Glycine to Methylamine

[Protium]

The long awaited Glycine to Methylamine reference

As i'm sure many of you know there has been sporatic talks of the conversion of glycine to methylamine throughout the history of the hive.  As many of you know glycine is about the simplest form of amino acid, and the only amino acid with no stereoisomers.  It is easily obtainable and is therefore a viable and expedient method of obtaining methylamine for bees with a knowledge of organic chemistry.

There was much talk of heating glycine with a base (as it turns out it seems that water is adequate), and a large following who considered the reaction very dirty, experiencing polymerization, byproducts, and after gassing recieving impurities in the salt.

Everyone could remember reading something about it years ago but no one could seem to come through with anything that explained the process in any detail for those who would like to optimize the reaction to obtain methylamine from this convienient method.  The article is not in direct reference to methylamine production, but explains the mechanics fairly well and will certainly help better the understanding of the reaction for it's optimization.

Herein is the recently published explanation of the migration of the methyl groups.


Migration of Methyl Groups between Aliphatic Amines in Water

Brian P. Callahan and Richard Wolfenden
Department of Biochemistry and Biophysics,
University of North Carolina, Chapel Hill, NC


Abstract :

Glycine undergoes spontaneous decarboxylation in dilute aqueous solution at elevated temperatures to form methylamine.  During that process, we noticed the apperance of dimethylamine and trimethylamine in smaller amounts that increased gradually with time.  These observations suggested the existence of disproportionation reactions of methylamines in water, for which there appears to be no direct precedent in the literature.  Every member of the methylamine series is found to yield other members of the methylamine series.  When the total concentraion of amine was held constant and the rate of reaction was examined as a function of changing pH using the amine itself as the buffer, the initial rate of appearance of the products was found to reach a maximum when the conjugate acid and the conjugate base were present at equivalent concentrations.  Near this equivalence point, the rate of reaction varied with pH as expected for a second-order reaction between the protonated and the unprotonated species.  Under similar conditions, methyl groups were also found to migrate between the nitrogen atoms of N,N-dimethyl-1,3-propanediamine in a first-order process.  With dimethylamine as a common acceptor, trimethlsulfonium ion was found to be ~10⁴-flod more reactive that the tetramethylammonium ion at ambient temperature.


Glycine undergoes spontaneous decarboxylation in dilute aqueous solution at elevated temperatures to form methylamine.  During that process, we noticed the apperance of dimethylamine and trimethylamine in smaller amounts that increased gradually with time.  These observations suggested the existence of disproportionation reactions of methylamines in water, for which there appears to be no direct precedent in the literature.  Here, we show that methyl groups migrate between aliphatic amines when they are incubated with their conjugate acids at elevated temperatures and that competition by water as a methyl acceptor is negligible.  Half-titrated dimethylamine (0.02 M), for example, yields trimethylamine and methylamine in equal amounts (Scheme 1a), with no appearance of methanol.  In addition to the apparent novelty of these reactions, these results are of interest in relation to the mechanism of methyl transfer in biological systems.


To determine the rates of methyl transfer between amines, we incubated aqueous amines, half-titrated with HCl, for various time intervals at high temperatures in stainless-steel bombs lined with PTFE.  After cooling, the reaction mixtures were removed and analyzed by proton NMR, using added pyrazine as an integration standard.   Every member of the methlamine series was found to yeild other members of the methylamine series.  AT each of a series of temperatures, the rate of disappearance of the starting material followed satisfactory first order kinetics and yielded a linear Arrhenius plot when the logarithm of the initial rate of reaction was plotted as a function of the reciprocal of the absolute temperature.  When the ratio of the protonated to the unprotonated species of mono-, di-, or trimethylamine was held constant but the total concentration of that amine varied, the initial rate of disappearance of the starting material was found to vary in proportion to the square of its concentration, as expected for a bimolecular reaction involving two molecules of amine (see for example Figure 1a).

When the total concentration of amine was held constant, and the rate of reaction was examined as a function of changing pH using the amine itself as the buffer, the initial rate of appearance of the products was found to reach a maximum when the conjugate acid and the conjugate base were present at equivalent concentrations. Near this equivalence point, the rate of reaction varied with pH as expected for a second-order reaction between the protonated and the unprotonated species, as shown by the solid line in Figure 1a. At pH values much below this equivalence point, product formation continued at a much slower rate (Figure 1b). The persistence of reactivity at low pH, which has also been reported for other transalkylation reactions, suggests that water may be acting as a general base catalyst.

