Chapter 15: Ethers

Contents

15.1 Definitions
15.2 Carbocation Stability
15.3 Synthesis of Ethers
     15.3.1 Williamson Synthesis of Ethers
     15.3.2 Synthesis of Cyclic Ethers - Williamson Synthesis
15.4 Synthesis of Oxiranes (Epoxides)
     15.4.1 Williamson Synthesis with Halohydrins (Stereospecific)
     15.4.2 Synthesis of Oxiranes with Peroxycarboxylic Acids
15.5 Synthesis of Ethers by Oxymercuration-Demercuration
15.6 Protecting Groups for Alcohols
     15.6.1 Synthesis of Tert-butyl Ethers by Alkylation of Alcohols
     15.6.2 Silyl Ether Protecting Groups
15.7 Reaction of Ethers
     15.7.1 Acidic Cleavage of Ethers
Keeping it Real
15.8 Nucleophilic Ring-Opening of Oxiranes
Keeping it Real
15.9 Chapter Summary

Learning Objectives

• Recognize the reagents needed and predict the products formed in the William synthesis of ethers.
• Distinguish between intermolecular and intramolecular cyclization reactions in the synthesis of ethers and cyclic ethers.
• Recognize reagents needed and predict the products formed in the synthesis of oxiranes.
• Predict the products formed in the oxymercuration-demercuration of alkenes in the synthesis of ethers.
• Understand how to protect alcohols in the synthesis of compounds by converting alcohols into tert-butyl and silyl ethers.
• Predict the products formed in the cleavage of ethers with strong acids in both S_N1 and S_N2 conditions.

15.1 Definitions

Note: Section 15.1 is the same as section 14.1, review as needed.

Hofmann Rule: This rule refers to a special β-elimination reaction in which the alkene having the smallest number of alkyl groups attached to the double bonded carbon atoms will be the predominant product (less stable alkene forms as the major product). The Hofmann rule is observed in elimination reactions with leaving groups like quaternary ammonium salts, tertiary sulfonium salts, and with bulky strong bases (NaOC(CH₃)₃) reacting with tertiary alkyl halides.

Markovnikov’s Rule: In the ionic addition of a polar reagent to an unsymmetrical alkene, the positive portion of the reagent being added attaches itself to a carbon atom of the double bond forming the more stable carbocation as an intermediate. Older definition: the hydrogen becomes attached to the carbon atom of the double bond with the greater number of hydrogens (for the addition of HX). It can also be stated: the hydrogen adds to the less substituted carbon.

Regiochemistry: A reaction that can occur with different regions on a molecule to produce different products. A region is defined as a site on a molecule where a reaction can occur. Regiochemistry is the difference in the reactivity of the various sites.

Regioselective reaction: When there is more than one reactive site a regioselective reaction can occur. A regioselective reaction is one that produces one major product when many possible products are possible. For example, the molecule 2-bromo-2-methylbutane has eight hydrogens on β carbons that can undergo elimination reaction in presence of a base such as sodium ethoxide. Removal of a H_a hydrogen produces the minor product 2-methyl-but-1-ene while removal of a H_b hydrogen produces the major product.

Stereoselective reaction: A reaction in which a single reactant can produce two or more stereoisomeric products and one of these products is preferred over another. For example, the reaction of either enantiomer of 2-bromobutane will stereoselectively produce (E)-but-2-ene as the major product. Notice that regardless of which starting material is used, the major product is (E)-but-2-ene and the ratio of the products is the same.

Stereospecific reaction: A reaction in which a single reactant can produce two or more stereoisomeric products and one of these products is exclusively formed over the other(s). For example; the elimination reaction of (1R,2R)-1-bromo-1,2-diphenylpropane with a strong base produces the (Z) stereoisomer whereas the elimination of the (1R,2S) diastereomer produces the (E) stereoisomer.

Similarly, a S_N2 reaction with 2-bromobutane and sodium methanethiolate (CH₃SNa) will produce either (S)-sec-butyl(methyl)sulfane or (R)-sec-butyl(methyl)sulfane depending on which enantiomer you start with. This is another example of a stereospecific reaction.

Zaitsev’s Rule: An empirical rule that states; when two or more alkenes can be produced in an elimination reaction, the thermodynamically most stable alkene will predominate. The most thermodynamically stable alkene will be the alkene that has the most alkyl groups attached to the alkene carbons.

15.2 Carbocation Stability

Neighboring functional groups can stabilize carbocations through hyperconjugation, adjacent lone pairs and adjacent π bonds. Carbocations can also be destabilized by nearby partial positive charges.

