Ethers, Epoxides, and Thioethers Flashcards Preview

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Flashcards in Ethers, Epoxides, and Thioethers Deck (110):




Ethers are coumpounds of formula R – O – R' , where R and R' may be alkyl or aryl (benzene ring) groups. Like, alcohols, ethers are related to water, with alkyl groups replacing the hydrogen atoms.

The two alkyl groups can either be the same (symmetrical ether) or distinct (unsymmetrical ether).


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Why are ethers not used as synthetic intermediates?

Ethers (other than epoxides) are relatively unreactive, as a result they are not frequently used as synthetic intermediates.

Because they are stable with many types of reagents, ethers are commonly used as solvents for organic reactions.


Which is the most commercial ether?

Diethyl Ether (CH3CH– O – CH2CH3)

  • Good Solvent for reactions and extractions
  • Volatile starting fluid for diesel/gasoline engines
  • Surgical anesthetic (starting 1842)

However, it is highly flammable; patients would vomit upon waking up.


Describe the geometric shape and hybridization of ethers

Ethers have a bent structure, with an sp3 hybrid oxygen atom giving a nearly tetrahedral bond angle. However, because of bulky alkyl group repulsion, the bond angle increases to 110°. 


Do ethers or alcohols have higher boiling points?

Alcohols have higher boiling points than ethers. 

This large difference results mostly from hydrogen bonding in the alcohols. Pure ethers cannot engage in hydrogen bonding, but have large dipole moments.


Can ethers hydrogen bond?

Ethers cannot hydrogen bond with each other, but they hydrogen with other compounds that have O – H or N – H groups.

Always need a hydrogen bond donor and an acceptor.

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Why are ethers good solvents?

They dissolve a wide range of polar and nonpolar substances, and their relatively low boiling points simpilify their evaporation from the reaction products. 

  • Nonpolar substances tend to be more soluble in ethers than in alcohols because eithers have no hydrogen-bonding network to be broken up by nonpolar solute.
  • Polar substances are nearly as soluble in ethers as alcohols. They have large dipole moments and hydrogen bond acceptors
  • The nonbonding electron pairs of an ether effectively solvate cations; not as good for anions. Largers, diffuse anions (iodides) are more soluble than smaller, harder anions (flourides)


How reactive are ethers to strong bases?

Unlike alcohols, ethers are nonhydroxylic (no hydroxyl group), and they are normally unreactive toward strong bases. For this reason, ethers are frequently used as solvents for very strong polar bases (like the Grignard Reagent) that require polar solvents. 

The four common ether solvents for organic reactions: diethyl ether, DME, THF, and dioxane. DME, THF, Dioxane = miscible in water. Diethyl Ether = not miscible in water.


Rank the given solvents in decreasing order of their ability to dissolve each compound (ethanol, water, dichloromethane, ethyl ether). 

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Ether Stabilization of Reagents

Grignard reagents cannot form unless an ether is present, possible to share its lone pairs of electrons with the magnesium atom. This sharing of electrons stabilizes the reagent and helps keep in in solution.


Complexes with Electrophiles

An ether’s nonbonding electrons also stabilize borane, BH3. Pure borane exists as a dimer called diborane, B2H6. Diborane is a toxic, flammable, and explosive gas, whose use is both dangerous and inconvenient. Borane forms a stable complex with tetrahydrofuran.

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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.

Oxygen shares one of its electron pairs with aluminum; oxygen is the Lewis base, and aluminum is the Lewis acid. An oxygen atom with three bonds and one unshared pair has a positive formal charge. An aluminum atom with four bonds has a negative formal charge.

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Crown Ether Complexes

Crown ethers large cyclic polyethers that specifically solvate metal cations by complexing the metal in the center of the ring. Different crown ethers solvate different cations, depending on the relative sizes of the crown ether and the cation and the number of binding sites around the cation.

The EPM of 18-crown-6 shows that the cavity in the center of the molecule is surrounded by electron-rich oxygen atoms that complex with the guest potassium cation.

