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Decarboxylation of primary amino acids
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Michael Geissler
Decarboxylation of primary amino acids
Since primary amino acids like glycine, alanine can't be decarboxylated under oxidative conditions, what would be the best catalyst for this reaction?
Decarboxylation of $\alpha$-amino acids is known enzymatic procedure in biological systems. Non-enzymatic decarboxylation of $\alpha$-amino acids is also a long-known reaction, which leads to amines with a range of applications (Ref.1 and 2). Initially, this type of decarboxylation was tried by heating them above $\pu{200 ^\circ C}$, often dissolved or dispersed in an inert solvent. As these reactions are always exothermic, heating is only required to reach the rather high energies of activation (Ref.1).
In enzymatic decarboxylation in which Nature lowers these activation energies by enzymatic reactions has been frequently discussed. For instance, the formation of a Schiff's base between an $\alpha$-amino acid and pyridoxal phosphate as the proved prosthetic group of most of the decarboxylases is postulated by many authors. The easiness of the expected decarboxylation in this way may be understood with the help of the electronic theory of valence (Ref.1). As a consequence, the most commonly used method to decarboxylate $\alpha$-amino acids employs thermolysis of the amino acid in the presence of catalytic amount of an aldehyde (usually, an aromatic aldehydes can act as catalysts). The earliest such attempt has been done by Curtius and Lederer in 1886, when they have obtained decarboxylation of glycine by heating a mixture of glycine and benzaldehyde up to $\pu{130 ^\circ C}$. But the end-product of this reaction was not methylamine as expected, but benzylamine, which could not be understood by the authors at the time (Ref.3):
The driving force of this reaction is the resonance stabilization of the intermediate carbanion:
During a intensive work in this subject, Dose found that in the o- or p-position to the aldehyde group there must be a group with free electrons (such as dimethylamino-group) significant enough to reduce fully the tendency of transamination in the Schiff's base (reverse the electron flow; Ref.1). For instance, when Dose has used p-dimethylaminobenzaldehyde instead of benzaldehyde as the catalyst in valine decarboxylation, isobutylamine was the single product isolated after a method similar to that suggested by Curtius and Lederer in Ref.3 (with benzaldehyde it was $2:1$ of benzyl amine to isobutylamine while it is $1:1$ with anisaldehyde). There is also use of non-aromatic aldehyde as a catalyst as well (Ref.4). In this sequence, the authors have obtained corresponding amines (some of them are optically active) in good to excellent yields. For example, 4-hydroxyproline has given $(3R)$-(-)-3-hydroxypyrrolidine in 93% yield (Ref.4). Note that the elevated temperature is an important factor in this decarboxylation.
Other non-enzymatic methods include irradiation with UV light, heating in diphenylmethane solvent, or thermolysis in a high boiling solvent in the presence of a peroxide catalyst (Ref.2). Since some unnatural $\alpha$-amino acids do not undergo decarboxylation under the above conditions described (e.g., compounds 1,2, and 3), a new general non-thermal procedure is introduced in 2003 (Ref.2):
The method can be described as a ‘one-pot’ combination of two known reactions, oxidative decarboxylation of $\alpha$-amino acids to nitriles induced by N-bromosuccinimide, and the reduction of resulting nitriles to amines effected by sodium borohydride-nickel chloride (Ref.2):
Using this two step one-pot procedure, compounds 1, 2, and 3 were successfully converted to their corresponding polyamines.
References:
Klaus Dose, “Catalytic Decarboxylation of $\alpha$-amino acids,” Nature1957, 179, 734-735 (DOI: https://doi.org/10.1038/179734b0).
Gilles Laval and Bernard T. Golding, “One-pot Sequence for the Decarboxylation of $\alpha$-amino acids,” Synlett2003, (4), 542-546 (DOI: 10.1055/s-2003-37512).
Th. Curtius and G. Lederer, “Notiz über Benzylamin,” Berichte der deutschen chemischen Gesellschaft1886, 19(2), 2462-2463 (DOI: https://doi.org/10.1002/cber.188601902184).