Hyperconjugation

The stability of a carbocation increases as the number of alkyl groups attached to the electron deficient carbon increases. Review: Substitution-elimination chapters: Effect of structure on the rate of reaction.

This can be explained by the electron donation of the adjacent C-C or C-H sigma bonds into the empty carbocation’s p orbital, which stabilizes the electron deficient carbon. Alkyl groups donate electron density inductively through σ bond conjugation or hyperconjugation.

Adjacent lone pairs

Atoms (possessing lone pair of electrons) that are bonded to the carbocation (N,O,S, and halogens) will stabilize carbocations through resonance.

You may be thinking that electronegative atoms such as oxygen and chlorine would destabilize the carbocation by inductively pulling electrons away from carbocation, but in most cases resonance between these heteroatoms and the carbocation  has a greater influence on carbocation stability than inductive effects, but in most cases resonance with the heteroatom has a greater influence than inductive effects.

Adjacent π bonds

Carbocations that are adjacent to π bonds (allyl, benzyl, and cyano) are stabilized through resonance, which delocalizes the charge onto different atoms.

Inductive effects

Carbocations are destabilized by electronegative atoms that inductively create a partial positive charge adjacent to the carbocation.

15.3  Synthesis of Ethers

15.3.1 Williamson Synthesis of Ethers

The Williamson synthesis of ethers is an S_N2 reaction of an alkoxide with an unhindered alkyl halide, alkyl sulfonate, or alkyl sulfate.

The alkoxide nucleophile can be prepared by adding a reactive metal (Na or K) or sodium hydride (NaH) to an alcohol.

Alkoxides are good nucleophiles that are also strong bases which may encourage elimination  reaction also. Thus, to only obtain the nucleophilic reaction product, the methodology and the reaction conditions must be selected carefully.

Question 15.2

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15.3.2 Synthesis of Cyclic Ethers - Williamson Synthesis

Substitution reactions can occur between two molecules (intermolecular) or within a molecule (intramolecular). An S_N2 cyclization reaction is an intramolecular reaction and is much faster than an intermolecular S_N2 reaction. For example, the reaction between sodium ethoxide and chloroethane is 5,000 times slower than the intramolecular cyclization of 4-chloro-1-butoxide.

Cyclic ethers can thus be synthesized in good yields using an intramolecular Williamson synthesis. The first step in the cyclization reaction is a rapid proton transfer between a hydroxide ion and a halohydrin to produce a haloalkoxide. The next step is an intramolecular cyclization reaction to form the cyclic ether.

Why is this faster than the reaction between two molecules?

For the intermolecular reaction to occur, the nucleophile and the electrophile must travel through the solvent so a collision can occur. This requires energy and places an entropic cost on the system. 

In contrast, in the intramolecular reaction, the nucleophile and the electrophilic carbon are on the same molecule and are in close proximity to each other. Thus, this system will experience a lower entropic cost in attaining the proper orientation required for the S_N2 reaction. Also, for the intramolecular reaction, the substrate which is one molecule, breaks into two particles, [an ether (tetrahydrofuran), and a salt (sodium bromide)] which is favorable entropically.

 is becoming two molecules which is a favorable entropy change.

Bimolecular reactions will occur but can be significantly reduced by using dilute reaction mixtures. This decreases the probability of two or more reagent molecules colliding with each other and reduces the probability of intermolecular S_N2 reactions.

15.4 Synthesis of Oxiranes (Epoxides)

15.4.1 Williamson Synthesis with Halohydrins (Stereospecific)

Oxiranes can be made readily from halohydrins.

The reaction may seem unfavorable, but in the anti staggered conformation the nucleophile and the electrophilic carbon are in very close proximity to each other. If you think of the reaction coordinate diagram of an S_N2 reaction, then the molecule in this conformation is well along the pathway to an S_N2 reaction.

Thus, once the alkoxide ion has formed, the formation of a 3-membered ring is highly favored due to the close proximity of the negatively charged oxygen to the antibonding orbital of the electrophilic carbon. The 3-membered ring is highly ring strained but once the oxirane has formed the reaction is not reversible because the displaced bromide ion is a much weaker base and than the alkoxide ion.

The formation of the oxirane is not an equilibrium reaction because the displaced bromide ion is a much weaker base (better leaving group) than the alkoxide ion.

