• Psychedelic Drugs Welcome Guest
    View threads about
    Posting RulesBluelight Rules
    PD's Best Threads Index
    Social ThreadSupport Bluelight
    Psychedelic Beginner's FAQ

☛ Official ☚ The Small & Handy BOHB (beta-hydroxy-2C-B) thread

shugenja said:
There are reports of 20-30 hour activity from 200+ mg doses of bk-2CB

Question: could the normal process of methylation in the liver result in the alpha methyl group attached to the 2-CB molecule when taking 200-300 mg of bk-2-CB, but it is not normally seen because nobody ever takes 200-300 mg of 2-CB

Question 2: could the beta-ketone of bk-2-CB be converted in the stomach to beta-hydroxy, then methylated to form BOB?? (more reasonable to me)
Click to expand...

Q1: No. Alkyl chains are never methylated in metabolism. In general, methyl groups connected to electronegative atoms will be removed in order to increase polarity of the compound, or to allow conjugation to more polar molecules (e.g. glucuronidation), both of which make the metabolite more easily excretable.

Q2. No, bk-2-CB needs to undergo a reduction to BOHB. This cannot occur in the stomach as there are neither the enzymes nor the reducing agents (probably NADH).
 
aced126 said:
Q2. No, bk-2-CB needs to undergo a reduction to BOHB. This cannot occur in the stomach as there are neither the enzymes nor the reducing agents (probably NADH).
Click to expand...


aqueous acid catalyzed nucleophilic acyl substitution from the ketone to the hydroxy alcohol

Under acidic conditions, the carbonyl group (the ketone) of an acyl compound can become protonated, which activates it towards nucleophilic attack. Next, the protonated carbonyl can be attacked by a nucleophile to give a tetrahedral intermediate, which center would be the beta carbon, and the legs would be the benzene ring carbon (R1) the alpha carbon (R2) the hydroxyl and the added hydrogen at the beta carbon now that the beta carbon only has a single bond to the oxygen -- and it would be stable until methylated making the hydroxy into a methoxy (which happens to hydroxyls in the liver quite often)

If only 10% of the dose was acted upon by this it puts BOHB at 15-30 mg from a 150-300 mg dose of bk-2C-b most of the BOHB should convert to BOB = 12-24 mg BOB
 
Last edited by a moderator:
shugenja said:
aqueous acid catalyzed nucleophilic acyl substitution from the ketone to the hydroxy alcohol

Under acidic conditions, the carbonyl group (the ketone) of an acyl compound can become protonated, which activates it towards nucleophilic attack. Next, the protonated carbonyl can be attacked by a nucleophile to give a tetrahedral intermediate, which center would be the beta carbon, and the legs would be the benzene ring carbon (R1) the alpha carbon (R2) the hydroxyl and the added hydrogen at the beta carbon now that the beta carbon only has a single bond to the oxygen -- and it would be stable until methylated making the hydroxy into a methoxy (which happens to hydroxyls in the liver quite often)

If only 10% of the dose was acted upon by this it puts BOHB at 15-30 mg from a 150-300 mg dose of bk-2C-b most of the BOHB should convert to BOB = 12-24 mg BOB
Click to expand...

lmao where are you getting this information from...

O-methylation happens a bit in the brain (e.g. catechol-O-methyltransferase) and it's not for metabolic purposes but rather to modulate neurotransmitter action.

Why would the liver methylate a hydroxyl and make the metabolite more lipophilic, and thus harder to excrete?

Hydroxyls are usually conjugated with glucuronic acid (this is called phase 2 metabolism).

Where is your "added hydrogen" going to come from lol? It ain't gonna magically appear from nowhere. If you want to nucleophilically add a hydrogen to a ketone or other reducible group, you need what is called a "hydride donor" or a reducing agent. Lab examples are LiAlH4 and NaCNBH3. The drug has to undergo a change in oxidation state. Our body uses NADH, which doesn't float around in stomach acid. You'll also require an enzyme to carry out the reduction, and these metabolic enzymes are only expressed in hepatocytes. They too will not be found in stomach acid.