Hashimoto Mitsunori, Eda Yutaka, Osanai Yasutomo, Iwai Toshiaki, and Aoki Seiichi, “A novel decarboxylation of $\alpha$-amino acids. A facile method of decarboxylation by the use of 2-cyclohexen-1-one as a catalyst,” Chemistry Letters1986, 15(6), 893-896 (DOI: https://doi.org/10.1246/cl.1986.893).
Since primary amino acids like glycine, alanine can't be decarboxylated under oxidative conditions, what would be the best catalyst for this reaction?
Decarboxylation of $\alpha$-amino acids is known enzymatic procedure in biological systems. Non-enzymatic decarboxylation of $\alpha$-amino acids is also a long-known reaction, which leads to amines with a range of applications (Ref.1 and 2). Initially, this type of decarboxylation was tried by heating them above $\pu{200 ^\circ C}$, often dissolved or dispersed in an inert solvent. As these reactions are always exothermic, heating is only required to reach the rather high energies of activation (Ref.1).
In enzymatic decarboxylation in which Nature lowers these activation energies by enzymatic reactions has been frequently discussed. For instance, the formation of a Schiff's base between an $\alpha$-amino acid and pyridoxal phosphate as the proved prosthetic group of most of the decarboxylases is postulated by many authors. The easiness of the expected decarboxylation in this way may be understood with the help of the electronic theory of valence (Ref.1). As a consequence, the most commonly used method to decarboxylate $\alpha$-amino acids employs thermolysis of the amino acid in the presence of catalytic amount of an aldehyde (usually, an aromatic aldehydes can act as catalysts). The earliest such attempt has been done by Curtius and Lederer in 1886, when they have obtained decarboxylation of glycine by heating a mixture of glycine and benzaldehyde up to $\pu{130 ^\circ C}$. But the end-product of this reaction was not methylamine as expected, but benzylamine, which could not be understood by the authors at the time (Ref.3):
The driving force of this reaction is the resonance stabilization of the intermediate carbanion:
During a intensive work in this subject, Dose found that in the o- or p-position to the aldehyde group there must be a group with free electrons (such as dimethylamino-group) significant enough to reduce fully the tendency of transamination in the Schiff's base (reverse the electron flow; Ref.1). For instance, when Dose has used p-dimethylaminobenzaldehyde instead of benzaldehyde as the catalyst in valine decarboxylation, isobutylamine was the single product isolated after a method similar to that suggested by Curtius and Lederer in Ref.3 (with benzaldehyde it was $2:1$ of benzyl amine to isobutylamine while it is $1:1$ with anisaldehyde). There is also use of non-aromatic aldehyde as a catalyst as well (Ref.4). In this sequence, the authors have obtained corresponding amines (some of them are optically active) in good to excellent yields. For example, 4-hydroxyproline has given $(3R)$-(-)-3-hydroxypyrrolidine in 93% yield (Ref.4). Note that the elevated temperature is an important factor in this decarboxylation.
Other non-enzymatic methods include irradiation with UV light, heating in diphenylmethane solvent, or thermolysis in a high boiling solvent in the presence of a peroxide catalyst (Ref.2). Since some unnatural $\alpha$-amino acids do not undergo decarboxylation under the above conditions described (e.g., compounds 1,2, and 3), a new general non-thermal procedure is introduced in 2003 (Ref.2):
The method can be described as a ‘one-pot’ combination of two known reactions, oxidative decarboxylation of $\alpha$-amino acids to nitriles induced by N-bromosuccinimide, and the reduction of resulting nitriles to amines effected by sodium borohydride-nickel chloride (Ref.2):
Using this two step one-pot procedure, compounds 1, 2, and 3 were successfully converted to their corresponding polyamines.
References:
Klaus Dose, “Catalytic Decarboxylation of $\alpha$-amino acids,” Nature1957, 179, 734-735 (DOI: https://doi.org/10.1038/179734b0).
Gilles Laval and Bernard T. Golding, “One-pot Sequence for the Decarboxylation of $\alpha$-amino acids,” Synlett2003, (4), 542-546 (DOI: 10.1055/s-2003-37512).
Th. Curtius and G. Lederer, “Notiz über Benzylamin,” Berichte der deutschen chemischen Gesellschaft1886, 19(2), 2462-2463 (DOI: https://doi.org/10.1002/cber.188601902184).
