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Ethers

Building Bridges to Knowledge

Photo of the Delicate Arch in Arches National Park near Moab, Utah

Ethers are compounds with two alkyl groups that sandwich an oxygen atom. Ethers are named by identifying, as separate words, the two alkyl groups (which sandwich the oxygen atom) in alphabetical order followed by the word ether. Therefore, CH3CH2OCH3, an unsymmetrical ether, is called ethyl methyl ether. CH3CH2OCH2CH3, a symmetrical ether, is called diethyl ether. (CH3)2CHOCH2CH2CH2CH2CH(Br)CH3 is 5-bromohexyl isopropyl

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ether.

The nomenclatures of five cyclic ethers are indicated in the following table:

Dioxane, compound 1, is an example of a diether; and diglyme (diethylene glycol dimethyl ether), compound 2, is an example of a triether solvent.

RSR are thiols. RS is referred to as an alkylthio group.

CH3CH2SCH2CH3 is referred to as diethyl sulfide or ethylthioethane.

In naming heterocyclic compounds containing sulfur, replace ”ox” with “thi.”

Five cyclic thiols, S as the heterocyclic atom, are identified in the following table:

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Crown Ethers

In 1967, Charles Pedersen of DuPont found that certain cyclic polyethers form stable complexes with cations. These complexes are referred to as crown ethers, and they promote the solubility of salts in organic solvents. For example, potassium permanganate, an oxidizing agent, can be dissolved in benzene in the presence of 18-crown-6. 18-Crown-6 ether dissolves in benzene, and the potassium ion of the potassium permanganate complexes with the crown ether and the permanganate ion is forced to dissolve in the benzene to ion-pair with the potassium ion. The ether functions as a host for the potassium ion, and the crown ether functions as a co-solvent.

The common names of crown ethers are based on the number of carbon atoms and the number of oxygen atoms in the cyclic polyether. For example, compound 3 contains eight (8) carbon atoms and four (4) oxygen atoms [8+4 =12]; the cyclic polyether is named by indicating the total number of carbon and oxygen atoms followed by the word crown followed by the number of oxygen atoms in the crown. Compound 3 is named 12-crown-4.

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Compound 4 is 15-crown-5

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Compound 5 is 18-crown-6

The crown ether (18-crown-6) functions as a host for the potassium ion in benzene, and the crown ether functions as a co-solvent. This is a way to get ionic compounds to dissolve in nonpolar solvents.

Preparation of Ethers

Reacting alcohols with mineral acids result in the formation of ethers. For example, diisopropyl ether can be prepared from 1-propanol by

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reacting 1-propanol with an aqueous acid such as sulfuric acid in water.

Following is a mechanism that may be used to explain the formation of di-n- ]propyl ether from 1-propanol. The pathway (mechanism) involves the protonation of the alcohol followed by a nucleophilic substitution of another 1-propanol molecule to displace water and form the ether.

(1)

(2)

(3)

2 CH3CH2CH2OH     H3O+  CH3CH2CH2OCH2CH2CH3  +  H2O

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Before tert-butyl methyl ether was banned as a fuel additive to increase the octane rating of gasoline, the following commercial process was used to make the compound from 2-methylpropene:

The three-step pathway that may be used to explain the formation of tert-butyl methyl ether from isobutylene and methanol involves the formation of a stable carbocation in a slow step, followed by the rapid nucleophilic attack of methanol on the tertiary carbocation intermediate.

(1)

(2)

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(3)

The Williamson Synthesis of Ethers

The Williamson synthesis involves the nucleophilic attack of alkoxides (a strong base) on primary alkyl halides to form ethers:

The reaction proceeds through a substitution bimolecular (SN2) mechanism where the alkoxide anion displaces the halogen of the primary alkyl halide to form an ether.

3-Phenylbutyl benzyl ether can be prepared from benzyl bromide and sodium 3-phenylbutoxide by the Williamson synthesis.

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3-phenylbutoxide can be made via the following reaction:

Alkyl halides are synthesized from alcohols and hydrogen halides or thionyl chloride, SOCl2, or phosphorous tribromide, PBr3.

Alkyl halides from HBr

This works well for primary alkyl halides.

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Alkyl halides from PBr3

This reaction works well for the formation of primary alcohols.

The mechanism for the reaction between benzyl alcohol and phosphorous tribromide involves nucleophilic attack of the alcohol on the phosphorous tribromide nucleus.

The reaction works best for primary alcohols.

(1)

(2)

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(3)

(4)

(5)

(6)

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Alkyl halides from SOCl2

This works well for primary alcohols.

Thionyl chloride is another reagent that could be used to prepare alkyl halides from primary alcohols. The reaction proceeds in an analogous manner as in the previous discussion about the nucleophilic attack of primary alcohols on phosphorous tribromide. The primary alcohol attacks the sulfur atom of thionyl chloride, then the reaction proceeds by an SN2 reaction to produce a primary alkyl chloride.

