Fischer esterification
Encyclopedia
Fischer esterification or Fischer–Speier esterification is a special type of esterification by reflux
ing a carboxylic acid
and an alcohol
in the presence of an acid
catalyst. The reaction was first described by Emil Fischer
and Arthur Speier in 1895. Most carboxylic acids are suitable for the reaction, but the alcohol should generally be a primary or secondary alkyl. Tertiary alcohols are prone to elimination
, and phenol
s are usually too unreactive to give useful yields. Commonly used catalysts for a Fischer esterification include sulfuric acid
, tosic acid, and Lewis acid
s such as scandium(III) triflate
. For more valuable or sensitive substrates (for example, biomaterials), dicyclohexylcarbodiimide is often used. The reaction is often carried out without a solvent (particularly when a large reagent excess (e.g. of MeOH is used) or in a non-polar solvent (e.g. toluene
) to facilitate the Dean-Stark method. Typical reaction times vary from 1–10 hours at temperatures of 60-110°C.
Direct acylation
s of alcohols with carboxylic acids is preferred over acylations with anhydrides (poor atom economy
) or acid chlorides (moisture sensitive). The main disadvantage of direct acylation is the unfavorable chemical equilibrium
that must be remedied e.g. by a large excess of one of the reagents, or by the removal of water (for example by Dean-Stark distillation, the use of molecular sieve
s, or the use of a stoichiometric quantity of concentrated sulfuric acid). In one study it is found that Tetrabutylammonium tribromide
(TBATB) is a very effective catalyst. For example the acylation of 3-phenylpropanol with glacial acetic acid and TBATB at reflux generates the ester in 15 minutes in a 95% chemical yield without the need to remove water. It is believed that hydrobromic acid
released by TBATB protonates the alcohol over the acid making the carboxylate the actual nucleophile in a reversal of the standard esterification mechanism.
based on the electrophilicity of the carbonyl
carbon and the nucleophilicity of an alcohol. However, carboxylic acids tend to be less reactive than esters as electrophiles. Additionally, In dilute neutral solutions they tend to be deprotonated anions (and thus unreactive as electrophiles). Though very kinetically slow without any catalysts (most esters are metastable), pure esters will tend to spontaneously hydrolyse in the presence of water, so when carried out "unaided", high yields for this reaction is quite unfavourable.
Several steps can be taken to turn this "unfavourable" reaction into a favourable one.
The reaction mechanism
for this reaction has several steps:
A generic mechanism for an acid Fischer esterification is shown below.
es or ozone depletors
and possible ecological poisons. Acid chlorides evolve hydrochloric acid
gas upon contact with atmospheric moisture, are corrosive, react vigorously with water and other nucleophiles (sometimes dangerously); they are easily quenched by other nucleophiles besides the desired alcohol; their most common synthesis routes involve the evolution of toxic carbon monoxide
or sulfur dioxide
gases (depending on the synthesis process used).
Acid anhydrides are more reactive than esters because the leaving group is a carboxylate anion—a better leaving group than an alkoxide anion because their negative charge is more delocalised. However, such routes generally result in poor atom economy
. For example, in reacting ethanol with acetic anhydride
, ethyl acetate
forms and acetic acid
is kicked out as a leaving group, which is considerably less reactive than an acid anhydride and will be left as a byproduct (in a wasteful 1:1 ratio with the ester product) if product is collected immediately. If conditions are acidic enough, the acetic acid can be further reacted via the Fischer esterification pathway, but at a much slower pace. However, in many carefully designed syntheses, reagents can be designed such that acid anhydrides are generated in situ and carboxylic acid byproducts are reactivated, and Fischer esterification routes are not necessarily mutually exclusive with acetic anhydride routes. (Examples of this include the common undergraduate organic lab experiment involving the acetylation of salicylic acid
to yield aspirin
.)