Hashimoto Mitsunori, Eda Yutaka, Osanai Yasutomo, Iwai Toshiaki, and Aoki Seiichi, “A novel decarboxylation of $\alpha$-amino acids. A facile method of decarboxylation by the use of 2-cyclohexen-1-one as a catalyst,” Chemistry Letters1986, 15(6), 893-896 (DOI: https://doi.org/10.1246/cl.1986.893).
Using pyridoxal might be viable option, but not sure if it also works for β-amino acids like β-alanine. According to the paper, decarboxylation catalyzed by glyoxal/ninhydrin on β-alanine or β-amino-n-butyric acid resulted also in deamination. So alanine produced acetaldehyde.More
@steve d.: Heating above $\pu{200 ^\circ C}$ is an earlier method for decarboxcylation regardless of it is $\alpha$-amino acid or not. Im sur it is okay for $\beta$-amino acids as well.More
This is very useful information. Especially the one using cyclohexenone as a catalyst. But these methods are for α-alanine and unfortunately, and the α-amino group seems vital for the reaction to proceed. Cant find any articles about decarboxylation of β-amino acids.More
@Mathew: I looked at the original paper. While they intimated that the process could occur, their examples retained the carboxyl group in the cycloaddition when the rxn. was run in acetic acid. They claim HOAc represses the decarboxylation. Perhaps CA was being overly generous. More
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I swear I read a paper where phenylalanine was decarboxylated in household bleach by heating for 30 minutes at 160 cel?
Wouldn't that work here.
to add further details, such as citations or documentation, so that others can confirm that your answer is correct. You can find more information on how to write good answers More
«I swear I read a paper» is better substituted by a reference from primary literature (like a journal article) or a textbook including a literature reference.More
Decarboxylation of $\alpha$-amino acids is known enzymatic procedure in biological systems. Non-enzymatic decarboxylation of $\alpha$-amino acids is also a long-known reaction, which leads to amines with a range of applications (Ref.1 and 2). Initially, this type of decarboxylation was tried by heating them above $\pu{200 ^\circ C}$, often dissolved or dispersed in an inert solvent. As these reactions are always exothermic, heating is only required to reach the rather high energies of activation (Ref.1).
In enzymatic decarboxylation in which Nature lowers these activation energies by enzymatic reactions has been frequently discussed. For instance, the formation of a Schiff's base between an $\alpha$-amino acid and pyridoxal phosphate as the proved prosthetic group of most of the decarboxylases is postulated by many authors. The easiness of the expected decarboxylation in this way may be understood with the help of the electronic theory of valence (Ref.1). As a consequence, the most commonly used method to decarboxylate $\alpha$-amino acids employs thermolysis of the amino acid in the presence of catalytic amount of an aldehyde (usually, an aromatic aldehydes can act as catalysts). The earliest such attempt has been done by Curtius and Lederer in 1886, when they have obtained decarboxylation of glycine by heating a mixture of glycine and benzaldehyde up to $\pu{130 ^\circ C}$. But the end-product of this reaction was not methylamine as expected, but benzylamine, which could not be understood by the authors at the time (Ref.3):
The driving force of this reaction is the resonance stabilization of the intermediate carbanion:
During a intensive work in this subject, Dose found that in the o- or p-position to the aldehyde group there must be a group with free electrons (such as dimethylamino-group) significant enough to reduce fully the tendency of transamination in the Schiff's base (reverse the electron flow; Ref.1). For instance, when Dose has used p-dimethylaminobenzaldehyde instead of benzaldehyde as the catalyst in valine decarboxylation, isobutylamine was the single product isolated after a method similar to that suggested by Curtius and Lederer in Ref.3 (with benzaldehyde it was $2:1$ of benzyl amine to isobutylamine while it is $1:1$ with anisaldehyde). There is also use of non-aromatic aldehyde as a catalyst as well (Ref.4). In this sequence, the authors have obtained corresponding amines (some of them are optically active) in good to excellent yields. For example, 4-hydroxyproline has given $(3R)$-(-)-3-hydroxypyrrolidine in 93% yield (Ref.4). Note that the elevated temperature is an important factor in this decarboxylation.