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Why is complexation by crown ethers important in solvation?

Complexation by crown ethers often helps polar inorganic salts to dissolve in nonpolar organic solvents. This enhanced solubility allows polar salts to be used under aprotic conditions, where the uncomplexed anions may show greatly enhanced reactivity.

18-crown-6 is used to dissolve potassium fluoride in acentonitrile (CH3CN), where the poorly solvated flouride ion is moderately strong nucleophile. Many other salts, including carboxylate salts (RCOO- +K), cyanides (KCN), and permanganates (KMnO4), can be dissolved in aprotic (and often nonpolar) organic solvents using crown ethers.


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.

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What is the (common) naming rules for ethers?

Common names of ethers are formed by naming the two alkyl groups on oxygen and adding the word ether. Under the current system, the alkyl groups should be named in alphabetical order.


What are the IUPAC naming rules for ethers?

  • IUPAC names use the more complex alkyl group as the root name, and the rest of the ether as an alkoxy group. For example, cyclohexyl methyl ether is named methoxycyclohexane. This systematic nomenclature is often the only clear way to name complex ethers.
  • The heteroatom (oxygen) is numbered 1 in numbering the ring atoms.

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How do you name epoxides?

Epoxides are three-membered cyclic ethers, usually formed by peroxyacid oxidation of the corresponding alkenes.

  • The common name of an epoxide is formed by adding “oxide” to the name of the alkene that is oxidized.

  • One systematic method for naming epoxides is to name the rest of the molecule and use the term “epoxy” as a substituent, giving the numbers of the two carbon atoms bonded to the epoxide oxygen.

Another systematic method names epoxides as derivatives of the parent compound, ethylene oxide, using “oxirane” as the systematic name for ethylene oxide.

  • In this system, the ring atoms of a heterocyclic compound are numbered starting with the heteroatom and going in the direction to give the lowest substituent numbers.

Pg. 633


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The least common cyclic ethers are the four-membered oxetanes. Because these four-membered rings are strained, they are more reactive than larger cyclic ethers and open-chain ethers. They are not as reactive as the highly strained oxiranes (epoxides), however.

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The five-membered cyclic ethers are commonly named after an aromatic member of this group, furan. The systematic term oxolane is also used for a five-membered ring containing an oxygen atom.

The saturated five-membered cyclic ether resembles furan but has four additional hydrogen atoms. Therefore, it is called tetrahydrofuran (THF). One of the most polar ethers, tetrahydrofuran is an excellent nonhydroxylic organic solvent for polar reagents. Grignard reactions sometimes succeed in THF even when they fail in diethyl ether.



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The six-membered cyclic ethers are commonly named as derivatives of pyran, an unsaturated ether. The saturated compound has four more hydrogen atoms, so it is called tetrahydropyran (THP). The systematic term oxane is also used for a six-membered ring containing an oxygen atom.

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Heterocyclic ethers with two oxygen atoms in a six-membered ring are called dioxanes. The most common form of dioxane is the one with the two oxygen atoms in a 1,4-relationship. 1,4-Dioxane is miscible with water, and it is widely used as a polar solvent for organic reactions

Most dioxins are toxic and carcinogenic (cause cancer) because they associate with DNA and cause a misreading of the genetic code.

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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.

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Name the following heterocyclic ethers.

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Describe the infrared spectroscopy features of Ethers

Infrared spectra do not show obvious or reliable absorptions for ethers. Most ethers give a moderate to strong C¬O stretch around 1000 to 1200 cm-1 (in the fingerprint region), but many compounds other than ethers give similar absorptions.

Nevertheless, the IR spectrum can be useful because it shows the absence of carbonyl (C=O) groups and hydroxyl (O – H) groups. If the molecular formula contains an oxygen atom, the lack of carbonyl or hydroxyl absorptions in the IR suggests an ether.