In experiments in which the tetramethylammonium ion (Me4N+) was employed as the methyl donor and dimethylamine was the acceptor, trimethylamine was formed at an initial rate proportional to the concentrations of each of these two reactants. When this reaction was followed as a function of increasing pH, using dimethylamine itself as a buffer,3 its initial rate of disappearance became half-maximal at the pH value where dimethylamine is half-converted to its uncharged form, approaching a constant value when dimethylamine is fully converted to its uncharged form but Me4N+ retains its positive charge (Figure 1c). Activation parameters based on the resulting Arrhenius plots are shown in Table 1.

Table 1.
Extrapolated Rate Constants and Activation Parameters
from Arrhenius Plots, Based on 10 or More Rate Constants
Obtained over a Range >50 C, with Estimated Errors in ^H and
T^S of ±1.5 kcal/mol
 
a. k (25 C) (M-1 s-1)
b. H, kcal/mol
c. TS, kcal/mol
 
dimethylamine + dimethylammonium
a. 4 × 10-13
b. 25.9
c. -8.5
 
N,N'-dimethyl-1,3-propanediamine (s-1)
a. 5 × 10-12
b. 30.4
c. -2.5
 
dimethylamine + tetramethylammonium
a. 1.9 × 10-12
b. 30.1
c. -3.4
 
dimethylamine + trimethylsulfonium
a. 1.5 × 10-8
b. 22.2
c. -5.9

Figure 1 (a) Initial rate of conversion of half-titrated dimethylamine to methylamine and trimethylamine at 226 C, plotted as a logarithmic function of changing initial concentration of dimethylamine. The line (slope = 2) is calculated for a reaction that is of the second order with respect to the total concentration of amine (Scheme 1a). (b) Initial rate of the same reaction at 226 C, at a fixed total concentration of dimethylamine (0.5 M), plotted as a function of changing pH. The line represents the behavior expected for the reaction shown in Scheme 1a. (c) Initial rate of reaction of dimethylamine (0.6 M) with tetramethylammonium chloride (0.25 M) at 171 C, plotted as a function of effective pH. The line represents the behavior expected for the reaction shown in Scheme 1c.

[Protium]

Under similar conditions, methyl groups were also found to migrate between the nitrogen atoms of N,N'-dimethyl-1,3-propanediamine in a first-order process, forming an equilibrium mixture containing nearly equivalent concentrations of 3-(dimethylamino)propylamine and N,N'-dimethyl-1,3-propanediamine. At amine concentrations up to ~1 M, this reaction (and its reverse) proceeded more rapidly than the bimolecular reactions described above, due to a more favorable entropy of activation (Table 1). This intramolecular reaction exhibits a larger ^H# that may reflect ring strain in the six-membered cyclic transition state.

Biological reactions that involve the transfer of acyl or glycosyl groups often involve the formation of discrete intermediates that differ substantially in structure from the substrates and products. Such reactions can be accelerated by enzyme active sites that have or can easily adopt structures with binding determinants that are complementary to the structures of intermediate forms of the substrate that approach the transition state in structure, forming new H-bonds and other polar interactions that were not present in the ground-state enzyme-substrate complex. Lacking such discrete intermediates, methyl-transfer reactions may be relatively difficult to catalyze except by desolvation and approximation effects that place the reactants in a position conducive to reaction. There are probably limits to the rate enhancements that can be achieved by these "physical" effects, so that the inherent reactivity of the substrate is of special importance.

If ammonium ions are capable of methyl transfer in water, then why are reactions that involve methyl transfer from ammonium ions less common than reactions using S-adenosylmethionine (SAM) as a methyl donor? To make a direct comparison of the inherent reactivities, we determined the rates of reaction of the trimethylsulfonium ion11 with the tetramethylammonium ion as donors to a common acceptor in dilute aqueous solution. With dimethylamine as the acceptor, trimethylsulfonium ion was found to be ~10⁴-fold more reactive than the tetramethylammonium ion at ambient temperature (Table 1). When the second-order rate constant for this trimethylsulfonium reaction (1.5 × 10^-8 M^-1 s^-1) is compared with the second-order rate constant (k_cat/K_m) for reaction of histamine with the SAM complex of guinea pig histamine N-methyl transferase (~7 × 10⁵ M^-1 s^-1), this enzyme is seen to enhance the rate of reaction with a nitrogen nucleophile by a factor of 5 × 10¹³. Catechol O-methyltransferase has been shown to enhance the rate of methyl transfer from SAM to an oxygen nucleophile by an even greater factor, approximately 10¹⁷. Thus, enzymes reinforce the inherently superior reactivity of sulfonium compounds, making large contributions to the reactivity of SAM as judged by the rate enhancements that they produce.