Other non-enzymatic methods include irradiation with UV light, heating in diphenylmethane solvent, or thermolysis in a high boiling solvent in the presence of a peroxide catalyst (Ref.2). Since some unnatural $\alpha$-amino acids do not undergo decarboxylation under the above conditions described (e.g., compounds 1,2, and 3), a new general non-thermal procedure is introduced in 2003 (Ref.2):
The method can be described as a ‘one-pot’ combination of two known reactions, oxidative decarboxylation of $\alpha$-amino acids to nitriles induced by N-bromosuccinimide, and the reduction of resulting nitriles to amines effected by sodium borohydride-nickel chloride (Ref.2):
Using this two step one-pot procedure, compounds 1, 2, and 3 were successfully converted to their corresponding polyamines.
References:
Decarboxylation of $\alpha$-amino acids is known enzymatic procedure in biological systems. Non-enzymatic decarboxylation of $\alpha$-amino acids is also a long-known reaction, which leads to amines with a range of applications (Ref.1 and 2). Initially, this type of decarboxylation was tried by heating them above $\pu{200 ^\circ C}$, often dissolved or dispersed in an inert solvent. As these reactions are always exothermic, heating is only required to reach the rather high energies of activation (Ref.1).
In enzymatic decarboxylation in which Nature lowers these activation energies by enzymatic reactions has been frequently discussed. For instance, the formation of a Schiff's base between an $\alpha$-amino acid and pyridoxal phosphate as the proved prosthetic group of most of the decarboxylases is postulated by many authors. The easiness of the expected decarboxylation in this way may be understood with the help of the electronic theory of valence (Ref.1). As a consequence, the most commonly used method to decarboxylate $\alpha$-amino acids employs thermolysis of the amino acid in the presence of catalytic amount of an aldehyde (usually, an aromatic aldehydes can act as catalysts). The earliest such attempt has been done by Curtius and Lederer in 1886, when they have obtained decarboxylation of glycine by heating a mixture of glycine and benzaldehyde up to $\pu{130 ^\circ C}$. But the end-product of this reaction was not methylamine as expected, but benzylamine, which could not be understood by the authors at the time (Ref.3):
The driving force of this reaction is the resonance stabilization of the intermediate carbanion:
During a intensive work in this subject, Dose found that in the o- or p-position to the aldehyde group there must be a group with free electrons (such as dimethylamino-group) significant enough to reduce fully the tendency of transamination in the Schiff's base (reverse the electron flow; Ref.1). For instance, when Dose has used p-dimethylaminobenzaldehyde instead of benzaldehyde as the catalyst in valine decarboxylation, isobutylamine was the single product isolated after a method similar to that suggested by Curtius and Lederer in Ref.3 (with benzaldehyde it was $2:1$ of benzyl amine to isobutylamine while it is $1:1$ with anisaldehyde). There is also use of non-aromatic aldehyde as a catalyst as well (Ref.4). In this sequence, the authors have obtained corresponding amines (some of them are optically active) in good to excellent yields. For example, 4-hydroxyproline has given $(3R)$-(-)-3-hydroxypyrrolidine in 93% yield (Ref.4). Note that the elevated temperature is an important factor in this decarboxylation.
Other non-enzymatic methods include irradiation with UV light, heating in diphenylmethane solvent, or thermolysis in a high boiling solvent in the presence of a peroxide catalyst (Ref.2). Since some unnatural $\alpha$-amino acids do not undergo decarboxylation under the above conditions described (e.g., compounds 1,2, and 3), a new general non-thermal procedure is introduced in 2003 (Ref.2):
The method can be described as a ‘one-pot’ combination of two known reactions, oxidative decarboxylation of $\alpha$-amino acids to nitriles induced by N-bromosuccinimide, and the reduction of resulting nitriles to amines effected by sodium borohydride-nickel chloride (Ref.2):
Using this two step one-pot procedure, compounds 1, 2, and 3 were successfully converted to their corresponding polyamines.
References:
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I swear I read a paper where phenylalanine was decarboxylated in household bleach by heating for 30 minutes at 160 cel? Wouldn't that work here.
I swear I read a paper where phenylalanine was decarboxylated in household bleach by heating for 30 minutes at 160 cel?Wouldn't that work here.
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