Describe the mass spectrometry features of Ethers

(α cleavage)

The most common fragmentation of ethers is cleavage next to one of the carbon atoms bonded to oxygen. Because this carbon is alpha to the oxygen atom, this fragmentation is called α​ cleavage. The resulting oxonium ion (oxygen with three bonds and a positive charge) is resonance-stabilized by the nonbonding electrons on oxygen.


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Describe the mass spectometry features of Ethers

(Alkyl Group Loss)

Another common cleavage is the loss of either of the two alkyl groups to give another oxonium ion or an alkyl cation.

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What are some features of diethyl ether's mass spectrum?

The four most abundant ions correspond to the molecular ion, loss of an ethyl group, a cleavage, and loss of an ethylene molecule combined with a cleavage. All these modes of cleavage form resonance-stabilized oxonium ions.

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

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Describe NMR Spectroscopy features of Ethers

In the 13C NMR spectrum, a carbon atom bonded to oxygen generally absorbs between δ 65 and δ 90. Protons on carbon atoms bonded to oxygen usually absorb at chemical shifts between δ 3.5 and δ 4 in the 1H NMR spectrum. Both alcohols and ethers have resonances in this range. 

If a compound containing C, H, and O has resonances in the correct range, and if there is no O – H stretch or C=O stretch in the IR spectrum, an ether is the most likely functional group.




Williamson Ether Synthesis

The Williamson ether synthesis is the most reliable and versatile ether synthesis. This method involves the SN2 attack of an alkoxide ion on an unhindered primary alkyl halide or tosylate.

Secondary alkyl halides and tosylates are occasionally used in the Williamson synthesis, but elimination competes, and the yields are often poor.

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What substances are commonly added to make alkoxides? (Williamson ES)

The alkoxide is commonly made by adding Na, K, or NaH to the alcohol.

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  • Why is the following reaction a poor method for the synthesis of tert-butyl propyl ether?
  • What would be the major product from this reaction?
  • Propose a better synthesis of tert-butyl propyl ether.


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

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What role to phenols play in Williamson ether synthesis?

A phenol (aromatic alcohol) can be used as the alkoxide fragment, but not the halide fragment, for the Williamson ether synthesis. Phenols are more acidic than aliphatic (non-ring) alcohols, and sodium hydroxide is sufficiently basic to form the phenoxide ion. As with other alkoxides, the electrophile should have an unhindered primary alkyl group and a good leaving group.

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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 = Ph – CH2 – )

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How are ethers synthesized through alkoxymercuration-demercuration?

The alkoxymercuration–demercuration process adds a molecule of an alcohol across the double bond of an alkene. The product is an ether, as shown here.

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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

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What is the industrial synthesis of ethers?

The least expensive method for synthesizing simple symmetrical ethers is the acid-catalyzed bimolecular condensation (joining of two molecules, often with loss of a small molecule like water). Unimolecular dehydration (to give an alkene) competes with bimolecular condensation. To form an ether, the alcohol must have an unhindered primary alkyl group, and the temperature must not be allowed to rise too high. If the alcohol is hindered or the temperature is too high, the delicate balance between substitution and elimination shifts in favor of elimination, and very little ether is formed.

Bimolecular condensation is used in industry to make symmetrical ethers from primary alcohols. Because the condensation is so limited in its scope, it finds little use in the laboratory synthesis of ethers.

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

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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.

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Which of the following ethers can be formed in good yield by condensation of the correspon- ding 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

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Although ethers are unreactive, what is one reaction that does involve ethers as reactants?

Ethers are cleaved by heating with HBr or HI to give alkyl bromides or alkyl iodides. Ethers are unreactive toward most bases, but they can react under acidic conditions. A protonated ether can undergo substitution or elimination with an alcohol serving as a neutral leaving group. Ethers react with concentrated HBr and HI because these reagents are sufficiently acidic to protonate the ether, while bromide and iodide are good nucleophiles for the substitution. Under these conditions, the alcohol leaving group usually reacts further with HX to give another alkyl halide.

