The
Williamson ether synthesis is an
organic reactionOrganic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions and redox reactions. In organic synthesis, organic reactions are used...
, forming an
etherEther is a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...
from a organohalide and an
alcoholIn chemistry, an alcohol is any organic compound in which a hydroxyl group is bound to a carbon atom of an alkyl or substituted alkyl group. An important group of acohols is formed by the simple acyclic alcohols, the general formula for which is C
nH
2n+1OH...
. This reaction was developed by
Alexander WilliamsonAlexander William Williamson FRS was an English chemist of Scottish descent. He is best known today for the Williamson ether synthesis.-Biography:...
in 1850 . Typically it involves the reaction of an alkoxide ion with a primary alkyl
halideA halide is a binary compound, of which one part is a halogen atom and the other part is an element or radical that is less electronegative than the halogen, to make a fluoride, chloride, bromide, iodide, or astatide compound. Many salts are halides...
via an
SN2 reactionThe S
N2 reaction is a type of nucleophilic substitution, where a lone pair from a nucleophile attacks an electron deficient electrophilic center and bonds to it, expelling another group called a leaving group. Thus the incoming group replaces the leaving group in one step...
. This reaction is important in the history of organic chemistry because it helped prove the structure of
etherEther is a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...
s.
The general reaction mechanism is as follows:
An example is the reaction of
sodium ethoxideSodium ethoxide is an alkoxide salt with the chemical formula C2H5ONa.-Preparation:It is commercially available as a dry yellow solid, or as a solution in ethanol...
with chloroethane to form
diethyl etherDiethyl ether, also known as ether, ethyl ether and ethoxyethane, is a clear, colorless, and highly flammable liquid with a low boiling point and a characteristic odor. It is the most common member of a class of chemical compounds known generically as ethers. It is an isomer of butanol...
and sodium chloride:
- Na+C2H5O− + C2H5Cl C2H5OC2H5 + Na+Cl−
The Williamson reaction is of broad scope, is widely used in both laboratory and industrial synthesis, and remains the simplest and most popular method of preparing ethers.
The
Williamson ether synthesis is an
organic reactionOrganic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions and redox reactions. In organic synthesis, organic reactions are used...
, forming an
etherEther is a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...
from a organohalide and an
alcoholIn chemistry, an alcohol is any organic compound in which a hydroxyl group is bound to a carbon atom of an alkyl or substituted alkyl group. An important group of acohols is formed by the simple acyclic alcohols, the general formula for which is C
nH
2n+1OH...
. This reaction was developed by
Alexander WilliamsonAlexander William Williamson FRS was an English chemist of Scottish descent. He is best known today for the Williamson ether synthesis.-Biography:...
in 1850 . Typically it involves the reaction of an alkoxide ion with a primary alkyl
halideA halide is a binary compound, of which one part is a halogen atom and the other part is an element or radical that is less electronegative than the halogen, to make a fluoride, chloride, bromide, iodide, or astatide compound. Many salts are halides...
via an
SN2 reactionThe S
N2 reaction is a type of nucleophilic substitution, where a lone pair from a nucleophile attacks an electron deficient electrophilic center and bonds to it, expelling another group called a leaving group. Thus the incoming group replaces the leaving group in one step...
. This reaction is important in the history of organic chemistry because it helped prove the structure of
etherEther is a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...
s.
The general reaction mechanism is as follows:
An example is the reaction of
sodium ethoxideSodium ethoxide is an alkoxide salt with the chemical formula C2H5ONa.-Preparation:It is commercially available as a dry yellow solid, or as a solution in ethanol...
with chloroethane to form
diethyl etherDiethyl ether, also known as ether, ethyl ether and ethoxyethane, is a clear, colorless, and highly flammable liquid with a low boiling point and a characteristic odor. It is the most common member of a class of chemical compounds known generically as ethers. It is an isomer of butanol...
and sodium chloride:
- Na+C2H5O− + C2H5Cl C2H5OC2H5 + Na+Cl−
Scope
The Williamson reaction is of broad scope, is widely used in both laboratory and industrial synthesis, and remains the simplest and most popular method of preparing ethers. Both symmetrical and asymmetrical ethers are easily prepared. The intramolecular reaction of
halohydrinA halohydrin is a type of chemical compound or functional group in which one carbon atom has a halogen substituent, and an adjacent carbon atom has a hydroxyl substituent.Halohydrin formation:* from an alkene in a halohydrin formation reaction...
s in particular, gives
epoxideAn epoxide is a cyclic ether with three ring atoms. This ring approximately defines an equilateral triangle, which makes it highly strained. The strained ring makes epoxides more reactive than other ethers. Simple epoxides are named from the parent compound ethylene oxide or oxirane, such as in...
s.