I'd also like to point out that 2-CB absolutely cannot be methylated to DOB in vivo. That is incorrect (sorry lol). Methylation in the body normally uses S-adenosyl methionine as an electrophilic methyl donor, along with an enzyme to accomodate for the particular reaction substrates. Even if 2-CB were converted to 2-(2,5-dimethoxy-4-bromophenyl)-ethanal by pyridoxal phosphate and some aminotransferase enzyme, it would then need a nucleophilic methyl donor, an oxidation to the ketone again and finally another reaction with pyridoxamine phosphate. This simply will not happen, for too many reasons.

Another point: "hydrolysis" specifically means when a bond is cleaved with water. So the reaction of bk-2-CB --> BOHB cannot be called a hydrolysis. As mentioned, this reaction is a reduction, because the beta carbon drops in oxidation state.

A very general rule to predict metabolic reactions is to compare polarities of the metabolites. A metabolic conversion that lowers the logP of a metabolite is likely to happen as it makes the drug easier to excrete. Adding methyl groups to random places on a molecule doesn't really accomplish this, so it generally is not observed in metabolic reactions. A few examples: aromatic rings are hydroxylated via epoxide intermediates (watch out, these intermediates can alkylate various things such as DNA and this is why benzene and other aromatic compounds can be carcinogenic). Esters are hydrolysed to leave polar carboxylic acids. Ethers are demethylated and prepared for conjugation. Aldehydes are oxidised to carboxylic acids. Benzylic/reactive carbons are oxidised as well (e.g toluene --> benzoic acid).

If you want to learn more about this stuff I recommend reading this book: https://www.amazon.co.uk/Organic-Chemistry-Jonathan-Clayden/dp/0198503466
And then this book: https://www.amazon.co.uk/Introduction-Medicinal-Chemistry-Graham-Patrick/dp/0199234477

The most likely reason to your question about bk-2-CB lasting long is that greater dosages take longer to excrete. You've probably heard of people tripping for much longer than they bargained for by taking an extremely large dose of LSD or Bromo-Dragonfly.
 
Last edited:
aced126 said:
l
Where is your "added hydrogen" going to come from lol? It ain't gonna magically appear from nowhere. If you want to nucleophilically add a hydrogen to a ketone or other reducible group, you need what is called a "hydride donor" or a reducing agent.
Click to expand...

Nope -- don't need a [metal] hydride donor -- Lewis Acids will do just fine -- guess what water and HCL (stomach acid) form -- a Lewis Acid called Hydronium (H3O+) that just happens to love to donate protons to the oxygen of ketones

Lewis acids act directly on the oxygen of a ketone converting it to a hydroxy through protonation because the carbonyl (ketone) oxygen is weakly basic and will readily accept the H+ from the Lewis Acid

The resulting hydroxy carbocation is quite stable

see page 11

http://www.ch.ic.ac.uk/local/organic/tutorial/DB_Carbonylnotes1.pdf
 
Last edited by a moderator:
aced126 said:
O-methylation happens a bit in the brain (e.g. catechol-O-methyltransferase) and it's not for metabolic purposes but rather to modulate neurotransmitter action.

Why would the liver methylate a hydroxyl and make the metabolite more lipophilic, and thus harder to excrete?
Click to expand...

Actually - COMT is primarily expressed in the Liver Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Golen pp 132 https://books.google.com/books?id=a...COMT primarily expressed in the liver&f=false



I don't know -- but it does it alot

MDMA -- demethylenated by CYP2D6 to 3,4-dihydroxymethamphetamine (HHMA)

HHMA is then methylated to HMMA (3-methoxy-4-hydroxymethamphetamine) by COMT in the Liver

does the same thing for HHA --> HMA for the MDA metabolic pathway

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495276/

The liver tends to methylate hydroxy groups in flavenoids like quercetin as well
 
"the resulting hydroxy carbocation is quite stable". You then need to reduce the carbocation with 2 electrons and a proton i.e. a reducing agent.

To go from a ketone or aldehyde to an alcohol, you need to perform a reduction that requires 2 protons and 2 electrons. Those electrons don't pop out from nowhere and they come from a reducing agent. This is high school chemistry man...

Next post: Ok, well anyways then, as the name suggests, it only methylates the aromatic hydroxyl groups, not aliphatic ones. A quick scan of the internet will show that COMT function is primarily to terminate dopamine action in areas of the brain with low DAT expression, like the PFC. To be fair I don't really know why it's expressed in the liver, and Wikipedia specifically mentions this weird expression as well.