In effect, this reaction converts a dialkyl ether into two alkyl halides. The conditions are very strong, however, and the molecule must not contain any acid-sensitive functional groups. Iodide and bromide ions are good nucleophiles but weak bases, so they are more likely to substitute by the SN2 mechanism than to promote elimination by the E2 mechanism.

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Describe the mechanism of ether cleavage by HBr or HI

Hydroiodic acid (HI) reacts with ethers the same way HBr does. Aqueous iodide is a stronger nucleophile than aqueous bromide, and iodide reacts at a faster rate. We can rank the hydrohalic acids in order of their reactivity toward the cleavage of ethers:

HI > HBr >> HCl

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Propose a mechanism for the following reaction.

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Descrbine the cleavage of phenyl ethers by HBr or HI

Phenyl ethers (one of the groups bonded to oxygen is a benzene ring) react with HBr or HI to give alkyl halides and phenols. Phenols do not react further to give halides because the sp2-hybridized carbon atom of the phenol cannot undergo the SN2 (or SN1) reaction needed for conversion to the halide.

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Predicts the products of the following reactions. An excess of acid is available in each case.


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When ethers are stored in the presence of atmospheric oxygen, they slowly oxidize to produce hydroperoxides and dialkyl peroxides, both of which are explosive. Such a spontaneous oxidation by atmospheric oxygen is called autoxidation.

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What may occur if a container of ethers is opened and left for months? What can be done to prevent this?

Organic chemists often buy large containers of ethers and use small quantities over several months. Once a container has been opened, it contains atmospheric oxygen, and the autoxidation process begins. After several months, a large amount of peroxide may be present. Distillation or evaporation concentrates the peroxides, and an explosion may occur.

Such an explosion may be avoided by taking a few simple precautions. Ethers should be bought in small quantities, kept in tightly sealed containers, and used promptly. Any procedure requiring evaporation or distillation should use only peroxide-free ether. Any ether that might be contaminated with peroxides should be discarded or treated to destroy the peroxides.





Thioethers, also called sulfides, are ethers with a sulfur atom replacing the oxygen atom of an ether, just like the sulfur in a thiol replaces the oxygen atom of an alcohol. The chemistry of thioethers is much like the chemistry of ethers, except that thioethers can undergo oxidation and alkylation of the sulfur atom.

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Silyl Ethers

Silyl ethers are ethers with a substituted silicon atom replacing one of the alkyl groups of an ether. Silyl ethers share some of the properties of ethers (resistant to some acids, bases, and oxidizing agents), but they are more easily formed and more easily hydrolyzed. These properties make them useful as protecting groups, and silyl ethers are frequently used to protect alcohols.

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How are thioethers (sulfides) named?

Like thiols, thioethers have strong characteristic odors: The odor of dimethyl sulfide is reminiscent of oysters that have been kept in the refrigerator for too long. Sulfides are named like ethers, with “sulfide” replacing “ether” in the common names. In the IUPAC (alkoxy alkane) names, “alkylthio” replaces “alkoxy.”

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What is one easy method for synthesizing thioethers?

Thioethers are easily synthesized by the Williamson ether synthesis, using a thiolate ion as the nucleophile.

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Thiolate ions are used to synthesize (Williamson) thioethers. How are they generally synthesized?

Thiols are more acidic than water. Therefore, thiolate ions are easily generated by treating thiols with aqueous sodium hydroxide.

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Are thiolate ions nucleophiles or electrophiles? 

(Williamson ES of Thioethers)

Because sulfur is larger and more polarizable than oxygen, thiolate ions are even better nucleophiles than alkoxide ions. Thiolates are such effective nucleophiles that secondary alkyl halides often react to give good yields of SN2 products.

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

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How reactive are sulfides?

Sulfides are much more reactive than ethers. In a sulfide, sulfur valence is not necessarily filled: Sulfur can form additional bonds with other atoms. Sulfur forms particularly strong bonds with oxygen, and sulfides are easily oxidized to sulfoxides and sulfones. Sulfoxides and sulfones are drawn using either hypervalent double-bonded structures or formally charged single-bonded structures as shown here.

