Chapter 1: Historical Background of Ether Synthesis and Their Properties

The oxygen atom of an ether has sp³ hybridization. Herein, we consider the structure of dimethyl ether as the simplest member of this family of compounds. The C–O–C bond angle of dimethyl ether is 112°, approximately the tetrahedral bond angle (Scheme 1.1). A similar situation occurs when we compare the conformations of cyclic ethers with those of the corresponding cycloalkanes. For example, tetrahydropyran reveals a chair conformation. Following the predictions of VSEPR theory, the two oxygen lone pair electrons are placed in positions corresponding to the axial and equatorial C–H bonds of cyclohexane.

A similar situation exists when we compare the conformations of cyclic ethers with those of the corresponding cycloalkanes. For example, tetrahydropyran reveals a chair conformation, as the most stable conformer. Based on the VSEPR theory rules, the two lone pairs of oxygen are placed in positions corresponding to the axial and equatorial cyclohexane C–H bonds (Scheme 1.2).

Ethers are named by both common and systematic nomenclature of the IUPAC rules. The common names are used for ethers with simple alkyl groups. When no other functional group is present, simple ethers are often given common functional class names. Both alkyl groups attached to the oxygen atom are named as substituents (in alphabetical order) and then the word ether is added.

Depending on the groups at R and R′, ethers are classified into two classes:

1. Mixed ethers or asymmetrical ethers, e.g. ethyl methyl ether, methyl phenyl ether, etc. (Scheme 1.3).

2. Simple ethers or symmetrical ethers, e.g. diethyl ether, dimethyl ether, dipropyl ether, etc. (Scheme 1.4).

For symmetrical ethers, the prefix “di” is added.

The systematic nomenclature is used for ethers with complex substituents and long chains. The idea here is to treat one of the alkoxy (alkyl with the oxygen) groups as a substituent connected to a parent chain (Scheme 1.4).

The alkoxy group with a shorter carbon part is a substituent.

The longest carbon chain is the parent chain.

The substituents are placed alphabetically (Scheme 1.5).

Polyethers are polymers consisting of monomers joined together by ether linkages (two carbon atoms bonded to an oxygen atom) (Table 1.1).^1–3 The word glycol generally points to polyether polyols with one or more functional end-groups such as a hydroxyl group. The term “oxide” or other terms are used for high molar mass polymers when end-groups no longer affect polymer properties. Crown ethers are examples of small polyethers. Some toxins produced by dinoflagellates such as brevetoxin and ciguatoxin are extremely large and are known as cyclic or ladder polyethers.

An ether molecule has a net dipole moment due to the difference between the electronegativities of carbon and oxygen (Scheme 1.6). Hence, ethers show a dipolar nature. Ethers are organic compounds with a sweet smell at room temperature. Dimethyl ether and ethyl methyl ether are gases at ordinary temperatures. The other lower homologs are colorless, pleasant-smelling, volatile liquids with a typical ether smell.^4,5

The C–O bonds in ether are polar, and thus, ethers have a net dipole moment. The weak polarity of ethers does not appreciably affect their boiling points which are comparable to those of the alkanes with close molecular mass.⁶ Ethers have much lower boiling points compared to their isomeric alcohols due to the formation of hydrogen bonds in alcohol molecules but not in ether molecules (Table 1.2). There are two main types of hydrogen bonds: intermolecular and intramolecular. Intermolecular hydrogen bonds occur between separate molecules while intramolecular bonds occur when a molecule bonds with itself (Scheme 1.7).⁷ 

Ethers containing up to 3 carbon atoms are soluble in water due to their hydrogen bond formation with water molecules. The solubility decreases by increasing the number of carbon atoms. The relative increase in the hydrocarbon portion of the molecule decreases the tendency of H-bond formation. Ethers are appreciably soluble in organic solvents like alcohol, benzene, acetone, etc.

The miscibility of ethers with water resembles that of alcohols with the same molecular mass; just like alcohols, the oxygen of ether can also form hydrogen bonds with water molecules (Scheme 1.8).

Ethers are relatively inert. They usually show good solvent properties for many non-polar organic compounds. Although ethers are the most unreactive functional groups, they still undergo a few chemical reactions, as discussed in this section.

Ethers are generally very unreactive. When an excess of hydrogen halide is added to the ether, cleavage of the C–O bond occurs leading to the formation of an alcohol and an alkyl halide molecule by either an S_N2 or S_N1 mechanism (Scheme 1.9). The order of reactivity of hydrogen halides can be presented as follows: HI > HBr > HCl.

