Acetaldehyde

Production

In 2013, global production was about 438,000 tonnes. Before 1962, ethanol and acetylene were the major sources of acetaldehyde. Since then, ethylene is the dominant feedstock.

The main method of production is the oxidation of ethylene by the Wacker process, which involves oxidation of ethylene using a homogeneous palladium/copper catalyst system:

2 CH₂=CH₂ + O₂ → 2 CH₃CH=O

In the 1970s, the world capacity of the Wacker-Hoechst direct oxidation process exceeded two million tonnes annually.

Smaller quantities can be prepared by the partial oxidation of ethanol in an exothermic reaction. This process typically is conducted over a silver catalyst at about 500–650 °C (950–1,200 °F).

2 CH₃CH₂OH + O₂ → 2 CH₃CH=O + 2 H₂O

This method is one of the oldest routes for the industrial preparation of acetaldehyde.

Other methods

Hydration of acetylene

Prior to the Wacker process and the availability of cheap ethylene, acetaldehyde was produced by the hydration of acetylene. This reaction is catalyzed by mercury(II) salts:

C₂H₂ + Hg²⁺ + H₂O → CH₃CH=O + Hg

The mechanism involves the intermediacy of vinyl alcohol, which tautomerizes to acetaldehyde. The reaction is conducted at 90–95 °C (194–203 °F), and the acetaldehyde formed is separated from water and mercury and cooled to 25–30 °C (77–86 °F). In the wet oxidation process, iron(III) sulfate is used to reoxidize the mercury back to the mercury(II) salt. The resulting iron(II) sulfate is oxidized in a separate reactor with nitric acid.

The enzyme Acetylene hydratase discovered in the strictly anaerobic bacterium Pelobacter acetylenicus can catalyze an analogous reaction without involving any compounds of mercury. However, it has thus far not been brought to any large-scale or commercial use.

Dehydrogenation of ethanol

Traditionally, acetaldehyde was produced by the partial dehydrogenation of ethanol:

CH₃CH₂OH → CH₃CH=O + H₂

In this endothermic process, ethanol vapor is passed at 260–290 °C over a copper-based catalyst. The process was once attractive because of the value of the hydrogen coproduct, but in modern times is not economically viable.

Hydroformylation of methanol

The hydroformylation of methanol with catalysts like cobalt, nickel, or iron salts also produces acetaldehyde, although this process is of no industrial importance. Similarly noncompetitive, acetaldehyde arises from synthesis gas with modest selectivity.

Reactions

Tautomerization to vinyl alcohol

Like many other carbonyl compounds, acetaldehyde tautomerizes to give an enol (vinyl alcohol; IUPAC name: ethenol):

CH₃CH=O ⇌ CH₂=CHOH ∆H_298,g = +42.7 kJ/mol

The equilibrium constant is 6×10⁻⁷ at room temperature, thus that the relative amount of the enol form in a sample of acetaldehyde is very small. At room temperature, acetaldehyde (CH₃CH=O) is more stable than vinyl alcohol (CH₂=CHOH) by 42.7 kJ/mol: Overall the keto-enol tautomerization occurs slowly but is catalyzed by acids.

Photo-induced keto-enol tautomerization is viable under atmospheric or stratospheric conditions. This photo-tautomerization is relevant to the Earth's atmosphere, because vinyl alcohol is thought to be a precursor to carboxylic acids in the atmosphere.

Addition and condensation reactions

Acetaldehyde is a common electrophile in organic synthesis. In addition reactions acetaldehyde is prochiral. It is used primarily as a source of the "CH₃C⁺H(OH)" synthon in aldol reactions and related condensation reactions. Grignard reagents and organolithium compounds react with MeCHO to give hydroxyethyl derivatives. In one of the more spectacular addition reactions, formaldehyde in the presence of calcium hydroxide adds to MeCHO to give pentaerythritol, C(CH₂OH)₄ and formate.