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Why are hydrogen peroxides and acetic acids used sulfoxide-sulfone reactions?

The hydrogen peroxide/acetic acid combination is a good oxidant for sulfides. One equivalent of peroxide gives the sulfoxide, and a second equivalent further oxidizes the sulfoxide to the sulfone. This reagent combination probably reacts via the peroxyacid, which is formed in equilibrium with hydrogen peroxide.

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Why would a sulfide be reacted with ozonides?

Because they are easily oxidized, sulfides are often used as mild reducing agents. For example, we have used dimethyl sulfide to reduce the potentially explosive ozonides that result from ozonolysis of alkenes.

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How are sulfonium salts created?

Sulfur compounds are more nucleophilic than the corresponding oxygen compounds, because sulfur is larger and more polarizable and its electrons are less tightly held in orbitals that are farther from the nucleus. Although ethers are weak nucleophiles, sulfides are relatively strong nucleophiles. Sulfides attack unhindered alkyl halides to give sulfonium salts.

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What type of agent can sulfonium salt be used as?

Sulfonium salts are strong alkylating agents because the leaving group is an uncharged sulfide. Sulfur’s polarizability enhances partial bonding in the transition state, lowering its energy.

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Sulfonium salts can be used as methylating agents; they can play this role in some biological systems. What is one system in which a sulfonium salt is used a component of a macromolecule ?

ATP activation of methionine forms the sulfonium salt S-adenosylmethionine (SAM), a biological methylating agent.


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SAM can be used as a methylating agent. What relationship does SAM have with the adrenal glands?

SAM converts norepinephrine to epinephrine (adrenaline) in the adrenal gland.

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Mustard gas, Cl – CH2CH2 – S – CH2CH2 – Cl, 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.

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What purpose do protecting groups serve?

If we have a compound with two or more functional groups, and we would like to modify just one of those functional groups, we often must protect any other functional groups to prevent them from reacting as well.


Why do alcohols and Grignard reagents rarely function together?

If we wanted to add a Grignard reagent to the carbonyl group of a keto-alcohol, the alcohol group would protonate the Grignard reagent and the reaction would fail.

Alcohol functional groups are common and useful, but they react with acids, bases, and oxidizing agents. Alcohols must be protected if they are to survive a reaction at another functional group on the molecule.

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What is considered a good protecting group? How do we protect the Grignard-Keto-Alcohol reaction?

A good protecting group must be easy to add to the group it protects, and then it must be resistant to the reagents used to modify other parts of the molecule. Finally, a good protecting group must be easy to remove to regenerate the original functional group.

To accomplish the Grignard reaction shown below, we would need to convert the hydroxyl group to something that is resistant to Grignard reagents. For example, we might consider using an ether to protect a hydroxyl group in a Grignard reaction.

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Which is the best protecting group for the Grignard-Keto-Alcohol reaction?

An ether protecting group can be difficult to remove (deprotect). It often requires strong acid, which can react with the free hydroxyl group or other parts of the molecule. Ethers based on silicon (silyl ethers) are much easier to remove than carbon-based ethers. In aqueous or organic solvents, fluoride ion removes silyl ethers under gentle conditions because the silicon–fluorine bond is exceptionally strong.





We will use the triisopropylsilyl (Tri-Iso-Propyl-Silyl or TIPS) protecting group, of structure R-O-Si(i-Pr)3 as our example. The three bulky isopropyl groups stabilize this silyl ether by hindering attack by nucleophiles. Silyl ethers are commonly formed by the reaction of alcohols with chlorosilanes in the presence of tertiary amines. We can form a TIPS ether by a reaction of chlorotriisopropylsilane (TIPSCl) with a tertiary amine such as triethylamine (Et3N:).

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How does TIPS play a role in the Grignard-Keto-Alcohol reaction?

