Ethers and Epoxides

Chapter 17

Ethers and Epoxides

Structure and nomenclature of ethers 

• Ethers are compounds of the general formula R -O R, Ar O R, or Ar-O Ar

• To name ethers we usually name the two groups that are attached to oxygen, and follow these names by the word ether:

• If one group has no simple name, the compound may be named as an alkoxy derivative:

Physical properties of ethers

• Since the C O C bond angle is not 180, the dipole moments of the two C O bonds do not cancel each other; consequently, ethers possess a small net dipole moment.

• This weak polarity does not appreciably affect the boiling points of ethers, which are about the same as those of alkanes having comparable molecular weights, and much lower than those of isomeric alcohols. Compare, for example, the boiling points of /i-heptane (98), methyl /i-pentyl ether (100), and w-hexyl alcohol. The hydrogen bonding that holds alcohol molecules strongly together is not possible for ethers, since they contain hydrogen bonded only to carbon.

• On the other hand, ethers show a solubility in water comparable to that of the alcohols, both ethyl ether and w-butyl alcohol, for example, being soluble to the extent of about 8 g per 100 g of water. We attributed the water solubility of the lower alcohols to hydrogen bonding between water molecules and alcohol molecules; presumably the water solubility of ether arises in the same way.

Industria sources of ethers. Dehydration of alcohols

• A number of symmetrical ethers containing the lower alkyl groups are prepared on a large scale, chiefly for use as solvents. The most important of these is ethyl ether, the familiar anesthetic and the solvent we use in extractions and in the preparation of Grignard reagents; others include isopropyl ether and tf-butyl ether.

• These ethers are prepared by reactions of the corresponding alcohols with sulfuric acid. Since a molecule of water is lost for every pair of alcohol molecules, the reaction is a kind of dehydration. Dehydration to ethers rather than to alkenes is controlled by the choice of reaction conditions. For example, ethylene is prepared by heating ethyl alcohol with concentrated sulfuric acid to 180 U ; ethyl ether is prepared by heating a mixture of ethyl alcohol and concentrated sulfuric acid to 140, alcohol being continuously added to keep it in excess.

• 2R 0-H H2S04t hat > R_Q_ 

• Dehydration is generally limited to the preparation of symmetrical ethers, because, as we might expect, a combination of two alcohols usually yields a mixture of three alcohols.

•  Ether formation by dehydration is an example of nucleophilic substitution^ with the protonated alcohol as substrate and a second molecule of alcohol as nucleophile.

Preparation of ethers. Williamson synthesis

• In the laboratory, the Williamson synthesis of ethers is important because of its versatility: it can be used to make unsymmetrical ethers as well as symmetrical ethers, and aryl alkyl ethers as well as dialkyl ethers. In the Williamson synthesis an alkyl halide (or substituted alkyl halide) is allowed to react with a sodium alkoxide or a sodium phenoxide:

R X + Na+-O R' > R-O-R' + Na + X

R X + Na 4 -O-Ar > R-O-Ar + Na 4

• For the preparation of methyl aryl ethers, methyl sulfate, (CH3)2SO4 , is frequently used instead of the more expensive methyl halides.

• The Williamson synthesis involves nucleophilic substitution of alkoxide ion or phenoxide ion for halide ion; it is strictly analogous to the preparation of alcohols by treatment of alkyl halides with aqueous hydroxide Aryl halides cannot in general be used, because of their low reactivity toward nucleophilic substitution.

Reactions of ethers. Cleavage by acids

• Ethers arc comparatively unreactive compounds. The ether linkage is quite stable toward bases, oxidizing agents, and reducing agents, fn so far as the ether linkage itself is concerned, ethers undergo just one kind of reaction, cleavage by acids:

• Cleavage takes place only under quite vigorous conditions: concentrated acids (usually HI or HBr) and high temperatures.

• An alkyl ether yields initially an alkyl halide and an alcohol; the alcohol may react further to form a second mole of alkyl halide. Because of the low reactivity at the bond between oxygen and an aromatic ring, an aryl alkyl ether undergoes cleavage of the alkyl-oxygen bond and yields a phenol and an alkyl halide. For example: 

• Cleavage involves nucleophilic attack by halide ion on the protonated ether, with displacement of the weakly basic alcohol molecule:

                ROR' + HX 7= ROR' + X- -|*i-> RX + R'OH S2 Weak base:

• Such a reaction occurs much more readily than displacement of the strongly basic alkoxide ion from the neutral ether.

• Reaction of a protonated ether with halide ion, like the corresponding reaction of a protonated alcohol, can proceed by either an SN 1 or SN2 mechanism, depending upon conditions and the structure of the ether. As we might expect, a primary alkyl group tends to undergo SN2 displacement, whereas a tertiary alkyl group tends to undergo SN l displacement.

Electrophilic substitution in aromatic ether

• The alkoxy group, OR, was listed as ortho,para-direclmg toward electrophilic aromatic substitution, and moderately activating. It is a much stronger activator than R, but much weaker than -OH.

• These structures are especially stable ones, since in them every atom (except hydrogen, of course) has a complete octet of electrons.

• The ability of the oxygen to share more than a pair of electrons with the ring and to accommodate a positives charge is consistent with the basic character of ethers.

Cyclic ethers 

• In their preparation and properties, most cyclic ethers are just like the ethers we have already studied: the chemistry of the ether linkage is essentially the same whether it forms part of an open chain or part of an aliphatic chain or part of an aliphatic ring.