In a Strecker reaction, acetaldehyde condenses with cyanide and ammonia to give, after hydrolysis, the amino acid alanine. Acetaldehyde can condense with amines to yield imines; for example, with cyclohexylamine to give N-ethylidenecyclohexylamine. These imines can be used to direct subsequent reactions like an aldol condensation.

It is also a building block in the synthesis of heterocyclic compounds. In one example, it converts, upon treatment with ammonia, to 5-ethyl-2-methylpyridine ("aldehyde-collidine").

Polymeric forms

Three molecules of acetaldehyde condense to form "paraldehyde", a cyclic trimer containing C-O single bonds. Similarly condensation of four molecules of acetaldehyde give the cyclic molecule metaldehyde. Paraldehyde can be produced in good yields, using a sulfuric acid catalyst. Metaldehyde is only obtained in a few percent yield and with cooling, often using HBr rather than H₂SO₄ as the catalyst. At −40 °C (−40 °F) in the presence of acid catalysts, polyacetaldehyde is produced. There are two stereomers of paraldehyde and four of metaldehyde.

The German chemist Valentin Hermann Weidenbusch (1821–1893) synthesized paraldehyde in 1848 by treating acetaldehyde with acid (either sulfuric or nitric acid) and cooling to 0 °C (32 °F). He found it quite remarkable that when paraldehyde was heated with a trace of the same acid, the reaction went the other way, recreating acetaldehyde.

Although vinyl alcohol is a tautomeric form of acetaldehyde (§ Tautomerization to vinyl alcohol), polyvinyl alcohol cannot be produced from acetaldehyde.

Acetal derivatives

Acetaldehyde forms a stable acetal upon reaction with ethanol under conditions that favor dehydration. The product, CH₃CH(OCH₂CH₃)₂, is formally named 1,1-diethoxyethane but is commonly referred to as "acetal". This can cause confusion as "acetal" is more commonly used to describe compounds with the functional groups RCH(OR')₂ or RR'C(OR'')₂ rather than referring to this specific compound — in fact, 1,1-diethoxyethane is also described as the diethyl acetal of acetaldehyde.

Precursor to vinylphosphonic acid

Acetaldehyde is a precursor to vinylphosphonic acid, which is used to make adhesives and ion conductive membranes. The synthesis sequence begins with a reaction with phosphorus trichloride:

1. PCl₃ + CH₃CHO → CH₃CH(O⁻)PCl+3
2. CH₃CH(O⁻)PCl+3 + 2 CH₃CO₂H → CH₃CH(Cl)PO(OH)₂ + 2 CH₃COCl
3. CH₃CH(Cl)PO(OH)₂ → CH₂=CHPO(OH)₂ + HCl

Biochemistry

In the liver, the enzyme alcohol dehydrogenase oxidizes ethanol into acetaldehyde, which is then further oxidized into harmless acetic acid by acetaldehyde dehydrogenase. These two oxidation reactions are coupled with the reduction of NAD⁺ to NADH. In the brain, the enzyme catalase is primarily responsible for oxidizing ethanol to acetaldehyde, and alcohol dehydrogenase plays a minor role. The last steps of alcoholic fermentation in bacteria, plants, and yeast involve the conversion of pyruvate into acetaldehyde and carbon dioxide by the enzyme pyruvate decarboxylase, followed by the conversion of acetaldehyde into ethanol. The latter reaction is again catalyzed by an alcohol dehydrogenase, now operating in the opposite direction.

Many East Asian people have an ALDH2 mutation which makes them significantly less efficient at oxidizing acetaldehyde to acetic acid. On consuming alcohol, their bodies tend to accumulate excessive amounts of acetaldehyde, causing the so-called alcohol flush reaction. They develop a characteristic reddening of the skin on the face and body, alongside nausea, headache and general physical discomfort.