Fischer esterification is primarily a thermodynamically-controlled process: because of its slowness, the most stable ester tends to be the major product. This can be a desirable trait if there are multiple reaction sites and side product esters to be avoided. In contrast, rapid reactions involving acid anhydrides or acid chlorides are often kinetically-controlled.
The primary disadvantages of Fischer esterification routes are its thermodynamic reversibility and relatively slow reaction rates—often on the scale of several hours to years, depending on the reaction conditions. Workarounds to this can be inconvenient if there are other functional groups sensitive to strong acid, in which case other catalytic acids may be chosen. If the product ester has a lower boiling point than either water or the reagents, the product may be distilled rather than water; this is common as esters with no protic functional groups tend to have lower boiling points than their protic parent reagents. Purification and extraction are easier if the ester product can be distilled away from the reagents and byproducts, but reaction rate can be slowed because overall reaction temperature can be limited in this scenario. A more inconvenient scenario is if the reagents have a lower boiling point than either the ester product or water, in which case the reaction mixture must be capped and refluxed and a large excess of starting material added.
s and other alcoholic beverages during the aging process is an example of acid-catalysed esterification. Over time, the acidity of the acetic acid
and tannins in an aging wine will catalytically protonate other organic acids (including acetic acid itself), encouraging ethanol
to react as a nucleophile. As a result, ethyl acetate
-- the ester of ethanol and acetic acid—is the most abundant ester in wines. Other combinations of organic alcohols (such as phenol-containing compounds) and organic acids lead to a variety of different esters in wines, contributing to their different flavours, smells and tastes. Of course, when compared to sulfuric acid conditions, the acid conditions in a wine are mild, so yield is low (often in tenths or hundredths of a percentage point by volume) and take years for ester to accumulate.
Reflux
Reflux is a technique involving the condensation of vapors and the return of this condensate to the system from which it originated. It is used in industrial and laboratory distillations...
ing a carboxylic acid
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
and an alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
in the presence of an acid
Acid
An acid is a substance which reacts with a base. Commonly, acids can be identified as tasting sour, reacting with metals such as calcium, and bases like sodium carbonate. Aqueous acids have a pH of less than 7, where an acid of lower pH is typically stronger, and turn blue litmus paper red...
catalyst. The reaction was first described by Emil Fischer
Hermann Emil Fischer
Hermann Emil Fischer, Emil Fischer was a German chemist and 1902 recipient of the Nobel Prize in Chemistry. He discovered the Fischer esterification. He developed the Fischer projection, a symbolic way of drawing asymmetric carbon atoms.-Early years:Fischer was born in Euskirchen, near Cologne,...
and Arthur Speier in 1895. Most carboxylic acids are suitable for the reaction, but the alcohol should generally be a primary or secondary alkyl. Tertiary alcohols are prone to elimination
Elimination reaction
An elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a one or two-step mechanism...
, and phenol
Phenol
Phenol, also known as carbolic acid, phenic acid, is an organic compound with the chemical formula C6H5OH. It is a white crystalline solid. The molecule consists of a phenyl , bonded to a hydroxyl group. It is produced on a large scale as a precursor to many materials and useful compounds...
s are usually too unreactive to give useful yields. Commonly used catalysts for a Fischer esterification include sulfuric acid
Sulfuric acid
Sulfuric acid is a strong mineral acid with the molecular formula . Its historical name is oil of vitriol. Pure sulfuric acid is a highly corrosive, colorless, viscous liquid. The salts of sulfuric acid are called sulfates...
, tosic acid, and Lewis acid
Lewis acid
]The term Lewis acid refers to a definition of acid published by Gilbert N. Lewis in 1923, specifically: An acid substance is one which can employ a lone pair from another molecule in completing the stable group of one of its own atoms. Thus, H+ is a Lewis acid, since it can accept a lone pair,...
s such as scandium(III) triflate
Scandium(III) triflate
Scandium trifluoromethanesulfonate, commonly called scandium triflate, is a chemical compound with formula Sc3, a salt consisting of scandium cations Sc3+ and triflate SO3CF3− anions....