In alkyl ethers including primary, secondary, or methyl alkyl groups, a selective cleavage will typically take place using an S_N2 mechanism. First, the strong acid protonates the ether oxygen. First, the strong acid protonates the ether oxygen, and after can be attacked by the halide conjugate base, then the protonated ether at the less sterically hindered alkyl substituent forms a halogen product. The more sterically hindered alkyl substituent of the ether is ejected as a leaving group and forms an alcohol product. The example in Scheme 1.10 shows that when n-propyl iso-propyl ether is cleaved with hydroiodic acid, iso-propyl alcohol and iodopropyl are produced. The iodide nucleophile preferably attacks the n-propyl substituent because it is less hindered (1°) than the iso-propyl substituent (2°).

It is important to note that the existence of a phenyl substituent on the ether in the presence of HX (X = Br or I) led to the formation of the corresponding phenol derivative, and this reaction cannot proceed by the S_N2-reaction mechanism. Because the halide nucleophile preferably attacks the alkyl substituent, the products are always ArOH and RX (the aryl halide and alcohol are not produced) (Scheme 1.11).

The acidic cleavage of ethers with tertiary, benzylic, or allylic substituents in the presence of HBr or HI proceeds through an S_N1 mechanism due to these substituents enhancing the stability of the carbocations (Scheme 1.12). Thus, the change in mechanism causes the tertiary, benzylic, or allylic group to preferably become the halogen product of the acidic cleavage.

Using strong acid results in a weak conjugate base, such as trifluoroacetic acid (CF₃CO₂H). For the acidic cleavage of ether with a tertiary alkyl substituent, the E1 mechanism is usually favored. E1 elimination, or unimolecular elimination, is a type of chemical reaction in organic chemistry where a substrate, under the influence of a weak base, undergoes removal of two substituents, resulting in the formation of a double bond (Scheme 1.13).

Due to the resonance donation of electrons by the methoxy group, anisole is more reactive than benzene in electrophilic aromatic substitution (Scheme 1.14). The alkoxy group (–OR) activates the aromatic ring towards electrophilic substitution in the same way as in phenol. Also, this group is ortho and para director in aromatic electrophilic substitution reactions. Common electrophilic substitution reactions are halogenation, Friedel–Crafts reaction, etc. Only aromatic ethers or alkyl aryl ethers undergo electrophilic substitution reactions.

Phenyl alkyl ethers undergo the usual halogenation in the benzene ring, e.g. anisole undergoes bromination with bromine in the presence of a Lewis acid as a catalyst, which produces ortho and para products. The para isomer is obtained in 90% yield (Scheme 1.15).

Anisole undergoes Friedel–Crafts reaction, i.e. the alkyl and acyl groups are bonded at ortho and para positions by reaction with alkyl halide and/or acyl halide in the presence of a Lewis acid as catalyst (Scheme 1.16).

Anisole reacts with a mixture of concentrated sulfuric and nitric acids yielding a mixture of ortho and para nitro anisole (Scheme 1.17).

When ethers are stored in clear glass bottles, many can react with atmospheric oxygen to form explosive peroxide compounds in a free radical process called autoxidation (Scheme 1.18). The danger is particularly acute when ether solutions are distilled to near dryness. The hydroperoxides can become more concentrated during a distillation because they tend to have a slightly higher boiling point than the corresponding ether. Before performing an ether distillation, great care should be taken to test for the presence of peroxides.

Symmetrical ethers are produced by heating an excess of alcohol with conc. H₂SO₄ at high temperatures. The reaction is catalyzed by acids, usually sulfuric acid. The method is effective for synthesizing symmetrical ethers but not unsymmetrical ethers since either OH can be protonated, which would give a mixture of products (Scheme 1.19).

The Williamson ether synthesis procedure involves the treatment of a sodium alkoxide (produced by reacting alcohol with sodium metal) with an appropriate aliphatic compound bearing a suitable leaving group (R–X). Suitable leaving groups (X) are usually iodide, bromide, or sulfonate groups. Similarly, alkyl aryl ethers (phenolic ethers) can be easily prepared by treating sodium phenoxide with alky halides. Both symmetrical as well as unsymmetrical ethers can be prepared by this method (Scheme 1.20). This method only gives the best yields for primary halides. Secondary and tertiary alkyl halides undergo an E2 elimination reaction on exposure to the basic alkoxide anion that is used in the reaction. Therefore, the applied alkyl halide in this reaction must be the primary one. If secondary or tertiary alkyl halides are used, the reaction goes mainly through alkene formation.

