14.1 Introduction to Ethers 14.1 Introduction to Ethers • Compounds Containing Ether Groups Are Quite Common

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14.1 Introduction to Ethers 14.1 Introduction to Ethers • Compounds containing ether groups are quite common. • An ether group includes an oxygen atom that is bonded to TWO –R groups:

• –R groups can be alkyl, aryl, or vinyl groups. • Would the compound below be considered an ether? O

14.2 Naming Ethers 14.2 Naming Ethers

• Common names are used frequently: • IUPAC systematic names are often used as well: 1. Name each –R group. 1. Make the larger of the –R groups the parent chain. 2. Arrange them alphabetically. 2. Name the smaller of the –R groups as an alkoxy substituent. 3. End with the word “ether.”

• Practice with SKILLBUILDER 14.1.

14.3 Structure and Properties of 14.2 Naming Ethers Ethers • Name the following molecule. • The bond angle in ethers is very similar to that found in water and in alcohols.

O Cl

• Draw the structure for (R)‐1‐methoxycyclohexen‐3‐ol. • Is the oxygen atom in an ether sp3, sp2, or sp hybridized?

• How do the –R groups affect the bond angle?

Copyright 2012 John Wiley & Sons, Inc. 14 -5 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 14 -6 Klein, Organic Chemistry 1e 14.3 Structure and Properties of 14.3 Structure and Properties of Ethers Ethers • In Chapter 13, we learned that due to hydrogen‐ • In Chapter 13, we learned that due to hydrogen‐ bonding (H‐bonding), alcohols have relatively high bonding (H‐bonding), alcohols have relatively high boiling points. boiling points.

• What is the maximum number of H‐bonds an alcohol can have? • Would you expect the boiling point of an ether to be elevated similar to alcohols? • Draw an H‐bond between an ether and an alcohol. • WHY or WHY not? • What is the maximum number of H‐bonds an ether can have? Copyright 2012 John Wiley & Sons, Inc. 14 -7 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 14 -8 Klein, Organic Chemistry 1e

14.3 Structure and Properties of 14.3 Structure and Properties of Ethers Ethers • Explain the boiling point trends below using all relevant • Ethers are often used by organic chemists as solvents: intermolecular attractions. – Relatively low boiling points allow them to be evaporated – Trend 1: after the reaction is complete. – Their dipole moment allows them to stabilize charged or partially charged transition states. HOW?

– They are NOT protic. WHY is that an advantage for a solvent in many reactions? – Trend 2:

14.4 Crown Ethers 14.4 Crown Ethers

• Metal atoms with a full or partial positive charge can be • Crown ethers have been shown to form especially stabilized by ether solvents. strong attractions to metal atoms. WHY? • Ethers are generally used as the solvent in Grignard reactions.

• Note how many carbon atoms separate the oxygen. • Give another reason why an ether makes a • Why are they called CROWN ethers? good solvent in this reaction. • Explain the numbers found in their names. Copyright 2012 John Wiley & Sons, Inc. 14 -11 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 14 -12 Klein, Organic Chemistry 1e 14.4 Crown Ethers 14.4 Crown Ethers • Normally metal ions are not soluble in low polarity • The size of the metal must match the size of the crown solvents. WHY? to form a strong attraction. • The crown ether–metal complex should dissolve nicely • 18‐crown‐6 fits a K+ ion just right. in low polarity solvents. WHY? • Imagine how a crown ether could be used to aid reactions between ions (especially anions) and low polarity organic substrates.

14.4 Crown Ethers 14.4 Crown Ethers

• The F– ion below is ready to react because the K+ ion is • Generally, the F– ion is not used as a nucleophile sequestered by the crown ether. because it is strongly solvated by polar solvents. • Such solvation greatly reduces its nucleophilic strength. • In the presence of the crown ether and in a nonpolar solvent, the F– ion is soluble enough that it can readily attack an electrophile.

