Decarboxylation · Lablypedia

In organic chemistry

The term decarboxylation usually means replacement of a carboxyl group (−C(O)OH) with a hydrogen atom:

RCO₂H → RH + CO₂

Decarboxylation is one of the oldest known organic reactions. It is one of the processes assumed to accompany pyrolysis and destructive distillation.

Overall, decarboxylation depends upon stability of the carbanion synthon R⁻
, although the anion may not be a true chemical intermediate. Typically, carboxylic acids decarboxylate slowly, but carboxylic acids with an α electron-withdrawing group (e.g. β‑keto acids, β‑nitriles, α‑nitro acids, or arylcarboxylic acids) decarboxylate easily. Decarboxylation of sodium chlorodifluoroacetate generates difluorocarbene:

CF₂ClCO₂Na → NaCl + CF₂ + CO₂

Decarboxylations are an important in the malonic and acetoacetic ester synthesis. The Knoevenagel condensation and they allow keto acids serve as a stabilizing protecting group for carboxylic acid enols.

For the free acids, conditions that deprotonate the carboxyl group (possibly protonating the electron-withdrawing group to form a zwitterionic tautomer) accelerate decarboxylation. A strong base is key to ketonization, in which a pair of carboxylic acids combine to the eponymous functional group:

Transition metal salts, especially copper compounds, facilitate decarboxylation via carboxylate complex intermediates. Metals that catalyze cross-coupling reactions thus treat aryl carboxylates as an aryl anion synthon; this synthetic strategy is the decarboxylative cross-coupling reaction.

Upon heating in cyclohexanone, amino acids decarboxylate. In the related Hammick reaction, uncatalyzed decarboxylation of a picolinic acid gives a stable carbene that attacks a carbonyl electrophile.

Oxidative decarboxylations are generally radical reactions. These include the Kolbe electrolysis and Hunsdiecker-Kochi reactions. The Barton decarboxylation is an unusual radical reductive decarboxylation.

As described above, most decarboxylations start with a carboxylic acid or its alkali metal salt, but the Krapcho decarboxylation starts with methyl esters. In this case, the reaction begins with halide-mediated cleavage of the ester, forming the carboxylate.

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In biochemistry

Decarboxylations are pervasive in biology. They are often classified according to the cofactors that catalyze the transformations. Biotin-coupled processes effect the decarboxylation of malonyl-CoA to acetyl-CoA. Thiamine (T:) is the active component for decarboxylation of alpha-ketoacids, including pyruvate:

T: + RC(O)CO₂H → T=C(OH)R + CO₂

T=C(OH)R + R'COOH → T! : + RC(O)CH(OH)R'

Pyridoxal phosphate promotes decarboxylation of amino acids. Flavin-dependent decarboxylases are involved in transformations of cysteine. Iron-based hydroxylases operate by reductive activation of O₂ using the decarboxylation of alpha-ketoglutarate as an electron donor. The decarboxylation can be depicted as such:

RC(O)CO₂Fe O₂ → RCO₂Fe{IV}=O + CO₂

RCO₂Fe=O + R'H → RCO₂Fe + R'OH

Decarboxylation of amino acids

Common biosynthetic oxidative decarboxylations of amino acids to amines are:

tryptophan to tryptamine
phenylalanine to phenylethylamine
tyrosine to tyramine
histidine to histamine
serine to ethanolamine
glutamic acid to GABA
lysine to cadaverine
arginine to agmatine
ornithine to putrescine
5-HTP to serotonin
L-DOPA to dopamine

Other decarboxylation reactions from the citric acid cycle include:

pyruvate to acetyl-CoA (see pyruvate decarboxylation)
oxalosuccinate to α-ketoglutarate
α-ketoglutarate to succinyl-CoA.

Fatty acid synthesis

Straight-chain fatty acid synthesis occurs by recurring reactions involving decarboxylation of malonyl-CoA.

Case studies

Upon heating, Δ9-tetrahydrocannabinolic acid decarboxylates to give the psychoactive compound Δ9-tetrahydrocannabinol. When cannabis is heated in vacuum, the decarboxylation of tetrahydrocannabinolic acid (THCA) appears to follow first order kinetics. The log fraction of THCA present decreases steadily over time, and the rate of decrease varies according to temperature. At 10-degree increments from 100 to 140 °C, half of the THCA is consumed in 30, 11, 6, 3, and 2 minutes; hence the rate constant follows Arrhenius' law, ranging between 10⁻⁸ and 10⁻⁵ in a linear log–log relationship with inverse temperature. However, modelling of decarboxylation of salicylic acid with a water molecule had suggested an activation barrier of 150 kJ/mol for a single molecule in solvent, much too high for the observed rate. Therefore, it was concluded that this reaction, conducted in the solid phase in plant material with a high fraction of carboxylic acids, follows pseudo–first-order kinetics in which a nearby carboxylic acid precipitates without affecting the observed rate constant. Two transition states corresponding to indirect and direct keto-enol routes are possible, with energies of 93 and 104 kJ/mol. Both intermediates involve protonation of the alpha carbon, disrupting one of the double bonds of the aromatic ring and permitting the beta-keto group (which takes the form of an enol in THCA and THC) to participate in decarboxylation.

In beverages stored for long periods, very small amounts of benzene may form from benzoic acid by decarboxylation catalyzed by the presence of ascorbic acid.

The addition of catalytic amounts of cyclohexenone has been reported to catalyze the decarboxylation of amino acids. However, using such catalysts may also yield an amount of unwanted by-products.