. For more valuable or sensitive substrates (for example, biomaterials), dicyclohexylcarbodiimide is often used. The reaction is often carried out without a solvent (particularly when a large reagent excess (e.g. of MeOH is used) or in a non-polar solvent (e.g. toluene
Toluene
Toluene, formerly known as toluol, is a clear, water-insoluble liquid with the typical smell of paint thinners. It is a mono-substituted benzene derivative, i.e., one in which a single hydrogen atom from the benzene molecule has been replaced by a univalent group, in this case CH3.It is an aromatic...
) to facilitate the Dean-Stark method. Typical reaction times vary from 1–10 hours at temperatures of 60-110°C.
Direct acylation
Acylation
In chemistry, acylation is the process of adding an acyl group to a compound. The compound providing the acyl group is called the acylating agent....
s of alcohols with carboxylic acids is preferred over acylations with anhydrides (poor atom economy
Atom economy
Atom economy describes the conversion efficiency of a chemical process in terms of all atoms involved . In an ideal chemical process, the amount of starting materials or reactants equals the amount of all products generated and no atom is wasted...
) or acid chlorides (moisture sensitive). The main disadvantage of direct acylation is the unfavorable chemical equilibrium
Chemical equilibrium
In a chemical reaction, chemical equilibrium is the state in which the concentrations of the reactants and products have not yet changed with time. It occurs only in reversible reactions, and not in irreversible reactions. Usually, this state results when the forward reaction proceeds at the same...
that must be remedied e.g. by a large excess of one of the reagents, or by the removal of water (for example by Dean-Stark distillation, the use of molecular sieve
Molecular sieve
A molecular sieve is a material containing tiny pores of a precise and uniform size that is used as an adsorbent for gases and liquids.Molecules small enough to pass through the pores are adsorbed while larger molecules are not. It is different from a common filter in that it operates on a...
s, or the use of a stoichiometric quantity of concentrated sulfuric acid). In one study it is found that Tetrabutylammonium tribromide
Tetrabutylammonium tribromide
Tetrabutylammonium tribromide is a reagent used in organic chemistry as a source of bromine. Its melting point ranges from 103-104 °C....
(TBATB) is a very effective catalyst. For example the acylation of 3-phenylpropanol with glacial acetic acid and TBATB at reflux generates the ester in 15 minutes in a 95% chemical yield without the need to remove water. It is believed that hydrobromic acid
Hydrobromic acid
Hydrobromic acid is a strong acid formed by dissolving the diatomic molecule hydrogen bromide in water. "Constant boiling" hydrobromic acid is an aqueous solution that distills at 124.3 °C and contains 47.6% HBr by weight, which is 8.89 mol/L. Hydrobromic acid has a pKa of −9, making it a...
released by TBATB protonates the alcohol over the acid making the carboxylate the actual nucleophile in a reversal of the standard esterification mechanism.
Overview
Fischer esterification is an example of nucleophilic acyl substitutionNucleophilic acyl substitution
Nucleophilic acyl substitution describes the substitution reaction involving nucleophiles and acyl compounds. Acyl compounds are carboxylic acid derivatives including esters, amides and acid halides...
based on the electrophilicity of the carbonyl
Carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
carbon and the nucleophilicity of an alcohol. However, carboxylic acids tend to be less reactive than esters as electrophiles. Additionally, In dilute neutral solutions they tend to be deprotonated anions (and thus unreactive as electrophiles). Though very kinetically slow without any catalysts (most esters are metastable), pure esters will tend to spontaneously hydrolyse in the presence of water, so when carried out "unaided", high yields for this reaction is quite unfavourable.
Several steps can be taken to turn this "unfavourable" reaction into a favourable one.