1. Aryl halides and vinyl halides cannot be used as substrates in this method because of their low reactivity in nucleophilic substitution reactions.

2. Secondary and tertiary alkyl halides, which are very prone to elimination, should be avoided as substrates. For example, tert-butyl ethyl ether should be prepared by the reaction of the tert-butoxide ion with ethyl bromide not by the action of the ethoxide ion on tert-butyl bromide. The primary alkyl halide (C₂H₅Br) as substrate is preferable to tert-alkyl halides [(CH₃)₃–C–Br] as the substrate since the latter halides are prone to elimination reaction (Scheme 1.21).

This method includes treating alkenes with mercuric trifluoroacetate in the presence of alcohol, followed by reduction with NaBH₄ in basic conditions giving ethers. The reaction is Markovnikov’s addition of alcohols to alkenes (Scheme 1.22). This method offers significant advantages compared to the Williamson synthesis:

• High yield of ethers.

• No rearrangement occurs.

• No competing elimination reactions.

Primary and secondary alcohols on treatment with diazomethane give methyl ether using fluoroboric acid as a catalyst (Scheme 1.23).

Ethers can also be produced by heating an alkyl halide with dry silver oxide (Scheme 1.24).

Ethers are useful intermediates in organic synthesis and have been employed as solvents in various reactions such as the production of Grignard reagents.⁸ They easily autoxidize and undergo autoxidation through a free radical mechanism.⁹ The autoxidation of ether performed through a radical chain mechanism is displayed in Scheme 1.25. The α-hydrogen to oxygen in THF (1a) is abstracted by the radical initiator to offer the tetrahydrofuran-2-yl radical (2a). Peroxy radical 3a, produced from radical 2a and O₂, abstracts the α-hydrogen from another THF molecule to provide hydroperoxide 4a and generate radical 2a.¹⁰ 

Diaryl ethers can be synthesized using a copper-catalyzed Ullmann diaryl ether coupling or a palladium-catalyzed Buchwald–Hartwig reaction. In 1905, Ullmann reported the production of biaryl ethers by treating phenols with aryl bromides in the presence of KOH.¹¹ However, the classical Ullmann procedure for biaryl ether formation is carried out using harsh reaction conditions, stoichiometric amounts of copper reagents, and high reaction temperatures (typically >160 °C). To overcome these synthetic drawbacks, in the mid-1990s, Buchwald and Hartwig introduced palladium-based approaches for the synthesis of diaryl ethers through the coupling of phenols with aryl boronic acids.¹² Zhou and co-workers reported Ullmann coupling of diiodo- and dibromoarenes and diphenols for the synthesis of aryl ether macrocycles using CuI/Fe(acac)₃ and K₂CO₃ in anhydrous DMSO at 110 °C for 7 days under nitrogen atmosphere (Scheme 1.26).¹³ 

In cyclic ethers (heterocyclic), one or more carbons are replaced with oxygen. Epoxides are cyclic ethers in which the ether oxygen is part of a three-membered ring. The simplest and most important epoxide is ethylene oxide. Although cyclic ethers have IUPAC names, their common names are more widely used (Scheme 1.27).

In IUPAC names, the prefix Ox- shows oxygen in the ring whereas the suffixes -irane, - etane, -olane, and -ane show three, four, five, and six atoms in a saturated ring.

Reacting a peroxyacid and an alkene leads to the production of an epoxide and a molecular acid (Scheme 1.28).

Epoxides are compounds that are very similar to ethers. Due to ring strain, epoxides are highly reactive and nucleophilic attack on the electrophilic carbon atoms results in a ring-opening reaction. It should be noted that depending on the nature of the epoxide and reaction conditions, a ring-opening epoxide reaction proceeds via the S_N1 or S_N2 mechanism.

When a weak nucleophile is used in acidic conditions, the nucleophilic attack occurs at the more substituted carbon which is consistent with the S_N1 mechanism (Scheme 1.29).

When a weak nucleophile is used in basic conditions, the nucleophilic attack occurs at the less substituted carbon which is consistent with the S_N2 mechanism (Scheme 1.30).

In recent years, ethers and crown ethers have attracted widespread interest due to their unique structure, and they are used in various fields such as drug delivery, solvent extraction, cosmetics manufacturing, material studies, catalysis, separation, and organic synthesis. In this chapter, we have discussed the physical and chemical properties of ethers, their applications in different areas, and also the nomenclature of these compounds and a brief review of known methods for the synthesis of these organic compounds.