Chapter 11. Structure. The functional group of an ether is an oxygen atom bonded to two carbon atoms.

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1 Ethers, Sulfides (omit), Ethers, and Epoxides hapter 11 1 Structure The functional group of an ether is an oxygen atom bonded to two carbon atoms. In dialkyl ethers, oxygen is sp 3 hybridized with bond angles of approximately In dimethyl ether, the -- bond angle is

2 Structure In other ethers, the ether oxygen is bonded to an sp hybridized carbon. In ethyl vinyl ether, for example, the ether oxygen is bonded to one sp 3 hybridized carbon and one sp hybridized carbon. Ethoxyethene (Ethyl vinyl ether) 3 -- = 3 Nomenclature IUPA: the longest carbon chain is the parent. Name the R group as an alkoxy substituent. ommon names: name the groups bonded to oxygen in alphabetical order followed by the word ether Ethoxyethane (Diethyl ether) trans- -Ethoxycyclohexanol -Methoxy-- methylpropane (tert- Butyl methyl ether) 4

3 Nomenclature Although cyclic ethers have IUPA names, their common names are more widely used. IUPA: prefix ox- shows oxygen in the ring. The suffixes -irane, -etane, -olane, and -ane show three, four, five, and six atoms in a saturated ring. 3 1 xirane (Ethylene oxide) xetan e xolane xane (Tetrahydrofuran) (Tetrahydropyran) 1,4-Dioxane 5 Physical Properties Although ethers are polar compounds, only weak dipole-dipole attractive forces exist between their molecules in the pure liquid state. Note bene: : there is N intramolecular -bonding 6

Physical Properties Boiling points of ethers are lower than alcohols of comparable MW. close to those of hydrocarbons of comparable MW. Ethers are hydrogen bond acceptors.

4 Physical Properties Boiling points of ethers are lower than alcohols of comparable MW. close to those of hydrocarbons of comparable MW. Ethers are hydrogen bond acceptors. They are NT soluble in, but They are more soluble in than are hydrocarbons.. Note bene: : there IS intermolecular -bonding 7 Williamson ether synthesis: Ether synthesis by the S N displacement of halide, tosylate, or mesylate by alkoxide ion Na S N 3 I 3 3 Na I - Sodium isopropoxide Preparation of Ethers Iodomethane (Methyl iodide) -Methoxypropane (Isopropyl methyl ether) 1) Na o R' R R() R() ) R'X 1 o or o R R() R() R Ether 8

5 Preparation of Ethers Yields are highest with methyl and 1 halides, lower with halides (competing β- elimination) K 3 Potassium tert-butoxide 3 Br Bromomethane (Methyl bromide) S N K Br - 3 -Methoxy--methylpropane (tert-bu tyl methyl ether) 9 Preparation of Ethers reaction fails with 3 halides (β-elimination only). 3 3 Br 3 - Na E 3 3 = 3 Na Br - 3 -Bromo-- methylpropane Sodium methoxide -Methylpropene 10

6 Preparation of Ethers Acid-catalyzed dehydration of alcohols Diethyl ether and several other ethers are made this way on an industrial scale. A specific example of an S N reaction in which a poor leaving group ( - ) is converted to a better one ( ). 3 S Ethanol 3 3 Diethyl ether 11 Preparation of Ethers Step 1: Proton transfer gives an oxonium ion S-- fast and reversib le 3 -- An oxonium ion - - S- - Step : Nucleophilic displacement of by the group of the alcohol gives a new oxonium ion S N A new oxonium ion - 1

7 Preparation of Ethers Step 3: Proton transfer to solvent completes the reaction proton transfer Preparation of Ethers Acid-catalyzed addition of alcohols to alkenes Yields are highest using an alkene that can form a stable carbocation and using methanol or a 1 alcohol that is not prone to undergo acid-catalyzed dehydration. 4 14

8 Preparation of Ethers 1. Use an alkene that can form a stable carbocation ( o or 3 o ). Use a 1 alcohol (that is not prone to undergo acid-catalyzed dehydration). acid 3 catalyst 3 3 = Methoxy--methyl propane 15 Preparation of Ethers Step 1: Protonation of the alkene gives a carbocation = Step : Reaction of the carbocation (an electrophile) with the alcohol (a nucleophile) gives an oxonium ion

9 Preparation of Ethers Step 3: Proton transfer to solvent completes the reaction Epoxide: A cyclic ether in which oxygen is one atom of a three-membered ring. Simple epoxides are named as derivatives of oxirane. Where the epoxide is part of another ring system, it is shown by the prefix epoxy xirane (Ethylene oxide) Epoxides 1,-Epoxycyclohexane (yclohexene oxide) 1 18

