylene oxide can react to give short polymers. Propose a mechanism for the base-catalyzed formation of the following trimer.

An acid-catalyzed reaction was carried out using methyl cellosolve (2-methoxyethanol) as the solvent. When the 2-methoxyethanol was redistilled, a higher-boiling fraction (bp 162 C) was also recovered. The mass spectrum of this fraction showed the molecular weight to be 134. The IR and NMR spectra are shown here. Determine the structure of this compound, and propose a mechanism for its formation.

Propylene oxide is a chiral molecule. Hydrolysis of propylene oxide gives propylene glycol, another chiral molecule. (a) Draw the enantiomers of propylene oxide. (b) Propose a mechanism for the acid-catalyzed hydrolysis of pure (R)-propylene oxide. (c) Propose a mechanism for the base-catalyzed hydrolysis of pure (R)-propylene oxide. (d) Explain why the acid-catalyzed hydrolysis of optically active propylene oxide gives a product with lower enantiomeric excess and a rotation opposite that of the product of the base-catalyzed hydrolysis.

A compound of molecular formula C8H8O gives the IR and NMR spectra shown here. Propose a structure, and show how it is consistent with the observed absorptions

(a) Tetramethyloxirane is too hindered to undergo nucleophilic substitution by the hindered alkoxide, potassium tert-butoxide. Instead, the product is the allylic alcohol shown. Propose a mechanism to explain this reaction. What type of mechanism does it follow? (b) Under mild acid catalysis, 1,1-diphenyloxirane undergoes a smooth conversion to diphenylethanal (diphenylacetaldehyde). Propose a mechanism for this reaction. (Hint: Think Pinacol.)

Under the right conditions, the following acid-catalyzed double cyclization proceeds in remarkably good yields. Propose a mechanism. Does this reaction resemble a biological process you have seen?

One of the crowning achievements of natural products synthesis was Bryostatin 1, published by Professor Gary Keck (University of Utah; Journal of the American Chemical Society, 2011, 133, 744–747). The Bryostatins are a family of compounds isolated from aquatic invertebrates known as Bryozoans. The compounds are of interest for a variety of biological effects, including anti-cancer activity and reversing brain damage in rodents. (a) How many ether functional groups are present in Bryostatin 1? (b) Identify the other oxygen-containing functional groups. (c) This is called a macrolide because it contains a large number of atoms in the large ring. How many atoms are in the large ring? (d) How many chiral centers are in this molecule? (e) Using the number of chiral centers you reported in part (d), calculate the number of stereoisomers possible at these chiral centers. (Ignore stereoisomers at double bonds.)

In 2012, a group led by Professor Masayuki Satake of the University of Tokyo reported the isolation and structure determination of a toxin from a marine algal bloom that decimated the fish population off the New Zealand coast in 1998. Extensive mass spectrometry and NMR experiments ultimately led to the structure shown below, named Brevisulcenal-F. (See Journal of the American Chemical Society, 2012, 134, 49634968.) This structure holds the record for the largest number of fused rings, at 17.