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Overview

In contrast to alcohols with their abundant capacity for chemical reactions, ethers (hydrocarbon compounds containing the C-O-C unit) are relatively non-reactive. This lack of reactivity makes them valuable as solvents in a number of synthetically important transformations. In this unit, We will discuss here the conditions in which the there C-O-C linkage acts as a functional group, as well as the methods by which ethers are prepared.

Unlike most ethers, epoxides (compounds which the C-O-C unit forms a three-membered ring) are very reactive substances. The principle of nucleophilic substitution are important in understanding the preparation and properties of epoxides.

Sulfides (R-S-R') are the sulfur analogs of ethers. In this unit, we will examine the differences between these two chemical families. 

I. Ethers

                       Ethers are compounds of the general formula:

                            R - O - R     /      Ar - O - R    /      Ar - O - Ar

                 (where Ar is is a phenyl or some other aromatic group)

In order to name ethers, we typically 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.

If two groups are identical, the ether is said to be symmetrical (e.g. diethyl ether, diisopropyl ether). It the two groups are different, the ether is said to be unsymmetrical (e.g. tert-butyl methyl ether).

Physical Properties

Since the C-O-C bond angle is not equal to 180 degrees, the dipole moment of the two C-O bonds do not cancel each other out. 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 (similar chemical formula). Compare, for example, the boiling points of n-heptane (98 C), methyl n-pentyl ether (100 C) and n-hexyl alcohol(157 C). The hydrogen bonding which holds alcohol molecules tightly together is not possible for ethers, since they contain hydrogen bonded only to carbon.

Ethers show a solubility in water which is comparable to that of the alcohols. For example, diethyl ether and n-butyl alcohol are both 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. The water solubility of ethers arises in a similar way. This occurs via the unshared electron pairs on oxygen.

Thus, ethers can accept hydrogen bonds which are provided by water molecules.

Industrial Sources: Dehydration of Alcohols

A number of symmetrical ethers containing the lower alkyl groups are prepared on a large scale, mainly for use as solvents. The most important of these is diethyl ether -- the familiar solvent we use in extractions and in the preparation of Grignard reagents. Others  include diisopropyl ether and di-n-butyl ether.

These ethers are prepared by reactions of the corresponding alcohols with sulfuric acid. Since one molecule of water is lost for every pair of alcohol molecules, the reaction is a kind of dehydration. As we have already seen (Unit 11: Alkenes II) alcohols can undergo another kind of dehydration, involving elimination, to give alkenes. Dehydration to ethers rather than to alkenes is controlled by the choice of reaction conditions. E.G. Ethylene is prepared by heating ethyl alcohol with concentrated sulfuric acid to 180 degrees C. Diethyl ether is prepared by heating a mixture of the alcohol with concentrated sulfuric acid to 140 degrees C (the alcohol being continuously added to maintain it in excess).

Dehydration is generally limited to the preparation of symmetrical ethers. This is due to the fact that a combination of two alcohols typically yields a mixture of three ethers. 

Ether formation by dehydration is an example of nucleophilic substitution with the alcohol playing two different roles. The protonated alcohol is the substrate, and the second molecule of alcohol is the nucleophile. The reaction could be either S_N1 or S_N2, depending upon whether the protonated alcohol loses water before or during the attack by the second alcohol molecule.

Thus, it is probable that 2° and 3° alcohols follow the S_N1 reaction sequence. Alternatively, n-butyl alcohol gives di-n-butyl ether without rearrangement  -- and thus, presumably, without intermediate carbocations. 1° alcohols -- being the least able to form carbocations and the most prone to backside attack -- follow the S_N2 reaction path.

When exposed to the atmosphere, most aliphatic ethers are converted slowly into unstable peroxides. Although present in only low concentrations, these peroxides are very dangerous, since they can cause violent explosions during the distillations which normally follow ether extractions. This cause solvents such as diethyl ether to be an extremely hazardous laboratory resource.

The presence of peroxides is indicated by the formation of a red color when the ether is shaken with an aqueous solution of ferrous ammonium sulfate and potassium thiocyanate. The peroxide oxidizes ferrous (+2) ion to ferric (+3) ion, which reacts with thiocyanate ion (SCN-) to give the characteristic blood-red color of the ferric thiocyanate complex. 

Peroxides can be removed from ethers in a number of ways, including washing with solutions of ferrous ion (which reduces peroxides) or distillation from concentrated sulfuric acid (which oxidizes peroxides).

For use in the preparation of Grignard reagents, the ether (usually diethyl) must be free of traces of water and alcohol. This so-called absolute ether can be prepared by distillation of ordinary ether from concentrated sulfuric acid (which also removes peroxides) and subsequent storing over metallic sodium.   