This intramolecular oxirane formation is an S_N2 reaction and since the haloalkoxide requires the nucleophile and the electrophile in an anti conformation, the reaction is stereospecific. For example, when (2R,3R)-2-bromopentan-3-ol is reacted with sodium hydroxide only one product is formed.

Question 15.6

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15.4.2 Synthesis of Oxiranes with Peroxycarboxylic Acids

For the synthesis of oxiranes with peroxycarboxylic acids refer to: Chapter 12.9

15.5 Synthesis of Ethers by Oxymercuration–Demercuration

The synthesis of alcohols by oxymercuration–demercuration was covered in Chapter 12.6. In these reactions, water was used as the nucleophile. When alcohols are used as the nucleophile, ethers are synthesized.

15.6 Protecting Groups for Alcohols

Alcohols are very reactive towards many reagents and must be masked or protected so that they are unreactive towards the reagents you are using. A good protecting group should be easy to put on, easy to remove and inert to the conditions of the reaction required. Conversion of alcohols to tert-butyl ethers or silyl ethers are two common methods use to protect alcohols.

15.6.1 Synthesis of Tert-butyl Ethers by Alkylation of Alcohols

Primary alcohols are converted to tert-butyl ethers by dissolving the alcohol in a strong acid like sulfuric acid and then adding isobutylene to the mixture. Isobutylene is added to the reaction mixture slowly to minimize the side reaction between the carbocation intermediate and isobutylene.

A tert-butyl ether can readily be converted back to the original alcohol and tert-butanol by treating the ether with dilute aqueous acid.

Since a primary alcohol can be converted to a tert-butyl ether and back to the original alcohol, a tert-butyl ether can be used to “protect” the alcohol while another reaction is being carried out on another part of the molecule. For example, how would you synthesize 3-ethoxypropan-1-ol starting with 3-bromopropan-1-ol?

Looking at the two structures, you might think you could add sodium ethoxide (NaOCH₂CH₃) and perform an S_N2 reaction to obtain the desired product. However, acid/base reactions are very rapid and would occur before an S_N2 reaction to produce  the haloalkoxide. The haloalkoxide itself can undergo S_N2 reaction with the excess ethoxide  and eventually lead to dimer, oligomers, and polymers. Cyclization may also occur which will give oxetane. Thus, using this method a number of possible side reactions would occur and decrease the yield of the desired product, 3-ethoxypropan-1-ol.

We can synthesize 3-ethoxypropan-1-ol by converting the alcohol to a tert-butoxy ether. This protects the alcohol because ethers are very stable in basic conditions and resist attack by nucleophiles. They are nonreactive because an alkoxide ion is a poor leaving group. Thus, 1-bromo-3-(tert-butoxy)propane will readily undergo an S_N2 reaction with sodium ethoxide to form 1-(tert-butoxy)-3-ethoxypropane. Treatment of the ether with a dilute acid produces the desired alcohol, 3-ethoxypropan-1-ol and tert-butanol.

15.6.2 Silyl Ether Protecting Groups

Silyl ethers are extensively used in laboratories to protect alcohols. A common reagent used to protect alcohols is chlorotrimethylsilane. This reagent converts an alcohol to a trimethylsilyl (TMS) ether.

The above reaction is believed to go through an S_N2 reaction, which is very surprising because tertiary alkyl halides do not undergo S_N2 reactions. However, the Si–C bond is generally longer and reduces the steric interaction between the incoming nucleophile and the electrophilic group.

Silicon has a strong affinity for electronegative elements, such as O, F, and Cl. Thus, trialkylsilyl ethers will be attacked by water, hydroxide, and fluoride ions. Trialkylsilyl ethers are less reactive towards carbon and nitrogen bases or nucleophiles, such as Grignard reagents. The protecting group can be removed with aqueous acid or fluoride salts. The most commonly use fluoride salt is Bu₄N⁺F^- (tetra-n-butylammonium fluoride, TBAF).

Example 

15.7 Reaction of Ethers

Ethers react with very few reagents, which makes them great solvents. They are very stable in basic conditions, and are resistant to nucleophilic attacks because an alkoxide ion is a poor leaving group. Ethers are also stable in mild acidic solution; however, ethers are not stable when heated with strong acids, in the presence of a good nucleophile.

15.7.1 Acidic Cleavage of Ethers

Ethers can be protonated to form oxonium ions with strong acids, such as HI, HBr, and H₂SO₄. For example, when a dialkyl ether is reacted with HBr, the strong acid will protonate the ether.

