Organic Chemistry Chapter 13 Ethers

Chapter 13 Ethers

Delicate Arch (Moab, Utah) David Richardson

“Science is my territory, but science fiction is the landscape of my dreams.”

Freeman John Dyson, Imagined Worlds

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Ethers are compounds with two alkyl groups that sandwich an oxygen atom. The nomenclature of ethers are relatively simple. Identify the groups that sandwich the oxygen atom and, as separate words, name the two alkyl groups 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 ether.

The following table lists the names of five cyclic ethers:

Dioxane, compound 1, is an example of a diether; and diglyme (diethylene glycol dimethyl ether), compound 2, is an example of a triether. Diethyl ether and diglyme are examples of aprotic solvents.

RSR are thiols. RS is an alkylthio group.

CH3CH2SCH2CH3 is diethyl sulfide or ethylthioethane.

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

The following table identifies five cyclic thiols (where S is the heterocyclic atom):

Crown Ethers In 1967, Charles Pedersen of DuPont found that certain cyclic polyethers form stable complexes with cations. These complexes are crown ethers, and they promote the solubility of salts in organic solvents. For example, in the presence of 18-crown-6, potassium permanganate, an oxidizing agent, dissolves in benzene (Figure 13.1). The 18-crown-6 ether dissolves in benzene, and the potassium ion of the potassium permanganate complexes with the crown ether and the permanganate ion dissolves 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 number of carbon atoms and the number of oxygen atoms in the cyclic polyether determine the common names for crown ethers. For example, compound 3 contains eight (8) carbon atoms and four (4) carbon atoms [8+4 =12]; therefore, the cyclic polyether for this "12" atom system is 12-crown-4. The name indicates the total number of carbon atoms in the crown followed by the word "crown" followed by the number of oxygen atoms in the crown.

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Compound 4 is 15-crown-5

Compound 5 is 18-crown-6

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Figure 13.1

Potassium is filling the “4s” energy level; therefore there are low lying “4p” and “4d” atomic orbitals available to accommodate the six 2sp3 atomic orbitals of the six lone pairs residing in the 2sp3 molecular orbitals of the oxygen atoms in the crown ether.

The six K+ ← O coordinate covalent bonds (also referred to as dative bonds) form the product of Figure 13.1. The potassium ion has the perfect radius to accommodate a “fit” within the dentate of the 18-crown-6 ether that loosely coordinates the K+ to conform to the conformation of the puckered ring system. The other alkali ions are either two small or too large for a perfect fit. Also, the potassium ion is in the complex where the six oxygens are in the same plane (Figure 13.2).

Figure 13.2

Preparation of Ethers Reacting alcohols with mineral acids results in the formation of ethers. For example, 1propanol reacts with an aqueous acid such as sulfuric acid in water to form diisopropyl ether.

2 CH3CH2CH2OH + H2SO4 (aq) → CH3CH2CH2OCH2CH2CH3 + H2O

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A pathway to explain the formation of diisopropyl ether from 1-propanol 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)

The following is a commercial synthesis for tert-butyl ether from 2-methylpropene:

Presently, tert-butyl methyl ether is no longer a commercial fuel additive for increasing the octane ratings of gasoline.

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The following is a three-step pathway to explain the formation of tert-butyl methyl ether from isobutylene and methanol: (The mechanism involves the formation of a stable carbocation in a slow step, followed by the rapid nucleophilic attack of methanol on the stable tertiary carbocation intermediate.)

(1) Slow step

(2) Fast step

(3)

The Williamson Synthesis of Ethers The Williamson synthesis involves the nucleophilic attack of alkoxides ( a strong base) 8

on primary alkyl halides to form ethers:

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

The preparation of 3-Phenylbutyl benzyl ether from benzyl bromide and sodium 3phenylbutoxide is an example of the Williamson synthesis.

The following reaction is a method for synthesizing 3-phenylbutoxide:

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

Alkyl halides from HBr This reaction works well for primary alkyl halides.

Alkyl halides from PBr3 This reaction works well for primary alcohols.

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

The reaction works best for primary alcohols.

(1)

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(2)

(3)

(4)

(5)

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(6)

Alkyl halides from SOCl2 This reaction works well for primary alcohols.

Thionyl chloride is another reagent that prepares alkyl halides from primary alcohols.

The reaction proceeds analogously as in the previous discussion concerning 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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Analogous to alkyl halides, alkyl p-toluenesulfonates is a precursor for synthesizing ethers.

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Ethers dissolve nonpolar substances, and they are not very reactive; therefore, they are excellent solvents for organic reactions. Diethyl ether is very flammable, and, as such, should be used cautiously.

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

Hydroiodic acid cleaves ethers.

The following four steps represent the mechanism for the cleavage of ethers with hydroiodic acid.

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(1)

(2)

(3)

(4)

The following is the order of reactivity for cleaving ethers with hydrohalic acids:

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HI > HBr > HCl 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)

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(4)

(5)

(6)

(7)

Preparation of Epoxides Peroxacids react with alkenes to produce epoxides. Epoxides (oxiranes) are cyclic ethers.

An example of the epoxidation of alkenes is the reaction between cyclohexene and peroxyacetic acid.

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The mechanism for the reaction involves syn addition to the double bond.

The following two-step mechanism (presented in Chapter 3) rationalizes the formation of an epoxide from the reaction of an alkene with a peroxyacid: (1)

(2)

If the starting alkene is a trans alkene, then the product will be a trans oxirane. If the starting alkene is a cis alkene, then 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 a process that led to the preparation of enantioselective epoxides. His Team synthesized enantioselected epoxides by reacting allylic alcohols with tert-butyl hydroperoxide, titanium(IV) isopropoxide, and diethyl (2R,3R)-tartrate or diethyl (2S,3S)-tartrate. The tartrate determined the outcome of a specific enantiomeric epoxide.