Following is a revisit of the three steps that rationalize the formation of a primary alkyl chloride from the reaction of thionyl chloride with a primary alcohol.

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In the place of alkyl halides, alkyl p-toluenesulfonates can be used to make the ether.

Ethers dissolve nonpolar substances, and they are not very reactive;

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therefore, they are useful as solvents in organic reactions. Diethyl ether is very flammable, and, as such, should be used with caution.

When ether is exposed to air, it will oxidize to form explosive peroxides.

Ethers can be cleaved by hydriodic acid.

Following four steps represent the mechanism for the cleavage of ethers with hydriodic acid.

(1)

(2)

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(3)

(4)

Following is the order of reactivity for cleaving ethers with hydrohalic acids.

HI > HBr > HCl

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Unsymmetrical ethers can also be cleaved using hydrohalic acids. For example, the following mechanism could explain the acid catalyzed cleavage of unsymmetrical ethers.

(1)

(2)

(3)

(4)

(5)

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(6)

The complete reaction is:

Preparation of Epoxides

Peroxyacids can be used to prepare expoxides with alkenes. Epoxides are cyclic ethers. An example of the expoxidation of alkenes is the reaction between cyclohexene and peroxyacetic acid.

The mechanism for the reaction involves syn addition to the double bond. The following two-step mechanism (presented in the paper titled “Alkenes, Building Bridges to Knowledge”) rationalizes the formation of an epoxide from the reaction of an alkene with a peroxyacid.

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(1)

(2)

If the starting alkene is a trans alkene, then the product will be a trans oxirane, and if the starting alkene is a cis alkene, the product will be a cis oxirane; consequently, the reaction is stereospecific.

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Kary Barry Sharpless, known for his work in stereoselective reactions, pioneered the process that lead to the preparation of enantioselective epoxides in the presence of tert-butyl hydroperoxide, titanium (IV) isopropoxide, and diethyl (2R,3R)-tartrate, starting with an allylic alcohol.

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The reaction is referred to as the Sharpless Epoxidation, and it is useful as an enantioselective epoxidation of prochiral allylic alcohols. The chiral centers formed are achieved by adding an enantiomeric tartrate derivative.

The oxidant in the reaction is tert-butyl hydroperoxide, and the reaction is catalyzed by titanium (IV) isopropoxide which binds with

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the hydroperoxide, the HO of the allylic alcohol, and the OH oxygen atoms of the optically active tartrate.

The mechanism of this reaction is complicated, but the reaction probably proceeds through the formation of a titanium complex. For example, trans-2-hexen-1-ol, titanium isopropoxide, tert-butyl hydroperoxide, and diethyl (2R,3R)-tartrate can form complex I. The red labeled oxygen of the tert-butyl hydroperoxide froms an epoxide with trans-2-hexen-1-ol as illustrated in the activated complex II formed at the transition state. The activated complex proceeds through a series of steps to produce the desired enantioselective epoxide, (2S,3R)-2,3-epoxy-1-hexanol. If diethyl (2S,3S)-tartrate were used instead of diethyl (2R,3R)-tartrate, than (2R,3S)-2,3-epoxy-1-hexanol would be the product.

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Complex 1

The activated complex goes through a process that forms the enantioselective epoxide.

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K. Barry Sharpless received the Nobel Prize for his work in 2001. His method of enantimeric expoxidation of allylic alcohols was useful in the synthesis of (+)-disparlure (I), cis-7.8-epoxy-2-methyloctadecane, a sex pheromone used to control gypsy moth

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infestation. Also, the Sharpless expoxidation method was used in the synthesis of (R)-glycidol, compound II. Compound II, R-(+)-Glycidol, is used in the synthesis of beta-blockers. Beta-blockers are used to treat patients with cardiac problems.

Halohydrins

Halohydrins can be converted into epoxides by the following sequence of reactions.

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Reactions of Epoxides

Epoxides, cyclic ethers, react with nucleophilic reagents whereas

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other ethers are resistant to attack by nucleophiles.

Organolithium reagents will also react with ethylene oxide in an analogous manner as Grignard reagents react with epoxides.

The mechanism for the addition of a Grignard reagent to ethylene oxide involves a nucleophilic attack on a carbon atom of ethylene oxide.

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(1)

(2)

Nucleophilic Attack on Epoxides

Nucleophiles react exothermically with Epoxides and can occur at two sites on the expoxide. The nature of the nucleophile determines which site functions as the Lewis acid. Strong nucleophiles will attack the less alkylated carbon atoms. Weak nucleophiles attack the carbon atom which is more alkylated. A nucleophile like RS-

will attack the carbon atom that is less hindered, followed by

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hydrolysis of the intermediate salt to form a thioalcohol.