The bromide ion can now act as a nucleophile in an S_N2 reaction and cleave the protonated ether.

Excess HBr will protonate the alcohol to generate an oxonium ion and subsequently undergo an S_N2 reaction with bromide to form another alkyl halide plus water.

Which reagent will react faster, HI or HCl? The first step in the acid cleavage of ethers is the protonation of the ether to form an oxonium ion. Since ethers are weak bases the stronger the acid the more the equilibrium is shifted to the formation of the oxonium ion. The second step of the mechanism involves the nucleophilic attack of a halogen on the oxonium ion. The stronger the nucleophile the faster the rate of cleavage of the oxygen-carbon bond will be. Thus HI is the most reactive (strongest acid, iodide ion is the strongest nucleophile) followed by HBr and HCl.

The reactivity of hydrogen halides toward the cleavage of ethers follows their general acidity and nucleophilicity:

Question 15.10

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The mechanism given for question 15.10 showed two S_N2 reactions. Will the acidic cleavage of ethers always follow an S_N2 mechanism?

Question 15.11

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Question 15.12

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Ethers in Medicine

Diethyl ether is commonly used today as a solvent for organic reactions. Did you know it has been used in medicinal applications too?

Diethyl ether was noted to have analgesic properties around the year 1525. Three hundred years later, diethyl ether was used in dental procedures, to remove tumors, and even in amputation procedures.

The first public demonstration of the use of diethyl ether as a general anesthetic was performed in 1846 by William T. G. Morton, in the so-called ‘Ether Dome’, which is part of the Massachusetts General Hospital. Many other anesthetics are commonly used today in place of ether.

15.8 Nucleophilic Ring-Opening of Oxiranes

Ring-opening of oxiranes refer to:

Chapter 14:  Alcohols and Oxiranes 

• 14.5.5 Nucleophilic Ring-Opening of Oxiranes to Produce Alcohols
• 14.5.5.1 Ring-Opening of an Asymmetrical Oxirane: Regioselective and Stereospecific
• 14.5.5.2 Acid-Catalyzed Ring-Opening of Oxiranes to Produce Alcohols
• 14.5.5.3 Acid-Catalyzed Ring-Opening of Asymmetrical Oxiranes: Regioselective and Stereospecific
• 14.5.5.4 Ring-Opening of Oxiranes: Strong nucleophile Versus Acid-Catalyzed

Ethers in Beastly Natural Products

A truly remarkable example involving epoxides and ethers can be seen in the biosynthesis of brevetoxin B. Brevetoxin B is a beastly polyether, which is secreted by dinoflagellate as a defense mechanism. Brevetoxin B binds to voltage-gated sodium channels in nerve cells, leading to over-activation of the channel and the repetitive firing of nerves.

Brevetoxin B causes neurological shellfish poisoning (NSP) in many fish and marine mammals, but not shellfish. In addition, humans have to be very careful to avoid eating toxic shellfish – so beware of “red tide”! 

Marine toxins in the movies?

In the classic Hitchcock horror film, The Birds, socialite Melanie Daniels (Tippi Hedren) follows love interest Mitch Brenner (Rod Taylor) to a small Northern California town, where the birds suddenly start assaulting townies.

Hitchcock never explains why the birds are attacking people, but some think it’s because the birds have been eating toxic algae.

Could it be the beastly neurotoxin brevetoxin or related compounds!?! 

15.9 Chapter Summary

The synthesis of ethers include the Williamson ether synthesis; cyclic and acylic; formation of epoxides including halohydrins and peroxycarboxylic acids, oxymercuration-demercuration, and the synthesis of tert-butyl ethers by alkylation of alcohols. A summary of these reactions are shown below:

Reactions of ethers include acidic cleavage and ring-openings of epoxides; classified as one of two types: ring-opening with a strong nucleophile and acid-catalyzed ring-opening. The acid-catalyzed ring-opening utilizes a weak nucleophile. A summary of these reactions is shown below.

End of Chapter 15

Answers

Video answer to Question 15.2  

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Video answer to Question 15.6

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Video answer to question: 15.10

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Video answer to question: 15.11

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Video answer to question: 15.12

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Image Credits

[1] Image courtesy of the  Official Navy Page in the Public Domain

[2] Image courtesy of Adam Lenhardt under CC BY-SA 3.0

[3] Image courtesy of US National Library of Medicine in the Public Domain

[4] Image courtesy of Alejandro Díaz and Ginny Velasquez in the Public Domain

[5]Image courtesy of Universal Pictures in the Public Domain