If the precursor is trans-2-hexen-1-ol, then adding diethyl (2R,3R)-tartrate to the reaction mixture would produce (2S,3R)-2,3-epoxy-1-hexanol. On the other hand, if diethyl (2S,3S)-tartrate is added to the reaction mixture, then (2R,3S)-2,3-epoxy-1hexanol forms.

The following illustrates the reaction schema:

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The above schema represents the Sharpless Epoxidation, and is useful as an enantioselective epoxidation of prochiral allylic alcohols since the schema develops chiral centers by including an enantiomeric tartrate into the reaction mix.

The oxirane ring forms from tert-butyl hydroperoxide and the reaction is catalyzed by titanium(IV) isopropoxide. Introducing diethyl (2R,3R)-tartrate results in an oxirane ring at the bottom of the plane containing the atoms where the double bond resided, and

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the presence of diethyl (2S,3S)-tartrate in the reaction mixture results in an oxirane ring at the top of the plane where the double bond resided.

The mechanism of this reaction is complexed, and the reaction proceeds through the formation of a titanium complex containing four dative bonds. Trans-2-hexen-1-ol, titanium isopropoxide, tert-butyl hydroperoxide, and diethyl (2R,3R)-tartrate form complex I. The red labeled oxygen of the tert-butyl hydroperoxide forms the oxirane ring system as illustrated in the activated complex at the transition state. The activated complex proceeds through a series of steps (not shown) to produce the desired enantioselective epoxide, (2S,3R)-2,3-epoxy-1-hexanol. Diethyl (2S,3S)-tartrate in the reaction mixture instead of diethyl (2R,3R)-tartrate gives rise to (2R,3S)-2,3-epoxy-1hexanol.

The following is a visual demonstrate the Sharpless reaction.

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Complex 1

activated complex

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

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Let’s look at the addition of diethyl (2S,3S)-tartrate to trans-2-hexen-1-ol.

Complex 2

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Activated complex

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K. Barry Sharpless received the Nobel Prize for his work in 2001.

His method of enantiomeric epoxidation 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 infestation. Also, the Sharpless epoxidation method is a pathway for making (R)-glycidol, compound II. Compound II, R-(+)-Glycidol, is used in the synthesis of beta-blockers. Beta-blockers are drugs for treating patients with cardiac problems.

Halohydrins The following sequence of reactions demonstrates a process for converting halohydrins into epoxides.

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Reactions of Epoxides Epoxides, cyclic ethers, react with nucleophilic reagents whereas other ethers are resistant to attack by nucleophiles.

Organolithium reagents will also analogously react with ethylene oxide 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 epoxide. 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.

The following is an example of this type of nucleophilic attack using RS- Na+, a strong base :

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The nucleophile will attack the carbon atom that is less hindered, followed by hydrolysis of the intermediate salt to form a thio alcohol.

The following is an acid-catalyzed attack demonstrating general illustration of a weak nucleophilic attack on an epoxide:

(1)

(2)

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(3)

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

(1)

(2)

Another example is the formation of (2S,3R)-3-cyano-2-butanol from (2S,3R)-2,3epoxybutane, the meso epoxide.

The following reaction is an illustration of this reaction:

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

Acid-Catalyzed Ring Opening of Epoxides The following reactions illustrate the acid-catalyzed ring opening of epoxides.

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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 a 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 the following sequence of elementary steps.

(1)

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(2)

a weak base

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

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

(1)

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(2)

(3)

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 antihydroxylation or trans-glycol product.

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Sulfonium Salts The following illustrates nucleophilic attacks of sulfides on alkyl halides leading to the formation of sulfonium salts via an SN2 reaction:

The following is a possible synthesis of 4-methylsulfinylbutyl isothiocyanate (sulforaphane), an anti-carcinogenic compound:

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sulforaphane

Sulforaphane, found in broccoli, is thought to be a nontoxic natural anticarcinogen.

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.

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

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

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Problems

1.

Write structural formulas for: 1,2-epoxyhexane diisopropyl ether diallyl ether 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.

6.

Suggest products from the following reactions (a)

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(b)

(c)

7.

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

8.

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

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9.

Suggest products for the following reactions. (a)

(b)

(c)

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

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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.

13.

Suggest mechanisms (a series of elementary steps) to rationalize the following observations: (a) H!

H! H3! !C!

H!

+!

-!

O!H!

2. H2O

S-1,2-propanediol!

O! !

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(b)

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Solutions to Problems Chapter 13

1.

Write structural formulas for: (a) 1,2-epoxyhexane

(b) diisopropyl ether

(c) diallyl ether

(d) dibenzyl ether

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2.

Write names for the following compounds (a)

di-4-methylpentyl ether or diisohexyl ether (b)

4-ethoxyphenyl phenyl ether or p-ethoxyphenyl phenyl ether (c)

benzyl vinyl ether

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(d)

isobutyl 3,3-dimethylbutyl ether or 3,3-dimethylbutyl 2-methylpropyl ether

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.

C8 H8 O

C8H8Br2 4.

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

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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.

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5.

Suggest a mechanism for the following conversion.

(1)

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(2)

(3)

(4)

(5)

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(6)

6.

Suggest products from the following reactions (a)

(b)

(c)

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7.

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

+ NaBr 8.

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

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R isomer

The objective is to synthesize the isomer with the R designation. The reaction sequence will give the racemic mixture, but the racemates are resolvable.

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The S isomer

The R isomer

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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.

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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)

(1)

(2)

S-1,2-propandiol

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(b)

(1)

(2)

(3)

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