[Rhodium]

Nice, what is the reference for this?

[Protium]

J. Am. Chem. Soc., 125(2), 310-311, 2003.

[Protium]

Wouldn't it be possible to simply decarboxylate glycine in H₂O Maillard-Browning style, in the presence of a ketone or aldehyde?  And would this be an effective method of producing methylamine?

[Protium]

Forgive the crappy illustration, but if i'm not mistaken, I believe that this is a possible new route to methylamine that might be very convienient.

[yellium]

Can you tell me why glycine wants to react this way?

[Protium]

I suppose it is much like in sugar chemistry, where glycine is reacted with glucose (in aldehyde form), in a reaction known as the Maillard Browning.  The imine formation to me seems pretty straightforward, and the resulting decarboxylation is concurrent with a known reaction.  After studying it I quickly adapted it to this application.

Although I cannot be positive that some other reaction may not be favored over the mechanism shown, this seems like a viable mechanism.  I'm hoping that some knowledgeable bees might shed some light on problems with the mechanism, if any.

[java]

This is part of what has been discussed in the past......

Post 108611 (missing)

(dormouse: "methylamine via glycine(Amino acid) (Page 1) -hellman", Novel Discourse)

the production of primary secondary and tertiary amines was a problem then also.........java

[hellman]

wow, the good ol' days,.
Kind of embarrasing looking back over 5 years,
some things change, and some never will ,
wow,.
Serious flash from the past,.
How we impress,how we grow old, how we hold ourselves, how we want things conveyed, how we have no idea, when we really do,.
scary,./


Anyway, we should reopen this thread, why not,.
If vogels says it works,
I believe it,.


hellman 3030

[Ziqquratu]

Not exactly the most brilliant route ever seen, but I think it does warrant a mention:

One-pot Sequence for the Decarboxylation of alpha-Amino Acids
Laval, G., and Golding, B. T., Synlett 2003, No. 4, 542-546

Abstract:
Treatment of an alpha-amino acid with N-bromosuccinimide in water at pH 5 or in an alcoholic-aqueous ammonium chloride mixture, followed by addition of nickel(II) chloride and sodium borohydride, effected an overall decarboxylation via an intermediate nitrile to afford the corresponding amine in good yield.

Typical Procedures:
(a) L-Asparagine (2.90 g, 19.3 mmol) was taken up in a pH 5 phosphate buffer (prepared from 100 mL of a 0.1 M solution of citric acid and 100 mL of a 0.2 M solution of disodium hydrogen orthophosphate dodecahydrate) (90 mL). To the stirred amino acid solution was added NBS (10.3 g, 57.9 mmol) in DMF (20 mL) at r.t., where upon CO2 gas was evolved immediately. After 30 min, nickel(II) dichloride hexahydrate (22.9 g, 96.5 mmol) was dissolved into the reaction mixture and NaBH4 (5.84 g, 154 mmol) was added in portions with vigorous stirring. Addition of the latter was exothermic and hydrogen gas was vigorously evolved. After 20 min at r.t., the reaction mixture was filtered through Celite® and diluted with distilled H2O (500 mL). The light green filtrate was loaded on a column (25 cm × 2 cm) of Dowex 50WX8-200 ion exchange resin, the column was washed well with H2O (400 mL) and the amine was eluted with a concentration gradient of ammonium hydroxide. Removal of the solvent under reduced pressure afforded the amine, which was treated with 1.0 M HCl to give 3-aminopropionamide (12) as its hydrochloride (1.68 g, 13.5 mmol).

(b) L-Phenylalanine (400 mg, 2.42 mmol) was taken up in a mixture of EtOH (40 mL), H2O (2 mL) and a sat. aq solution of NH4Cl (1.5 mL). To the stirred amino acid solution was added NBS (1.07 g, 6.05 mmol) in DMF (5 mL) at r.t., whereupon CO2 was evolved immediately. After 20 min, nickel(II) dichloride hexahydrate (2.30 g, 9.68 mmol) was dissolved into the reaction mixture and NaBH4 (915 mg, 24.2 mmol) was added in portions with vigorous stirring. Addition of the latter was exothermic and hydrogen was vigorously evolved. After 30 min at r.t., the reaction was filtered through Celite®, and the ethanol was removed. The liquid residue was taken up in water (20 mL) and basified to pH 10 with aq 1.0 M NaOH. The aq solution was extracted with Et2O (2 × 30 mL). The combined organic extracts were washed with a sat. aq solution of NaHCO3 (20 mL) and dried over MgSO4. Removal of the solvent afforded 2-phenylethylamine (9a) (208 mg, 71%) as a colourless oil.