Uses

Traditionally, acetaldehyde was mainly used as a precursor to acetic acid. This application has declined because acetic acid is produced more efficiently from methanol by the Monsanto and Cativa processes. Acetaldehyde is an important precursor to pyridine derivatives, pentaerythritol, and crotonaldehyde. Urea and acetaldehyde combine to give a useful resin. Acetic anhydride reacts with acetaldehyde to give ethylidene diacetate, a precursor to vinyl acetate, which is used to produce polyvinyl acetate.

The global market for acetaldehyde is declining. Demand has been impacted by changes in the production of plasticizer alcohols, which has shifted because n-butyraldehyde is less often produced from acetaldehyde, instead being generated by hydroformylation of propylene. Likewise, acetic acid, once produced from acetaldehyde, is made predominantly by the lower-cost methanol carbonylation process. The impact on demand has led to increase in prices and thus slowdown in the market.

China is the largest consumer of acetaldehyde in the world, accounting for almost half of global consumption in 2012. Major use has been the production of acetic acid. Other uses such as pyridines and pentaerythritol are expected to grow faster than acetic acid, but the volumes are not large enough to offset the decline in acetic acid. As a consequence, overall acetaldehyde consumption in China may grow slightly at 1.6% per year through 2018. Western Europe is the second-largest consumer of acetaldehyde worldwide, accounting for 20% of world consumption in 2012. As with China, the Western European acetaldehyde market is expected to increase only very slightly at 1% per year during 2012–2018. However, Japan could emerge as a potential consumer for acetaldehyde in the next five years due to newfound use in commercial production of butadiene. The supply of butadiene has been volatile in Japan and the rest of Asia. This should provide the much needed boost to the flat market, as of 2013.

Safety

Exposure limits

The threshold limit value is 25 ppm (STEL/ceiling value) and the MAK (Maximum Workplace Concentration) is 50 ppm. At 50 ppm acetaldehyde, no irritation or local tissue damage in the nasal mucosa is observed. When taken up by the organism, acetaldehyde is metabolized rapidly in the liver to acetic acid. Only a small proportion is exhaled unchanged. After intravenous injection, the half-life in the blood is approximately 90 seconds.

Toxicity

Cases of acute intoxication have been recorded. Acetaldehyde naturally breaks down in the human body.

Irritation

Acetaldehyde is an irritant of the skin, eyes, mucous membranes, throat, and respiratory tract. This occurs at concentrations as low as 1000 ppm. Symptoms of exposure to this compound include nausea, vomiting, and headache. These symptoms may not happen immediately. The perception threshold for acetaldehyde in air is in the range between 0.07 and 0.25 ppm. At such concentrations, the fruity odor of acetaldehyde is apparent. Conjunctival irritations have been observed after a 15-minute exposure to concentrations of 25 and 50 ppm, but transient conjunctivitis and irritation of the respiratory tract have been reported after exposure to 200 ppm acetaldehyde for 15 minutes.

Potential for carcinogenicity

According to a 2021 assessment of animal studies by the US National Toxicology Program, acetaldehyde is reasonably anticipated to be a human carcinogen, although epidemiological studies have not produced sufficient evidence to establish a relationship between human cancer and specific acetaldehyde exposure. In 2023, a Working Group of the International Agency for Research on Cancer (IARC) concluded that risks for oral and esophageal cancer could be reduced by abstaining from alcohol consumption, thereby reducing intake of acetaldehyde, which is implicated as a possible cancer factor when alcohol is metabolized.

In 2009, IARC had concluded that acetaldehyde in alcoholic beverages was a Group I human carcinogen, as estimated from dose-response relationships between alcohol use and the incidence of cancers in the mouth and esophagus.

Despite concerns for its potential carcinogenicity in higher concentrations, acetaldehyde is an approved food flavoring ingredient in the European Union and United States where the Food and Drug Administration lists it as generally recognized as safe. With a concentration typically less than 0.05% in foods, acetaldehyde is used as a fruit or butter flavor in manufactured milk products, baked goods, juices and soft drinks, candies, and desserts. A scientific review in 2012 by a safety committee for the European Commission concluded that acetaldehyde in foods or beverages at an estimated amount of 11 mg per person per day would not be a safety concern. A 2023 review by the German Research Foundation stated that use of acetaldehyde as a food ingredient should be reassessed due to its toxicity potential.