TIPS ethers are stable to most acids and bases and oxidizing and reducing agents. Our keto-alcohol shown above would react with TIPS chloride (TIPSCl) and triethylamine (Et3N:) to give a protected alcohol. In our example, we can add a Grignard reagent to the carbonyl group in the presence of the protected alcohol.

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

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Why are epoxides valuable synthetic intermediates?

Epoxides are easily made from alkenes, and (unlike other ethers) they undergo a variety of useful synthetic reactions. For these reasons, epoxides are valuable synthetic intermediates.


What role do peroxyacids play in epoxidation?

Peroxyacids (sometimes called peracids) are used to convert alkenes to epoxides. If the reaction takes place in aqueous acid, the epoxide opens to a glycol. Therefore, to make an epoxide, we avoid strong acids. Because of its desirable solubility properties, meta- chloroperoxybenzoic acid (MCPBA) is often used for these epoxidations. MCPBA is a weakly acidic peroxyacid that is soluble in aprotic solvents such as CH2Cl2.

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How many steps are involved in epoxidation by peroxyacids?

The epoxidation takes place in a one-step, concerted reaction that maintains the stereochemistry of any substituents on the double bond.

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What peroxyacid is used for the epoxidation of difficult transformations?

The peroxyacid epoxidation is quite general, with electron-rich double bonds reacting fastest. The following reactions are difficult transformations made possible by this selective, stereospecific epoxidation procedure. The second example uses magnesium monoperoxyphthalate (MMPP), a relatively stable water-soluble peroxyacid often used in large-scale epoxidations. These aqueous MMPP epoxidations, carried out at neutral pH to avoid opening the epoxide, avoid the large-scale use of hazardous chlorinated solvents.

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Besides peroxyacid epoxidation, what other ways can epoxides be made?

Base-Promoted Cyclization of Halohydrins. A second synthesis of epoxides and other cyclic ethers involves a variation of the Williamson ether synthesis. If an alkoxide ion and a halogen atom are located in the same molecule, the alkoxide may displace a halide ion and form a ring. Treatment of a halohydrin with base leads to an epoxide through this internal SN2 attack.

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How are halohydrins generated?

Halohydrins are easily generated by treating alkenes with aqueous solutions of halogens. Bromine water and chlorine water add across double bonds with Markovnikov orientation. The following reaction shows cyclopentene reacting with chlorine water to give the chlorohydrin. Treatment of the chlorohydrin with aqueous sodium hydroxide gives the epoxide.

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Halohydrin cyclization can be used to synthesize larger rings. However, there can be certain difficulties with these reactions. What are they, and how can they be overcome?

This reaction can be used to synthesize cyclic ethers with larger rings. The difficulty lies in preventing the base (added to deprotonate the alcohol) from attacking and displacing the halide. 2,6-Lutidine, a bulky base that cannot easily attack a carbon atom, can deprotonate the hydroxyl group to give a five-membered cyclic ether. Five-, six-, and seven-membered (and occasionally four-membered) cyclic ethers are formed this way.

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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

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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.

  • (a) Which of these reagents is most likely to be the actual oxidizing agent? That is, which reagent is reduced in the reaction? What is the likely function of the other reagents?
  • (b) When achiral reagents react to give a chiral product, that product is normally formed as a racemic mixture of enantiomers. How can the Sharpless epoxidation give just one nearly pure enantiomer of the product?
  • (c) Draw the other enantiomer of the product. What reagents would you use if you wanted to epoxidize geraniol to give this other enantiomer?

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Why are epoxides more reative than common dialkyl ethers?

Epoxides are much more reactive than common dialkyl ethers because of the large strain energy (about 105 kJ/mol or 25 kcal/mol) associated with the three-membered ring. Unlike other ethers, epoxides react under both acidic and basic conditions. The products of acid-catalyzed opening depend primarily on the solvent used.


What is the epoxide opening reaction in water?

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Is possible to perform a direct hydroxylation of an alkene?