The reaction mechanism
Reaction mechanism
In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical change occurs.Although only the net chemical change is directly observable for most chemical reactions, experiments can often be designed that suggest the possible sequence of steps in...
for this reaction has several steps:
- Proton transfer from acid catalyst to carbonylCarbonylIn organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
oxygen increases electrophilicityElectrophileIn general electrophiles are positively charged species that are attracted to an electron rich centre. In chemistry, an electrophile is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile...
of carbonyl carbon. - The carbonyl carbon is then attacked by the nucleophilicNucleophileA nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...
oxygen atom of the alcohol - Proton transfer from the oxonium ionOxonium ionThe oxonium ion in chemistry is any oxygen cation with three bonds. The simplest oxonium ion is the hydronium ion H3O+. Another oxonium ion frequently encountered in organic chemistry is obtained by protonation or alkylation of a carbonyl group e.g...
to a second molecule of the alcohol gives an activated complex - Protonation of one of the hydroxyl groups of the activated complex gives a new oxonium ion.
- Loss of water from this oxonium ion and subsequent deprotonation gives the esterEsterEsters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
.
A generic mechanism for an acid Fischer esterification is shown below.
Advantages and disadvantages
The primary advantages of Fischer esterification compared to other esterification processes are based on its relative simplicity. Straightforward acidic conditions can be used if acid-sensitive functional groups are not an issue; sulfuric acid can be used; softer acids can be used with a tradeoff of longer reaction times. Because the reagents used are "direct," there is less environmental impact in terms of waste products and harmfulness of the reagents. Alkyl halides are potential greenhouse gasGreenhouse gas
A greenhouse gas is a gas in an atmosphere that absorbs and emits radiation within the thermal infrared range. This process is the fundamental cause of the greenhouse effect. The primary greenhouse gases in the Earth's atmosphere are water vapor, carbon dioxide, methane, nitrous oxide, and ozone...
es or ozone depletors
Ozone depletion
Ozone depletion describes two distinct but related phenomena observed since the late 1970s: a steady decline of about 4% per decade in the total volume of ozone in Earth's stratosphere , and a much larger springtime decrease in stratospheric ozone over Earth's polar regions. The latter phenomenon...
and possible ecological poisons. Acid chlorides evolve hydrochloric acid
Hydrochloric acid
Hydrochloric acid is a solution of hydrogen chloride in water, that is a highly corrosive, strong mineral acid with many industrial uses. It is found naturally in gastric acid....
gas upon contact with atmospheric moisture, are corrosive, react vigorously with water and other nucleophiles (sometimes dangerously); they are easily quenched by other nucleophiles besides the desired alcohol; their most common synthesis routes involve the evolution of toxic carbon monoxide
Carbon monoxide
Carbon monoxide , also called carbonous oxide, is a colorless, odorless, and tasteless gas that is slightly lighter than air. It is highly toxic to humans and animals in higher quantities, although it is also produced in normal animal metabolism in low quantities, and is thought to have some normal...
or sulfur dioxide
Sulfur dioxide
Sulfur dioxide is the chemical compound with the formula . It is released by volcanoes and in various industrial processes. Since coal and petroleum often contain sulfur compounds, their combustion generates sulfur dioxide unless the sulfur compounds are removed before burning the fuel...
gases (depending on the synthesis process used).
Acid anhydrides are more reactive than esters because the leaving group is a carboxylate anion—a better leaving group than an alkoxide anion because their negative charge is more delocalised. However, such routes generally result in poor atom economy
Atom economy
Atom economy describes the conversion efficiency of a chemical process in terms of all atoms involved . In an ideal chemical process, the amount of starting materials or reactants equals the amount of all products generated and no atom is wasted...
. For example, in reacting ethanol with acetic anhydride
Acetic anhydride
Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula 2O. Commonly abbreviated Ac2O, it is the simplest isolatable acid anhydride and is a widely used reagent in organic synthesis...
