DubiousPie - 8-6-2019 at 01:13
Hi. First post here, because I got curious about something (not a chemist by any stretch, but NileRed and the like got me interested in chemistry).
Basically, I got interested in the chemistry of amino acid monomethylation, and ended up reading a bunch of research papers on the subject.
I came across a paper ("Reductive methylation of primary and secondary amines and amino acids by aqueous formaldehyde and zinc", DOI:
10.1016/j.tetlet.2007.08.092) that - as far as I can understand - involves an intermediate imine formation using formaldehyde, which is reduced by a
hydride transfer using zinc in acidic solution.
From a lot of Googling, I realized that this is probably a modified Eschweiler-Clarke reaction, with zinc being the reducing agent rather than formic
acid. And because of that, it also allows dimethyl substitution.
However, then it got me thinking - since this procedure could theoretically result in some degree of N,N-dimethyl substitution no matter how much the
conditions are controlled, how could it be improved to specifically yield monomethylation?
A lot of research later, I came across hydroxymethyl substitution using formaldehyde in basic solution. I couldn't find any particular procedures for
doing this to amino acids, but did find plenty of references to this being performed anyway (usually for corrosion-prevention additives). That leads
me to assume it's a pretty simple reaction (eg. 1.5 molar equivalents formaldehyde at pH 10 for 30-60 minutes at 70-80C, or something like that). And
from attempting to research some more, it appears that amino acids can't form N,N-bis(hydroxymethyl) derivatives (and as a nice bonus resulting from
that, can't combine together to form triazines and the like).
From there, I thought of an idea: If N,N-bis(hydroxymethyl) substitution can't happen and only N-hydroxymethyl substitution occurs, could the
hydroxymethyl group be reduced to yield exclusively monomethylation under mild conditions?
I'm not sure if it would work, to be honest. My only chemistry instruction was during high school and even then was limited to the basics (eg.
balancing equations, simple substitutions, etc.); everything else has just been researched when I get interested in the topic.
However, my thinking goes: The nitrogen of an amine is weakly basic, and so are hydroxyl groups. Therefore, under neutral conditions, the carbon of a
hydroxymethyl derivative becomes slightly acidic (pKa of around 4-5?). However, if the substituted amino acid is placed in acidic conditions, the
nitrogen becomes charged, and shares its proton with the hydroxyl group of its substituent, making the carbon somewhat neutral to basic. However,
because of oxygen's high electronegativity, the proton spends most of its time at the -OH side, which makes for a good leaving group (H2O). Therefore,
my thinking goes: What if the amino acid is placed in a slightly acidic solution (eg. pH of around 4-5) at room temperature, and zinc is added?
Ideally, the hydride transfer would go on the side of the leaving group (from the carbon being neutral to slightly basic), and yield an N-methyl
substituted amino acid and water (as opposed to hydrolysis of the hydroxymethyl group). But I'm not sure if this would actually happen.
Any thoughts on this idea? Or is my chemistry-fu really bad haha?
I can't really test this, as I don't actually have any chemistry equipment or anything, so it's just an idea I had, and was hoping to learn some more
about the reactions that would actually happen.
Cheers!