10 Epoxides Epoxide: A cyclic ether in which oxygen is one atom of a three-membered ring. ommon names are derived from the name of the alkene from which the epoxide is formally derived. 3 1 xirane (Ethylene oxide) 3 3 cis-,3-dimethyloxirane (cis- -Butene oxide) 1,-Epoxycyclohexane (yclohexene oxide) 1 19 Synthesis of Epoxides Ethylene oxide, one of the few epoxides manufactured on an industrial scale, is prepared by air oxidation of ethylene. = Ag xirane (Ethylene oxide) procaine 0

11 Synthesis of Epoxides The most common laboratory method is oxidation of an alkene using a peroxycarboxylic acid (a peracid). l meta- hloroperoxybenzoic acid (MPBA) 3 Peroxyacetic acid (Peracetic acid) 1 Synthesis of Epoxides Epoxidation of cyclohexene yclohexene R l A peroxy- 1,-Epoxycyclohexane carboxylic acid (yclohexene oxide) R A carboxylic acid

12 Synthesis of Epoxides Epoxidation is stereospecific: Epoxidation of cis--butene gives only cis-,3- dimethyloxirane. Epoxidation of trans--butene gives only trans-,3-dimethyloxirane. 3 3 trans--buten e R trans-,3-dimethyloxirane (a racemic mixture) 3 Synthesis of Epoxides A mechanism for alkene epoxidation. 4 3 R 1 R 4

13 Synthesis of Epoxides Epoxides are also synthesized via halohydrins. l 3 =, Na, 3 - S l N Propene A chlorohydrin (racemic) 3 Methyloxirane (racemic) 5 Synthesis of Epoxides The second step is an internal S N reaction. internal S N l l An epoxide 6

14 Synthesis of Epoxides alohydrin formation is both regioselective and stereoselective; for alkenes that show cis,trans isomerism, it is also stereospecific. onversion of a halohydrin to an epoxide is stereoselective: 3 3 cis- -Butene 1. l,. Na, 3 3 cis-,3-dimethyloxirane 7 Synthesis of Epoxides Problem: Account for the fact that conversion of cis--butene to an epoxide by the halohydrin method gives only cis-,3-dimethyloxirane. 3 3 cis- -Butene 1. l,. Na, 3 3 cis-,3-dimethyloxirane 8

15 Reactions of Epoxides Ethers are not normally susceptible to attack by nucleophiles. Because of the strain associated with the three-membered ring, epoxides readily undergo a variety of ring-opening reactions. Nu Nu: 9 Reactions of Epoxides Acid-catalyzed ring opening In the presence of an acid catalyst, such as sulfuric acid, epoxides are hydrolyzed to glycols. xirane (Ethylene oxide) 1,-Ethanediol (Ethylene glycol) 30

16 Reactions of Epoxides Step 1: Proton transfer to oxygen gives a bridged oxonium ion intermediate. Step : Backside attack by water (a nucleophile) on the oxonium ion (an electrophile) opens the ring. Step 3: Proton transfer to solvent completes the reaction. 1 (1) Attack of the nucleophile on the protonated epoxide shows anti stereoselectivity. ydrolysis of an epoxycycloalkane gives a trans- 1,-diol. 1,-Epoxycyclopentane (yclopentene oxide) (achiral) Reactions of Epoxides trans- 1,-yclopentanediol (a racemic mixture) 3

R R 3 R R 33 Reactions of Epoxides The value of epoxides is the variety of nucleophiles that will open the ring and the combinations of functional groups that can be

17 R R 3 R R 33 Reactions of Epoxides The value of epoxides is the variety of nucleophiles that will open the ring and the combinations of functional groups that can be prepared from them. 3 S A β-mercaptoalcohol Na S - / Na N - / 3 N A β-hydroxynitrile 3 A glycol / 3 3 Methyloxirane N 3 3 A β-alkynylalcohol 1. - Na. 3 N A β-aminoalcohol 34

18 Medicinal hemistry ocaine Topical anesthetic (local) NS stimulant NT exam material 35 Medicinal hemistry Alkanolamines (Ethanolamines) Procaine 36

19 Medicinal hemistry Synthesis of Procaine 37 Medicinal hemistry Synthesis of Procaine N( 3 ) 38

20 Medicinal hemistry Synthesis of Procaine Ni Procaine (novocaine) 39 Medicinal hemistry 40

But in organic terms: Oxidation: loss of H 2 ; addition of O or O 2 ; addition of X 2 (halogens).

But in organic terms: Oxidation: loss of H 2 ; addition of O or O 2 ; addition of X 2 (halogens). Reactions of Alcohols Alcohols are versatile organic compounds since they undergo a wide variety of transformations the majority of which are either oxidation or reduction type reactions. Normally: Oxidation