Preparation: Williamson synthesis

In the laboratory, the Williamson synthesis can be used to make unsymmetrical ethers as well as symmetrical ethers. Using this method, an alkyl halide (or substituted alkyl halide) is allowed to react with a sodium alkoxide as follows:

or more simply:

                                                  For example:

The reaction involves nucleophilic substitution of an alkoxide ion for a halide ion. It is strictly analogous to the formation of alcohols by treatment of alkyl halides with aqueous hydroxide as follows.

Since alkoxides and alkyl halides are both prepared form alcohols, the Williamson method ultimately involves the synthesis of an ether from two alcohols. If we wish to make an unsymmetrical dialkyl ether, we have a choice of two combinations of reagents. One of these is nearly always better than the other. In the preparation of tert-butyl ether, for example, the following combinations are possible:

Bases tend to react with alkyl halides by elimination to yield alkenes (Unit 11: Alkenes II). Alkoxides are not only nucleophiles, but also act as strong bases. We have seen before (Unit10: Alkenes I) that whenever attempting to implement nucleophilic substitution, we risk the hazard of a competing elimination reaction. Recall that the tendency of alkyl halides to undergo elimination is: 3°  >  2°  >  1°.  

In the present case, we reject the use of the tertiary halide, which would be expected to yield mostly (or all) elimination product. We must therefore use the other combination.

Oxymercuration - Reduction

Discussed in Unit 11: Alkenes II.

Reactions: Cleavage By Acids

Ethers are comparatively stable non-reactive compounds. The ether linkage is quite stable towards bases, oxidizing agents, and reducing agents. Ethers undergo just one kind of basic chemical reaction: cleavage by acids.

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

A dialkyl ether yields initially an alkyl halide and an alcohol. The alcohol may react further to form a second mole of alkyl halide. For example:

The oxygen of an ether is basic - much like the oxygen of an alcohol. The initial reaction between an ether and an acid is undoubtedly the formation of the protonated ether. Cleavage then involves nucleophilic attack by halide ion on this protonated ether, with displacement of the weakly basic alcohol molecule.

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 a halide ion, like the corresponding reaction of a protonated alcohol, can proceed either by an S_N1 mechanism as follows:

or the reaction can occur by way of an S_N2 mechanism as follows.

The reaction mechanism depends upon the reaction conditions and the structure of the ether. As may be expected, a primary alkyl group tends to undergo S_N2 displacement, whereas a tertiary alkyl group tends to undergo S_N1 displacement.

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II. Epoxides

Epoxides are compounds containing the three-membered ring:

They are ethers, but the three-membered ring gives them unusual properties which make them an exceedingly important class of compounds. Epoxides are commonly made by the oxidation of alkenes by peroxy compounds, such as benzoic acid:

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

Epoxides owe their importance to the ease of opening of the highly strained three-membered ring. They undergo acid-catalyzed reactions with extreme ease and -- unlike ordinary ethers -- can even be cleaved by bases.

A polymer made of epoxide units is called a polyepoxide or an epoxy. Epoxy resins are used as adhesives and structural materials; one such example is epoxyethane.

Acid-catalyzed Cleavage  

Like other ethers, an epoxide is protonated by acid.

The protonated epoxide can then undergo attack by any number of nucleophilic reagents.                            

An important feature of the reactions of epoxides is the formation of compounds that contain two functional groups. Thus, reaction with water yields a 1,2-diol. Reaction with an alcohol yields a compound that is both ether and alcohol.

The two-stage process of epoxidation followed by hydrolysis is stereoselective, and gives 1,2-diols corresponding to anti-addition to the C=C double bond. The same stereochemistry was observed for hydroxylation of alkenes by formic acid. There, an epoxide is formed as a reaction intermediate which is rapidly cleaved in the acidic medium. The interpretation is exactly the same as that given to account for anti-addition of halogens. Indeed, epoxides and their hydrolysis served as a model on which the halonium ion mechanism was patterned.  

Base-catalyzed Cleavage  

Unlike ordinary ethers, epoxides can be cleaved under alkaline conditions. Here it is the epoxide itself -- not the protonated epoxide -- which undergoes nucleophilic attack.

The lower reactivity of the non-protonated epoxide is compensated for by the more basic, more strongly nucleophilic reagents that are compatible with the alkaline solution (e.g. alkoxides, phenoxides, ammonia, etc.).

Like alkyl halides and sulfonates, and like carbonyl compounds, epoxides are an important source of electrophilic carbon -- of carbon that is highly susceptible to attack by a wide variety of nucleophiles. (E.G. Epoxides generated form carcinogenic hydrocarbons are even attacked by the nucleophilic portion of the genetic material DNA and thereby induce mutation and tumors).  