Direct anti hydroxylation of an alkene (without isolation of the epoxide intermediate) is possibly by using acidic aqueous solution of a peroxyacid. As soon as the epoxide is formed, it hydrolyzes to the glycol. Peroxyacetic acid (CH3CO3H) and peroxyformic acid (HCO3H) are often used for the anti hydroxylation of alkenes. 

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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.



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What is the mechanism of epoxide opening in alcohol solution?

When the acid-catalyzed opening of an epoxide takes place with an alcohol as the solvent, a molecule of alcohol acts as the nucleophile. This reaction pro- duces an alkoxy alcohol with anti stereochemistry. This is an excellent method for making compounds with ether and alcohol functional groups on adjacent carbon atoms. For example, the acid-catalyzed opening of 1,2-epoxycyclopentane in a methanol solution gives trans-2-methoxycyclopentanol.

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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.

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How are epoxides opened using hydrohalic acids?

When an epoxide reacts with a hydrohalic acid (HCl, HBr, or HI), a halide ion attacks the protonated epoxide. This reaction is analogous to the cleavage of ethers by HBr or HI. The halohydrin initially formed reacts further with HX to give a 1,2-dihalide. This is rarely a useful synthetic reaction, because the 1,2-dihalide can be made directly from the alkene by electrophilic addition of X2.

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Describe the Opening of Squalene-2,3-epoxide.

Steroids are tetracyclic compounds that serve a wide variety of biological functions, including hormones (sex hormones), emulsifiers (bile acids), and membrane components (cholesterol). The biosynthesis of steroids is believed to involve an acid-catalyzed opening of squalene-2,3-epoxide (Figure 14-6). Squalene is a member of the class of natural products called terpenes (see Section 25-8). The enzyme squalene epoxidase oxidizes squalene to the epoxide, which opens and forms a carbocation that cyclizes under the control of another enzyme. The cyclized intermediate rearranges to lanosterol, which is converted to cholesterol and other steroids.

Although cyclization of squalene-2,3-epoxide is controlled by an enzyme, its mech- anism is similar to the acid-catalyzed opening of other epoxides. The epoxide oxygen becomes protonated and is attacked by a nucleophile. In this case, the nucleophile is a pi bond. The initial result is a tertiary carbocation (Figure 14-7).

This initial carbocation is attacked by another double bond, leading to the forma- tion of another ring and another tertiary carbocation. A repetition of this process leads to the cyclized intermediate shown in Figure 14-6. Note that this sequence of steps con- verts an achiral, acyclic starting material (squalene) into a compound with four rings and seven asymmetric carbon atoms. The enzyme-catalyzed sequence takes place with high yields and complete stereospecificity, providing a striking example of asymmetric induc- tion in a biological system.

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

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Describe the energy profiles of nucleophilic attacks on ethers and epoxides.

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What is the difference between base-catalyzed and acid-catalyzed epoxide opening?

The reaction of an epoxide with hydroxide ion leads to the same product as the acid-catalyzed opening of the epoxide: a 1,2-diol (glycol), with anti stereochemistry. In fact, either the acid-catalyzed or base-catalyzed reaction may be used to open an epoxide, but the acid-catalyzed reaction takes place under milder conditions. Unless there is an acid-sensitive functional group present, the acid-catalyzed hydrolysis is preferred.


Describe the base-catalyzed opening of epoxides.

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How do alkoxide ions open epoxides?

Like hydroxide, alkoxide ions react with epoxides to form ring-opened products. For example, cyclopentene oxide reacts with sodium methoxide in methanol to give the same trans-2-methoxycyclopentanol produced in the acid-catalyzed opening in methanol.

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Can amines open epoxides?

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Amines can also open epoxides. Ethylene oxide reacts with aqueous ammonia to give ethanolamine, an important industrial reagent. The nitrogen atom in ethanolamine is still nucleophilic, and ethanolamine can react further to give diethanolamine and triethanolamine. Good yields of ethanolamine are achieved by using excess ammonia.


