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Since primary amino acids like glycine, alanine can't be decarboxylated under oxidative conditions, what would be the best catalyst for this reaction?

I was thinking about copying decarboxylases with $\ce{Cu^2+}$ catalyst, but not sure how that would work.

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  • $\begingroup$ Might be a starting point: chemistry.stackexchange.com/questions/89054 $\endgroup$
    – andselisk
    Jul 12 at 20:44
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    $\begingroup$ I've noticed this question before, but this procedure is for alpha amino acids, not sure if that would work for alanine as well. $\endgroup$
    – steve d.
    Jul 12 at 21:35
  • $\begingroup$ But Cu+2 is an oxidative condition! Did you mean under some oxidative conditions? $\endgroup$
    – user55119
    Jul 12 at 21:44
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    $\begingroup$ @steved. Alanine and glycine both are alpha amino acids. Primary refers to the set coded by the genetic code, alpha refers to the position of the amino group with respect to the carboxylic acid group. $\endgroup$ Jul 13 at 7:44
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    $\begingroup$ Depending on the amino acid of interest and the scale and cost required, you might be able to use a PLP-dependent decarboxylase enzyme. They are typically soluble stable enzymes that can be overproduced easily in recombinant systems. $\endgroup$
    – Andrew
    Jul 13 at 13:04
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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):

Decarboxylation of a-amino acids

The driving force of this reaction is the resonance stabilization of the intermediate carbanion:

Resenance Stabilisation of the caranion

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):

Unnatural Amino Acids

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):

Generaal Decarboxylation Reaction

Using this two step one-pot procedure, compounds 1, 2, and 3 were successfully converted to their corresponding polyamines.

References:

  1. Klaus Dose, “Catalytic Decarboxylation of $\alpha$-amino acids,” Nature 1957, 179, 734-735 (DOI: https://doi.org/10.1038/179734b0).
  2. Gilles Laval and Bernard T. Golding, “One-pot Sequence for the Decarboxylation of $\alpha$-amino acids,” Synlett 2003, (4), 542-546 (DOI: 10.1055/s-2003-37512).
  3. Th. Curtius and G. Lederer, “Notiz über Benzylamin,” Berichte der deutschen chemischen Gesellschaft 1886, 19(2), 2462-2463 (DOI: https://doi.org/10.1002/cber.188601902184).
  4. 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 Letters 1986, 15(6), 893-896 (DOI: https://doi.org/10.1246/cl.1986.893).
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  • $\begingroup$ 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. Can't find any articles about decarboxylation of β-amino acids. $\endgroup$
    – steve d.
    Jul 20 at 16:11
  • $\begingroup$ Regarding decarboxylation by heating above 200°C, could refluxing β-amino acids in naphtalene/nitrobenzene be an acceptable method? $\endgroup$
    – steve d.
    Jul 20 at 17:25
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    $\begingroup$ @steve d.: Heating above $\pu{200 ^\circ C}$ is an earlier method for decarboxcylation regardless of it is $\alpha$-amino acid or not. I'm sur it is okay for $\beta$-amino acids as well. $\endgroup$ Jul 20 at 18:20
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One paper1 suggested use of pyridoxal as catalyst:

When α-amino acid are heated with pyridoxal in dilute aqueous solution in the absence of metal ions, two closely but independent reaction takes place:

$$ \begin{align} \ce{RR'CNH2COOH ->[Pyridoxal] RR'CHNH2 + CO2} & \tag{R1}\\ \ce{RR'CNH2COOH ->[Pyridoxal] RR'C=O + CO2 + Pyridoxamine} & \tag{R2}\\ \end{align} $$

(R1) is analogous to decarboxylation of amino acid by pyridoxal phosphate enzymes. (R2) is a decarboxylation-dependent transamination which doesn't have any enzymatic analogy. The reactions get partially inhibited if metal ions are used as catalyst along with pyridoxal (activity of pyridoxal on the reaction is reduced).

One more paper2 suggested use of glyoxal/ninhydrin as catalyst. However, oxygen absorption was noted in the reactions.

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References

  1. Pyridoxal-Catalyzed Decarboxylation of Amino Acids, G. D. Kalyankar and Esmond E. Snell, Biochemistry 1962 1 (4), 594-600, DOI: 10.1021/bi00910a008
  2. Masao Fujimaki, Nguyen Van Chuyen, Tadao Kurata, Studies on the Decarboxylation of Amino Acids with Glyoxal, Agricultural and Biological Chemistry, Volume 35, Issue 13, 1 January 1971, Pages 2043–2049, DOI: 10.1080/00021369.1971.10860189 (full paper here)
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  • $\begingroup$ 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. $\endgroup$
    – steve d.
    Jul 20 at 16:43

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