Cleavage Orientation

There are tow C atoms in an epoxide ring. In principle, either one can suffer nucleophilic attack. In a symmetrical epoxide like ethylene oxide, the two carbons are equivalent, and attack occurs randomly at either site. But in an asymmetrical epoxide molecule, the C atoms are not equivalent, and the product obtained depends upon which one is preferentially attacked.

It turns out that the preferred point of attack 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 an acid-catalyzed cleavage, and the less substituted carbon in a base catalyzed cleavage.

Our first thought might be that there are two different reaction mechanisms (e.g. SN1 vs. SN2). But the evidence indicates clearly that both are of the SN2 type. This is characterized typically by cleavage of the C-O bond and attack by the nucleophile in a single step.

How, then, are we to account for the difference in orientation -- particularly for the SN2 attack at the more hindered position in acid-catalyzed cleavage ?

The answer to this query lies in the transition state (or reaction intermediate).

In the transition state of most SN2 reactions, bond-breaking and bond-making have proceeded to about the same extent, and carbon has not become appreciably positive or negative. Therefore steric factors, not electronic factors, chiefly determine reactivity.

But in acid-catalyzed cleavage of an epoxide, the C-O 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 -- the weakly basic alcohol hydroxyl (OH) group. Alternatively, the nucleophile is a poor one (e.g. water, alcohol). In the transition state, bond-breaking has proceeded further than bond-making, and thus carbon has acquired a considerable positive charge.

Since both leaving group and nucleophile are far away, crowding is relatively unimportant here. The stability of the transition state is determined chiefly by electronic factors and not steric factors. Thus the reaction has considerable SN1 character. In this case:

    Attack occurs at the C atom 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 (e.g. hydroxide, alkoxide).

Bond-breaking and bond-making are more nearly balanced, and reactivity is controlled in the more usual way -- by steric factors. In this case:

                                  Attack occurs at the less hindered carbon.

Epoxides in Biochemistry

Functional group transformations of epoxides rank among the fundamental reactions of organic chemistry, and epoxides are commonplace natural products. The female gypsy moth, for example, attracts the male by emitting an epoxide known as disparlure. On detecting the presence of this pheromone, the male follows the scent to its origin and mates with the female.

The reactivity of epoxides toward nucleophilic ring opening is responsible for one of the biological roles they play. Squalene 2,3-epoxide, for example, is the biological precursor to cholesterol and the steroid hormones, including testosterone, progesterone, estrone, and cortisone.

The pathway from squalene 2,3-epoxide to these compounds is triggered by an epoxide ring opening (see Unit 24: Lipids).

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III. Sulfides

Sulfides, compounds of the type RSR', are prepared by the method of nucleophilic substitution. Treatment of a primary or secondary alkyl halide with an alkane thiolate ion (RS-) gives a sulfide. It is not necessary to prepare and isolate the sodium alkane thiolate in a separate operation. Because thiols are more acidic than water (see Unit 7: Alcohols and Thiols) they are quantitatively converted to their alkane thiolate anions by sodium hydroxide. Thus, all that needs to be done is to add a thiol to sodium hydroxide in an appropriate solvent (water or an alcohol) followed by the alkyl halide.

Oxidation

Thiols differ form alcohols with respect to their behavior toward oxidation. Similarly, sulfides differ from ethers in their behavior toward oxidizing agents. Whereas ethers tend to undergo oxidation at carbon to give hydroperoxides, sulfides are oxidized at sulfur to give sulfoxides (RSOR').

When the desired product is a sulfoxide, sodium metaperiodate (NaIO4) is an ideal reagent. It oxidizes sulfides in high yield but shows no tendency to oxidize sulfoxides to sulfones (RSOOR').

Peroxy acids, usually in dichloromethane as the solvent, are also reliable reagents for converting sulfides to sulfoxides. One equivalent of a peroxy acid or of hydrogen peroxide converts sulfides to sulfoxides. Two equivalents gives the corresponding sulfone.

Oxidation of sulfides occurs in living systems as well. Among naturally occurring sulfoxides, one that has received recent attention is sulforaphane, which is present in brussel sprouts, broccoli, cauliflower and other cruciferous vegetables.

Sulforaphane holds promise as a potential anticancer agent because, unlike most anticancer drugs, which act by killing rapidly dividing tumor cells faster than they kill normal cells, sulforaphane is non-toxic and may simply inhibit formation of tumors.

Alkylation

Sulfur is more nucleophilic than oxygen, and sulfides react with alkyl halides much faster than do ethers. The products of these reactions, called sulfonium salts, are also more chemically stable than the corresponding oxygen analogs.

An example of this type of reaction is as follows: