Esterification

[Physics131]

Hello,

as I was not able to find anything about this in the forum I will drop points of my theoretical thought process here. I am not a chemist so please bear with me

Intro:
I know esterification from steroids.
The complexity of the ester has impact on the half life.
From my knowledge the body has first to break down the ester before the substance is available.
As example testosterone propionate (20 hours half life) which has a low ester chain and
testosterone enanthate (4,5 days) which has a high ester chain.
Types of esters I am aware of: propionate, enanthate, acetate, cypionate.
I also think that the same concept is applied to some medications, I currently cannot think of any.

Intention:
Finding another sensible way to extend the journey.

Questions:
1. Would it be possible to apply esterification on psychoactive substances as well for oral or vaping use?
2. Does it make any sense?
3. Would it be safe to process and use?
4. I am aware of the tolerances but would it make even more sense to combine it with MAOIs?

References for chemical structures:
Propionate: Testosterone propionate - Wikipedia
Enanthate: Testosterone enanthate - Wikipedia

 

[Hailstorm]

One example of esterification of a medication is acetylation of morphine, which yields diacetylmorphine, originally marketed as Heroin and sold over-the-counter as a cough suppressant (apparently the users would stop coughing).

To answer your 4 questions,

1. Yes
2. Yes
3. It depends on the compound
4. It depends on your goals

Take a look at 4-AcO-DMT, an ester of psilocin, relatively widespread and, in some jurisdictions, still legal. The acetoxy group decreases the rates of metabolism and degradation in air.

One could also try to add the ester group to the nitrogen atom, producing carbamate esters like N-methoxycarbonyl-NMT. Such compounds are not studied much yet. If they are more polar, they will have a harder time crossing the blood-brain barrier.

 

[downwardsfromzero]

Good call on the carbamate there, Hailstorm. It manages to be both an ester and an amide at the same time.
Somewhat out of reach for the kitchen chemist, though - I don't think many of us would want to get methyl chloroformate anywhere near the croissants! The BDO dimer analogue of this one might be fun to take a look at.

Esterification is just one type of chemical modification and is best understood in the wider context of chemistry; at the same time one does inevitably end up regarding chemistry concepts individually during the learning process.

One of the main things to remember here is that - other than in the exception of forming a carbamate, which brings its own oxygen atom with it so to speak - only compounds with a suitable free hydroxy group can be esterified, which rules out a large number of the usual psychedelics.

There have been experiments around the esterification (O-acetylation) of bufotenine, but I've never seen any conclusive results from that. Harmol would be another one to look at esterifying.

 

[Hailstorm]

In terms of safe/kitchen chemistry, it should be possible to react NMT with dimethylcarbonate to yield N-methoxycarbonyl-NMT. Apparently, in presence of alkoxides, aliphatic amines undergo carbamation in mere minutes (see the attached paper: reflux in DMC at 90 °C, 1/1.2/40 molar ratios of amine/base/DMC, forced CO₂ displacement).

If one uses tryptamine T (or even tryptophan Trp) instead of NMT, carbamation would happen first, yielding N-methoxycarbonyl-T(rp), which could have psychoactive properties similar to those of melatonin.

Continuing to reflux, under argon, for a day, should add a methyl group, yielding N-methoxycarbonyl-NMT(rp) (melatonin, already available OTC, may be easier to test that second step with). It is, however, unclear what a prolonged reflux with DMC and a strong base would do to the indolic nitrogen. It could lead to a substitution, for better or worse.

 

[nen888]

^..now that's an interesting experiment , Hailstorm thanks

regarding Physics131's general idea of extending half life, there's Deuterated Tryptamines, which only have some animal experiments at this stage..it's been done to DMT and 5meoDMT..
recent paper attached, someone is probably trying to patent this...

 

[Physics131]

Ty for your interesting replies.

 

[downwardsfromzero]

The dimethyl carbonate reaction is indeed an interesting one, Hialstorm. The only kind of OTC drugstore carbonate ester I've noticed in my corner of northwest Europe has been propylene carbonate (4-methyl-1,3-dioxolan-2-one) in the form of low odor nail polish remover and I'm not wholly covinced it will make a useful reagent in this context.

While on the subject of carbamates, we should remember the "auto-carbamates" formed by secondary amines when treated with carbon dioxide. This reaction has been used to separate NMT from DMT, but I don't recall having seen any reports of experiments using the NMT self-carbamate, NMTH⊕.⊖O(CO)NMT (roughly speaking).

 

[Hailstorm]

Propylene carbonate could be an interesting electrophile. I don't know if it can form interesting (psychoactive) products though.

I discovered that heating tryptophan in propylene carbonate causes its rapid decarboxylation, without any catalysts. I don't know why, but my suggested mechanism is below.

 

[downwardsfromzero]

Ooooh, that's interesting! Thanks for the diagrams; to my mind the carbamate mimics the imine intermediate of the various ketone-based Trp decarboxylations. But - does dimethyl carbonate catalyse the decarb? Is perhaps its BP too low for the requisite thermal energy to drive the reaction?

Does the spare hydroxy group in the intermediate propylene glycol monocarbamate assist the reaction? How was the workup of the resulting N-(hydroxypropyloxycarbonyl)T, and how easy was it to obtain T from it?

You know what, this deserves its own topic in the appropriate subforum...

 

[Hailstorm]

But - does dimethyl carbonate catalyse the decarb? Is perhaps its BP too low for the requisite thermal energy to drive the reaction?

I ran this experiment a long time ago, when looking for a convenient decarb solvent. To my surprise, the characteristic CO2 bubbles began to evolve from the mixture without any ketone present. The temperature was above 150 °C under argon. I never tried it with DMC. Its low boiling point indeed makes it an unlikely decarboxylation catalyst (although, considering how much sodium methoxide alters its reactivity, maybe there's a chance; perhaps I'll give it a try).

...Update: nope, it does not look promising. For once, Trp, due to its zwitterionic nature, is poorly soluble in DMC. Boiling it (with excess sodium methoxide) does not seem to result in decarboxylation.

How was the workup of the resulting N-(hydroxypropyloxycarbonyl)T, and how easy was it to obtain T from it?

Sadly, I did not isolate the hydroxycarbamates. A naive liquid-liquid extraction attempt yielded nothing – not at all surprising, given how polar they probably are.