This reaction can be written generally in the following manner.

Following is an example of a nucleophilic attack of a strong base on an epoxide.

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(1)

(2)

Another example is the formation of (2S,3R)-3-cyano-2-butanol from (2S,3R)-2,3-epoxybutane, the meso epoxide. The following reaction is an illustration of this reaction.

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(2S,3R)-3-cyano-2-butanol

Formation of (2R,3R)-3-cyano-2-butanol from (2R,3R)-2,3-epoxybutane

(2R,3R)-3-cyano-2-butanol

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Acid-Catalyzed Ring Opening of Epoxides

The following reactions illustrate the acid-catalyzed ring opening of epoxides.

As indicated previously, the nucleophilic attack on epoxides depends on the nature of the nucleophile. Strong bases tend to attack the less alkylated carbon atom of the epoxide. Whereas, weak bases tend to attack the more alkylated carbon atom. This phenomenon is related to SN1 and SN2 reactions. For substitution nucleophilic bimolecular reactions, a strong base prefers to attack the primary carbon atom. For substitution nucleophilic unimolecular reactions, a weak base prefers to attack the more alkylated carbon atom, because the incipient carbocation is more stable.

Acid catalyzed ring opening of an epoxide involves nucleophilic attack by a weak base. For example, I- is a weak base that attacks the more alkylated portion of the epoxide in a manner illustrated in

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the following sequence of elementary steps.

(1)

(2)

a weak base

In addition, the following reaction is an illustration of the acid catalyzed ring opening of 1-methyl-1,2-epoxycyclohexane. The acid catalyzed opening of an epoxide results in nucleophilic attack on the more alkylated carbon atom of the epoxide or oxirane ring.

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The reaction proceeds through steps (1) through (3).

(1)

(2)

(3)

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Formation of the trans-glycol

The anti-hydroxylation product (the trans-glycol) can be formed from peroxyacid by epoxidation, followed by acid hydrolysis. The following sequence of steps illustrates the mechanism for the formation of the anti-hydroxylation or trans-glycol product.

(1)

(2)

(3)

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(4)

Sulfonium Salts

Sulfonium salts are formed from the nucleophilic attack of a sulfide on an alkyl halide via an SN2 reaction:

Following is a possible synthesis of 4-methylsulfinylbutyl isothiocyanate (sulforaphane), an anti-carcinogenic compound.

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+ H2O

+ NaBr

+ HCl

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sulforaphane

Sulforaphane, found in broccoli, is thought to be a nontoxic potential anticarcinogenic compound.

SAM-Adensylmethionine

S-adenosylmethionine (SAM) is a natural sulfonium salt. SAM is a biological methyl transfer agent, and an important agent used in the biological synthesis of epinephrine.

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Following is the biological synthesis for SAM from the amino acid methionine, and adenosine triphosphate in the presence of an enzyme and water:

SAM, S-adenosylmethionine, can be used to transfer a methyl group to norepinephrine in the presence of a biological catalyst. The reaction follows an SN2 mechanism.

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Ethers

Problems

1. Write structural formulas for:

(a) 1,2-epoxyhexane

(b) diisopropyl ether

(c) diallyl ether

(d) dibenzyl ether

2. Write names for the following compounds

(a)

(b)

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(c)

(d)

3. The proton magnetic spectrum and carbon thirteen magnetic spectrum of an unknown compound, C8H8O, are illustrated below.

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When HBr is added to C8H8O, C8H8Br2 is obtained. The proton magnetic spectrum and carbon thirteen magnetic spectrum of C8H8Br2 are illustrated below.

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Suggest structures for C8H8O and C8H8Br2.

4. Compounds A and B can be formed via the following reaction.

Compounds A and B react with lithium methide, followed by acid hydrolysis to produce compounds C and D. Compound A and B react with dilute hydrochloric acid to produce compounds E and F. Suggest structures for compounds A, B, C, D, and E.

5.

Suggest a mechanism for the following conversion.

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6. Suggest products from the following reactions

(a)

(b)

(c)

7. Suggest a synthesis for the following from the indicated starting material and any other necessary organic or inorganic materials.

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8. Suggest a synthesis for the following from the indicated starting material and any other necessary organic or inorganic materials.

9. Suggest products for the following reactions.

(a)

(b)

(c)

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10. Suggest a synthesis for the following molecule from the indicated starting materials and any other necessary organic or inorganic materials.

11. Suggest a synthesis for the following molecules using an analogous format you used to synthesis the ether in problem 10.

12. If the following proton magnetic spectrum represents the product of problem 10, sketch the H1 NMR spectrum for the product of problem 11.

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13. Suggest mechanisms (a series of elementary steps) to rationalize the following observations:

(a)

(b)

O

H3C

H H

H + -OH S-1,2-propanediolH2O2.