• Without the crown ether, the solubility of KF in benzene is miniscule.

14.4 Crown Ethers 14.5 Preparation of Ethers • Diethyl ether is prepared industrially by the acid‐ • Smaller crown ethers bind smaller cations. catalyzed dehydration of ethanol.

• How is it a dehydration? • Can this method be used to make asymmetrical ethers?

• Practice with CONCEPTUAL CHECKPOINT 14.4.

Copyright 2012 John Wiley & Sons, Inc. 14 -17 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 14 -18 Klein, Organic Chemistry 1e 14.5 Preparation of Ethers 14.5 Preparation of Ethers

• The Williamson ether synthesis is a viable approach for • The Williamson ether synthesis is a viable approach for many asymmetrical ethers. many asymmetrical ethers.

• The alkoxide that forms in step 1 is also a strong base. • What happens to the halide? • Are elimination products likely for methyl, primary, secondary, or tertiary alkyl halides?

14.5 Preparation of Ethers 14.5 Preparation of Ethers

• Use the Williamson ether approach to prepare MTBE. • Use the Williamson ether approach to synthesize the following molecule.

• Consider a retrosynthetic disconnect on the t‐butyl side. • It is better to make your retrosynthetic disconnect on the methyl side. WHY? • Practice with SKILLBUILDER 14.2. Copyright 2012 John Wiley & Sons, Inc. 14 -21 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 14 -22 Klein, Organic Chemistry 1e

14.5 Preparation of Ethers 14.5 Preparation of Ethers • Similarly, alkoxymercuration‐demercuration can be • Recall from Section 9.5 that oxymercuration‐ used to synthesize ethers. demercuration can be used to synthesize alcohols.

• Is the addition Markovnikov or anti‐Markovnikov? • Is the addition Markovnikov or anti‐Markovnikov? • Is the addition syn or anti? • Is the addition syn or anti? • Practice CONCEPTUAL CHECKPOINTs 14.8‐14.10.

• As we mentioned earlier because they are aprotic, • Ethers can undergo acid‐promoted cleavage. ethers are generally unreactive. • However, ethers can react under the right conditions. • Consider the ether below.

• Where are the most reactive sites? • Is it most likely to react as an acid, base, nucleophile, electrophile, etc.? Copyright 2012 John Wiley & Sons, Inc. 14 -25 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 14 -26 Klein, Organic Chemistry 1e

14.6 Reactions of Ethers 14.6 Reactions of Ethers

• Draw a complete mechanism and predict the products • To promote cleavage, HI and HBr are generally for the following acid‐promoted cleavage. effective. • HCl is less effective, and HF does not cause significant cleavage. • Explain the trend above considering the relative strength of the halide nucleophiles.

• Why is the cleavage considered acid‐promoted rather than acid‐catalyzed?

14.6 Reactions of Ethers 14.6 Reactions of Ethers

• Predict products for the reaction below, and draw a • Recall from Section 11.9 that ethers can undergo complete mechanism. autooxidation.

• Hydroperoxides can be explosive, so laboratory samples of ether must be frequently tested for the presence of hydroperoxides before they are used. • The autooxidation occurs through a free radical mechanism.

• Recall that the net reaction is the sum of the propagation steps:

14.7 Naming Epoxides 14.7 Naming Epoxides • An epoxide can have up to 4 –R groups. • For cyclic ethers, the size of the ring determines the parent name of the molecule.

• Although they are unstable, epoxides are found commonly in nature.

• Oxiranes are also known as epoxides. • Which cyclic ether system do you think is most reactive? WHY?

14.7 Naming Epoxides 14.7 Naming Epoxides • There are two methods for naming epoxides: 1. The oxygen is treated as a side group, and two numbers are • Name the molecules below by both methods if possible. given as its locants.

2. Oxirane is used as the parent name.

• Practice CONCEPTUAL CHECKPOINTs 14.12 and 14.13.