In the case of asymmetrical ethers there are two possibilities for the choice of reactants, and one is usually preferable either on the basis of availability or reactivity. The Williamson reaction is also frequently used to prepare an ether indirectly from two alcohols. One of the alcohols is first converted to a leaving group (usually tosylate), then the two are reacted together.
The alkoxide (or aroxide) may be primary, secondary or tertiary. The alkylating agent, on the other hand is most preferably primary. Secondary alkylating agents also react, but tertiary ones are usually too prone to side reactions to be of practical use. The leaving group is most often a halide or a sulfonate ester synthesized for the purpose of the reaction. Since the conditions of the reaction are rather forcing,
protecting groupA protecting group or protective group is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction...
s are often used to pacify other parts of the reacting molecules (e.g. other alcohols,
amineAmines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
s, etc.)
Conditions
Since alkoxide ions are highly reactive, they are usually prepared immediately prior to the reaction, or are generated
in situ. In laboratory chemistry,
in situ generation is most often accomplished by the use of a
carbonateIn chemistry, a carbonate is a salt or ester of carbonic acid, characterized by the presence of the carbonate ion, or a carbonate functional group O=C2....
base or
potassium hydroxidePotassium hydroxide is an inorganic compound with the formula KOH. Along with sodium hydroxide, this colourless solid is a prototypical "strong base". It has many industrial and niche applications. Most applications exploit its reactivity toward acids and its corrosive nature. In 2005, an...
, while in industrial syntheses phase transfer catalysis is very common. A wide range of solvents can be used, but it should be noted that protic solvents and apolar solvents tend to slow the reaction rate strongly, as a result of lowering the availability of the free nucleophile. For this reason,
acetonitrileAcetonitrile is the chemical compound with formula CH3CN. This colourless liquid is the simplest organic nitrile. It is produced mainly as a byproduct of acrylonitrile manufacture. It is widely used as a polar aprotic solvent in synthetic chemistry, and as a medium-polarity solvent in...
and N,N-dimethylformamide are particularly commonly used.
A typical Williamson reaction is conducted at 50–100°C and is complete in 1–8 hours. Often the complete disappearance of the starting material is difficult to achieve, and side reactions are common. Yields of 50–95% are generally achieved in laboratory syntheses, while near-quantitative conversion can be achieved in industrial procedures.
Catalysis is not usually necessary in laboratory syntheses. However, if an unreactive alkylating agent is used (e.g. an alkyl chloride) then the rate of reaction can be greatly improved by the addition of a catalytic quantity of a soluble iodide salt (which undergoes halide exchange with the chloride to yield a much more reactive iodide, a variant of the
Finkelstein reactionThe Finkelstein reaction, named for the German chemist Hans Finkelstein , is an S
N2 reaction that involves the exchange of one halogen atom for another...
). In extreme cases, silver salts may be added for example silver oxide :
The silver ion coordinates with the halide leaving group to make its departure more facile. Finally, phase transfer catalysts are sometimes used (e.g. tetrabutylammonium bromide or
18-crown-618-Crown-6 is an organic compound with the formula [C2H4O]6 and the IUPAC name of 1,4,7,10,13,16-hexaoxacyclooctadecane. The compound is a crown ether. Crown ethers coordinate some metal ions in their central cavity; 18-crown-6 displays a particular affinity for...
) in order to increase the solubility of the alkoxide by offering a softer
counter-ionA counterion is the ion that accompanies an ionic species in order to maintain electric neutrality. In table salt the sodium cation is the counterion for the chlorine anion and vice versa.In a charged transition metal complex, a simple A counterion is the ion that accompanies an ionic species in...
.
Side reactions
The Williamson reaction often competes with the base-catalyzed elimination of the alkylating agent, and the nature of the leaving group as well as the reaction conditions (particularly the temperature and solvent) can have a strong effect on which is favored. In particular, some structures of alkylating agent can be particularly prone to elimination.
When the nucleophile is an aroxide ion, the Williamson reaction can also compete with alkylation on the ring since the aroxide is an ambident nucleophile.