Download pdf - 14 -1 Klein, Organic Chemistry 1e 14 -2 Klein, …...• Generally, the F– ion is not used as a nucleophile because it is strongly solvated by polar solvents. • Such solvation

• 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?

14.1 Introduction to Ethers

Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e14 -1

O

O

• Compounds containing ether groups are quite common.

14.1 Introduction to Ethers


• Common names are used frequently:1. Name each –R group.

2. Arrange them alphabetically.

3. End with the word “ether.”

14.2 Naming Ethers


• IUPAC systematic names are often used as well:1. Make the larger of the –R groups the parent chain.

2. Name the smaller of the –R groups as an alkoxy substituent.

• Practice with SKILLBUILDER 14.1.

14.2 Naming Ethers


• Name the following molecule.

• Draw the structure for (R)‐1‐methoxycyclohexen‐3‐ol.

14.2 Naming Ethers


O Cl

• The bond angle in ethers is very similar to that found in water and in alcohols.

• Is the oxygen atom in an ether sp3, sp2, or sp hybridized?

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

14.3 Structure and Properties of Ethers


• In Chapter 13, we learned that due to hydrogen‐bonding (H‐bonding), alcohols have relatively high boiling points.

• What is the maximum number of H‐bonds an alcohol can have?

• Draw an H‐bond between an ether and an alcohol.

• What is the maximum number of H‐bonds an ether can have?



• In Chapter 13, we learned that due to hydrogen‐bonding (H‐bonding), alcohols have relatively high boiling points.

• Would you expect the boiling point of an ether to be elevated similar to alcohols?

• WHY or WHY not?



• Explain the boiling point trends below using all relevant intermolecular attractions.– Trend 1:

– Trend 2:



• Ethers are often used by organic chemists as solvents:– Relatively low boiling points allow them to be evaporated

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?



• Metal atoms with a full or partial positive charge can be stabilized by ether solvents.

• Ethers are generally used as the solvent in Grignard reactions.

• Give another reason why an ether makes a good solvent in this reaction.

14.4 Crown Ethers


• Crown ethers have been shown to form especially strong attractions to metal atoms. WHY?

• Note how many carbon atoms separate the oxygen.

• Why are they called CROWN ethers?

• Explain the numbers found in their names.

14.4 Crown Ethers


• The size of the metal must match the size of the crown to form a strong attraction.

• 18‐crown‐6 fits a K+ ion just right.

14.4 Crown Ethers


• Normally metal ions are not soluble in low polarity solvents. WHY?

• The crown ether–metal complex should dissolve nicely 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


• The F– ion below is ready to react because the K+ ion is sequestered by the crown ether.

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

14.4 Crown Ethers


• Generally, the F– ion is not used as a nucleophile 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.

14.4 Crown Ethers


• Smaller crown ethers bind smaller cations.

• Practice with CONCEPTUAL CHECKPOINT 14.4.

14.4 Crown Ethers


• Diethyl ether is prepared industrially by the acid‐catalyzed dehydration of ethanol.

• How is it a dehydration?

• Can this method be used to make asymmetrical ethers?

14.5 Preparation of Ethers


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

• What happens to the halide?



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

• The alkoxide that forms in step 1 is also a strong base.

• Are elimination products likely for methyl, primary, secondary, or tertiary alkyl halides?



• Use the Williamson ether approach to prepare MTBE.

• Consider a retrosynthetic disconnect on the t‐butyl side.

• It is better to make your retrosynthetic disconnect on the methyl side. WHY?




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



• Recall from Section 9.5 that oxymercuration‐demercuration can be used to synthesize alcohols.

• Is the addition Markovnikov or anti‐Markovnikov?

• Is the addition syn or anti?



• Similarly, alkoxymercuration‐demercuration can be used to synthesize ethers.

• Is the addition Markovnikov or anti‐Markovnikov?

• Is the addition syn or anti?

• Practice CONCEPTUAL CHECKPOINTs 14.8‐14.10.



• As we mentioned earlier because they are aprotic, 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.?

14.6 Reactions of Ethers


• Ethers can undergo acid‐promoted cleavage.



• Draw a complete mechanism and predict the products for the following acid‐promoted cleavage.



• To promote cleavage, HI and HBr are generally 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?




• Predict products for the reaction below, and draw a complete mechanism.



• Recall from Section 11.9 that ethers can undergo 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:



• For cyclic ethers, the size of the ring determines the parent name of the molecule.

• Oxiranes are also known as epoxides.

• Which cyclic ether system do you think is most reactive? WHY?

14.7 Naming Epoxides


• An epoxide can have up to 4 –R groups.

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



• There are two methods for naming epoxides:1. The oxygen is treated as a side group, and two numbers are

given as its locants.

2. Oxirane is used as the parent name.



• Name the molecules below by both methods if possible.

• Practice CONCEPTUAL CHECKPOINTs 14.12 and 14.13.



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

• MCPBA and peroxyacetic acid are most commonly used.

14.8 Preparation of Epoxides


• Recall that the process is stereospecific.



• 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.





• Assess the overall stereochemistry of the epoxidation that occurs through the halohydrin intermediate.