, ethyl acetate
Ethyl acetate
Ethyl acetate is the organic compound with the formula CH3COOCH2CH3. This colorless liquid has a characteristic sweet smell and is used in glues, nail polish removers, and cigarettes...
forms and acetic acid
Acetic acid
Acetic acid is an organic compound with the chemical formula CH3CO2H . It is a colourless liquid that when undiluted is also called glacial acetic acid. Acetic acid is the main component of vinegar , and has a distinctive sour taste and pungent smell...
is kicked out as a leaving group, which is considerably less reactive than an acid anhydride and will be left as a byproduct (in a wasteful 1:1 ratio with the ester product) if product is collected immediately. If conditions are acidic enough, the acetic acid can be further reacted via the Fischer esterification pathway, but at a much slower pace. However, in many carefully designed syntheses, reagents can be designed such that acid anhydrides are generated in situ and carboxylic acid byproducts are reactivated, and Fischer esterification routes are not necessarily mutually exclusive with acetic anhydride routes. (Examples of this include the common undergraduate organic lab experiment involving the acetylation of salicylic acid
Salicylic acid
Salicylic acid is a monohydroxybenzoic acid, a type of phenolic acid and a beta hydroxy acid. This colorless crystalline organic acid is widely used in organic synthesis and functions as a plant hormone. It is derived from the metabolism of salicin...
to yield aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
.)
Fischer esterification is primarily a thermodynamically-controlled process: because of its slowness, the most stable ester tends to be the major product. This can be a desirable trait if there are multiple reaction sites and side product esters to be avoided. In contrast, rapid reactions involving acid anhydrides or acid chlorides are often kinetically-controlled.
The primary disadvantages of Fischer esterification routes are its thermodynamic reversibility and relatively slow reaction rates—often on the scale of several hours to years, depending on the reaction conditions. Workarounds to this can be inconvenient if there are other functional groups sensitive to strong acid, in which case other catalytic acids may be chosen. If the product ester has a lower boiling point than either water or the reagents, the product may be distilled rather than water; this is common as esters with no protic functional groups tend to have lower boiling points than their protic parent reagents. Purification and extraction are easier if the ester product can be distilled away from the reagents and byproducts, but reaction rate can be slowed because overall reaction temperature can be limited in this scenario. A more inconvenient scenario is if the reagents have a lower boiling point than either the ester product or water, in which case the reaction mixture must be capped and refluxed and a large excess of starting material added.
Examples in alcoholic beverages
The natural esterification that takes place in wineWine
Wine is an alcoholic beverage, made of fermented fruit juice, usually from grapes. The natural chemical balance of grapes lets them ferment without the addition of sugars, acids, enzymes, or other nutrients. Grape wine is produced by fermenting crushed grapes using various types of yeast. Yeast...
s and other alcoholic beverages during the aging process is an example of acid-catalysed esterification. Over time, the acidity of the acetic acid
Acetic acid
Acetic acid is an organic compound with the chemical formula CH3CO2H . It is a colourless liquid that when undiluted is also called glacial acetic acid. Acetic acid is the main component of vinegar , and has a distinctive sour taste and pungent smell...
and tannins in an aging wine will catalytically protonate other organic acids (including acetic acid itself), encouraging ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
to react as a nucleophile. As a result, ethyl acetate
Ethyl acetate
Ethyl acetate is the organic compound with the formula CH3COOCH2CH3. This colorless liquid has a characteristic sweet smell and is used in glues, nail polish removers, and cigarettes...
-- the ester of ethanol and acetic acid—is the most abundant ester in wines. Other combinations of organic alcohols (such as phenol-containing compounds) and organic acids lead to a variety of different esters in wines, contributing to their different flavours, smells and tastes. Of course, when compared to sulfuric acid conditions, the acid conditions in a wine are mild, so yield is low (often in tenths or hundredths of a percentage point by volume) and take years for ester to accumulate.