Read pg 37 on the notes you linked. But seriously though, if you want to know properly about this stuff (which I can tell you really do) I would recommend reading the first book I posted and you'll pick it up rapidly since you're so interested in this area.
 
Last edited:
aced126 said:
To go from a ketone or aldehyde to an alcohol, you need to perform a reduction that requires 2 protons and 2 electrons.
Click to expand...

For a nucleophilic attack on the Carbon, yes. But for an electrophilic attack on the O, actually you don't. All you need is an acid and water.


Electrophilic attack on the carbonyl oxygen is sufficient.

The carbonyl oxygen is a weak Lewis Base, as such it will gladly accept an H+ from the Lewis Acid Hydronium -- which is formed by HCl and Water.

Because the carbonyl has a slightly polar double bond between the C=O the electrophile can attack either the pi or sigma bond.

The electrons in the carbonyl pi bond are highly distorted toward the Oxygen (because O is much more electro-negative than C)

When the H+ electrophile attacks the pi bond, the electrons that were shared with the Carbon bond to the H+ the result is a hydroxyl with lone pairs balanced on either side of the O and a single bond (sigma) between the O and C.

The resulting group is resonance stabilized.
 
shugenja said:
For a nucleophilic attack on the Carbon, yes. But for an electrophilic attack on the O, actually you don't. All you need is an acid and water.


Electrophilic attack on the carbonyl oxygen is sufficient.

The carbonyl oxygen is a weak Lewis Base, as such it will gladly accept an H+ from the Lewis Acid Hydronium -- which is formed by HCl and Water.

Because the carbonyl has a slightly polar double bond between the C=O the electrophile can attack either the pi or sigma bond.

The electrons in the carbonyl pi bond are highly distorted toward the Oxygen (because O is much more electro-negative than C)

When the H+ electrophile attacks the pi bond, the electrons that were shared with the Carbon bond to the H+ the result is a hydroxyl with lone pairs balanced on either side of the O and a single bond (sigma) between the O and C.

The resulting group is resonance stabilized.
Click to expand...

I'm not sure what your point is. Carbonyl oxygens are very weak bases, with pKas of about -10, compared to water with pKa of -1.7. So, in an aqueous environment, protonation of a carbonyl oxygen is extremely unfavorable, with an equilibrium constant of about 10-12 at pH 2, like in the stomach. And the protonated product is an oxonium ion, not an alcohol. Oxonium ions are intermediates in chemical reactions, not stable molecules.
 
shugenja said:
For a nucleophilic attack on the Carbon, yes. But for an electrophilic attack on the O, actually you don't. All you need is an acid and water.


Electrophilic attack on the carbonyl oxygen is sufficient.

The carbonyl oxygen is a weak Lewis Base, as such it will gladly accept an H+ from the Lewis Acid Hydronium -- which is formed by HCl and Water.

Because the carbonyl has a slightly polar double bond between the C=O the electrophile can attack either the pi or sigma bond.

The electrons in the carbonyl pi bond are highly distorted toward the Oxygen (because O is much more electro-negative than C)

When the H+ electrophile attacks the pi bond, the electrons that were shared with the Carbon bond to the H+ the result is a hydroxyl with lone pairs balanced on either side of the O and a single bond (sigma) between the O and C.

The resulting group is resonance stabilized.
Click to expand...

I suggest writing your proposed mechanism out on paper and using some curly arrows to push the electrons around. Once you have your carbocation you are not going to get a second positively charged species (H+ from H3O+ as you claim) on there for love nor money.


Please let us know if you work it out how to reduce ketones with just an acid as I would like to claim the nobel prize for chemistry and this would certainly be groundbreaking enough.
 
None of these compounds like BOHB are catechols like dopamine or catechol-like e.g. that MDMA metabolite, or (poly)phenols so the specific situations where methylation takes place are not necessarily that relevant. As was already said, much more similar compounds with beta-hydroxys are not metabolized that way so there isn't really much of a reason to suspect BOHB is.
Not that it's not interesting but it is a poor argument in the context of the thread.
 