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

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Does symmetry affect the products of acid/base-catalyzed ring openings?

Symmetrically substituted epoxides give the same product in both the acid-catalyzed and base-catalyzed ring openings. An unsymmetrical epoxide may produce different products under acid-catalyzed and base-catalyzed conditions, however.

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For unsymmetric ether epoxides, how do acid-catalyzed ring openings proceed?

Under basic conditions, the alkoxide ion simply attacks the less hindered carbon atom in an SN2 displacement.

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What occurs when the epoxide oxygen is protonated in acid conditions?

In the protonated epoxide, there is a balancing act between ring strain and the energy it costs to put some of the positive charge on the carbon atoms. We can represent this sharing of positive charge by drawing resonance forms that suggest what the cations would look like if the ring started to open. These "no-bond" resonance forms help us to visualize the charge distribution in the protonated epoxide.

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For unsymmetric ether epoxides, how does acid-catalyzed ring openings proceed?

Under acidic conditions, the alcohol attacks the protonated epoxide. It might seem that the alcohol would attack at the less hindered oxirane carbon, but this is not the case.

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Predict the major products for the reaction of 1-methyl-1,2-epoxycyclopentane with:

  • sodium ethoxide in ethanol
  • H2SO4 in ethanol

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How do epoxides react with Grignard/Organolithium Reagents?

Like other strong nucleophiles, Grignard and organolithium reagents attack epoxides to give (after protonation) ring-opened alcohols.

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What are some of the conditions necessary for good epoxide and Grignard/Organolithium reaction?

Substituted epoxides can be used in this reaction, with the carbanion usually attacking the less hindered epoxide carbon atom. This reaction works best if one of the oxirane carbons is unsubstituted, to allow an unhindered nucleophilic attack. Organolithium reagents (RLi) are more selective than Grignard reagents in attacking the less hindered epoxide carbon atom. Unless one carbon atom is very strongly hindered, Grignard reagents may give mixtures of products.

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Give the expected products of the following reactions. Include a protonation step where necessary.


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Epoxy Adhesives

This ideal glue was only a dream until the development of epoxy adhesives. Epoxies polymerize in place, so they match the shape of the joint perfectly and adhere to micro- scopic irregularities in the surfaces. There is no solvent to evaporate, so there is no shrinkage. Epoxies are bonded by ether linkages, so they are unaffected by water. Epoxies use a prepolymer that can be made as runny or as gummy as desired, and they use a hardening agent that can be modified to control the curing time. In the absence of the hardening agent, they have a long shelf life.

The most common epoxy resins use a prepolymer made from bisphenol A and epichlorohydrin.

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How does bisphenol A open the epoxide?

Under base-catalyzed conditions, the anion of bisphenol A opens the epoxide of epichlorohydrin to give an alkoxide that snaps shut on the other end, forming another epoxide.

This second epoxide reacts with another molecule of bisphenol A. Each molecule of bisphenol A can also react with two molecules of epichlorohydrin.

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What ratio is needed between bisphenol A and epichlorohydrin for polymerization?

With exactly equal amounts of bisphenol A and epichlorohydrin, this polymerization would continue until the polymer chains were very long and the material would be a solid polymer. In making epoxy resins, however, excess epichlorohydrin is added to form short chains with epichlorohydrins on both ends. More epichlorohydrin gives shorter chains and a runny prepolymer. Less epichlorohydrin gives longer chains (containing up to 25 epichlorohydrin/bisphenol A units) and a more viscous prepolymer.


Why are harderner used in epoxy glues?

When you buy epoxy glues, they come in two parts: the resin (prepolymer) and the hardener. The hardener can be any of a wide variety of compounds having basic or nucleophilic properties. Polyamines are the most common hardeners. The hardener can attack a terminal epoxide group, initiating a polymerization of the chain ends.

Or the hardener can deprotonate a hydroxyl group from the interior of a chain, cross- linking one chain with another. The final polymer is an intricate three-dimensional net- work that is strong and resistant to chemical attack.

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