 

Preparation of epoxides

• The conversion of halohydrins into epoxides by the action of base is simply an adaptation of the Williamson synthesis a cyclic compound is obtained because both alcohol and halide happen to be part of the same molecule. In the presence of hydroxide ion a small proportion of the alcohol exists as alkoxide; this alkoxide displaces halide ion from another portion of the same molecule to yield the cyclic ether.

• Since halohydrins are nearly always prepared from alkenes by addition of halogen and water to the carbon -carbon double bond (Sec. 6.14), this method amounts to the conversion of an alkene into an epoxide. Alternatively, the carbon-carbon double bond may be oxidized directly to the epoxide group by peroxybenzoic acid:

• When allowed to stand in ether or chloroform solution, the proxy acid and the unsaturated compound which need not be a simple alkene react to yield benzoic acid and the epoxide. For example:

Reactions of epoxides

• Epoxides owe their importance to their high reactivity, which is due to the ease of opening of the highly strained three-membered ring. The bond angles of the ring, which average 60, are considerably less than the normal tetrahedral carbon angle of 109.5, or the divalent oxygen angle of 1 10 r for open-chain ethers). Since the atoms cannot be located to permit maximum overlap of orbitals, the bonds are weaker than in an ordinary ether, and the molecule is less stable.

Acid-catalyzed cleavage of epoxides. attn.-Hydroxylation

• Like other ethers, aji epoxide is converted by acid into the protonated epoxide, which can then undergo attack by any. of a number of-nucleophilic reagent.

• An important feature of the reactions of epoxides is the formation of compounds that contain two functional groups. Thus, reaction with water yields a glycol; reaction with an alcohol yields a compound that is both ether and alcohol.

Base-catalyzed cleavage of epoxides

• Unlike ordinary ethers, epoxides can be cleaved under alkaline conditions. Here it is the epoxide itself, not the protonated epoxide, that undergoes nucleophilic attack. The lower reactivity of the non-protonated epoxide is compensated for by the more basic, more strongly nucleophilic reagent: alkoxide, phenoxide, ammonia, etc.

• Let us look, for example, at the reaction of ethylene oxide with phenol. Acid catalyzes reaction by converting the epoxide into the highly reactive protonated epoxide. Base catalyzes reaction by converting the phenol into the more strongly nucleophilic phenoxide ion.

Reaction of ethylene oxide with Grignard reagents

• Reaction of Grignard reagents with ethylene oxide is an important method of preparing primary alcohols since the product contains two carbons more than the alkyl or aryl group of the Grignard reagent. As in reaction with the carbonyl group we see the nucleophilic (basic) alkyl or aryl group of the Grignard reagent attach itself to the relatively positive carbon and the electrophilic (acidic) magnesium attach itself to the relatively negative oxygen. Use of higher epoxides is complicated by rearrangements and formation of mixtures.

Orientation of cleavage of epoxides

• The preferred point of attack, it turns out, depends chiefly on whether the reaction is acid-catalyzed or base-catalyzed. Consider, for example, two reactions of isobutylene oxide:

• Here, as in general, the nucleophile attacks the more substituted carbon in acidcatalyzed cleavage, and the less substituted carbon in base-catalyzed cleavage.

• Tn an SN2 reaction, we said earlier (Sec. 14.11), carbon loses electrons to the leaving group and gains electrons from the nucleophile, and as a result does not become appreciably positive or negative in the transition state; electronic factors are unimportant, and steric factors control reactivity. But in acid-catalyzed cleavage of an epoxide, the carbon-oxygen bond, already weak because of the angle strain of the three-membered ring, is further weakened by protonation: the leaving group is a very good one, a weakly basic alcohol hydroxyl. The nucleophile, on the other hand, is a poor one (water, alcohol, phenol), Although there are both bond-breaking and bond-making in the transition state, bond-breaking has proceeded further than bond-making; the leaving group has taken electrons away to a much greater extent than the nucleophile has brought them up, and the carbon has acquired a considerable positive charge. 

• Crowding, on the other hand, is relatively unimportant, because both leaving group and nucleophile arc far away. Stability of the transition state is determined chiefly by electronic factors, not steric factors. We speak of such a reaction as having considerable SN 1 character. Attack occurs not at the less hindered carbon, but at the carbon that can best accommodate the positive charge.

• In base-catalyzed cleavage, the leaving group is a poorer one a strongly basic alkoxide oxygen-- and the nucleophile is a good one (hydroxide, alkoxide, phenoxide). Bond-breaking and bond-making are more nearly balanced, and reactivity is controlled in the more usual way, by steric factors. Attack occurs at the less hindered.

Analysis of ethers

•  Because of the low reactivity of the functional group, the chemical behavior of ethers both aliphatic and aromatic resembles that of the hydrocarbons to which they are related. They are distinguished from hydrocarbons, however, by their solubility in cold concentrated sulfuric acid through formation of oxonium salts.

• Identification as a previously reported ether is accomplished through the usual comparison of physical properties. This can be confirmed by cleavage with hot concentrated hydriodic acid and identification of one or both products. Aromatic ethers can be converted into solid bromination or nitration products whose melting points can then be compared with those of previously reported derivatives.

• Proof of structure of a new ether would involve cleavage by hydriodic acid and identification of the products formed. Cleavage is used quantitatively in the Zeisel method to show the number of alkoxyl groups in an alkyl aryl ether.

Spectroscopic analysis of ethers

• Infrared. The infrared spectrum of an ether does not, of course, show the O H band characteristic of alcohols; but the strong band due to C O stretching is still present, in the 1060-1300 cm" 1 range, and is the striking feature of the spectrum.

• Carboxylic acids and esters show C O stretching but show carbonyl absorption as well. (For a comparison of certain oxygen compounds