Although they didn't mention it, I assume this should work on glycine to yield methylamine. It may also prove a means of making, say, acetonitrile from alanine fairly simply by isolating the intermediate rather than reducing it.  At the very least it gives a decent yield of 2-phenylethylamine from phenylalanine.  And perhaps the nitrile --> amine reduction could be carried out with reagents other than Sodium Borohydride (although this is reasonably simple to deal with anyway).

[java]

Just a thought,  " When an alpha- amino acid is treated with an anhydride  in the presence of pyridine, the carboxyl group is replaced by an acyl group and the NH2 becomes acylated. this is called the Dakin-West reaction * 

R-CH-(NH2)-COOH +(R'CO)2O>.pyridine>>R-CH(NHCOR)-COR'

The mechanism involves formation of an oxazolone.**  The reaction sometimes takes place on carboxylic acids even when the amino group is not present. A number of N-substituded amino acids, RCH-(NHR')COOH, give the corresponding N-alkylated products." excerp from March's 5th edition page 812.

So in our case Glycine would end up like this,

R'-CO-NH-CH2COR', , now this need some uncupling and the result , acetone and an ethyl amid , which can be reduced with the Hoffman elimination to  CH3NH2, just a thought......java

REF.
* For a review, see Buchanan, G.L.  Chem.Soc. Rev. 1988,17,91
** Allinger,N.L. ;  Wang, G.L. : Dewhurst, B.B. ; J. Org.         Chem.1974,39,1730

http://www.dmapcatalyst.com/Reaction%20Pages/dakin.htm

[java]

Edit. On my last post it should have read Hoffman's degradation not elimination. Also what happen to the acetic acid>>>amide>>Hoffman degradation >>>amine. True acetic acid may have to go through an acid chloride then an amide but it seems like a sure thing.  At least that's how I read it in Morrison & boyd.....java

[java]

What can you make out of this comment as to the synthesis of Methyl amine...as the dialogue went on then this comment was made........

"I once performed the synthesis of benzylamine amide in CH2Cl2
and observed benzaldehyde formation. I explained it to myself that
the amine reacted with CH2Cl2 to give imine:

Ph-CH2-NH=CH2

that was in equilibrium with the form in which the double bond
migrated to give the more stable conjugated system:

Ph-CH2-NH=CH2 <-> Ph-CH2=NH-CH3

after aqueous workup the latter compound hydrolysed to give
benzaldehyde and methylamine.

If I am right it means that CH2Cl2 is not so "neutral" solvent for
amines afterall. What do you think? "

I found the comment  interesting enough to share........java

[java]

Then based on the hint on making methylamine I would then suppose that if one would get  benzamide and reflux in dichloromethane,

C6H5CONH2   +  CH2Cl2>>>>reflux >>C6H5CHNH=CH3,

 then by adding some KOH  and refluxing it helps the double bond shift to the conjugate position,( more stable position,)

C6H5CH=NHCH3  and now on aqueous workup, meaning washing the product in water,  the benzaldehyde will separate so that , the oil is the benzaldehyde and the water contains your methylamine,....

C6H5CH=NHCH3  >>>C6H5COH (oil) + CH3NH2(in water)

I think this is how the reaction works , I would appreciate some help or clarification in  this  theoretical process....java

[java]

I never did get a feed back on the possibility of starting with Benzylamine (C6H5-CH2-NH2) and under reflux with dichloromethane the product to produce an imine (C6H5-CH2-NH=CH2) , and wanting to be more stable, it migrates to a more conjugate system (C6H5-CH2=NH-Ch3) which after an aqueous work up the compound hydrolysed to give benzaldehyde and methylamine, so that dichloromethane is not such a neutral solvent for amines. This would be a good method to provide benzaldehyde for the biotransformation method to l-PAC and a good source of methylamine for the reduction afterwards.

Note : the chemistry seems to be straight forward in making higher types of amines  the reaction of the dichloromethane seems to react with the amine and make a double bond with the added methyl group., which I have no reference for.......java