According to one review, acetaldehyde is among environmental "air toxins with cancer risk".

Genetic conditions

A study of 818 heavy drinkers found that those exposed to more acetaldehyde than normal through a genetic variant of the gene encoding for ADH1C, ADH1C*1, are at greater risk of developing cancers of the upper gastrointestinal tract and liver.

Sources of exposure

Indoor air

Acetaldehyde is a potential contaminant in workplace, indoors, and ambient environments. Moreover, the majority of humans spend more than 90% of their time in indoor environments, increasing any exposure and the risk to human health.

In a study in France, the mean indoor concentration of acetaldehydes measured in 16 homes was approximately seven times higher than the outside acetaldehyde concentration. The living room had a mean of 18.1±17.5 μg m⁻³ and the bedroom was 18.2±16.9 μg m⁻³, whereas the outdoor air had a mean concentration of 2.3±2.6 μg m⁻³.

It has been concluded that volatile organic compounds (VOC) such as benzene, formaldehyde, acetaldehyde, toluene, and xylenes have to be considered priority pollutants with respect to their health effects. It has been pointed that in renovated or completely new buildings, the VOCs concentration levels are often several orders of magnitude higher. The main sources of acetaldehydes in homes include building materials, laminate, PVC flooring, varnished wood flooring, and varnished cork/pine flooring (found in the varnish, not the wood). It is also found in plastics, oil-based and water-based paints, in composite wood ceilings, particle-board, plywood, treated pine wood, and laminated chipboard furniture.

Outdoor air

The use of acetaldehyde is widespread in different industries, and it may be released into waste water or the air during production, use, transportation and storage. Sources of acetaldehyde include fuel combustion emissions from stationary internal combustion engines and power plants that burn fossil fuels, wood, or trash, oil and gas extraction, refineries, cement kilns, lumber and wood mills and paper mills. Acetaldehyde is also present in automobile and diesel exhaust. As a result, acetaldehyde is "one of the most frequently found air toxics with cancer risk greater than one in a million".

Tobacco smoke

Cellulose has been shown to be the primary precursor that makes acetaldehyde a significant constituent of tobacco smoke. It has been demonstrated to have a synergistic effect with nicotine in rodent studies of addiction. Acetaldehyde is also the most abundant polar carcinogen in tobacco smoke; it is dissolved into the saliva while smoking.

Cannabis smoke

Acetaldehyde has been found in cannabis smoke. This finding emerged through the use of new chemical techniques that demonstrated the acetaldehyde present was causing DNA damage in laboratory settings.

Alcohol consumption

Many microbes produce acetaldehyde from ethanol, but they have a lower capacity to eliminate the acetaldehyde, which can lead to the accumulation of acetaldehyde in saliva, stomach acid, and intestinal contents. Fermented food and many alcoholic beverages can also contain significant amounts of acetaldehyde. Acetaldehyde, derived from mucosal or microbial oxidation of ethanol, tobacco smoke, and diet, appears to act as a cumulative carcinogen in the upper digestive tract of humans. According to European Commission's Scientific Committee on Consumer Safety's (SCCS) "Opinion on Acetaldehyde" (2012) the cosmetic products special risk limit is 5 mg/L and acetaldehyde should not be used in mouth-washing products.

Plastics

Acetaldehyde can be produced by the photolysis of polyethylene terephthalate (PET), via a Type II Norrish reaction.

Although this process is generally harmless to humans, acetaldehyde has an exceedingly low odor threshold of around 30 parts per billion and can thus cause unusual tastes and smells in bottled water.

Candida overgrowth

The yeast Candida albicans in patients with potentially carcinogenic oral diseases has been shown to produce acetaldehyde in quantities sufficient to cause problems.