Transform said:
I suggest writing your proposed mechanism out on paper and using some curly arrows to push the electrons around. Once you have your carbocation you are not going to get a second positively charged species (H+ from H3O+ as you claim) on there for love nor money.


Please let us know if you work it out how to reduce ketones with just an acid as I would like to claim the nobel prize for chemistry and this would certainly be groundbreaking enough.
Click to expand...


Look up electrophilic reactions at the carbonyl oxygen. It is not a reduction.
 
tryp2fun said:
I'm not sure what your point is. Carbonyl oxygens are very weak bases, with pKas of about -10, compared to water with pKa of -1.7. So, in an aqueous environment, protonation of a carbonyl oxygen is extremely unfavorable, with an equilibrium constant of about 10-12 at pH 2, like in the stomach. And the protonated product is an oxonium ion, not an alcohol. Oxonium ions are intermediates in chemical reactions, not stable molecules.
Click to expand...


The oxonium formed is a resonance stable hydroxyl


H
l
:O:
/ \
R R

http://www.ochempal.org/index.php/alphabetical/o-p/oxonium-ion/
 
aced126 said:
Dude honestly just read the first book I linked. You'll find it interesting.
Click to expand...


Dude read the citations i cited.

An electrophilic attack on the Oxygen -- will result in the hydrogen bonding to one of the C=O bonds.

Resulting in a hybrid, resonance stabilized carbocation, that also happens to be a hydroxyl (no longer a ketone it only has 1 c to O bond.

This is a valid and known chemical reaction.
 
Yes yes nobody refuted that it is a 'valid reaction', but it is an intermediate reaction an unfavorable step that needs to be followed by the actual substitution reaction on that cation. Otherwise it is unfinished and will just revert back once the pH is neutralized again. "Resonance stable"? I think it's only relatively stable, that doesn't mean the conjugate acid which is very weak compared to water, will actually accept anions to finish the alpha electrophilic substitution you are suggesting. Resonance stabilized means that the charge is spreaded because of conjugation, making it more stable than it would be otherwise. Doesn't mean it's perfectly stable forevermore.
The acidity of the carbonyl is very important here if you're talking about spontanous acid-catalyzed reactions - it makes that 10% you might think is a modest request too much to ask for.

No electrophilic reaction will happen at the carbonyl oxygen itself as the oxonium is absolutely not the end-product and it is also not fit to have any substitution finished there itself. It conjugates to the acid: the hydroxy compound with the carbocationic alpha. And stops there.
 
Alright I'll try explain it a final time although as I have said it's much better that you actually study organic chemistry so you can see the full picture. In bk-2-CB the ketone gets protonated by the stomach acid to form a resonance stabilised hydroxy carbocation. This is an equilibrium reaction which stays far to the left. The only way to trap the hydroxy carbocation and convert it into a neutral alcohol is to provide 1 proton and 2 electrons to the positive carbocation carbon. To do this in the body you need one of the body's reducing agents, for example nicotinamide adenine dinucleotide (NADH). You need this is molar amounts to convert all the ketone to an alcohol, and as well as this, you will need an enzyme which accomodates for both of the substrates. The stomach has neither of these.

Why try to argue with something quite basic in the fields we study when instead it's much better to listen to our advice lol...
 
Hello guys,
One intriguing thought crossed my mind in the last few weeks.
What if you protect the amine with an acetyl group to reduce the carbonyl group with LiAlH4 so that you receive the beta hydroxy compound. From there on you use something like 1-Bromo-2-chloroethane to close the ring on the hydroxy and amine group to form a morpholine ring after work up. It would be like phenmetrazine just as the 2cb analogue. I never read anything about it so I'm not sure if it was ever synthesized. But i suspect it would be active.

Btw, Im new on Bluelight and hope to have some good discussions here.
Have a nice day

PS. Maybe NaBH3CN would be better but thats a side note
 
:) Hi. and welcome to bluelight. Synthesis discussion isn't allowed here, sorry. Maybe have a look at the rules before posting again.

About the compound you propose, I don't think that it's becuse no one has had the idea before, but I'm quite sure that that much bulk at the amine will abolish any psychedelic effects what so ever. No PEA with tertiary amine's are psychedelics, as far as I know.
 
You must log in or register to reply here.
Top