Copyright 2012 John Wiley & Sons, Inc. 14 -35 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 14 -36 Klein, Organic Chemistry 1e 14.8 Preparation of Epoxides 14.8 Preparation of Epoxides

• Recall from Section 9.9 that epoxides can be formed • Recall that the process is stereospecific. when an alkene is treated with a peroxy acid.

• MCPBA and peroxyacetic acid are most commonly used.

14.8 Preparation of Epoxides 14.8 Preparation of Epoxides

• Epoxides can also be formed from halohydrins. • What is a halohydrin? • How are halohydrins formed from alkenes? • When a halohydrin is treated with NaOH, a ring‐closing reaction can occur.

14.8 Preparation of Epoxides 14.9 Enantioselective Epoxidation

• Assess the overall stereochemistry of the epoxidation • The epoxidation methods we have discussed so far are that occurs through the halohydrin intermediate. NOT enantioselective. • Draw the products.

• Practice with SKILLBUILDER 14.3.

Copyright 2012 John Wiley & Sons, Inc. 14 -41 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 14 -42 Klein, Organic Chemistry 1e 14.9 Enantioselective Epoxidation 14.9 Enantioselective Epoxidation

• The epoxidation forms a racemic mixture because the • To be enantioselective at least one of the reagents (or flat alkene can react on either face. the catalyst) in a reaction must be chiral. • The Sharpless catalyst forms such a chiral complex with an allylic alcohol.

14.9 Enantioselective Epoxidation 14.10 Ring‐opening of Epoxides • The desired epoxide can be formed if the right catalyst is chosen. Note the position of the –OH group. • Because of their significant ring strain, epoxides have great synthetic utility as intermediates. • Propose some reagents that might react with an epoxide to provide a specific functional group.

• Propose some reagents that might react with an epoxide to alter the carbon skeleton. • How does the catalyst favor just one epoxide product? • Practice with CONCEPTUAL CHECKPOINT 14.16.

14.10 Ring‐opening of Epoxides 14.10 Ring‐opening of Epoxides

• Strong nucleophiles react readily with epoxides. • In general, alkoxides are not good leaving groups.

• Predict whether each step is product‐ or reactant‐ • The ring strain associated with the epoxide increases its favored, and explain WHY. potential energy making it more reactive.

Copyright 2012 John Wiley & Sons, Inc. 14 -47 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 14 -48 Klein, Organic Chemistry 1e 14.10 Ring‐opening of Epoxides 14.10 Ring‐opening of Epoxides

• The epoxide reaction is both more kinetically and more • Epoxides can be opened by many other strong thermodynamically favored. WHY? nucleophiles as well.

• Both regioselectivity and stereoselectivity must be considered.

14.10 Ring‐opening of Epoxides 14.10 Ring‐opening of Epoxides

• Given that the epoxide ring‐opening is SN2, predict the • Acidic conditions can also be used to open epoxides. outcome of the following reactions. • Pay attention to regio‐ and stereoselectivity. Explain WHY.

14.10 Ring‐opening of Epoxides 14.10 Ring‐opening of Epoxides • Propose an explanation for the following regiochemical • Water or an alcohol can also be used as the nucleophile observations. under acidic conditions. • Consider both steric and electronic effects (induction). • Predict the products and draw a complete mechanism.

• Antifreeze (ethylene glycol) is made industrially by this method. Copyright 2012 John Wiley & Sons, Inc. 14 -53 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 14 -54 Klein, Organic Chemistry 1e 14.10 Ring‐opening of Epoxides 14.10 Ring‐opening of Epoxides

• If the nucleophile preferentially attacks the tertiary • When the nucleophile attacks a tertiary carbon under acidic conditions, is the mechanism likely center of the epoxide, the intermediate it

SN1 or SN2? attacks takes on some carbocation character • Considering the observations below, is the mechanism (SN1), but not completely.

likely SN1 or SN2? • Give reaction conditions for the following reaction.