• The epoxidation methods we have discussed so far are NOT enantioselective.

• Draw the products.

14.9 Enantioselective Epoxidation


• The epoxidation forms a racemic mixture because the flat alkene can react on either face.



• To be enantioselective at least one of the reagents (or the catalyst) in a reaction must be chiral.

• The Sharpless catalyst forms such a chiral complex with an allylic alcohol.



• The desired epoxide can be formed if the right catalyst is chosen. Note the position of the –OH group.

• How does the catalyst favor just one epoxide product?




• 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.

14.10 Ring‐opening of Epoxides


• Strong nucleophiles react readily with epoxides.

• Predict whether each step is product‐ or reactant‐favored, and explain WHY.



• In general, alkoxides are not good leaving groups.

• The ring strain associated with the epoxide increases its potential energy making it more reactive.



• The epoxide reaction is both more kinetically and more thermodynamically favored. WHY?



• Epoxides can be opened by many other strong nucleophiles as well.

• Both regioselectivity and stereoselectivity must be considered.



• Given that the epoxide ring‐opening is SN2, predict the outcome of the following reactions.

• Pay attention to regio‐ and stereoselectivity. Explain WHY.




O

• Acidic conditions can also be used to open epoxides.



• Water or an alcohol can also be used as the nucleophile under acidic conditions.

• Predict the products and draw a complete mechanism.

• Antifreeze (ethylene glycol) is made industrially by this method.



• Propose an explanation for the following regiochemical observations.

• Consider both steric and electronic effects (induction).



• If the nucleophile preferentially attacks the tertiary carbon under acidic conditions, is the mechanism likely SN1 or SN2?

• Considering the observations below, is the mechanism likely SN1 or SN2?



• When the nucleophile attacks a tertiary center of the epoxide, the intermediate it attacks takes on some carbocation character (SN1), but not completely.

• Give reaction conditions for the following reaction.




• Sulfur appears just under oxygen on the periodic table.

• Sulfur appears in THIOLS as an –SH group analogous to the –OH group in alcohols.

• The name of a compound with an –SH group ends in “thiol” rather than “ol.”

• Note that the “e” of butane is not dropped in the name of the thiol.

14.11 Thiols and Sulfides


• Thiols are also known as mercaptans.

• The –SH group can also be named as part of a side group rather than as part of the parent chain.

• The mercaptan name comes from their ability to complex mercury.

• 2,3‐dimercapto‐1‐propanol is used to treat mercury poisoning. WHY? Draw its structure.



• Thiols are known for their unpleasant odor.

• Skunks use thiols as a defense mechanism.

• Methanethiol is added to natural gas (methane) so that gas leaks can be detected.

• Your nose is a very sensitive instrument.

• The hydrosulfide ion (HS–) is a strong nucleophile and a weak base.

• HS– promotes SN2 rather than E2.



• Predict the outcome of the following reactions, and draw a complete mechanism.




• Thiols have a pKa of about 10.5.

• Recall that water has a pKa of 15.7.

• Predict whether the equilibrium below will favor products or reactants and draw the mechanism.

• Thiolates are excellent nucleophiles.



thiolate ion

• Once a thiolate forms, it can attack Br2 to produce a disulfide.

• How does the oxidation number change?



• Disulfides can be reduced by the reverse reaction.

• The interconversion between thiol and disulfide can also occur directly via a free radical mechanism. Propose a mechanism.

• The bond dissociation energy of a S–S bond is only about 53 kcal/mol. WHY is that significant?



• Sulfur analogs of ethers are called SULFIDES or THIOETHERS.

• Sulfides can also be named as a side group.



• Sulfides are generally prepared by nucleophilic attack of a thiolate on an alkyl halide.

• How are thiolates generally prepared?



• Sulfides undergo a number of reactions:1. Attack on an alkyl halide:

– The process produces a strong alkylating reagent that can add an alkyl group to a variety of nucleophiles.



• Sulfides undergo a number of reactions:2. Sulfides can also be oxidized.

– Sodium meta‐periodate can be used to form the sulfoxide.



• Sulfides undergo a number of reactions:2. Sulfides can also be oxidized.

– Hydrogen peroxide can be used to give the sulfone.



• Sulfoxides and sulfones have very little double bond character.

• Which resonance contributor for each is the major contributor, and WHY?



• Because sulfides are readily oxidized, they make good reducing agents.

• Recall the ozonolysis reaction from Section 9.11.




• Predict any products or necessary reagents in the reaction sequence below.

• Verify the formal charge on the sulfur in the final product above.



BrHS

1) NaOH

2)

• Epoxides can be used to install functional groups on adjacent carbons.

• Give necessary reagents for the reaction below.


14.12 Synthetic Strategies Involving Epoxides


• By reacting an epoxide with a Grignard reagent, the carbon skeleton can be modified.

• You may think of an alkyl halide as the starting material.



• Recall that a carbonyl can be used to install a one carbon chain between an R group and an OH group.

• An epoxide can be used to install a two carbon chain between an R group and an OH group.



• Give necessary reagents for the reaction below.


